A Phase II Study of Pembrolizumab and Bavituximab in Patients With Advanced Hepatocellular Carcinoma
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: David Hsieh

 
STU102017-015, Hsieh, FormA-Protocol, Mod_27, 08-21-23(3).docm 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020 
 
A Phase II Study of Pembrolizumab and Bavituximab in Patients with Advanced 
Hepatocellular Carcinoma 
 
 
Principal Investigator: 
David Hsieh, MD 
Assistant Professor of Hematology Oncology  
University of Texas Southwestern Medical Center  
Harold C. Simmons Comprehensive Cancer Center  
5323 Harry Hines Boulevard  
Dallas, TX 75390-9179  
Ph: 214-648-1996  
Fx: 214-645-2542 
Email: david.hsieh@utsouthwestern.edu  
  
 
Co-Principal Investigators 
or Lead Sub-
Investigator(s): 
 
Adam Yopp, MD   
Assistant Professor of Surgery  
University of Texas Southwestern Medical Center  
Harold C. Simmons Comprehensive Cancer Center 
5323 Harry Hines Boulevard 
Dallas, TX 75390-8852 
Ph: 214-648-5870 
Fx: 214-648-1118 
Email: adam.yopp@utsouthwestern.edu 
 
Biostatistician: 
Chul Ahn 
University of Texas Southwestern Medical Center 
5323 Harry Hines Boulevard  
Dallas, TX 75390-9179  
214-648-9418 
chul.ahn@UTSouthwestern.edu 
 
 
NCT Number: 
03519997  
 
Amended: 
v7.0 30-DEC-2022 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 

 
STU102017-015, Hsieh, FormA-Protocol, Mod_27, 08-21-23(3).docm 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
Amendment/Version #_____________________________ 
A Phase II Study of Pembrolizumab and Bavituximab in Patients with Advanced 
Hepatocellular Carcinoma  
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS (EXAMPLES) ..................................................................... 1 
STUDY SCHEMA............................................................................................................ 2 
STUDY SUMMARY ......................................................................................................... 3 
1.0 BACKGROUND AND RATIONALE ......................................................................... 4 
1.1 
HEPATOCELLULAR DISEASE BACKGROUND ................................................................... 4 
1.2 
HEPATOCELLULAR CARCINOMA MANAGEMENT ............................................................ 4 
1.3 
DOSE RATIONALE ................................................................................................................ 5 
 
INTRODUCTION OF INVESTIGATIONAL TREATMENT(S) AND OTHER STUDY ............. 7 
1.4 
TREATMENT(S) ..................................................................................................................... 7 
1.5 
STUDY RATIONALE ............................................................................................................ 20 
1.6 
RATIONALE FOR TREATMENT BEYOND PROGRESSION ............................................. 21 
1.7 
RATIONALE FOR EFFICACY ENDPOINTS ........................................................................ 21 
1.8 
RESEARCH HYPOTHESIS ................................................................................................. 21 
2.0 STUDY OBJECTIVES .......................................................................................... 22 
2.1 
PRIMARY OBJECTIVE ........................................................................................................ 22 
2.2 
SECONDARY OBJECTIVES ............................................................................................... 22 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................... 22 
3.0 STUDY DESIGN ................................................................................................... 22 
3.1 
DESIGN ................................................................................................................................ 22 
3.2 
ENDPOINTS AND SAMPLE SIZE JUSTIFICATION ........................................................... 24 
4.0 SUBJECT ELIGIBILITY ........................................................................................ 24 
4.1 
INCLUSION CRITERIA ........................................................................................................ 24 
4.2 
EXCLUSION CRITERIA ....................................................................................................... 26 

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5.0 TREATMENT PLAN ............................................................................................. 28 
5.1 
OVERVIEW .......................................................................................................................... 28 
5.2 
TREATMENT REGIMEN SCHEDULE AND DOSE ADJUSTMENTS ................................. 28 
5.3 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 28 
5.4 
MONITORING OF STUDY TREATMENT DOSE ADMINISTRATION ................................. 30 
5.5 
TREATMENT DURATION .................................................................................................... 30 
5.6 
CONCOMITANT MEDICATIONS-ALLOWED AND PROHIBITED ...................................... 31 
5.7 
DOSE MODIFICATION GUIDELINES ................................................................................. 32 
Table 5.2 Dose Modification Guidelines for Drug-Related Adverse Events ........... 33 
5.8 
RESCUE MEDICATION AND SUPPORTIVE CARE ........................................................... 35 
Diagnosis and Management of Non-Overdose Hepatic ECIs .................................. 39 
5.9 
CONTRACEPTION .............................................................................................................. 42 
5.10 DRUG SUPPLY AND STORAGE......................................................................................... 44 
6.0 STUDY PROCEDURES ........................................................................................ 44 
6.1 
SCREENING PHASE ........................................................................................................... 44 
6.2 
TREATMENT PHASE .......................................................................................................... 45 
6.3 
POST – TREATMENT FOLLOW-UP PHASE ...................................................................... 45 
7.0 MEASUREMENT OF EFFECT ............................................................................. 49 
7.1 
ANTITUMOR EFFECT- SOLID TUMORS ........................................................................... 49 
7.2 
TREATMENT BEYOND PROGRESSION ........................................................................... 52 
7.3 
SAFETY/TOLERABILITY ..................................................................................................... 52 
8.0 ADVERSE EVENTS.............................................................................................. 52 
8.1 
PEMBROLIZUMAB TREATMENT RELATED EVENTS ...................................................... 53 
8.2 
BAVITUXIMAB TREATMENT RELATED EVENTS ............................................................. 53 
8.3 
ADVERSE EVENT MONITORING ....................................................................................... 53 
8.4 
STOPPING RULES .............................................................................................................. 59 

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8.5 
STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES EXPEDITED        
REPORTING ........................................................................................................................ 59 
8.6 
DEFINITION OF AN OVERDOSE FOR THIS PROTOCOL AND REPORTING OF 
OVERDOSE TO MERCK ..................................................................................................... 59 
8.7 
REPORTING OF PREGNANCY AND LACTATION TO MERCK ........................................ 60 
8.8 
EVENTS OF CLINICAL INTEREST ..................................................................................... 60 
9.0 CORRELATIVES/SPECIAL STUDIES ................................................................. 61 
10.0 STUDY MANAGEMENT ....................................................................................... 61 
10.1 CONFLICT OF INTEREST ................................................................................................... 61 
10.2 INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT ............................ 61 
10.3 RECRUITMENT PLAN ......................................................................................................... 62 
10.4 STUDY SUBJECT IDENTIFICATION NUMBER .................................................................. 62 
10.5 SUBJECT REGISTRATION ................................................................................................. 63 
10.6 PROTECTION OF HUMAN SUBJECTS .............................................................................. 63 
10.7 DATA MANAGEMENT AND MONITORING/AUDITING ...................................................... 64 
10.8 ADHERENCE TO THE PROTOCOL ................................................................................... 64 
10.9 AMENDMENTS TO THE PROTOCOL ................................................................................ 66 
10.10 RECORD RETENTION ........................................................................................................ 66 
10.11 OBLIGATIONS OF INVESTIGATORS ................................................................................. 66 
11.0 REFERENCES ...................................................................................................... 66 
12.0 APPENDICES ....................................................................................................... 69 
Appendix A: ECOG Performance Status ................................................................... 69 
Appendix B: Child-Pugh Score .................................................................................. 69 
Appendix C: NYHA Classification .............................................................................. 69 

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1  
LIST OF ABBREVIATIONS (EXAMPLES) 
AE  
  
Adverse Event  
ALT   
  
Alanine Aminotransferase  
ALC    
Absolute Lymphocyte Count  
AST  
  
Aspartate Aminotransferase  
BUN    
Blood Urea Nitrogen  
CBC  
  
Complete Blood Count  
CMP    
Comprehensive Metabolic Panel  
CR   
  
Complete Response  
CT  
  
Computed Tomography  
CTCAE  
Common Terminology Criteria for Adverse Events  
DLT    
Dose Limiting Toxicity  
DSMB   
Data and Safety Monitoring Board  
ECOG   
Eastern Cooperative Oncology Group  
H&P  
  
History and Physical Exam  
HRPP               Human Research Protections Program 
IV  
  
Intravenously  
mAB   
Monoclonal antibody  
MTD   
Maximum Tolerated Dose  
NCI  
  
National Cancer Institute  
ORR   
Overall Response Rate  
OS  
  
Overall Survival  
PBMCs  
Peripheral Blood Mononuclear Cells  
PD  
  
Progressive Disease  
PFS  
  
Progression Free Survival  
p.o.  
  
Per os  
PR  
  
Partial Response  
SAE  
  
Serious Adverse Event  
SD  
  
Stable Disease  
WBC    
White Blood Count  
  
 
 
 
 
 

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2  
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SUMMARY 
Title  
A Phase II Study of Pembrolizumab and Bavituximab In Patients With 
Advanced Hepatocellular Carcinoma (HCC)  
Phase  
Phase II  
Methodology  
Open label  
Study Duration  
24 months accrual/12 months follow-up  
Study Center(s)  
UT Southwestern Medical Center (UTSW) and  
Parkland Health and Hospital System (PHHS)  
Objectives  
Primary Objective:  
1. To determine the overall response rate (ORR) of combination 
pembrolizumab and bavituximab in patients with advanced HCC.   
Secondary Objectives:  
1. To determine overall survival, 6 month PFS, and duration of response of 
combination pembrolizumab and bavituximab compared to historical 
controls.  
2. To determine the safety and tolerability of combination pembrolizumab 
and bavituximab as measured by rates of adverse events according to 
the CTCAE v. 4.03.  
Exploratory Objectives:  
1. To determine treatment response with pre- and intra-treatment biopsies 
and plasma/serum correlative studies. 
Number of Subjects  
10-28  
Diagnosis and Main Inclusion 
Criteria  
1. Patients must have a histologically confirmed diagnosis hepatocellular 
carcinoma;   
2. At least 4 weeks since prior therapy;   
3. No history of prior systemic therapy for HCC;  
4. Patients with advanced HCC not eligible for curative and/or locoregional 
therapies;  
5. Age ≥ 18 years;  
6. Child-Pugh Score A   
Study Product(s), Dose, 
Route, Regimen  
Pembrolizumab: 200 mg IV every 3 weeks Bavituximab: 3 mg/kg 
IV weekly  
Duration of Administration  
Study treatment will continue until disease progression, unacceptable toxicity, 
death or discontinuation from the study treatment for any other reason. 
Subjects will be allowed to continue study therapy after an initial investigator-
assessed RECIST 1.1-defined progression as long as the following criteria are 
met:  
• 
Investigator assessed clinical benefit, and  
• 
Subject is tolerating the study drug (pembrolizumab and 
bavituximab).  
Statistical Methodology  
The primary endpoint of the trial will be overall response rate (ORR) of HCC 
patients. A minimax two-stage method will be used to analyze ORR after the 
first 15 patients are accrued. 13 additional patients will be enrolled if 3 or more 
of the first 15 patients have either a complete or partial response. ORR will be 
analyzed by RECIST 1.1 criteria.  
 
 

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BACKGROUND AND RATIONALE 
1.1 HEPATOCELLULAR DISEASE BACKGROUND  
 
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is responsible for 
more than 500,000 deaths annually. (1) Previously considered uncommon in Western countries, 
the incidence and mortality of HCC have increased three-fold in the United States over the past 
two decades. (2) 
1.2 HEPATOCELLULAR CARCINOMA MANAGEMENT  
 
Although complete resection or hepatic transplantation remains the most effective therapies for 
localized HCC, 50-70% of patients present with advanced disease not amenable to curative 
surgical approaches. (3,4) Disease that is diagnosed at an advanced stage or with progression 
after locoregional therapy has a dismal prognosis with a median overall survival of < 12 months 
mainly due to underlying liver dysfunction and suboptimal treatment options. (2) Ablative therapies 
are commonly used in this setting but are ineffective for large (>5 cm) or multifocal tumors, both 
commonly found in advanced disease. (5, 6) Hepatic artery chemoembolization may have utility in 
patients with HCC but there are conflicting reports regarding its efficacy and in advanced disease 
a survival benefit has not been demonstrated. (7, 8)   
  
 
Systemic Therapy for Advanced Hepatocellular Carcinoma  
  
 
The use of single agent systemic cytotoxic chemotherapy regimens including irinotecan, 
gemcitabine or doxorubicin have historically demonstrated low response rates with little to no 
clinical efficacy. (9-11) Combination chemotherapy regimens using cytotoxic chemotherapeutic 
agents have fared no better with response rates ranging from 0% to 40% and limited clinical 
efficacy. A recent study compared single agent doxorubicin to a combination of cisplatin, 
interferon, doxorubicin and 5fluorouracil (PIAF). Despite an improvement in response (10% for 
doxorubicin vs. 21% for PIAF) the study failed to show an improvement in survival (6.8 vs. 8.6 
months, respectively; P=0.83). (12)  
  
 
The lack of appropriate traditional chemotherapeutic agents led to the investigation of molecular 
targeted agents, which have been shown to be efficacious in other tumor models.  Sorafenib, an 
oral multikinase inhibitor that blocks tumor cell proliferation by targeting the Raf/MEK/ERK 
signaling pathway and exerts an antiangiogenic effect by targeting the tyrosine kinase receptors, 
VEGFR-2, VEGFR-3 and PDGF- , is the first biologically targeted agent to show efficacy in the 
treatment of advanced stage HCC. (13, 14) In a phase III randomized controlled trial (SHARP 
trial), patients with advanced hepatocellular carcinoma (not eligible for surgical resection or 
transplantation) and preserved liver function (Child-Pugh A score) were randomly assigned to 
either systemic sorafenib or placebo. There was a significantly longer survival and radiologic time 
to progression (TTP) outcome in the cohort of patients that received sorafenib. Grade 3 drug 
related events included diarrhea (8% in the sorafenib group vs. 2% in the placebo group), hand-
foot skin reaction (8% vs. 1%), hypertension (2% vs. 1%) and abdominal pain (2% vs. 1%); there 
were no grade 4 drug-related adverse events in any of these categories in either study group.  
Currently sorafenib is the only drug that has FDA approval for the systemic treatment of HCC.  
Although sorafenib is the current standard of care for patients with advanced HCC, it prolonged 
radiologic time to progression less than 3 months when compared to best supportive care: 5.5 
months versus 2.8 months, respectively.  Overall survival was prolonged less than 3 months 
compared to best supportive care, 10.7 months versus 7.9 months, respectively. (14) Although 
systemic treatment with sorafenib shows statistically significant clinical efficacy, its overall benefit 
is modest.   
  
 
Post-marketing clinical studies demonstrated that although sorafenib treatment has shown a 
significant increase in mean overall survival in different studies, only a portion of patients show 

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real benefits, while the incidence of drug related significant adverse effects and the economic 
costs are relatively high. (15) Finally, predictive biomarkers for sorafenib benefit that could refine 
the risk-benefit ratio for therapy have not yet been validated. Although Regorafenib was approved 
by the FDA for treatment in a second line setting following Sorafenib in the first line setting,(16) 
there is a real need for treatment options for patients with advanced HCC.  
  
