1922GCCC: PHASE 2 STUDY OF PEMBROLIZUMAB AND BAVITUXIMAB FOR PROGRESSIVE RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
Phase: PHASE2
Conditions: Squamous Cell Carcinoma
Sponsor: University of Maryland, Baltimore

 
 
 
 
Protocol Version 6; 11 November 2019 
 
UMGCCC Protocol #: 1922GCCC 
TITLE:  PHASE 2 STUDY OF PEMBROLIZUMAB AND BAVITUXIMAB FOR PROGRESSIVE 
RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK 
 
Lead Site: 
University of Maryland Greenebaum Comprehensive 
Cancer Center 
 
 
 
 
Principal Investigators: 
Ranee Mehra, MD 
 
Phone: 410-328-7394  
 
 
Fax: 410-328-6896 
 
 
ranee.mehra@umm.edu 
 
 
 
 
 
 
 
 
Co-PI: 
 
Kevin Cullen, MD 
 
 
Statistician: 
 
Soren Bentzen, PhD, DMSc 
 
 
 
 
 
 
 
Laboratory 
Collaborators: 
 
Daria Gaykalova, PhD 
Johns Hopkins University 
 
Rena Lapidus, PhD 
University of Maryland 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lead Study Coordinator: 
Joann Alimurong 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version Date, Number: 
September 20 2016, version 1.0 
 
 
January 20, 2017, version 1.1 
 
 
June 16, 2017, version 2 
 
 
 
 
June 22, 2017, version 3 
 
 
 
 
February 8, 2018, version 4 
 
 
 
 
February 12, 2019 Version 5 
 
 
 
 
November 11, 2019 Version 6 
 
 
Supported by: 
 
Oncologie 
 
 
 
 
Merck 
 
 
 
 
 
 
 
Supplied Agents: 
 
Pembrolizumab 
Bavituximab 
 
 
 
 
 
 
 
IND Number: 
 
136586 
 
 

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The goal of this study is to assess whether treatment with bavituximab shifts the cellular balance to favor 
an effective T-cell mediated antitumor response resulting to an enhanced response in conjunction with 
pembrolizumab.  Bavituximab is a chimeric (human/mouse) monoclonal antibody that targets 
phosphatidylserine (PS).  PS facilitates the recognition and clearance of dying cells, triggering the release 
of immunosuppressive cytokines and inhibiting the production of proinflammatory cytokines. Within the 
tumor microenvironment, PS polarizes macrophages toward an immunosuppressive phenotype.  
Bavituximab upregulates the adaptive T cell-mediated response through crosslinking FCRγ and 
dampening of signaling between PS and PS receptors on immunosuppressive myeloid-derived suppressor 
cells.  
Thus, we are doing this phase II single arm study to determine if bavituximab could potentially synergize 
with PD-1 inhibitor therapy to generate an effective anti-tumor immune response in patients with 
recurrent/metastatic squamous cell head and neck cancer (HNSCC) who progressed on a PD-1 inhibitor. 
Schema: 
Pembrolizumab 200mg IV every 21 days for a maximum of 24 months. 
Bavituximab 3mg/kg IV weekly 
Progression on PD1 inhibitor (if on pembrolizumab, can continue until enrollment) 
P               P               P              P              P      (Q3 week) 
B   B   B   B   B   B   B   B   B   B   B   B   B        (weekly) 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
HYPOTHESIS AND OBJECTIVES ................................................................................................. 4 
2. 
BACKGROUND.................................................................................................................................. 4 
3. 
PATIENT SELECTION ................................................................................................................... 10 
4. 
STUDY VISIT SCHEDULE AND PROCEDURES ...................................................................... 15 
5. 
TREATMENT PLAN ....................................................................................................................... 16 
6. 
DIET/ACTIVITY/OTHER CONSIDERATIONS ......................................................................... 28 
7. 
ADVERSE EVENT REPORTING .................................................................................................. 31 
8. 
LABORATORY EVALUATIONS .................................................................................................. 47 
9. 
STUDY CALENDAR ........................................................................................................................ 49 
10. MEASUREMENT OF EFFECT ...................................................................................................... 50 
11. STATISTICAL CONSIDERATIONS ............................................................................................. 61 
12. ADMINISTRATIVE ITEMS ........................................................................................................... 62 
13. DATA SAFETY AND MONITORING BOARD (DSMB) ............................................................ 69 
 