  
1.3 DOSE RATIONALE  
 
Rationale for Pembrolizumab in HCC  
  
The liver has developed intrinsic mechanisms of immune tolerance to prevent abnormal 
immune responses to antigens. In HCC, this inherent anti-hepatic immunosuppressive 
environment is exacerbated by the chronic inflammation that underlies the development of 
fibrosis and cirrhosis. The altered environment results in oncogenic transformation and 
further activation of immunosuppressive mechanism, resulting in an inability to escalate a 
meaningful antitumor response. (17-19) Immune changes reported in HCC include tumor-
associated antigen-specific CD8+ T-cell immune responses, T-cell infiltration after 
locoregional therapy, T regulatory cell (Treg) intratumoral accumulation, and myeloid-
derived suppressor cells (MDSCs) accumulation. These changes have been correlated 
with disease progression and poor survival. (17)  
  
  
  
There are reasons to believe that HCC is amenable to immunotherapy in that it has the 
highest reported rate of spontaneous regression, which is primarily attributed to antitumor 
immunity. Spontaneous regression of untreated lesions has been reported after 
locoregional treatment of liver tumors. (20, 21) These observations suggest that anti-
tumor immune responses can be effective in HCC control.  
  
There are data supporting a role for immunotherapy in HCC. Lymphocytic infiltration of 
the tumor and a high CD4+: CD8+ T-cell ratio has been associated with reduced risk of 
tumor recurrence following liver transplantation for HCC. (22) Adoptive immunotherapy 
with autologous lymphocytes activated with recombinant interleukin2 and antibody to CD3 
in patients who had undergone curative resection resulted in a significantly longer 
recurrence-free and disease-specific survival, although overall survival did not differ 
significantly between treated and control groups. (23) The data nonetheless imply a 
central role of T cells in modulating tumor progression and provide a strong justification 
for T cell immunotherapy. (24)  
  
Preliminary data in HCC are available for inhibitors on the CTLA-4 and PD-1 checkpoint 
pathways. The CTLA-4 pathway inhibits T-cell activation, specifically Tregs. The phase II 
study of tremelimumab, a CTLA-4 blocking antibody, in HCC patients reported a partial 
response rate (PR) of 17.6%, a disease control rate (DCR) of 76.4%, and a time to 
progression of 6.5 months. (25) This compares favorably with sorafenib data (1% PR, 
43% DCR, 5.5 months radiologic time to progression). (14)  
  
A 2015 systemic review and meta-analysis investigated the potential value of PD-L1 in 
the prognostic prediction in human solid tumors. A total of 3107 patients with solid tumors 
from 28 published studies were included in the meta-analysis. The median percentage of 
solid tumors with PD-L1 overexpression was 53%. In this analysis, PD-L1 overexpression 
was associated with worse three-year OS in HCC. PD-L1 tumor staining of 40 commercial 
HCC tumor samples yielded positive staining in 13 of 40 (33%) including 45% of HCC 
samples without active hepatitis virus infection, 22% of HBV related HCC, and 0% with 
co-infected HCC. (26)  
  

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The phase I/II study of nivolumab, a PD-1 inhibitor, in HCC patients reported a 14% 
partial response rate, a 2% complete response rate, and an OS of 14.1 months.  
Median duration of response was 17 months. Treatment-related serious adverse events 
was 7% with only 4% of patients discontinuing therapy due to adverse events. There were 
no treatment-related deaths. This compares a historical rate of 12-month OS after 
sorafenib failure of 30% and a grade 3 or 4 adverse event rate of 39% in sorafenib alone. 
(27)  
  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2. Based on preclinical, in vitro data, pembrolizumab has high affinity and 
potent receptor blocking activity for PD-1. The PD-1 checkpoint mediates the 
differentiation and proliferation of Tregs and also regulates peripheral tolerance and 
autoimmunity. The PD-1 pathway is activated binding of PD-1 to its ligands, PD-L1 and 
PD-L2, resulting in inhibition of T-cell proliferation and cytokine release. Animal data and 
translational clinical studies support a potential role of the PD-1/PD-L1 pathway as a 
mechanism for immune tolerance in HCC. PD-L1 is expressed by HCC cells and PD-1 is 
expressed by CD 8+ T cells in HCC tissue specimens. The level of expression 
significantly correlates with HCC stage, local recurrence rate, and poor prognosis. In 
addition, the frequency of intratumoral or circulating PD-1+ CD8+T cells correlates with 
HCC progression and postoperative recurrence.   
  
Pembrolizumab is currently being investigated in multiple tumor types. Pembrolizumab 
treatment has demonstrated overall survival benefit in a phase 3 clinical trial in advanced 
melanoma and is currently approved for patients with nonsmall cell lung cancer with 
tumors expressing PD-L1. (28,29) In a trial of pembrolizumab versus ipilimumab in 
advanced melanoma one-year survival was 74% (every 2 week dosing) and 68% (every 3 
week dosing) for pembrolizumab and 58% for ipilimumab. The median progression free 
survival (PFS) was 5.5 months (every 2 week dosing) and 4.1 months (every 3 week 
dosing) for pembrolizumab and 2.8 months for ipilimumab. (28)  
  
 
Rationale for Pembrolizumab Dose  
  
The pembrolizumab dose of 200 mg every three weeks (Q3W) was selected based on 
clinical data and modeling and simulation approaches using population pharmacokinetics 
(PPK) and exposure-response analyses of data from studies in multiple tumor types 
(melanoma and NSCLC) where body weight normalized dosing (mg/kg) has been used.  
  
PPK analyses have shown that the PK of pembrolizumab is linear with proportional 
exposure over a dose range of 1 to 10 mg/kg, and no differences in PK across ethnicities 
and tumor types were observed.    
  
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of pembrolizumab were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  Pembrolizumab has been 
found to have a wide therapeutic range based on the melanoma indication.  The 
differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body 
weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg 
Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and 
exposure). The population PK evaluation revealed that there was no significant impact of 

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tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings.  
  
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.   
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage.  
 
 
Rationale for Bavituximab in HCC  
 
Bavituximab is a genetically engineered immunoglobulin gamma 1 (IgG1) chimeric 
(human/mouse) mAb containing the variable region sequences of the murine PStargeting 
mouse antibody 3G4(2aG4) and human IgG1 k constant region sequences that targets 
PS after binding to 2-glycoprotein 1 ( 2GP1). PS is a highly immunosuppressive 
molecule typically expressed on the inner leaflet of the plasma membrane of normal cells 
but “flips” and becomes externalized to the outer leaflet of the plasma membrane on cells 
that line tumor blood vessels, tumor cells and exosomes in the tumor microenvironment 
creating a specific target for anticancer treatments.  
 
Bavituximab is a novel immunotherapeutic approach because its primary mechanism of 
action involves modulating the tumor microenvironment from a primarily 
immunosuppressive, angiogenesis-promoting state (with infiltrating myeloid-derived 
suppressor cells [MDSCs] and M2-macrophages) to an immune activating state (with 
long-term tumor specific-immunity facilitated by M1 macrophages, mature dendritic cells, 
and activated T lymphocytes) that drives both innate and adaptive immunity. Bavituximab 
blocks the immunosuppressive signaling of myeloid derived cells and sends and alternate 
immune activation signal leading to an adaptive T-cell mediated anti-tumor response. In 
addition, through activation of innate immunity (i.e., M1 macrophages and natural killer 
[NK] cells), bavituximab causes tumor cell destruction and the selective shutdown of pre-
existing tumor blood vessels expressing PS via antibody-dependent cell mediated 
cytotoxicity.  
 
To date, the clinical development program of bavituximab has enrolled approximately 900 
patients in oncology studies. Specifically a phase I/II clinical trial has demonstrated that 
radiological TTP with bavituximab combined with sorafenib was 6.7 months compared to 
the historical controls of 5.5 months from the SHARP trial with sorafenib alone. The 6-
month PFS in the bavituximab and sorafenib combination group was 20%. The dosage of 
bavituximab in the phase I/II trial in HCC patients was 3.0 mg/kg weekly intravenously and 
not associated with any severe treatment related adverse events.(30)  
 
1.4 INTRODUCTION OF INVESTIGATIONAL TREATMENT(S) AND OTHER STUDY 
TREATMENT(S)  
 

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Overview of pembrolizumab  
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, programmed cell death ligand 1 (PDL1) and programmed 
cell death ligand 2 (PD-L2). This blockade enhances functional activity of the target 
lymphocytes to facilitate tumor regression and ultimately immune rejection.  
 
 
Pembrolizumab non-clinical experience  
Nonclinical Pharmacology  
Pembrolizumab binds to human and Cynomolgus monkey PD-1 with comparable affinity 
and blocks the binding of human and Cynomolgus monkey PD-1 to PDL1 and PD-L2 with 
comparable potency. Pembrolizumab does not cross-react with dog, rat, or mouse PD-1. 
Pembrolizumab does not bind immunoglobulin superfamily members cluster of 
differentiation 28 (CD28), cytotoxic Tlymphocyte-associated protein 4 (CTLA-4), or 
inducible T-cell costimulator (ICOS).  
  
Pembrolizumab strongly enhances T-lymphocyte immune responses in cultured blood 
cells from healthy human donors, cancer subjects, and nonhuman primates. In T-cell 
activation assays using human donor blood cells, the halfmaximal effective concentration 
(EC50) has been approximately 0.1 to 0.3 nM. In addition to interleukin-2 (IL-2), tumor 
necrosis factor alpha (TNFα), interferon gamma (IFN ), and levels of other cytokines were 
found to be modulated by pembrolizumab. The antibody potentiates existing immune 
responses only in the presence of antigen and does not nonspecifically activate T-cells. In 
the in vitro peripheral blood mononuclear cell (PBMC) and whole blood cytokine release 
assays, the cytokine levels induced by pembrolizumab were low and comparable to those 
induced by trastuzumab. Pembrolizumab does not induce antibodydependent cell-
mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).  
  
Using anti–murine PD-1 surrogate antibodies, PD-1 blockade has been shown to 
significantly inhibit tumor growth in a variety of syngeneic murine tumor models. In these 
experiments in mice, anti–PD-1 therapy is synergistic with chemotherapeutic agents such 
as gemcitabine and 5-fluorouracil (5-FU), and combination therapy results in increased 
complete tumor regression rates in vivo. Studies also revealed that immunosuppressive 
doses of dexamethasone included in combination with agents used in standard-of-care 
treatment for NSCLC do not reduce the anti-tumor efficacy of an anti–murine PD-1 
surrogate antibody.  
  
Nonclinical Pharmacokinetics  
The pharmacokinetics (PK) of pembrolizumab were evaluated in a non–Good Laboratory 
Practices (GLP) single dose PK study and two GLP repeat-dose toxicokinetic (TK) studies 
(1 month and 6 month) in Cynomolgus monkeys. Pembrolizumab stability as a modified 
IgG4 molecule was evaluated in vivo in mice.  
  
After single-dose IV administration at 0.3, 3, or 30 mg/kg in Cynomolgus monkeys, 
decline of serum concentration followed multiphasic kinetics. Anti–drug antibodies (ADAs) 
were detected in most of the treated animals. Clearance (CL) and terminal half-life (t1/2) 
appeared to be dose-dependent in the dose range tested with t1/2 varying from 4 to 10 
days.  
  
In the 1-month repeat-dose (once weekly) GLP toxicity study at 6, 40, or 200 mg/kg in 
Cynomolgus monkeys, ADAs were detected in most of the low-dose (6 mg/kg) treated 
animals. The systemic exposure over the 7-day dosing interval (AUC0-7 days) was sex-
independent and increased with increasing dose. The mean t1/2 values in individual ADA-
negative animals ranged from 15.7 to 22.3 days across doses.  

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In the 6-month repeat-dose (every other week) GLP toxicity study at 6, 40, or 200 mg/kg 
in Cynomolgus monkeys, ADAs were detected in most of the low-dose (6 mg/kg) treated 
animals. The systemic exposure to pembrolizumab was independent of sex and was 
approximately dose-proportional across all doses. The mean t1/2 values in individual 
ADA-negative animals ranged from 21 to 22 days across doses.  
  
IgG4 wild type molecule can undergo in vivo molecular rearrangement called Fabarm (or 
half molecule) exchange by swapping their half molecule with other IgG4 half molecules, 
thereby generating bispecific or hybrid antibodies. Pembrolizumab is a hinge mutated 
IgG4 (S228P), which prevents in vivo half-molecule swap (formation of hybrid). An in vivo 
mice experiment has demonstrated that pembrolizumab did not form hybrid antibody with 
another wild type IgG4 molecule.  
  
Safety Pharmacology/Toxicology  
The potential for systemic toxicity of pembrolizumab was assessed in a 1-month repeat-
dose toxicity study with a 4-month recovery in Cynomolgus monkeys and in a 6-month 
repeat-dose toxicity study with a 4-month recovery period in Cynomolgus monkeys. In the 
1-month toxicity study, Cynomolgus monkeys were administered an IV dose of 6, 40, or 
200 mg/kg once weekly for a total of 5 doses. Four monkeys/sex/group were euthanized 
during Week 5.  The remaining 2 monkeys/sex/group were euthanized during Week 23, 
after a 4-month postdose period. In this study, pembrolizumab was well-tolerated in 
monkeys with the systemic exposure (AUC) up to approximately 170,000 μg·day/mL over 
the course of the study. There was no test article–related mortality, and test article–
related changes were limited to an increased incidence of inguinal swelling, and 
increased splenic weights in males receiving 200 mg/kg. Both of these findings were not 
considered adverse and there was no histopathologic correlation. Splenic weights were 
normal at the postdose necropsy. Anti–pembrolizumab antibodies were detected in 7 out 
of 8 animals in the 6 mg/kg dose group and 1 animal out of 8 in the 40 mg/kg dose group 
and were associated with an apparent increase in clearance of pembrolizumab. The 
presence of ADA in monkeys in the low-dose group and in 1 monkey in the mid-dose 
group did not impact the pharmacodynamic response, because sufficient target 
engagement was demonstrated for the duration of the study (with the exception of 1 low-
dose monkey). Additionally, anti–pembrolizumab antibodies were not detected in any 
monkeys in the highdose group, suggesting that potential toxicity has been evaluated at 
the highest exposure levels in the study. Based on the lack of adverse test article–related 
findings in this study, the no observed adverse effect level (NOAEL) was ≥200 mg/kg.  
In the 6-month toxicity study, the potential for systemic toxicity was assessed in 
Cynomolgus monkeys administered an IV dose of 6, 40, or 200 mg/kg once every other 
week for approximately 6 months (a total of 12 doses) followed by a 4-month treatment-
free period. Three animals/sex/group were designated for interim necropsy at the end of 
the 6-monthdosing phase (3 days after receiving the last dose in Study Week 23); and the 
remaining monkeys were designated for final necropsy following the 4-month treatment-
free period. Pembrolizumab was well tolerated at all dose levels. There were no test 
article–related antemortem findings, electrocardiographic or ophthalmic findings, changes 
at injection sites, gross observations or organ weight changes at the interim or final 
necropsy. Because there were no test article–related histomorphologic findings at interim 
necropsy, histomorphologic evaluation of tissues collected at final necropsy was not 
conducted. The presence of ADA was observed in 5 out of 10 animals at 6 mg/kg/dose 
during the dosing phase, which correlated with an apparent increased rate of elimination 
of pembrolizumab in these animals. No anti–pembrolizumab antibodies were detected at 
40 or 200 mg/kg/dose during the dosing phase, and no pembrolizumab serum 
concentration profiles in these 2 groups suggested an effect of ADA on pembrolizumab 
elimination rate. During the treatment-free period, anti– pembrolizumab antibodies were 
detected in 2 animals at the 6 mg/kg/dose, which already had ADA present during the 
dosing phase, and in 2 additional animals (1 at the 6 mg/kg/dose and 1 at the 200 

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mg/kg/dose), which were ADA-negative during the dosing phase. The detection of anti-
pembrolizumab antibodies had a minimal effect on the mean group systemic exposure to 
pembrolizumab during the study and did not impact the evaluation of potential toxicity of 
pembrolizumab for the duration of the 6-month study, because there were no test article– 
related effects on any of the parameters examined and no monkey in the mid- and high-
dose groups developed ADA during the dosing phase. In conclusion, pembrolizumab 
administered once every other week over a 6-month duration to Cynomolgus monkeys 
was well tolerated and the NOAEL was ≥200 mg/kg/dose (the highest dose tested).  
In addition, tissue cross-reactivity studies using monkey and human specimens were 
conducted to evaluate the potential cross reactivity of pembrolizumab with cryosections of 
Cynomolgus monkey tissues and normal human tissues. Results demonstrated the 
expected on-target staining of the membranes of mononuclear leukocytes in both species. 
The off-target staining (cytoplasmic and stromal) that occurred in many tissues of both 
species was considered spurious binding inherent to the experimental conditions of the in 
vitro tissue cross-reactivity studies with no in vivo toxicological significance.  
Detailed information about the comprehensive nonclinical safety, immunology, and 
pharmacokinetic (PK) testing program is provided in the current version of the 
pembrolizumab Investigator’s Brochure.  
 