 
 

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1. 
HYPOTHESIS AND OBJECTIVES 
1.1 
Hypothesis 
The addition of bavituximab to pembrolizumab will result in an enhanced anti-tumor response 
among SCCHN tumors that progressed on immune checkpoint inhibitor therapy. 
1.2 
Primary Endpoint 
The primary outcome of this study will be objective overall response rate (CR+PR via RECIST 
1.1).  
1.3 
Secondary Endpoints 
1.1.1 
Progression free survival 
Progression-free survival will be measured from the time of study enrollment until   
radiologic, clinical progression or death.   
1.1.2 
Duration of response 
Time (time of first response until progression). 
1.1.3 
Overall survival 
Overall survival will be measured from the time of enrollment until death. 
1.1.4 
Safety and tolerability 
Toxicities observed in the study will be assessed by CTCAE 5.0 criteria. 
1.1.5 
Laboratory correlates of response 
1.1.5.1 
PD-L1 expression pre and post treatment 
1.1.5.2 
Presence of TILs (tumor infiltrating lymphocytes) pre and post 
treatment 
1.1.5.3 
Assessment of immune markers in pre-treatment fresh and post-
treatment biopsies and blood. 
1.1.5.4 
Assessment of genomics and tumor mutation burden in select 
patients. 
2. 
BACKGROUND 
2.1 
Squamous Cell Head and Neck Cancer 
Recurrent/metastatic (R/M) squamous cell head and neck cancer (SCCHN) is a 
uniformly fatal disease with limited treatment options.  Platinum doublet therapy with 
cetuximab has resulted in a median survival of 10 months and options have been 
limited for patients with platinum refractory disease.1  PD-1 inhibitors have activity in a 
subset of patients, with the response rate of pembrolizumab being about 18%.2  
Similarly, nivolumab has also resulted in a survival benefit compared to standard 
therapies in the platinum refractory setting.3  These  agents are  now FDA approved for 
patients who have progressed on or after platinum therapy.  A majority of patients, 
though, do not have a response to PD-1 inhibitors and even nivolumab had a modest 
response rate of 13%.  Primary and acquired resistance is a concern and treatment 

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options are limited in this setting.  Strategies are needed to salvage the response in 
patients who progress on PD-1 inhibitor therapy. 
2.2 
PD-1 Inhibitor Rationale 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies.4-9  In particular, the presence of CD8+ T-
cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway used to suppress immune 
control.10  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune conditions.  PD-1 (encoded by the gene Pdcd1) is an 
Ig superfamily member related to CD28 and CTLA-4 which negatively regulates 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).11  
PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail 
which is responsible for the binding of signaling molecules.  The cytoplasmic tail of 
PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-
2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-
cell signaling cascade.  The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural 
Killer cells.12 13,14 Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic 
cells.  The ligands for PD-1 (PD-L1 and PD-L2) can be induced in a variety of cell 
types, including non-hematopoietic tissues as well as in various tumors.  Binding of 
either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor. A variety of head and neck cancers were demonstrated to express elevated 
levels of this T-cell inhibitor.15  Inhibition of PD-1 has already been demonstrated to 
provide significant anti-tumor effect for the treatment of melanoma and NSCLC, in 
addition to head and neck cancer. Thus, the PD-1/PD-L1 pathway plays a critical role 
in tumor immune evasion.  
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has been approved by the 
FDA in the United Stated for the treatment of patients with unresectable or metastatic 
melanoma, metastatic non-small cell lung cancer and recurrent/metastatic squamous cell 