Pembrolizumab clinical experience  
As of August 15, 2015, 1195 patients with melanoma have being treated in 2 clinical trials 
(P01 and P02). Patients in P01 were treated with 2 mg/kg every 3 weeks, 10 mg/kg every 
three weeks, or 10 mg/kg every 2 weeks. The primary endpoint was objective response 
rate (ORR) with disease control rate (DCR) a secondary endpoint. Overall there were 44 
complete responses and 159 partial responses. The ORR was 31% (95% CI: 28% to 
35%). DCR was achieved in 51% of all subjects. Patients in P02 were treated with 2 
mg/kg every 3 weeks and 10 mg/kg every 3 weeks versus investigator choice 
chemotherapy in a 1:1:1 ratio in subjects with IPIrefractory melanoma. The two coprimary 
efficacy endpoints were PFS and OS. The median PFS was 2.9 months in both 
pembrolizumab arms and 2.7 months in the control arm. A preliminary analysis of OS 
indicated that the hazard ration was 0.88 in the pembrolizumab 2 mg/kg Q3W arm over 
the control arm and 0.78 in the pembrolizumab 10 mg/kg Q3W arm over the control arm. 
The one-sided p-value was 0.229 and 0.066 in 2 mg/kg Q3W and 10 mg/kg Q3W over the 
control arm, respectively, both favoring pembrolizumab.   
  
 
 

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The most common all-grade adverse events (>10%) for the P01 and P02 clinical trials are 
shown below.  
 
 
 

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The most common grade 3-5 adverse events in P01 and P02 clinical trials are shown 
below. 
 
 
 

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15  
 
 

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Refer to the current version of the pembrolizumab Investigator’s Brochure for additional details.  
 
Overview of bavituximab  
Bavituximab is a genetically engineered immunoglobulin gamma 1 (IgG1) chimeric 
(human/mouse) mAb containing the variable region sequences of the murine PStargeting 
mouse antibody 3G4(2aG4) and human IgG1 k constant region sequences that targets 
PS after binding to 2-glycoprotein 1 ( 2GP1). PS is a highly immunosuppressive molecule 
typically expressed on the inner leaflet of the plasma membrane of normal cells but “flips” 
and becomes externalized to the outer leaflet of the plasma membrane on cells that line 
tumor blood vessels, tumor cells and exosomes in the tumor microenvironment creating a 
specific target for anticancer treatments.  
 
Bavituximab is a novel immunotherapeutic approach because its primary mechanism of 
action involves modulating the tumor microenvironment from a primarily 
immunosuppressive, angiogenesis-promoting state (with infiltrating myeloid-derived 
suppressor cells [MDSCs] and M2-macrophages) to an immune activating state (with 
long-term tumor specific-immunity facilitated by M1 macrophages, mature dendritic cells, 
and activated T lymphocytes) that drives both innate and adaptive immunity. Bavituximab 
blocks the immunosuppressive signaling of myeloid derived cells and sends and alternate 

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immune activation signal leading to an adaptive T-cell mediated anti-tumor response. In 
addition, through activation of innate immunity (i.e., M1 macrophages and natural killer 
[NK] cells), bavituximab causes tumor cell destruction and the selective shutdown of pre-
existing tumor blood vessels expressing PS via antibody-dependent cell mediated 
cytotoxicity.  
 
Bavituximab non-clinical experience  
Nonclinical experiments have shown that antibody-mediated PS targeting can override 
PS-mediated immunosuppression, reactivate innate tumor immunity, and evoke adaptive 
antitumor immunity. In genetically modified nonclinical murine tumor models, PS targeting 
induces potent tumor-specific T-cell immunity in the transgenic adenocarcinoma mouse 
prostate tumor model such that the combination of anti-PS with castration cured 35% of 
the animals, compared to none in control groups. In separate pre-clinical studies, the use 
of antibodies against PD-1 or PD-L1 have demonstrated similar activity as single agents 
and when combined with other immune oncology agents.  
 
To support clinical development, bavituximab was evaluated in a series of dose range 
finding, repeated dose and specialized IV toxicology studies in appropriate species and in 
vitro systems. In vivo toxicology studies consisted of nonGLP dose range finding studies 
in the Sprague-Dawley® (SD) rat, rabbit and cynomolgus monkey as single IV dose 
administration, followed by GLP 8-week once-weekly dosing toxicology studies in the rat 
and monkey. The reversibility of any observed toxicity was determined in recovery studies 
included as part of the protocol for selected studies. The in vivo studies employed 
intravenous bolus dosing of bavituximab according to the current clinical dosing regimen 
and route of administration. Toxicokinetic (TK) analyses were conducted in rats and 
monkeys to facilitate correlating observed toxicity to systemic exposure to bavituximab.  
 
The nonclinical safety assessment program that has been undertaken fully supports the 
continual use of bavituximab in clinical trials in oncology patients. The nonclinical effects 
of bavituximab have been assessed in a comprehensive panel of studies, addressing the 
relationships of pharmacology, pharmacokinetics/toxicokinetics, immunogenicity and 
toxicology; the target tissues for toxicity; the NOAELs and LOAELs; the noninvasive 
monitors for the key toxicologic responses; and the reversibility of adverse effects. Among 
the recovery animals at the high dose (100 mg/kg) in the rat toxicology study, there 
remained evidence of microscopic sub endocardial inflammation and/or fibrosis, however, 
there were no coagulation abnormalities. Similarly, bavituximab-related microscopic 
changes in monkeys were confined to a mild, thrombus within the right ventricle of one 
male at 100 mg/kg and no coagulation abnormalities in the recovery phase. Results from 
the bavituximab nonclinical program to date indicate a therapeutic benefit of combining 
bavituximab with conventional (chemotherapy) or immunotherapy (checkpoint blockade) 
for continued clinical evaluations and support the safety of the proposed dose of 3 mg/kg 
bavituximab administered intravenously once weekly in patients.  
 
Detailed information about the comprehensive nonclinical safety, immunology, and 
pharmacokinetic (PK) testing program is provided in the current version of the 
bavituximab Investigator’s Brochure.  
 
Bavituximab clinical experience  
To date, the clinical development program of bavituximab has enrolled approximately 900 
patients, of whom over 600 patients have been treated with bavituximab. Most patients 
were treated with combination therapy in oncology studies.  
 
In the oncology program, where bavituximab was given in combination with cytotoxic 
chemotherapy in all but 26 patients, common adverse events (20%) were reported in 
patients receiving bavituximab include the following: nausea, alopecia, fatigue, diarrhea, 

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neutropenia, anemia, pyrexia, and asthenia. Many of the reported common AEs were 
considered to be related to the concomitant administration of chemotherapy or the 
patient’s underlying malignancy.  
 
AEs reported with bavituximab clinical trials and a summary of clinical experience are 
described in the current version of the bavituximab Investigator’s Brochure.  
Phase I and Ib single-agent studies of bavituximab in combination with chemotherapy 
have been completed in patients with advanced cancer. Based on efficacy results from 
these studies and on PK data (which determined the maximum binding of β2-GP1), a 
dose of 3 mg/kg bavituximab was determined and selected for further clinical study. The 
studies also showed the tolerability profile to be consistent with expectations based on 
animal studies, and demonstrated adequate efficacy to warrant further study. Several 
Phase II studies of bavituximab in combination with chemotherapy have been completed. 
A Phase III study to evaluate the efficacy and safety of bavituximab combined with 
docetaxel in patients with previously treated Stage IIIb/IV non-squamous NSCLC is 
ongoing.  
 
In a Phase II, randomized, double-blind study, 121 patients with previously treated, locally 
advanced, or metastatic non-squamous NSCLC were randomized to receive docetaxel 
plus placebo, docetaxel plus 1 mg/kg bavituximab, or docetaxel plus 3 mg/kg 
bavituximab. Due to a labeling error between the placebo and 1 mg product, efficacy 
analyses were performed comparing the 3 mg/kg group to a pooled control group of 1 
mg/kg and placebo. There was an improvement of almost 50% in ORR favoring the 3 
mg/kg bavituximab group compared to the pooled (placebo and 1 mg/kg) group, although 
this trend was not statistically significant. There was a positive trend in median PFS 
favoring the 3 mg/kg bavituximab group compared to the pooled control group (placebo 
and 1 mg/kg). Consistent with the trends observed in ORR and PFS, there was an 
improvement (60%) in median OS and hazard ratio (0.66) favoring the 3 mg/kg 
bavituximab group compared to the pooled control group (placebo and 1 mg/kg). Though 
the differences were not statistically significant, there was clear and persistent separation 
in the Kaplan-Meier survival curves.  
 
Overall, results from Phase I and Phase II studies suggested a beneficial treatment effect 
of bavituximab, and results were consistent among studies. The overall safety profile of 
bavituximab was acceptable, and the safety data were consistent with those observed in 
other clinical studies. Combination therapy did not substantially increase the risks of side 
effects. The adverse events observed in the phase 1 study of bavituxumab and sorafenib 
in patients with hepatocellular cancer are summarized in the table below:  
  
Adverse Events Observed in the Phase 1 Study of Bavituxumab Plus 
Sorafenib Attributed to be Possibly, Probably, and Definitely Related to 
Treatment (n=9): 
Event Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hand/Foot Syndrome 
3 
2 
0 
0 
Hypertension  
1 
0 
2 
0 
Pruritus  
3 
0 
0 
0 
Fatigue 
2 
0 
0 
0 
Headache 
2 
0 
0 
0 
Hyponatremia 
1 
0 
1 
0 
Diarrhea 
1 
0 
0 
0 
Erythema R index finger 
1 
0 
0 
0 

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Adverse Events Observed in the Phase 1 Study of Bavituxumab Plus 
Sorafenib Attributed to be Possibly, Probably, and Definitely Related to 
Treatment (n=9): 
Generalized muscle weakness 
1 
0 
0 
0 
Leukopenia 
0 
1 
0 
0 
Mucositis 
1 
0 
0 
0 
Neutropenia 
0 
1 
0 
0 
Pain; Bilateral Feet 
1 
0 
0 
0 
Peripheral Neuropathy 
1 
0 
0 
0 
Right foot tenderness  
1 
0 
0 
0 
Thrombocytopenia 
1 
0 
0 
0 
Hypocalcemia 
0 
1 
0 
0 
Nausea 
1 
0 
0 
0 
Vomiting 
0 
1 
0 
0 
Anorexia 
1 
0 
0 
0 
 
Thus the potential additional benefits of combination therapy are likely to outweigh the risk 
of bavituximab-related adverse events. Refer to the current version of the bavituximab 
Investigator’s Brochure for additional details.  
 
1.5 STUDY RATIONALE  
The major challenge to effective immunotherapy is to overcome multiple pathways that inhibit 
innate or adaptive immune activation. Although anti-tumor effects have been observed in a 
percentage of cancer patients by blockade of immune checkpoints like PD-1; only a limited 
number of patients benefit from this therapy. Recent preclinical results indicate that the 
combination of PS targeting with PD-1 blockade demonstrated additive to synergistic antitumor 
efficacy in mice bearing K1735 and B-16F10 melanoma as well as EMT-6 and E077.1 breast 
carcinoma. This antitumor efficacy was associated with increases in intratumoral activated CD8 T 
cells (Ki67, IL-2 and Granzyme B positive), a reduction of M2 macrophages and MDSCs, and 
increased tumor reactive T cells in the spleen. Preclinical results indicate that antibody-mediated 
PS targeting with bavituximab reverses PS-mediated immunosuppression and initiates 
therapeutically effective adaptive antitumor immunity. (31,32,33) Thus, treatment with bavituximab 
in combination with a downstream immune checkpoint antagonist like pembrolizumab, may result 
in robust and long- lasting antitumor immunity that significantly improves clinical outcomes of 
duration and levels of response.  
 
Novel combinations are being explored for synergistic mechanisms of action to increase the 
limited anti-tumor immunity in cancer patients and evaluate the potential for new therapies for 
patients who are refractory to or progress on checkpoint blockade.  
Clinical studies with bavituximab in combination with chemotherapy in HCC, NSCLC, breast, and 
other cancers have shown signs of improved antitumor activity relative to chemotherapy alone.   
Based on these data, and the preclinical results demonstrating synergism between bavituximab 
and anti-PD-1/PD-L1 therapy noted above, this study will test the hypothesis that bavituximab can 
improve the outcome for patients with HCC treated with pembrolizumab, a PD-1 inhibitor.  
 
Since the efficacy of sorafenib, the only currently FDA approved systemic therapy, for advanced 
HCC is modest at best with overall survival and radiologic time to progression increased by under 

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3 months compared to placebo the need for more efficacious therapies is paramount. In addition, 
the adverse effects of sorafenib are high enough that over one-third of patients discontinue 
therapy due to drug-related toxicity.  
1.6 RATIONALE FOR TREATMENT BEYOND PROGRESSION  
For cytotoxic agents, an increase in tumor burden of the appearance of new lesions signals 
progressive disease and has become synonymous with drug failure. An assessment of 
progressive disease (PD) signifies the need for alternative management and discontinuation of 
current therapy. Recent experience indicates that the parameters for cytotoxic drug response 
assessment may not be sufficient to fully characterize the activity of targeted therapies, biologics, 
and/or immunotherapy agents.   
  
Immunotherapeutic agents such as pembrolizumab and bavituximab, produce antitumor effects 
by inducing cancer-specific immune responses or by modifying native immune processes. 
Traditional parameters for defining PD may not adequately assess the activity of 
immunotherapeutic agents because a) the appearance of measurable antitumor activity may take 
longer for immune therapies than for cytotoxic therapies; b) responses to immune therapies may 
occur after conventional PD; c) discontinuation of immune therapy may not be appropriate in 
some cases, unless PD is confirmed (as is usually done for response); d) allowance for clinically 
insignificant PD (i.e. small new lesions in the presence of other responsive lesions) is 
recommended; and e) durable stable disease (SD) may represent antitumor activity. (34)  
  
In a phase I clinical trial (KEYNOTE-001) administering pembrolizumab in advanced melanoma, 
14% of patients (84/600) experienced progressive disease per RECIST 1.1 but non-progressive 
disease per immune-related response criteria (irRC). The 84 patients with progressive disease by 
RECIST but non-progressive disease by irRC had a longer overall survival than the 177 patients 
with progressive disease per both criteria, which suggests that RECIST might underestimate the 
benefit of pembrolizumab in approximately 15% of patients. (35) These data suggest that patients 
may benefit from receiving treatment beyond initial evidence of radiographic progression and thus 
support the use of modified response criteria on the basis of immune-related response patterns. 
The data support study treatment with pembrolizumab and bavituximab beyond progression in 
this study under the parameters outlined in section 7.2.  
1.7 RATIONALE FOR EFFICACY ENDPOINTS  
Overall response rate (ORR) is the primary endpoint for this study (see section 3.2). ORR will be 
estimated as the number of responders (either partial or complete response) as a percent of the 
number of eligible participants who received at least one dose of bavituximab and 
pembrolizumab. Best overall response requires confirmation based on RECIST 1.1 on one 
imaging test greater than or equal to 9 weeks. ORR is generally favored as a progression 
endpoint in solid tumor treatment and has been associated with overall survival in HCC. (14)  
1.8 RESEARCH HYPOTHESIS   
It is our hypothesis that combination therapy pembrolizumab and bavituximab in patients with 
locally advanced HCC not amenable to curative therapies will provide greater efficacy than 
historical systemic therapy alone with a tolerable safety profile. 
 
 
 
 

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 STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE  
 
To determine the overall response rate (ORR) of combination pembrolizumab and 
bavituximab in patients with advanced HCC.   
  
2.2 
SECONDARY OBJECTIVES  
 
To determine overall survival, 6-month progression free survival, and duration of response 
of combination pembrolizumab and bavituximab compared to historical controls; 
 
To determine the safety and tolerability of combination pembrolizumab and bavituximab 
as measured by rates of adverse events according to the CTCAE v. 4.03;  
  
2.3 
EXPLORATORY OBJECTIVES  
 
To determine treatment response with pre- and intra-treatment biopsies and 
plasma/serum. Correlative studies will be performed on the collected tissue and blood 
samples to determine if predictive markers of response can be generated 
 
 STUDY DESIGN  
3.1 DESIGN  
This is a non-randomized, open-label, multi-site phase II therapeutic trial of pembrolizumab and 
bavituximab in patients with locally advanced HCC. Locally advanced or metastatic HCC is 
defined as disease that is not amenable to surgical and/or locoregional therapies.  Subjects must 
not have received prior systemic therapy for advanced HCC in keeping with the first-line setting of 
this study.  
Overall response rate (ORR) as assessed by the investigators and using RECIST 1.1 criteria, will 
be the primary endpoint.  
 
Screening Phase 
Prior to initiation of treatment, all patients will sign an informed consent form. Only patients that 
meet all inclusion criteria and none of the exclusion criteria will be eligible for treatment.  
 
Treatment Phase  
The treatment phase for each patient will begin on the initiation of treatment with both 
pembrolizumab and bavituximab study drug on Cycle 1 Day 1 (C1D1). Patients will continue study 
treatment until disease progression (or until discontinuation of study therapy in patient receiving 
pembrolizumab and bavituximab beyond progression), discontinuation due to toxicity, withdrawal 
of consent, or the study ends. Patients with radiological progression using RECIST may continue 
on study treatment if in the investigator’s assessment the patient is experiencing clinical benefit 
and tolerating the treatment. A safety follow-up is mandatory at 30 days post the last dose of 
Bavituximab.  
  
Efficacy, safety, and correlative assessments will be performed as outlined in the Schedule of 
Visits and Procedures (section 6.0).  

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Dose Limiting Toxicity:  
Initially, enrollment will be limited to 10 evaluable patients with no more than two patients enrolled 
per week. A safety committee comprised of the investigators and institutional GI Disease 
Orientated Team will monitor the occurrence of dose limiting toxicities (DLTs) for the first 10 
patients prior to enrolling the remainder of the trial following the DSMC guidelines. The period for 
evaluating DLTs will be from the time of the first administration of study treatment through Study 
Day 28. DLTs will follow the guidelines provided in the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.  
  
If three or more DLTs occur during this period, enrollment will be suspended and the DSMC will 
make a determination of whether to reduce the bavituximab dose to 1 mg/kg. After the DLT safety 
assessment period for the initial 10 patients, enrollment may proceed for the remainder of the 
trial. Patient safety is evaluated on a regular basis by the institutional data safety monitoring 
committee (DSMC). A DLT will be defined as any treatment related toxicity in the list below that 
occurs during the DLT evaluation period. Toxicity that is clearly and directly related to the primary 
disease or to another etiology is excluded from this definition. The following will be considered 
DLTs:  
  
• 
Any grade 4 immune-related adverse events (irAE)  
• 
Any ≥ grade 3 colitis  
• 
Any grade 3 or 4 noninfectious pneumonitis irrespective of duration  
• 
Any grade 2 pneumonitis that does not resolve to grade 1 within 5 days of the initiation of 
maximum supportive care  
• 
Any grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to grade 2 
within 5 days of the event despite optimal medical management including systemic 
corticosteroids or does not downgrade to grade 1 or baseline within 14 days  
• 
Liver transaminase elevation >8 x ULN or total bilirubin > 5 x ULN  
• 
Any ≥ grade 3 non-irAE, except for the exclusions listed below The definition excludes the 
following conditions:  
o 
Grade 3 fatigue ≤ 7days  
o 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the patient is asymptomatic  
o 
Grade 3 inflammatory reaction attributed to a local antitumor response o Concurrent 
vitiligo or alopecia of any grade  
o 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management  
o 
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Grade 3 or 4 febrile neutropenia will be 
considered a DLT regardless of duration or reversibility  
o 
Grade 3 or 4 lymphopenia  
o 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days  
o 
Isolated grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 
days  
o 
Isolated grade 3 amylase or lipase abnormalities that are not associated with clinical 
signs/symptoms or findings on imaging consistent with pancreatitis.   
  
Survival Follow-Up Phase  

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Patients who are no longer receiving study treatment on this clinical trial, for any reason, will enter 
survival follow-up, regardless of whether they have initiated subsequent anticancer therapy. 
Survival follow-up information (by chart review, phone call or clinic visits) will be collected 
approximately every 12 weeks until death, loss to follow-up, withdrawal of consent or study 
termination.  
3.2 ENDPOINTS AND SAMPLE SIZE JUSTIFICATION  
  
The primary endpoint of the phase II trial will be overall response rate (ORR) of HCC patients 
receiving at least one dose of pembrolizumab and bavituximab. ORR is defined as number of 
responders (either complete or partial response as best overall response) of evaluable patients. 
Evaluable is defined as having remained on study through the first on-treatment scan timepoint at 
9 weeks. Best overall response requires confirmation imaging greater than or equal to 9 weeks 
after initial best response. The historical ORR for systemic therapy with the PD-1 inhibitor, 
nivolumab, in the phase I/II CHECKMATE trial is between 15 and 20% (42 of 262 patients 
currently examined)1.   
 
We used minimax two-stage design method to develop phase II trial to compare the ORR of 0.35 
(alternative hypothesis) for the treatment cohort versus 0.15 (null hypothesis) for the historical 
control. In the first stage 15 evaluable patients will be accrued. If there are 3 or more responses 
then 13 additional, evaluable patients will be accrued for a total of 28 evaluable patients. The null 
hypothesis will be rejected if 8 or more responses are observed in 28 evaluable patients. This 
design yields a type I error rate of 0.05 and power of 0.80 when the true response rate is 0.35%.  
 
Patients who attain a complete response or partial response but do not have two consecutive 
imaging assessments to confirm response will be replaced. Patients who have progressive 
disease at any imaging assessment do not require subsequent confirmation. 
  
PFS will be estimated using the Kaplan-Meier method, and Greenwood’s formula will be used to 
calculate the standard error of the corresponding Kaplan-Meier estimate and 95% confidence 
interval. Secondary endpoints of efficacy are to evaluate OS. The statistical methods used for the 
analysis of PFS will be used for the analysis of OS.   
  
For exploratory endpoints including pathology- and laboratory-correlative studies, Cox regression 
analysis will be conducted to investigate the association between ORR and parameters from 
correlative studies.   
 SUBJECT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. (See Section 13.3) 
4.1 INCLUSION CRITERIA 
 
Patient must have a histologically confirmed diagnosis hepatocellular carcinoma; known 
fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC will be 
excluded  
 
Locally advanced or metastatic disease  
 

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4.1.2.1 
Patients with locally advanced or metastatic disease not eligible for surgical 
and/or locoregional therapies.  
4.1.2.2 
Measurable disease, as defined as lesions that can accurately be measured in 
at least one dimension according to RECIST version 1.1. 
 
Child-Pugh Score A   
 
Age ≥ 18 years;  
 
ECOG Performance score of 0-1;  
 
Life expectancy greater than 6 months;  
 
Following baseline laboratory values:  
4.1.7.1 
Total bilirubin ≤ 2.0 mg/ml   
4.1.7.2 
INR ≤ 1.7;  
4.1.7.3 
Hgb ≥ 8.5 g/dl;  
4.1.7.4 
AST, ALT ≤5 times ULN;  
4.1.7.5 
Platelet count ≥ 50,000/mm3;  
4.1.7.6 
Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min;  
4.1.7.7 
Albumin ≥ 2.5 g/dl;  
4.1.7.8 
Absolute neutrophil ≥ 1,500 cells/mm3;  
 
Male and female subjects of child bearing potential must agree to use an adequate 
method of contraception beginning Cycle 1 Day 1 through the course of the study, and 
120 days after the last dose of study medication;  
 
Women of childbearing potential must have a negative pregnancy test; 
 Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBVHCC, or 
HCV-HCC defined as follows:  
HBV-HCC:  Controlled (treated) hepatitis B subjects will be allowed if 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.  Subjects on active 
HBV therapy with viral loads under 100 IU/ml should stay on the same therapy throughout 
study treatment. Subjects who are anti-HBc (+), negative for HBsAg, negative for anti-
HBs, and have an HBV viral load under 100 IU/mL do not require HBV anti-viral 
prophylaxis.    
HCV-HCC: active or resolved HCV infection as evidenced by detectable HCV RNA or 
antibody. Patients who have failed HCV therapy as evidenced by detectable HCV RNA 
will be eligible. Subjects with chronic infection by HCV who are treated (successfully or 
treatment failure) or untreated are allowed on study.  In addition, subjects with successful 

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HCV treatment are allowed as long as there are ≥4 weeks between completion of HCV 
therapy and start of study drug. Successful HCV treatment definition: SVR12. 
 Prior therapy is allowed provided the following are met: at least 4 weeks since prior 
locoregional therapy including surgical resection, chemoembolization, radiotherapy, or 
ablation. Provided target lesion has increased in size by 25% or more or the target lesion 
was not treated with locoregional therapy. Patients treated with palliative radiotherapy for 
symptoms will be eligible 1 week after treatment as long as the target lesion is not the 
treated lesion.  
 
4.2 EXCLUSION CRITERIA 
 
Prior liver transplant;  
 
Patient who has received previous systemic therapy for HCC;  
 
Clinically significant, uncontrolled heart disease and/or recent events including any of the 
following within 12 months of screening date:  
4.2.3.1 
History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting,   
4.2.3.2 
Coronary angioplasty, or stenting) or symptomatic pericarditis;  
4.2.3.3 
History of documented congestive heart failure (New York Heart Association 
functional classification III-IV);  
4.2.3.4 
Documented cardiomyopathy;  
4.2.3.5 
Left ventricular ejection fraction <40% as determined by MUGA scan or ECHO 
(MUGA and ECHO are not required for enrollment);  
 
Known human immunodeficiency virus (HIV) positive (testing not required);  
 
History of thromboembolic events (including both pulmonary embolism and deep venous 
thrombus but not including tumor thrombus) within the last 6 months;  
 
Hypersensitivity to IV contrast; not suitable for pre-medication;  
 
Active or fungal infections requiring systemic treatment within 7 days prior to screening;  
 
Known history of, or any evidence of, interstitial lung disease or active noninfectious 
pneumonitis;  
 
Evidence of poorly controlled hypertension which is defined as systolic blood pressure 
>150 mmHg or diastolic pressure >90 mmHg despite optimal medical management;  
 Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the 
normal range with medication;  
 Active, known, or suspected autoimmune disease with the following exceptions:  
i) 
Subjects with vitiligo, type I diabetes mellitus, resolved childhood asthma or atopy 
are permitted to enroll;  

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ii) Subjects with suspected autoimmune thyroid disorders may be enrolled if they 
are currently euthyroid or with residual hypothyroidism requiring only hormone 
replacement.  
iii) Subjects with psoriasis requiring systemic therapy must be excluded from 
enrollment.  
 Patient has any other concurrent severe and/or uncontrolled medical condition that would, 
in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient 
participation in the study or compromise compliance with the protocol (e.g. chronic 
pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral infections, etc.);  
 Known history of active bacillus tuberculosis;   
 Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg/day prednisone equivalent) or other immunosuppressive medications within 14 days 
of study administration. Inhaled or topical steroids and adrenal replacement doses >10 
mg/day prednisone equivalents are permitted in the absence of autoimmune disease;   
 Patient who has received radiotherapy ≤ 4 weeks prior to study entry. Palliative 
radiotherapy for symptomatic control is acceptable (if completed at least 2 weeks prior to 
study drug administration and no additional radiotherapy for the same lesion is planned);  
 Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects (tumor biopsy is not considered as major surgery);  
 Clinically apparent ascites on physical examination, ascites present on imaging studies is 
allowed;  
 Patient has a known hypersensitivity to any of the excipients of bavituximab or 
pembrolizumab or monoclonal antibody;  
 Active gastrointestinal bleeding within previous 2 months;  
 History of any condition requiring anti-platelet therapy (aspirin >300 mg/day, clopidogrel 
>75 mg/day);  
 Prisoners or subjects who are involuntarily incarcerated;  
 Symptomatic or clinically active brain metastases;  
 Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after contraception and until the termination of gestation, confirmed by a positive 
hCG laboratory test;  
 Prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents;  
 Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV 
infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.  
 
 
 

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 TREATMENT PLAN 
5.1 OVERVIEW  
 
STUDY TREATMENT  
For this study, the term “study treatment” refers to the combination of pembrolizumab and 
bavituximab.  
  
Bavituximab will be provided by OncXerna Therapeutics (Boston, MA) as a 5ml  
vial of sterile solution in borosilicate type I glass vials that contains 120 mg bavituximab (24 
mg/ml), 10mM acetate at pH 5.0, and water for injection, United States Pharmacopeia.  
  