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carcinoma of the head and neck with disease progression on or after platinum-containing 
chemotherapy. 
2.3 
Phosphatidylserine (PS and PS Targeting) Therapy 
Bavituximab is a chimeric (human/mouse) monoclonal antibody (mAb) derived from murine 
mAb 3G4 that targets phosphatidylserine (PS) after binding to β2-glycoprotein 1 (β2-GP1).16  
This highly immunosuppressive membrane phospholipid, PS, acts as an upstream immune 
checkpoint. In normal non-tumorigenic cells, PS is segregated to the inner leaflet of the plasma 
membrane but becomes externalized to the outer leaflet of the plasma membrane in cells in the 
tumor microenvironment (tumor cells, exosomes, and vascular endothelial cells).17 
Phosphatidylserine is recognized and bound by PS receptors on immune cells where it induces 
and maintains immune suppression. In the absence of a tumor microenvironment and PS-
exosome mediated signaling, this process occurs under conditions of normal cell death and 
immune phagocytic cell clearance18.  
Phosphatidylserine-targeting agents block PS-mediated immunosuppression via reprogramming 
of the immune cells in the tumor microenvironment to support immune activation.19 Antibody-
mediated PS blockade reduces the levels of myeloid-derived suppressor cells (MDSC), 
transforming growth factor-beta (TGF-β), and interleukin (IL) -10, and increases the levels of 
tumor necrosis factor-alpha (TNF-α) and IL-12. Phosphatidylserine blockade also repolarizes 
tumor-associated macrophages (TAMs) from predominant M2 to predominant M1 phenotype, 
promotes the maturation of dendritic cells (DCs), and induces potent adaptive antitumor T-cell 
immunity.20,21 
Experimental studies have shown that bavituximab binds to PS in the presence of β2-GP1 as a 
high affinity complex, modulating β2-GP1 binding to PS from 1 μM to 1 nM. In experimental 
cancer models, bavituximab treatment reduced tumor growth and prolonged survival, where the 
anti-tumor effects are enhanced by co-administration of chemotherapy or radiation (conditions 
that increase expression of PS). 
2.4 
Rationale for the combination of bavituximab and pembrolizumab 
Within the tumor microenvironment, phosphatidylserine polarizes macrophages toward an 
immunosuppressive phenotype.  While under normal circumstances it is on the internal surface 
of the plasma membrane, PS becomes externalized in tumors where it is recognized by 
macrophages and dendritic cells. Cell damage from anti-cancer therapy such as chemotherapy 
and radiation further increases external PS exposure.  Bavituximab blocks the 
immunosuppressive signaling of myeloid-derived cells (eg, MDSCs, M2 macrophages) and 
sends an alternate immune activation signal (FcR-ɣ) leading to an adaptive T-cell mediated 
anti-tumor response.  Thus, treatment with bavituximab shifts the cellular balance to favor an 
effective T-cell mediated antitumor response. In addition, in vivo studies have shown that 
inhibition of phosphatidylserine results in differentiation of myeloid derived suppressor cells 
(MDSC) into M1-like macrophages and dendritic cells.22 19 
MDSCs are known to inhibit T cell production and function.23-25   In squamous cell head and 
neck tumors, MDSC’s have been identified to occur in higher levels in tumor, compared to 
peripheral blood.26  Horinaka et al. showed increased levels of CD15+ granulocytic MDSC (G-
MDSC) and CD14+ monocytic MDSC (M-MDSC) in HNSCC patients. This was inversely 
related to the percentage of T cells in the peripheral blood.27  

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Thus, bavituximab could potentially synergize with PD-1 inhibitor therapy to generate an 
effective anti-tumor immune response, by stimulation of a T cell response and abrogation of the 
inhibitory effects of MDSCs.  In preclinical studies of melanoma and breast cancer models, the 
combination of bavituximab and PD-1 inhibitor therapy resulted in immune stimulation with an 
increase in CD8+ TILs, in particular compared to PD-1 inhibitor monotherapy.28  This has been 
reproduced in breast cancer mouse models, with increased anti-tumor activity noted with the 
combination compared to monotherapy with either agent.  Therefore, there is a rationale for the 
combination and in particular as a mechanism to stimulate anti-tumor activity in the checkpoint 
inhibitor resistance setting. 
2.5 
Agents under Investigation 
2.5.1 
Bavituximab 
Bavituximab is a chimeric (human/mouse) monoclonal antibody (mAb) derived from 
murine mAb 3G4 that targets phosphatidylserine (PS) after binding to β2-
glycoprotein 1 (β2-GP1).  This highly immunosuppressive membrane phospholipid, 
PS, acts as an upstream immune checkpoint. In normal non-tumorigenic cells, PS is 
segregated to the inner leaflet of the plasma membrane but becomes externalized to 
the outer leaflet of the plasma membrane in cells in the tumor microenvironment 
(tumor cells, exosomes, and vascular endothelial cells). Phosphatidylserine is 
recognized and bound by PS receptors on immune cells where it induces and 
maintains immune suppression. In the absence of a tumor microenvironment and PS-
exosome mediated signaling, this process occurs under conditions of normal cell 
death and immune phagocytic cell clearance.18 
Bavituximab is a viable 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). This process occurs via fc-mediated signaling and 
direct cell killing (antibody-dependent cellular cytotoxicity). In essence, expression 
of PS on the external surface of the cell acts as an immunosuppressive signal in 
normal cell death and immune phagocytic clearance. Tumor PS exposure in the 
microenvironment is immunosuppressive in malignant transformation and 
progression. Thus bavituximab has been shown to overcome immune suppression 
and stimulate antitumor immunity in nonclinical models.19,21 
2.5.2.1 
Nonclinical Experience 
Data suggest that PS is primarily responsible for expansion of MDSCs and M2-like 
tumor-associated macrophages (TAMs) in tumors, and that bavituximab could 
reverse this process and reactivate antitumor immunity. Treatment of tumor-bearing 
mice with docetaxel in combination with 2aG4 (a PS-targeting antibody and the 
murine precursor to bavituximab), has been shown to potently suppress the growth 
and progression of prostate tumors and increase the presence of M1-like TAMs and 
mature dendritic cells in the tumor microenvironment.29  
The tumor and tumor vasculature localization of PS-targeting antibodies is followed 
by tumor immunity enhancing effects, tumor vessel damage, tumor vascularity 