Pembrolizumab will be provided by Merck Pharmaceutical, Inc (Kenilworth, NJ) as a white to off 
while lyophilized powder (50 mg/vial) or as a liquid solution (100 mg/vial) in Type I glass vials 
intended for single use only.   
 
5.2 TREATMENT REGIMEN SCHEDULE AND DOSE ADJUSTMENTS  
Pembrolizumab and bavituximab will identified as investigational product. Patients will receive 200 
mg pembrolizumab every three weeks in combination with 3 mg/kg of bavituximab weekly. 
Each patient will be dosed at a frequency until second confirmed disease progression, 
discontinuation due to toxicity, withdrawal of consent, or the study ends.   
    
 
 Table 5.1 Dose and Treatment Schedule  
  
Study Treatment 
Pharmaceutical Form and 
Route of Administration 
Total Dose 
Frequency and/or 
Regimen 
Pembrolizumab 
Intravenous 
200 mg 
Once every three weeks 
Bavituximab 
Intravenous 
3 mg/kg 
Once every week 
  
Pembrolizumab will be administered as a flat-fixed dose, and not by body weight or body surface 
area. Bavituximab will be administered at 3 mg/kg body weight and diluted with normal saline to a 
volume no less than 100 ml. The total dose is only required to be recalculated if there is a ≥ 10% 
change in weight from C1D1. There will be otherwise no modification of dose level or schedule or 
bavituximab or pembrolizumab treatment.  
  
Pre-medication(s) is not required, but can be added after C1 in the event of an infusion reaction. 
Follow packet insert or institutional guidelines for pre-medication regimen.   
  
5.3 THERAPEUTIC/DIAGNOSTIC AGENTS  
 
BAVITUXIMAB  
  
IND Number: 135123  
Finished Product  
Presentation and Composition  
Bavituximab is supplied as a sterile, preservative-free solution with 10 mM acetate at pH 
5.0 and diluted with 0.9% (w/v) saline (normal saline) to a final volume of 100 mL.  

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Storage: 
Bavituximab is stored at 2°C to 8°C. Once diluted, it should be stored at room 
temperature and used within 8 hours.   
Availability and Accountability  
OncXerna Therapeutics in Boston, MA will provide bavituximab. The pharmacist or 
designee must keep an accurate accounting of the number of investigational units 
received from OncXerna Therapeutics, dispensed to patients, and returned to OncXerna 
Therapeutics during and at the completion of the study. A detailed inventory must be 
completed for the study medication. The study medication must be dispensed only by an 
appropriately qualified person to patients in the study. The medication is to be used in 
accordance with the protocol in patients who are under the direct supervision of an 
investigator.  All unused clinical study medications/treatments will be returned to 
OncXerna Therapeutics.  
  
Administration  
Bavituximab will be administered weekly.   
Infusion preparation and administration are to be performed as follows:   
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used). Fill 
treatment into a sterile glass bottle or plastic IV bag.  
2. Using aseptic techniques, repeat procedure until the calculated volume has been 
put in to the container. Bring the final volume to 100 mL using 0.9% Sodium 
Chloride Injection, USP.   
3. Administer through a low protein binding 0.2-micrometer in-line filter (placed as 
proximal to the patient as practical).  
4. Affix the infusion line and prime it with infusate before starting the infusion. Infuse 
the solution intravenously over 90 (± 10) minutes. No reduction in infusion time will 
be permitted. Flush the line with normal saline after infusion.  
 
PEMBROLIZUMAB  
IND Number 135123  
Finished Product:  
Presentation and Composition  
Pembrolizumab is supplied as a lyophilized powder and reconstituted with 2.3 ml sterile 
water for injection to yield a 2.4 ml solution containing 25 mg/ml of pembrolizumab at pH 
5.2-5.8.  
Storage:  
Pembrolizumab powder for solution for infusion vials should be stored at 2°C to 8°C.  
Prior to reconstitution, the vial of lyophilized powder can out of refrigeration (temperatures 
at or below 25°C for up to 24 hours. Following reconstitution with sterile water for 
injection, pembrolizumab infusion solutions should be prepared in 0.9% sodium chloride 
injection or regional equivalent and the final concentration of pembrolizumab in the 
infusion solutions should be between 1mg/ml and 10 mg/ml.   
Availability and Accountability:  

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Merck Pharmaceuticals will provide pembrolizumab. The pharmacist or designee must 
keep an accurate accounting of the number of investigational units received from Merck 
dispensed to patients, and returned to Merck during and at the completion of the study. A 
detailed inventory must be completed for the study medication. The study medication 
must be dispensed only by an appropriately qualified person to patients in the study. The 
medication is to be used in accordance with the protocol in patients who are under the 
direct supervision of an investigator.  All unused clinical study medications/treatments will 
be returned to Merck.  
Administration:  
Pembrolizumab will be administered every three weeks. Pembrolizumab should be 
administered over 30 minutes, with a window of -5 and +10 minutes, using an infusion 
pump. Pembrolizumab should be administered at least 30 minutes after the bavituximab 
infusion (on days when both are administered). The infusion line should be flushed with 
50 ml normal saline prior to pembrolizumab infusion.  
Please refer to packet insert or local institutional guidelines. 
5.4 MONITORING OF STUDY TREATMENT DOSE ADMINISTRATION  
In the event of a ≤ grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For patients with a ≤ grade 2 infusion-related 
reaction, subsequent infusions may be administered at 50% of the initial rate. Acetaminophen 
and/or antihistamines, corticosteroids or equivalent medication may be administered at the 
discretion of the principal investigator. If the infusion-related reaction is ≥ grade 3, study drug will 
be discontinued.   
5.5 TREATMENT DURATION  
Study treatment with pembrolizumab and bavituximab will continue until protocol specified 2nd 
occurrence disease progression, unacceptable toxicity, maximum treatments (35) reached for 
pembrolizumab, death or discontinuation from the study treatment for any other reason.  
 
Bavituximab may continue past pembrolizumab administration. All participants who stop study 
treatment with SD or better may be eligible for up to an additional 17 cycles (approximately 1 
year) of pembrolizumab treatment if they progress after stopping study treatment from the initial 
treatment phase.  This retreatment is termed the Second Course Phase of this study and is only 
available if the study remains open and the participant meets the following conditions: 
 
 
Either 
• Stopped initial treatment with study treatment after attaining an investigator-determined 
confirmed CR based on RECIST 1.1, and 
• Was treated with at least 8 cycles of study treatment before discontinuing treatment, and 
• Received at least 2 treatments with pembrolizumab beyond the date when the initial CR was 
declared 
OR 
• Had SD, PR, or CR and stopped study treatment after completion of 35 administrations 
(approximately 2 years) of study treatment for reasons other than disease progression or 
intolerability 
 
AND 

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• Experienced an investigator-determined radiographic disease progression by RECIST 1.1 
after stopping initial treatment, and 
• No new anticancer treatment was administered after the last dose of study treatment, and 
• The participant meets all of the safety parameters listed in the inclusion criteria and none of 
the safety parameters listed in the exclusion criteria, and 
• The study is ongoing 
An objective response or disease progression that occurs during the Second Course Phase for a 
participant will not be counted as an event for the primary analysis of either endpoint in this study. 
*Note: patients must have measurable disease at the start of protocol treatment to be eligible for 
this provision. 
 
5.6 CONCOMITANT MEDICATIONS-ALLOWED AND PROHIBITED  
Medications or vaccinations prohibited in the exclusion criteria are not allowed. 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.  
  
 
Acceptable Concomitant Medications  
All treatments that the principal investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the community 
standards of medical care. All concomitant medications 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.   
  
 
Prohibited Concomitant Medications  
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phase of this trial:  
• Antineoplastic systemic chemotherapy or biological therapy;  
• Immunotherapy not specified in this protocol;  
• Chemotherapy not specified in this protocol;  
• Investigational agents other than pembrolizumab and bavituximab;  
• Radiation therapy;  
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of the live vaccines included, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine;  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.   
  
There are no prohibited therapies during the post-treatment follow-up phase.  

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5.7 DOSE MODIFICATION GUIDELINES  
Adverse events (both non-serious and serious) associated with pembrolizumab and bavituximab 
exposure may represent an immunologic etiology. The adverse events may occur shortly after the 
first dose or several months after the last dose of treatment. Drug therapy must be withheld for 
drug-related toxicities and severe or life-threatening adverse events as per Table 5.2 below. See 
section 5.8 for supportive care guidelines, including the use of corticosteroids.   

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Table 5.2 Dose Modification Guidelines for Drug-Related Adverse Events 
General Instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
Treatment can be resumed after AE has been reduced to Grade 1 or less and corticosteroid has been tapered.  
3. 
Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last corticosteroid dose or corticosteroids cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 12 weeks.  
4. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs 
cannot be controlled by corticosteroids. 
Immune-Related 
AEs 
Toxicity Grade or 
Conditions 
(CTCAEv4.0) 
Action 
Event Management 
Monitor and Follow-Up 
Pneumonitis 
Gr 2 
Withhold 
Administer corticosteroids (initial dose of 1-
2 mg/kg prednisone or equivalent) followed 
by taper 
• Monitor participants for signs and symptoms of 
pneumonitis 
• Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid treatment 
• Add prophylactic antibiotics for opportunistic infections 
Gr 3 or Gr 4, or 
recurrent Gr 2 
Permanently 
discontinue 
Diarrhea/Colitis 
Gr 2 or Gr 3 
Withhold 
Administer corticosteroids (initial dose of 1-
2 mg/kg prednisone or equivalent) followed 
by taper 
• Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or mucus 
in stool with or without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• Participants with ≥ Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis.  
• Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids.  If sufficient oral fluid 
intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Gr 4 
Permanently 
discontinue 
AST/ ALT Elevation or 
Increased bilirubin 
Gr 2 
Withhold 
• Administer corticosteroids (initial dose 
of 1-2 mg/kg prednisone or equivalent) 
followed by taper 
• Monitor with liver function tests (weekly is recommended) 
until resolves to baseline 
Gr 3 or Gr 4 
Permanently 
discontinue 
Type 1 Diabetes 
Mellitus (T1DM) or 
Hyperglycemia 
Newly onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
• Initiate insulin replacement therapy for 
participants with T1DM  
Administer anti-hyperglycemic in 
participants with hyperglycemia  
Monitor participants for hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Gr 2 
Withhold 
• Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.   
Monitor for signs and symptoms of hypophysitis (including 
hypopituitarism and adrenal insufficiency) 
Gr 3 or Gr 4 
 

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Immune-Related AEs 
Toxicity Grade or 
Conditions 
(CTCAEv4.0) 
Action 
Event Management 
Monitor and Follow-Up 
Hyperthyroidism 
Gr 2 
Continue 
• Treat with non-selective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate  
• Monitor for signs and symptoms of thyroid disorders.  
Gr 3 or Gr 4 
Withhold or 
permanently 
discontinue 
Hypothyroidism 
Gr 2 – Gr 4 
Continue 
• Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyroinine) per 
standard of care  
• Monitor for signs and symptoms of thyroid disorders.  
Myocarditis 
Gr 1 or Gr 2 
Withhold 
• Based on severity of AE administer 
corticosteroids  
• Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
Gr 3 or Gr 4 
Permanently 
discontinue 
Nephritis and Renal 
Dysfunction  
Gr 2 
Toxicity 
resolves to 
Grade 0-1  
• Administer corticosteroids (prednisone 
1-2 mg/kg or equivalent) followed by 
taper. 
• Monitor changes of renal function 
Gr 3 or Gr 4 
Permanently 
discontinue 
All Other Immune-
Related Events 
Intolerable or persistent 
Gr 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids 
• Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
Gr 3 
Withhold or 
discontinuea 
Gr 4 or 
recurrent Gr 3 
Permanently 
discontinue 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
a 
Withhold or continue based on the type of event. Events that require discontinuation include and not limited to: Gullain-Barre Syndrome, encephalitis 
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ 
Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 

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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). Subjects should be placed on study therapy within 4 
weeks of the scheduled interruption. The reason for interruption should be documented in 
the patient’s study record.  
  
5.8 RESCUE MEDICATION AND SUPPORTIVE CARE  
 
Supportive Care Guidelines  
Subjects 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 either study drug.   
  
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 5.7 
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:   
o 
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.  
o 
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed.  
o 
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).    
o 
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.  
o 
For Grade 2 diarrhea/colitis, administer oral corticosteroids.   
o 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.    
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  

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• 
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:  
o 
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. 
o 
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 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.  
o 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):  
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.  
▪ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.  
o 
Grade 3-4 hyperthyroidism   
▪ 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.  
• 
Renal Failure or Nephritis:  
o 
For Grade 2 events, treat with corticosteroids.  
o 
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.   
Below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab.  
 

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Table 5.3 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 therapy or infusion interruption but responds 
promptly to symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate (e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug treatment 
Participant may be 
premedicated 1.5h  
(± 30 minutes) prior to 
infusion of _____ with: 
• 
Diphenhydramine 50 
mg po (or equivalent 
dose of 
antihistamine). 
• 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 
Grade 3: 
Prolonged (i.e., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
• 
Epinephrine** 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug treatment. 
No subsequent dosing.  
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 

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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 (in combination) will require holding 
pembrolizumab and bavituximab treatment, notification of the Sponsor within 24 
hours, and a hepatology consultation is strongly recommended. 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×ULN, ECI = ALT ≥5×ULN  
ii. Among subjects with Baseline ALT ≥2×ULN, ECI = ALT >3× the Baseline 
level  
iii. ALT > 500 U/L regardless of Baseline level 
  
b. AST:  
i. 
Among subjects with Baseline AST <2×ULN, ECI = AST ≥5×ULN  
ii. Among subjects with Baseline AST ≥2×ULN, ECI = AST >3× 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, ECI = >2.0 mg/dL  
ii. Among subjects with Baseline levels that are ≥1.5 mg/dL, ECI = ≥2× 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. Encephalopathy  
Immediate assessment  
All subjects  
• 
All subjects should be evaluated according to directions below within 72 hours of 
alert for non-overdose ECI   
• 
Procedures:  
o 
Obtain a consultation with a hepatologist  
o 
Obtain a work-up for hepatitis if there is no underlying hepatitis, including 
hepatitis A, B,C, D, E, Epstein-Barr virus, and cytomegalovirus  
o 
Assess for ingestion of drugs/supplements with hepatotoxic 
potential 
o 
Assess for alcohol ingestion  
o 
Assess for potential bacterial infection, biliary obstruction, or occult 
gastrointestinal bleeding  

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o 
Repeat ALT, AST, Tbil, Dbil, ALP, gamma-glutamyl transpeptidase (GGT), 
INR, and CBC with differential   
o 
Other laboratories or imaging studies as clinically indicated o Consider liver 
biopsy if indicated by hepatologist  
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×ULN  
• 
CP score of ≥9 points  
• 
Gastrointestinal bleeding suggestive of portal hypertension (e.g., esophageal or 
gastric varices)  
• 
New onset clinically detectable ascites  
• 
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.  
Other subjects may be eligible for treatment interruption (and potential re-start) of 
pembrolizumab after discussion with the Sponsor.   
 
Diagnosis and Management of Non-Overdose Hepatic ECIs  
HCC subjects 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 ~1% of subjects who received pembrolizumab.  
The following section provides further guidance on the diagnosis and management of 
potential hepatic complications among HCC subjects.   
a. Hepatitis B Flare  
Hepatitis B flares are characterized by rapid elevations of ALT and AST to 
>5×ULN and/or >3× baseline.  ALT elevation to ≥10×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 no evidence of an alternative etiology.  Guidelines for subjects with a 
diagnosis of HBV flare are as follows:  

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• 
Care should be instituted in consultation with a hepatologist whenever 
possible.  
• 
For subjects who have detectable HBV DNA, re-institute anti-viral therapy.  
• 
If the subject is clinically stable, pembrolizumab dosing may be interrupted 
for up to 12 weeks.  Subjects should undergo weekly laboratory tests 
including: AST, ALT, ALP, Tbil, Dbil, INR, HBsAg, 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 23 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 pembrolizumab treatment.  If these conditions 
are not met, then pembrolizumab 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×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×ULN and/or >3× baseline along with a rise in HCV RNA.  ALT elevation to 
≥10×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  
• 
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.   

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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 
pembrolizumab treatment.  If these conditions are not met, then 
pembrolizumab treatment should be permanently discontinued.  
c. Immune-Related Hepatitis   
i. 
Description:  Immune-related hepatitis due to pembrolizumab should be 
suspected if any of the following is seen:  
• 
AST or ALT baseline values are less than 2×ULN, and AST or ALT 
laboratory values increase to ≥5×ULN  
• 
Among subjects with Day 1 ALT or AST ≥2×ULN, levels increase to >3× 
the Day 1 level  
• 
AST/ALT >500 U/L regardless of baseline level  
• 
Among subjects with Day 1 Tbil levels <1.5 mg/dL:  a value of >2.0 
mg/dL  
• 
 Among subjects with Day 1 Tbil levels that are ≥1.5 mg/dL:  a value of 
≥2× the Day 1 level  
• 
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  
• 
Interrupt pembrolizumab treatment and alert the sponsor as per ECI 
criteria above for ALT, AST, bilirubin, and hepatic decompensation.    
• 
Start IV corticosteroid (methylprednisolone 125 mg) followed by oral 
corticosteroid (1-2 mg/kg/day).    
• 
Monitor with biweekly laboratory tests including AST, ALT, Tbil, Dbil, 
ALP, and INR.  
• 
If symptoms and laboratory tests resolve to Grade ≤1 or baseline (if 
abnormal at baseline), taper steroids over 28 days.  Pembrolizumab 
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 CRF.  
• 
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.  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 cholangiopan-
creatography or ultrasound with doppler should be obtained to rule out 
vascular compromise, biliary obstruction, and/or tumor progression.  If biliary 

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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.  See Section 5.5.2 for drugs 
which may interfere with hepatic function.   
• 
For all of these cases, subjects may resume pembrolizumab 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 
pembrolizumab 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.  
5.9 CONTRACEPTION  
Pembrolizumab and bavituximab may have adverse effects on a fetus in utero.   
Furthermore, it is not known if pembrolizumab or bavituximab 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) 
postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  OR   
(2) 
have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  OR   
(3) 
has a congenital or acquired condition that prevents childbearing.  
 
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  
   

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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 subject’s preferred and usual lifestyle and if 
considered 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 subjects participating at sites 
in this country/region.  
  
Subjects 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 subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation) throughout the study period, 
and through 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 subject should not be entered into the study.  
  
 
Use in Pregnancy  
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab 
or bavituximab, the subject will immediately be removed from the study.  The site will 
contact the subject at least monthly and document the subject’s status until the 
pregnancy has been completed or terminated.  The outcome of the pregnancy will be 
reported to Merck without delay and within 24 hours 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 Sponsor.   If 
a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to Merck and followed as described 
above.  
 
Use in Nursing Women  
It is unknown whether pembrolizumab or bavituximab is excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible 
for enrollment.  

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5.10 DRUG SUPPLY AND STORAGE  
Study drug must be received by the designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only designated personnel 
have access. Upon receipt, the study drug should be stored according to the instructions 
specified on the drug labels and in the Investigators Brochure. Medication labels will comply 
with the legal requirements of each country and be printed in the local language.  
 STUDY PROCEDURES 
 
6.1 SCREENING PHASE  
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the studies 
were done before informed consent was obtained.  
  
All screening procedures must be performed within 28 days prior to first treatment (Cycle 1, 
Day 1), unless otherwise stated. The screening procedures include the following: (See Table 
6.1 above for the list of assessments to be performed.)  
 
Informed Consent  
Patients must provide a signed informed consent form prior to any study specific 
evaluations including screening. Eligibility will be determined according to the 
inclusion/exclusion criteria as described in Section 4. A list of procedures to be 
performed at time of screening is summarized in Table 6.1. Patients must meet all 
eligibility criteria to be considered for enrollment in the study.   
 
Eligibility Checklist (Inclusion/Exclusion)  
In order to determine and confirm the eligibility of the patient, once all screening 
procedures are completed.  
 
Patient Demographics and other Baseline Characteristics  
The data that will be collected on patient characteristics at screening includes:  
• 
Demographic (name, date of birth, age), sex, race/ethnicity;  
• 
Diagnosis, and extent of cancer (staging);  
• 
Pertinent Medical History;  
• 
Prior cancer treatment;  
• 
All medications taken within 30 days before first treatment. If there are any 
changes, medications are to be updated on a continual basis.  
  
Furthermore the following assessments will be performed:  
• 
Vital Signs (BP, HR, T, RR);  
• 
Adverse Events / Concomitant medications;  
• 
Height and Weight;  
• 
Physical Examination (PE);  
• 
ECOG Performance Status (PS);  
• 
Child-Pugh Score  
• 
Laboratory Evaluations (CMP, CBC, PT/INR and aPTT, thyroid panel, AFP, 
Hepatitis B and C panel, and UA)  

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• 
ECG   
• 
Collection of your tissue from a previous biopsy or surgery 
• 
Radiological Assessments (RECIST 1.1) (CT - chest/abdomen/pelvis or MRI – 
abdomen/pelvis). Chest CT will be performed at baseline only. During the 
treatment phase, a Chest CT will be performed as clinically indicated;  
• 
Urine or serum Pregnancy Test (Women of Child-bearing Potential Only).  
 
Pre-Treatment - Tissue Biopsy   
Unless the patient has archival formalin fixed paraffin embedded tissue to document 
a diagnosis of HCC, a biopsy confirming HCC diagnosis must be completed within 28 
days prior to Cycle 1 Day 1.   
 
Biomarker / DNA Blood Collection (Optional)  
After signing the optional biomarker / DNA consent for future biomarker and DNA 
blood, samples will be collected at baseline, during treatment, and at the end of 
treatment or early-term visit. This procedure is for research and will not be used to 
make medical decisions regarding the patient’s treatment.   
6.2 TREATMENT PHASE  
 
Study Treatment  
Patients will be treated with pembrolizumab with 200 mg intravenously once every 3 
weeks (for a maximum of 35 treatments). In addition, patients will be treated with 
bavituximab (3.0 mg/kg intravenously weekly) until disease progression, 
unacceptable toxicity, death, or discontinuation from the study treatment due to any 
other reason. For details of assessment, refer to Table 6.1.  
If the patient is unable to receive treatment on D1 for any other reason than the listed 
dosing parameters in section 5, the entire cycle will be delayed no longer than 6 
weeks. 
 
Post-Treatment – Biomarker Tissue Biopsy (Optional)  
The post treatment biopsy is optional and will be performed for patients who 
consented to the procedure during the initial consenting process. Following the initial 
treatment of study drug, one correlative biopsy will be performed between the 3rd 
and 4th week of treatment. Most accessible site will be biopsied based on 
investigators judgement and performed with imaging guidance, as indicated. Tissue 
will be processed using institutional protocols. Tissue from sub sites will be shipped 
to UTSW. Samples will be analyzed in batches during and after enrollment.   
6.3 POST – TREATMENT FOLLOW-UP PHASE  
 
End of Treatment  
 
Patients who completely discontinue study treatment should complete an End of 
Treatment (EOT) visit at the time of discontinuation. For details of the assessment, 
see Table 6-1.   
  
 
At a minimum, all patients who discontinue study treatment, including those who 
refuse to return for a final visit, will be contacted for study evaluations during the 30 
days following the last dose date of study treatment.  

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6.3.1.1 
Criteria for Early Withdrawal  
Patients may voluntarily withdraw from the study treatment or be taken off 
study at the discretion of the investigator at any time. Patients may be 
withdrawn from the study treatment if any of the following occur:  
• 
Adverse event  
• 
Lost to follow-up  
• 
Physician decision  
• 
2nd occurrence of progressive disease  
• 
Protocol deviation  
• 
Study terminated by the sponsor  
• 
Technical problems  
 
Safety Follow-Up  
All patients will be followed for safety up to 30 days after last dose of Bavituximab 
treatment. Patients whose treatment is interrupted or permanently discontinued due 
to an AE, including abnormal laboratory value, must be followed until resolution or 
stabilization of the event, whichever comes first.  
 
Serious adverse events that occur within 90 days (or 30 days if a new anti-cancer 
therapy is started) of the End of Treatment visit should be followed and recorded, 
regardless of drug relationship. 
 
 
Survival Follow-Up  
All patients will be followed for survival status every 12 weeks, starting from the 
Safety Follow-Up visit, regardless of treatment discontinuation, until death, lost to 
follow-up, or withdrawal of consent to survival follow-up.   
  
Survival follow-up assessment may be made by a phone call to the patient or 
designated PHI, EPIC medical record review, or certified mail. At least 3 documented 
attempts should be made to contact the patient before the patient is considered lost 
to follow-up.  
 
Beginning and End of the Trial  
  
The study begins when the first patient signs the informed consent. The end of the 
study may be designated as the time point when all patients have discontinued the 
study or are a minimum of 6 months post-study medication. At this point, a database 
lock of the trial may occur to allow the analysis of the study data. Any remaining 
patients may continue to receive study medication and be seen by the investigator 
per usual standard of care for this patient population. 

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Trial Period:  
Screen 
Treatment 
End of Treatment 
Follow-up 
Treatment Cycle/Title: 
Screen 
C1D1 C1D8 C1D15 C2D1+ C2D8+ C2D15+ 
Time of 
Discontinuation 
Safety 
Follow-up 
Survival 
Follow-upa 
 
  
  
  
  
  
  
  
 
30 Days  
Post Last 
Dose 
Scheduling Window (Days)  
-28 to -1 
  
±3  
±3  
±3  
±3  
±3  
±3  
±7  
±7  
Administrative Procedures  
  
  
  
  
  
  
  
  
  
  
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Optional consent for future research  
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
 
 
 
 
 
 
 
 
 
Demographics and medical history   
X 
 
 
 
 
 
 
 
 
 
Prior and concomitant medication review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Post-study anticancer therapy status  
 
 
 
 
 
 
 
 
X 
X 
Survival status  
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments  
 
 
 
 
 
 
 
 
 
 
Review adverse events   
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
History and Physical examination  
X 
X 
 
X 
X 
 
 
 
 
 
Child-Pugh Score   
X 
 
 
 
 
 
 
 
 
 
Height, weight, and vital signs (T, HR, RR, 
BP) c  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-Lead electrocardiogram  
X 
 
 
 
 
 
 
 
 
 
ECOG performance status  
X 
X 
 
X 
X 
 
 
X 
 
 
Trial treatment administration d  
 
X b 
X 
X 
X 
X 
X 
 
 
 
LOCAL Laboratory Assessments  
 
 
 
 
 
 
 
 
 
 
Pregnancy test   
X 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT  
X 
X 
 
 
 
 
 
X 
X 
 

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Trial Period:  
Screen  
Treatment 
End of 
Treatment  
Follow- up 
Treatment Cycle/Title:  
Screen  C1D1 C1D8 C1D15 C2D1+ C2D8+ C2D15+ 
Time of 
Discontinuation 
Safety Follow-up  
Survival  
Follow-upa 
  
  
  
  
  
  
  
  
 
30 Days  
Post Last Dosei  
 
Scheduling Window (Days) -28 to -1  
  
±3  
±3  
±3  
±3  
±3  
±3  
±7  
±7  
LOCAL Laboratory Assessments 
  
  
  
  
  
  
  
  
  
  
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
Xi 
 
 
X 
 
 
FT3, FT4, TSH 
X 
 
 
 
Xi 
 
 
X 
X 
 
AFP 
X 
 
 
 
X 
 
 
X 
X 
 
Anti-HCV 
X 
 
 
 
 
 
 
 
 
 
If Anti-HCV positive: 
 
 
 
 
 
 
 
 
 
 
HCV genotype  
X 
 
 
 
 
 
 
 
 
 
HCV viral load, HBsAg, HBV viral loade 
X 
 
 
 
X 
 
 
 
X 
 
Anti-HBc (total and IgM), anti-HBs 
X 
 
 
 
 
 
 
 
 
 
If HbsAg+ or anti-HBc+,  anti-HBs-, 
HbsAg- and  viral load <100 IU/mL: 
 
 
 
 
 
 
 
 
 
 
Anti-HDV  
X 
 
 
 
 
 
 
 
 
 
HBeAg and anti-HBe 
X 
 
 
 
Xf 
 
 
 
X 
 
Anti-HBc (total) and anti-HBs 
 
 
 
 
Xf 
 
 
 
X 
 
Research Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy: Tumor tissue for biomarker 
analysisg 
X 
 
 
 
Xg 
 
 
 
 
 
Archived Tumor Tissue Collection  
X 
 
 
 
 
 
 
 
 
 
Tumor assessment by RECIST 1.1 
X 
Q 9 weeks for the 1st 54 weeks and Q 12 weeks 
until PD 
Xh 
 
 

 
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49 
 
a. 
In subjects that experience PD or start a new anti-cancer therapy, contact should be made (by 
telephone, medical record review or visit) Q12W from Safety Follow-up Visit to assess for survival 
status.   
b. 
Screening labs can be used for C1W1 if performed within 72 hours.   
c. 
Height will be measured at Visit 1 only.   
d. 
Treatment will consist of Bavituximab administered weekly and Pembrolizumab administered every 
three weeks; cycles will consist of three week long periods with Pembrolizumab constituting the 
beginning of a new cycle.  
e. 
Can be performed earlier if clinically indicated.   
f. 
Performed every 12 weeks during treatment, or earlier if clinically indicated. Additional tests to be 
performed for ECIs are described in Section 5.2.1.38.2.  If the viral load results are not reported in 
IU/mL, the site should provide the conversion factor specific for the assay method used to convert 
the assay units of measure to IU/mL.  For HbsAg, quantitative and/or qualitative results are 
submitted.  
g. 
Biomarker blood collection is an optional research procedure and patients must have consented to 
the additional blood collection to participate. Blood will be collected according to the schedule in the 
table.  
h. 
The biopsy performed during screening for HCC diagnosis and must be performed for the subject to 
be eligible for the study. If the patient has archival formalin fixed paraffin embedded tissue no 
additional baseline biopsy will be done.  The post-treatment biopsy is optional and for research 
purposes only. If the subject consents to the research biopsy during the consent process, it will be 
performed during the 3rd and 4th week after initiating Bavituximab/Pembrolizumab therapy. 
i. 
Completed on Day 1 of even cycles, beginning with Cycle 2.  
j. 
Only required if discontinued for any reason other than PD. Continue with tumor assessments per 
schedule until radiographic progression.  
k. 
30 days post last dose of Bavituximab 
.  
 MEASUREMENT OF EFFECT 
For the purposes of this study, patients will be evaluated for progression every 9 weeks for the first 
54 weeks, then every 12 weeks thereafter following the initial study drug (pembrolizumab and 
bavituximab) administration. Imaging will consist of a CT or MRI abdomen with liver protocol. The 
same imaging modality used at baseline will be used for further scans unless documented by 
primary investigator.  CT Chest or additional imaging will be at the discretion of the investigator 
based on clinical suspicion of additional progressive disease.  
7.1 ANTITUMOR EFFECT- SOLID TUMORS  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) 
of the tumor lesions are used in the RECIST 1.1 criteria. Note:  Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy.  
 