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reduction, tumor necrosis, and tumor growth retardation in multiple models.20 The 
synergistic antitumor activity of antibodies targeting PS in combination with 
cytotoxic chemotherapy has been demonstrated in animal models, including but not 
limited to the Pan02 pancreatic adenocarcinoma cell line with gemcitabine and the 
MDA MB 435 breast cancer cell line with docetaxel.29,30  
In toxicology studies, no target organs of toxicity were identified in rats (up to 20 
mg/kg) and monkeys (up to 10 mg/kg) receiving weekly doses for 8 weeks of 
bavituximab, and minimal histological findings in heart and lung were noted when 
administered to monkeys at 100 mg/kg. Detailed information about comprehensive 
nonclinical safety, immunology, and pharmacokinetics (PK) is provided in the 
current Investigator’s Brochure for bavituximab. (IB) 
2.5.2.2 
Clinical Experience 
Bavituximab has been evaluated by Peregrine in clinical studies in over 800 patients 
(as of July 2016), most of whom were treated with combination therapy. These 
clinical trials have included patients with a number of tumor types, including 
pancreatic, breast, lung, and hepatocellular carcinoma, and in chronic HCV. A dose 
of 3 mg/kg bavituximab given intravenously (IV) was determined and selected for 
further clinical study based on Phase 1 single-agent and combination therapy 
studies.31   
In a Phase II, multicenter, breast cancer trial (PPHM 0702), bavituximab (3 mg/kg), 
given weekly until progression, was combined with paclitaxel (100 mg/m2) and 
carboplatin (area under the concentration-time curve = 2), given on Days 1, 8 and 15 
of planned 4 week cycles for up to 6 cycles, to 46 patients with metastatic disease, 
unrestricted by hormone or HER2 status. Objective response per Response 
Evaluation Criteria in Solid Tumors (RECIST) occurred in 34 of 46 patients (73.9%) 
with a median duration of response (DOR) of 3.7 months (95% confidence interval 
[CI]: 3.1, 5.8) and median PFS of 6.9 months (95% CI: 5.6, 7.7)12. The most 
common Grade 4 treatment-emergent adverse event (TEAE) was neutropenia (12 
patients, 26.1%), and the most common Grade 3 TEAEs were leukopenia (11 
patients, 23.9%), neutropenia (9 patients, 19.6%), and anemia (5 patients, 10.9%).32   
In another Phase II, multicenter, breast cancer trial (PPHM 0704), bavituximab (3 
mg/kg), given weekly until progression, was combined with docetaxel (35 mg/m2), 
given on Days 1, 8, and 15 of planned 4-week cycles for up to 6 cycles, to 46 patients 
with MBC (with any hormone or HER2 status). Objective response occurred in 28 of 
46 patients (60.9%) with median DOR of 6.1 months (95% CI: 5.7, 7.5) and median 
PFS of 7.4 (95% CI: 6.1, 9.1) months.  Of the most common TEAEs reported, only 
fatigue, headache, back pain, and hypertension were Grade ≥3.33  
In a single-center, investigator sponsored study, breast cancer patients received 
bavituximab 3 mg/kg weekly in combination with paclitaxel (80 mg/m2) given on 
Days 1, 8, and 15 in 4-week cycles to 14 patients with HER2-negative MBC. 
Treatment resulted in an ORR of 85% (2 patients had complete responses) and a 
median PFS of 7.3 months (95% CI: 2.8, 10.8)14. Bone pain, fatigue, headache, and 
neutropenia were the most common AEs. Infusion-related reactions were the most 
common AE related to bavituximab. (IB)   