Disease Parameters  
Measurable Disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm 
with conventional techniques (CT, MRI, x-ray) or as ≥ 10 mm with spiral CT scan. All 
tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). A “high-resolution” CT scan is one in which images are recorded at 
least every 5 mm.  
  

 
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50 
 
Non-Measurable Disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
spiral CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT 
or MRI), and cystic lesions are all non-measurable.  
  
Target Lesions. All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter) and their suitability for 
accurate repeated measurements (either by imaging techniques or clinically). A sum 
of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response.  
  
Non-Target Lesions. All other lesions (or sites of disease) that are not target lesions, 
as defined in the section above, will be identified as non-target lesions and should 
also be recorded at baseline. Non-target lesions include measurable lesions that 
exceed the maximum numbers per organ or total of all involved organs as well as 
non-measurable lesions. Measurements of these lesions are required when feasible, 
since a patient may have progressive disease on the basis of larger non-target 
lesions. The presence or absence of each non-target lesion should be noted 
throughout follow-up.  
 
Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 28 days 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 when 
both methods have been used to assess the antitumor effect of a treatment.  
 
Response Criteria  
7.1.3.1 
Evaluation of Target Lesions  
Complete Response (CR): Disappearance of all target lesions, determined 
by two separate observations conducted not less than 4 weeks apart. 
There can be no appearance of new lesions.  
  
Partial Response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD. 
There can be no appearance of new lesions.  
  
Progressive Disease (PD): At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum LD recorded since the 
treatment started, or the appearance of one or more new lesions.  
  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started.  

 
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51 
 
7.1.3.2 
Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  
  
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits.  
  
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions  
7.1.3.3 
Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). The patient’s best response assignment will depend on 
the achievement of both measurement and confirmation criteria.  
  
   
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response 
for this 
Category Also Requires: 
CR 
CR 
No 
CR 
≥ 4 weeks confirmation 
CR 
Non- 
CR/Non-PD 
No 
PR 
≥ 4 weeks confirmation 
PR 
Non-PD 
No 
PR 
≥ 4 weeks confirmation 
SD 
Non-PD 
No 
SD 
≥ 4 weeks confirmation 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*  
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
 
disease progression. 
 
Note: Subjects with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
  
Note: If subjects respond to treatment and are able to have their disease resected, the patient’s response 
will be assessed prior to the surgery.  
 
Duration of Response  
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started).  
  

 
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52 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.   
  
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started.   
 
Progression Free Survival  
Progression free survival (PFS) is defined as the duration of time from start of drug 
treatment (pembrolizumab and bavituximab) to time of progression. Deaths during 
the study period will be included as an event.  
7.2 TREATMENT BEYOND PROGRESSION  
Accumulating clinic evidence indicates some subjects treated with immune system 
stimulating agents may develop disease progression by conventional response criteria before 
demonstrating clinical objective responses and/or stable disease (see section 1.6). This study 
was observed in the phase Ib study of pembrolizumab, KEYNOTE -001, and confirmed in 
multiple phase 3 clinical trials using PD-1 inhibitors. Two hypotheses explain this 
phenomenon. First, enhanced inflammation within tumor could lead to an increase in tumor 
size, which would appear as enlarged index lesions and as newly visible small non-index 
lesion. Over time, both malignant and inflammatory portions of the mass may then decrease, 
leading to overt signs of clinical improvement. Alternatively, in some individuals, the kinetics 
of tumor growth may initially outpace anti-tumor immune activity. With sufficient time, the anti-
tumor activity will dominate and become clinically apparent.   
  
Therefore, subjects should continue study therapy after an initial investigator-assessed 
RECIST 1.1-defined progression (section 7.1) as long as they meet the following criteria:  
• 
Investigator assessed clinical benefit, and   
• 
Subject is tolerating the study drug (pembrolizumab and bavituximab)  
  
Subjects should discontinue study therapy upon evidence of further progression, defined as 
an additional 10% or greater increase in tumor burden from time of initial progression 
(including all target lesions and new measurable lesions). New lesions are considered 
measurable if the longest diameter is at least 10 mm (except for pathological lymph nodes, 
which must have a short axis of at least 15 mm). Any new lesion considered non-measurable 
may become measurable and therefore included in the tumor burden measurement if the 
longest diameter increases to at least 10 mm (except for pathological lymph nodes, which 
must have an increase in short axis to at least 15 mm).  
  
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed RECIST 1.1 defined progression will 
be considered to have progressive disease at the time of the initial progression event 
irrespective of confirmation on subsequent imaging.  
7.3 SAFETY/TOLERABILITY  
 Analyses will be performed for all subjects having received at least one dose of study drug. 
The study will use the CTCAE version 4.03 for reporting of adverse events (Common 
Terminology Criteria for Adverse Events (CTCAE) (nih.gov)).  
 ADVERSE EVENTS 

 
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53 
 
8.1 PEMBROLIZUMAB TREATMENT RELATED EVENTS  
The following side effects are suspected to be related to pembrolizumab treatment for 
reporting purposes:  
>20% of patients  
• 
Itching of the skin  
• 
Loose or watery stools  
• 
Cough  
 
10-20% of patients  
• 
Joint pain  
• 
Fever  
• 
Back pain  
• 
Rash  
 
1 to 10% of patients  
• 
Hypo- or hyperthyroidism  
• 
Inflammation in the lungs  
• 
Inflammation in the colon  
• 
Inflammation in the skin  
• 
Abdominal pain  
• 
Loss of skin color  
• 
Hyponatremia  
• 
Hypotension, flushing, rash, fever, shortness of breath or abdominal pain at the time of 
the infusion or just after  
 
8.2 BAVITUXIMAB TREATMENT RELATED EVENTS  
The following side effects are suspected to be related to bavituximab treatment for reporting 
purposes:   
• 
Infusion reaction  
• 
Thromboembolic events  
• 
Nausea, vomiting, anorexia 
• 
Prolonged coagulation times 
 
8.3 ADVERSE EVENT MONITORING  
Adverse event data collection and reporting, which are required as part of every clinical trial, 
are done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of subject safety and care.   
  
All subjects experiencing an adverse event, regardless of its relationship to study drug, will 
be monitored until:   
➢ the adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline;   
➢ any abnormal laboratory values have returned to baseline;   
➢ there is a satisfactory explanation other than the study drug for the changes observed; or 
death.  

 
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54 
 
  
 
Definition   
 
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, 
abnormal physical exam or clinically significant laboratory finding), symptom, clinical 
event, or disease, temporarily associated with the subject’s participation in the 
research, whether or not it is considered related to the subject’s participation in the 
research.  
  
 
Adverse events encompass clinical, physical and psychological harms. Adverse 
events occur most commonly in the context of biomedical research, although on 
occasion, they can occur in the context of social and behavioral research. Adverse 
events may be expected or unexpected.  
  
 
Severity   
 
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE v 4.0). Adverse 
events not specifically defined in the NCI CTCAE will be scored on the Adverse 
Event log according to the general guidelines provided by the NCI CTCAE and as 
outlined below.    
  
• 
Grade 1: Mild;   
• 
Grade 2: Moderate;  
• 
Grade 3: Severe or medically significant but not immediately life threatening;  
• 
Grade 4: Life threatening consequences;  
• 
Grade 5: Death related to the adverse event  
  
 
Serious Adverse Events   
 
ICH Guideline E2A and the UTSW IRB define serious adverse events as those 
events, occurring at any dose, which meets any of the following criteria:   
  
• 
Results in death;    
• 
Immediately life-threatening;   
• 
Results in inpatient hospitalization or prolongation of existing hospitalization;   
• 
Results in persistent or significant disability/incapacity;   
• 
Results in a congenital anomaly/birth defect;   
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition.  
  
 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 

 
STU102017-015, Hsieh, FormA-Protocol, Mod_27, 08-21-23(3).docm 
 
55 
 
hospitalization or death would be a serious adverse event, even if the event 
observed is a primary clinical endpoint of the study.   
  
 
Refer to the UTSW IRB website at 
http://www.utsouthwestern.net/intranet/research/research-
administration/irb/studymanagement/adverse-events.html to determine when a 
serious adverse event requires reporting to the IRB.  
 
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, 
but not defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 
CFR 56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance 
from the regulatory agencies considers unanticipated problems to include any 
incident, experience, or outcome that meets ALL three (3) of the following criteria: 
• Unexpected in terms of nature, severity or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied;  
 
 
 
 
AND 
• 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); 
   
 
 
AND  
• Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. Note: According to OHRP, if the adverse event is serious, it 
would always suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
 
Steps to Determine If a Serious Adverse Event Requires Expedited Reporting 
to the SCCC DSMC 
 
Step 1: Identify the type of adverse event using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE may NOT be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment (alternatively, to the end of the acute adverse events reporting period as 

 
STU102017-015, Hsieh, FormA-Protocol, Mod_27, 08-21-23(3).docm 
 
56 
 
defined in section XX). Any event that occurs more than 30 days after the last dose of 
treatment (alternatively, during the late adverse event period as defined in section 
XX) and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported as indicated in the sections below. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are 
those that have been previously identified as resulting from administration of the 
treatment. An adverse event is considered unexpected, for expedited reporting 
purposes only, when either the type of event or the severity of the event is not listed 
in: 
• the current known adverse events listed in the Agent Information Section of 
this protocol (if applicable); 
• the drug package insert (if applicable); 
• the current Investigator’s Brochure (if applicable) 
• the Study Agent(s)/Therapy(ies) Background and Associated Known 
Toxicities section of this protocol 
 
 
Reporting SAEs and UPIRSOs  
8.3.4.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive 
Cancer Center (SCCC) Data Safety Monitoring Committee (DSMC) 
 
SAEs and UPIRSOs at all sites, which occur in research subjects on 
protocols for which the SCCC is the DSMC of record require reporting to the 
DSMC regardless of whether IRB reporting is required. All SAEs occurring 
during the protocol-specified monitoring period and all UPIRSOs should be 
submitted to the SCCC DSMC within 5 business days of the study team 
members awareness of the event(s). In addition, for participating centers 
other than UTSW, local IRB guidance should be followed for local reporting 
of serious adverse events or unanticipated problems. 
 
The UTSW study PI is responsible for ensuring SAEs/UPIRSOs are 
submitted to the SCCC DSMC Coordinator. This may be facilitated by the IIT 
project manager, study team, sub-site or other designee. Hardcopies or 
electronic versions of the eIRB Reportable Event report; FDA Form #3500A 
forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the DSMC Coordinator.  The 
DSMC Coordinator forwards the information onto the DSMC Chairman who 
determines if immediate action is required.  Follow-up eIRB reports, and all 
subsequent SAE or UPIRSO documentation that is available are also 
submitted to the DSMC Chair who determines if further action is required. 
(See Appendix III of the SCCC DSMC Plan for a template Serious Adverse 
Event Form which may be utilized). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the 
UTSW Simmons Comprehensive Cancer Center, the IIT Project Manager or 
designee ensures that all participating sites are notified of the event and 
resulting action, according to FDA guidance for expedited reporting. DSMC 
Chairperson reviews all SAEs and UPIRSOs upon receipt from the DSMC 
Coordinator.  The DSMC Chairperson determines whether action is required 
and either takes action immediately, convenes a special DSMC session 
(physical or electronic), or defers the action until a regularly scheduled 
DSMC meeting.  

 
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57 
 
 
Written reports to:  
  
David Hsieh, MD  
c/o GI Clinical Research Manager  
5323 Harry Hines Blvd, NB2.418  
Dallas, Texas 75390  
Phone: 214-648-7031  
Fax: 214-648-1906  
Email: David.hsieh@utsouthwestern.edu  
  
UTSW SCCC Data Safety Monitoring Committee Coordinator  
Email: SCCCDSMC@utsouthwestern.edu  
Fax: 214-648-5949 or deliver to BLB.306  
  
UTSW Institutional Review Board (IRB)  
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation. 
  
8.3.4.2 
Reporting Unanticipated Problems Involving Risks to Subjects or 
Others (UPIRSOs) to the UTSW HRPP 
 
UTSW reportable event guidance applies to all research conducted by or on 
behalf of UT Southwestern, its affiliates, and investigators, sites, or 
institutions relying on the UT Southwestern IRB. Additional reporting 
requirements apply for research relying on a non-UT Southwestern IRB. 
 
According to UTSW HRPP policy, UPIRSOs are incidents, experiences, 
outcomes, etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected 
in a subject’s underlying condition or not expected as a risk of the study; 
therefore, not included in the investigator’s brochure, protocol, or 
informed consent document), 
AND 
2. Probably or definitely related to participation in the research,  
AND 
3. Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.  Note: According to OHRP, if the 
adverse event is serious, it would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device 
effects (UADEs) and death or serious injury related to a humanitarian use 
device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW HRPP within 5 working 
days of 
study team awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or 

 
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58 
 
single IRB): 
 
Investigators relying on an external IRB who are conducting research on 
behalf of UT Southwestern or its affiliates are responsible for submitting 
LOCAL UPIRSOs to the UT Southwestern IRB within 5 working days of 
study team awareness. Investigators must report to their relying IRB 
according to the relying IRB’s policy. In addition, the external IRB’s 
responses or determinations on these local events must be submitted to the 
UT Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, 
summarized, and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/hrpp/quality-assurance/ 
 
8.3.4.3 
Reporting SAEs to Study Sponsors 
Local serious adverse events (SAEs) for studies where SCCC DSMC is the 
DSMC of record require reporting to the DSMC coordinator within 2 working 
days of PI awareness, or as described in the protocol.    
  
For all IST studies using a OncXerna Therapeutics Product: OncXerna 
Therapeutics requires that, within 24 hours of first awareness of event (or 
immediately if the event is fatal or life-threatening), the principal investigator 
will report to OncXerna Therapeutics by e-mail any Serious Adverse Event 
(SAE) that occurs during the SAE reporting period in a study subject 
assigned to receive the OncXerna Therapeutics product.  
Contact information for SAE reporting to MedAssessment 
Pharmacovigilance and PPD medical monitors is as follows:  
  
Safety Reporting Email (for submission of SAE related source 
documents): oncxernasafety@medassessment.com. 
  
Additionally, any serious adverse event, considered by an investigator who is 
a qualified physician to be related to Merck product that is brought to the 
attention of the investigator at any time following consent through the end of 
the specified safety follow-up period or at any time outside of the time period 
specified in the previous paragraph also must be reported within 24 hours of 
first awareness of event to Merck Global Safety. All subjects with serious 
adverse events must be followed up for outcome.  
SAE reports and any other relevant safety information are to be forwarded to 
the Merck Global Safety facsimile number:  +1-215-661-6229 A copy of all 
15 Day Reports and Annual Progress Reports is submitted as required by 
FDA, European Union (EU), Pharmaceutical and Medical Devices agency 
(PMDA) or other local regulators. Investigators will cross reference this 
submission according to local regulations to the Merck Investigational 
Compound Number (IND, CSA, etc.) at the time of submission.  Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to 
FDA.  

 
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59 
 
  
8.4 STOPPING RULES  
  
Simmons Comprehensive Cancer Center Data and Safety Monitoring Board (DSMB) will 
oversee this study and will determine if early stoppage of the trial is needed due to 
unacceptable rates of drug related serious adverse events.  
 
8.5 STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES EXPEDITED        
REPORTING  
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE v. 4.03).   
  
Step 2: Grade the adverse event using the NCI CTCAE v. 4.03.  
  
Step 3: Determine whether the adverse event is related to the protocol therapy Attribution 
categories are as follows:  
- Definite – The AE is clearly related to the study treatment.  
- Probable – The AE is likely related to the study treatment.  
- Possible – The AE may be related to the study treatment.  
- Unrelated – The AE is clearly NOT related to the study treatment.  
Note: This includes all events that occur within 30 days of the last dose of protocol treatment. 
Any event that occurs more than 30 days after the last dose of treatment and is attributed 
(possibly, probably, or definitely) to the agent(s) must also be reported accordingly.  
  
Step 4: Determine the prior experience of the adverse event.   
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not listed 
in:  
• the current known adverse events listed in the Agent Information Section of this protocol;  
• the drug package insert;  
• the current Investigator’s Brochure  
8.6 DEFINITION OF AN OVERDOSE FOR THIS PROTOCOL AND REPORTING OF 
OVERDOSE TO MERCK  
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. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated.  
  
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. If a dose of Merck’s product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical  

 
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Interest (ECI), using the terminology “accidental or intentional overdose without adverse 
effect.”  
  
All reports of overdose with and without an adverse event must be reported within 24 hours 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229-1220).  
8.7 REPORTING OF PREGNANCY AND LACTATION TO MERCK  
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 treatment 
allocation/randomization 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 treatment  
allocation/randomization through 120 days following cessation of Sponsor’s product, 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 Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229).  
  
8.8 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 Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229).  
  
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours 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.  
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 24 hours to Merck Global Safety.  
Events of clinical interest for this trial include:  
1.  An overdose of Merck product, as defined in Section 8.6 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated 
with clinical symptoms or abnormal laboratory results.   
2.  An elevated AST or ALT lab value as referenced in Section 5.8  
  
 
 

 
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61 
 
 CORRELATIVES/SPECIAL STUDIES 
 
Pathology Correlative Studies  
 A major obstacle to molecularly targeted chemotherapeutic agents has been obtaining relevant 
tumor tissue to measure the agents’ biologic effects on target molecules or cellular pathways within 
the tumor.  The utilization of sequential tumor biopsies to obtain tissue following treatment is well 
established in breast and colorectal carcinoma. (35). Liver biopsies of HCC have been shown to be 
safe. A large, multi-institutional trial where patients with advanced chronic Hepatitis C underwent 
sequential liver biopsies demonstrated 16 cases (0.6%) of bleeding following 2740 liver biopsies. 
There were no deaths from periprocedural bleeding and a platelet count under 60000 was identified 
as a risk factor. (38) Two large published series of core needle biopsy of HCC as a diagnostic 
measure report bleeding events in less than 1% of patients with no reported mortalities. In both 
series capsular location of HCC was associated with increased incidence of bleeding event. (39, 
40) In this study all patients will potentially undergo up to two image-guided (either CT or 
Ultrasound) core needle biopsy of a single site of HCC at baseline (for clinical care) and between 
three and four weeks after the initiation of study drug (research only). The biopsy between three 
and four weeks following study drug initiation is not mandatory to initiate or continue with therapy 
and is subject to a separate informed consent.  The baseline biopsy is needed to confirm HCC as 
an eligibility criterion.  If archival formalin fixed paraffin embedded tissue is available for HCC status 
analysis, a pre-treatment biopsy will not be required. To increase patient safety the following 
conditions must be met prior to liver biopsy:  
• Platelet count ≥ 70,000;  
• INR ≤ 1.8;  
• Target lesion not subcapsular in nature as determined by the participating interventional 
radiology team;  
  
The patient will sign the informed consent for participation in research liver biopsy prior to the 
procedure. The liver biopsy will be performed by radiologists and the ancillary staff of Department 
of Radiology following the standard clinical protocol, which includes obtaining a separate informed 
consent for the procedure itself.  The core samples will be provided to the Department of Pathology 
for histological confirmation in addition to the pathology laboratory. If a core biopsy is performed as 
a part of the patient’s clinical care, extra cores will be obtained for surgical oncology laboratory, in 
addition to the cores necessary for clinical care.  All cores will be obtained through the same needle 
to avoid the need of additional punctures and to minimize associated risks.  
Tumor tissue may be used for RNA, DNA, and/or protein testing. 
 STUDY MANAGEMENT 
10.1 CONFLICT OF INTEREST  
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy on  
Conflicts of Interest. All investigators will follow the University conflict of interest policy.  
10.2 INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT  
It is expected that the IRB will have the proper representation and function in accordance    
with federally mandated regulations. The IRB must approve the consent form and protocol.  
  

 
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In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.  
    
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form.  
  
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion.  
10.3 RECRUITMENT PLAN  
The study will be open to all patients seen at the UT Southwestern Medical Center  
(including Parkland Health & Hospital System, University Hospital-Clements and Zale, and 
the Harold C. Simmons Comprehensive Cancer Center) and participating subsites. 
  
Patients will be identified from surgical, hepatology, gastroenterology, radiology and 
medical oncology clinics for treatment of their disease.  After a discussion of the patient’s 
disease and a formulation of the initial treatment plan, the physician-investigator will 
describe the study to the patient.  The protocol will be discussed in a private clinic room or 
office.  Details including the risks and obligations of the subjects will be explained.  For 
non-English speaking patients, an independent translator will be available to communicate 
the details of the protocol.  A research coordinator will be available either in the clinic or by 
phone to answer any additional questions.   
  
Upon completion of the informed consent form and confirmation of protocol eligibility, the 
Clinical Research Office (CRO) at the Harold C. Simmons Comprehensive Cancer Center 
will be notified of the new enrollment.  All patients will be entered into the Velos Clinical 
Trials Management System for ongoing monitoring. All data collected will be entered into 
the password protected REDCap electronic data capture system.  
  
The investigators take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations.  There will be no limitation to access with regard 
to race or gender.  Patients will be required to read, agree to and sign an IRB-approved 
informed consent form prior to registration on this trial.  The registration procedure will be 
conducted as described above.  Patients will not receive payment for their participation on 
this study.   
10.4 STUDY SUBJECT IDENTIFICATION NUMBER  
All subjects will be assigned a study number that is not linked to their personal 
identifiers to prevent loss of confidentiality. The number will be the Site Number, 01, 
02, etc. followed by a sequential number starting with number 001. For example, the 
first subject enrolled from site # 01 will be assigned study subject number 01-001; the 
next will be 01-002, and so forth. For this protocol, current sites are: 01 – UTSW and 
02 – PHHS. Any additional sites added to this protocol will be numbered 
sequentially…03, 04, etc. This number will be assigned by the UTSW - Clinical 
Research Manager (CRM) or delegate upon confirmation of subject eligibility during 
the subject registration process.   
 

 
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10.5 SUBJECT REGISTRATION  
Following completion of baseline assessments and confirmation of subject eligibility, 
patients will be assigned a subject identification number by the UTSW - CRM or 
delegate and registered into Velos, the UTSW Clinical Trial  
Management System (CTMS). Subject registration will be confirmed (within 24 hours) 
once the following documents have been received by the UTSWCRM or delegate.   
  
• Signed copy of the Informed Consent signature page;  
• Inclusion/Exclusion worksheet signed by the coordinator and treating physician;  
  
All subjects must be registered with the UTSW - CRM before enrollment to study. To 
register a subject, email the above supporting documents to the UTSW – CRM: Ellen 
Siglinsky, ellen.siglinsky@utsouthwestern.edu or call 214-648-7029, Monday through 
Friday, 9:00a.m. - 5:00p.m. CST.  
10.6 PROTECTION OF HUMAN SUBJECTS  
Participation in this trial is voluntary.  All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines.  
    
Inclusion of Women and Minorities:  Patients of all races, both male and female, will be 
accepted into the protocol.  
  
Exclusion of Lactating or Pregnant Women:  Children have been excluded from this study.  
Hepatocellular carcinoma is an adult cancer.  Thus, the relevance of this drug to the 
pediatric population has not been established.  Lactating and pregnant women are also 
excluded because of potential anti-proliferative effects of therapy that may be harmful to 
the developing fetus or nursing infant.  
  
Benefits:  It is possible that this treatment will result in shrinkage of hepatocellular 
carcinoma or in a stabilization of an otherwise progressing disease.  It is not known, of 
course, whether these or any other favorable events will occur.  It is not known whether this 
treatment will affect overall survival of the patients.  
  
Costs:  The patient will be responsible for the costs of standard medical care.   
Pembrolizumab and bavituximab will be supplied to patients without costs from Merck and 
OncXerna Therapeutics.  Patients will not be responsible for the costs of tissue or serum 
procurement (including image guided biopsies) obtained for research purposes.  
  
Incentives:  No incentives will be offered to patients/subjects for participation in this study.  
  
Alternatives:  For patients with advanced hepatocellular carcinoma, alternative treatments 
may include other chemotherapy regimens or loco-regional therapies including transarterial 
chemoembolization and radiofrequency ablation.  At present, no specific treatment 
approach is considered standard of care for the disease.  Patients may be eligible for other 
investigational studies.  
  
Confidentiality:  Every effort will be made to maintain patient confidentiality.  Research and 
hospital records are confidential.  Patient’s name or any personally identifying information 
will not be used in reports or publications resulting from this study.  The Food and Drug 
Administration or other authorized agencies (i.e., qualified monitors from UT Southwestern 
Medical Center, the NCI, etc.), may review patients records and pathology slides, as 
required.  

 
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10.7 Data Management and Monitoring/Auditing 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for this and all SCCC Investigator Initiated Trials. REDCap will be used for 
electronic case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements.  
 
Trial monitoring will be conducted according to the study specific monitoring plan. For 
guidance on creating a monitoring plan, refer to the UTSW SCCC IIT Management Manual.   
 
Toxicity and dose escalation reviews will be performed in real-time by the GI DOT and 
DSMC.  These reviews will be documented by distributing reports of the findings to the 
members of the GI DOT and investigators.  
  
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring  
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and unanticipated problems in real time as they are reported and 
reviews adverse events on a quarterly basis. The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure 
data integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request.  
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing 
clinical trials, for which it serves as the DSMC of record. The QAC works as part of the 
DSMC to conduct regular audits based on the level of risk. Audit findings are reviewed at 
the next available DSMC meeting.  In this way, frequency of DSMC monitoring is 
dependent upon the level of risk.  Risk level is determined by the DSMC Chairman and a 
number of factors such as the phase of the study; the type of investigational agent, device 
or intervention being studied; and monitoring required to ensure the safety of study 
subjects based on the associated risks of the study. Protocol-specific DSMC plans must be  
consistent with these principles. Safety is monitored in real-time as adverse events are 
submitted to the DSMC and IRB with attributions.  
.  
10.8 Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
 Exceptions  
Exceptions (also called single-subject exceptions or single-subject waivers) include 
any departure from IRB-approved research that is not due to an emergency and is: 
• intentional on part of the investigator; or 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 

 
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Reporting requirement*: Exceptions are non-emergency deviations that require 
prospective IRB approval before being implemented. Call the IRB if your request 
is urgent. If IRB approval is not obtained beforehand, this constitutes a major 
deviation. For eligibility waivers, studies which utilize the SCCC-DSMC as the 
DSMC of record must also obtain approval from the DSMC prior to submitting to 
IRB for approval.  
 Emergency Deviations: include any departure from IRB-approved research that is 
necessary to:  
• avoid immediate apparent harm, or 
• protect the life or physical well-being of subjects or others 
Reporting requirement*: Emergency deviations must be promptly reported to the 
IRB within 5 working days of occurrence. 
  
 Serious Noncompliance (formerly called major deviations or violations): include any 
departure from IRB-approved research that: 
• Increase risk of harm to subjects; and/or 
adversely affects the rights, safety, or welfare of subjects (any of which may 
also be an unanticipated problem); and/or  
• adversely affects the integrity of the data and research (i.e., substantially 
compromises the integrity, reliability, or validity of the research) 
Reporting requirement*: Serious Noncompliance must be promptly reported to 
the IRB within 5 working days of discovery. 
 
 Continuing Noncompliance: includes a pattern of repeated    noncompliance (in  or 
more protocols simultaneously, or over a period of time) which continues after initial 
discovery, including inadequate efforts to take or implement corrective or preventive 
action within a reasonable time frame. 
Reporting requirement*: Continuing Noncompliance must be promptly reported to 
the IRB within 5 working days of discovery. 
 
 Noncompliance (that is neither serious nor continuing; formerly called minor 
deviations) any departure from IRB-approved research that: 
 
• 
Does not meet the definition of serious noncompliance or continuing noncompliance 
 Reporting requirement*: Noncompliance that is neither serious nor continuing 
should be tracked and summarized the next IRB continuing review, or the notice of 
study closure- whichever comes first.. 
 
*Reporting Requirements reflect UTSW HRPP/IRB guidelines; participating sites 
should follow the reporting guidelines for their IRB of record 

 
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10.9 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
10.10 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with 
a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region. In all other cases, study documents should be 
kept on file until three years after the completion and final study report of this investigational 
study. 
10.11 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment of 
all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and 
all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
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 APPENDICES  
Appendix A: ECOG Performance Status  
 
Grade  
ECOG  
0 
Fully active, able to carry on all pre-disease performance without restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, i.e., light house work, office work  
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.    
3 
Capable of only limited self-care, confined to be or chair more than 50% of waking 
hours.  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.  
5 
Dead  
  
Appendix B: Child-Pugh Score 
 
 
Appendix C: NYHA Classification  
  
Class 
Patient Symptoms  
I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath).  
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea.  
III 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea.  
IV 
Unable to carry out any physical activity without discomfort.  
Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, 
discomfort is increased  
  
Measure  
1 point  
2 points  
3 points  
Total bilirubin (mg/dl)  
<2.0 
2.0-3.0 
>3.0 
Serum albumin (g/l)  
>3.5 
2.8-3.5 
<3.5 
INR   
<1.7 
1.7-2.2 
>2.2 
Ascites  
None 
Mild (based 
on clinical 
findings) 
Severe 
(based on 
clinical 
findings) 
Hepatic Encephalopathy  
None 
Controlled 
Medically 
Refractory 
 
5-6 points 
— 
Child-Pugh A 
7-9 points 
— 
Child-Pugh B 
10-15 points 
— 
Child-Pugh C 
 
 
 

 
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