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A Phase II, single institution study of bavituximab and sorafenib in advanced 
hepatocellular carcinoma (HCC) was also conducted.  Patients received 3 mg/kg IV 
weekly of bavituximab and 400 mg PO BID of sorafenib until radiologic progression.  
Secondary endpoints included overall survival, disease specific survival, 4-month 
progression free survival, safety, and response rate.  The study accrued 38 patients.  
Median OS was 6.2 months.  Two patients achieved partial response and four moth 
PFS was 61%.  There were no grade 4 or 5 adverse events recorded.  Most common 
all grade events were diarrhea (32%), fatigue (26%), and anorexia (24%)15.  These 
results demonstrated that bavituximab and sorafenib were well tolerated in patients 
with advanced HCC.34 
Overall, results from Phase I and Phase II studies have demonstrated a clinically 
meaningful treatment effect of bavituximab, and results were consistent among the 
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. Thus the potential additional 
benefits of combination therapy are likely to outweigh the risk of AEs experienced 
during bavituximab treatment. 
2.5.2 
Pembrolizumab 
Pembrolizumab is a highly selective humanized mAb designed to block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4/kappa 
isotype with a stabilizing sequence alteration in the Fc region. 
2.5.2.1 
Head and Neck Squamous Cell Carcinoma 
Keynote-012 (KN012) was a Phase 1b trial of pembrolizumab in subjects with 
advanced solid tumors, including subjects with human papillomavirus (HPV)-
negative and HPV-positive squamous cell carcinomas of the head and neck.36, 37  
The primary population for analysis included HNSCC subjects who previously 
progressed on prior platinum therapy, regardless of prior cetuximab exposure.  Two 
dose levels were studied in two cohorts.  ORR in KN012 for the platinum-progressed 
population was 16.7%.  The durability of responses to pembrolizumab ranged from 
≥2.4 to ≥18.7 months. 
2.5.2.2 
Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) evaluated the safety and clinical activity of 
single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no 
dose-limiting toxicities were observed.  This first in human study of MK-3475 
showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has 
been identified to date.  10.0 mg/kg Q2W, was the highest dose tested in PN001. 
Recent data from other clinical studies within the MK-3475 program has shown that 
a lower dose of MK-3475 with a fixed schedule of 200mg Q3weeks may be 
sufficient for target engagement and clinical activity.35,36 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). 

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Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days).  This early PK and pharmacodynamic data 
provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
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 MK-3475 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.  MK-
3475 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 MK-3475 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 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. 
3. 
PATIENT SELECTION 
3.1 
Eligibility Criteria 
In order to be eligible for participation in this trial, the subject must: 
3.1.1 
Patients will have recurrent/metastatic head and neck cancer and will have 
radiographic evidence of progression on prior immune checkpoint inhibitor 
therapy, including nivolumab, pembrolizumab, durvalumab and atezolizumab. 
Patients must have progressed on prior platinum therapy either in the recurrent 
setting or within 6 months of treatment with cisplatin and radiation in the 
potentially curative setting.   
3.1.2 
Be willing and able to provide written informed consent/assent for the trial. 
3.1.3 
Be  18 years of age on day of signing informed consent. 
3.1.4 
Have measurable disease based on RECIST 1.1.   

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3.1.5 
Be willing to provide tissue from a newly obtained core or excisional biopsy of a 
tumor lesion.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on Day 1.  Subjects for whom newly-obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may 
submit an archived specimen only upon agreement from the PI. 
3.1.6 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 
3.1.7 
Demonstrate adequate organ function as defined in Table 1, all screening labs 
should be performed within 10 days of treatment initiation.   
 
 

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Table 1 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 
X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 

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aCreatinine clearance should be calculated per institutional standard. 
 
3.1.8 
Female subject of childbearing potential  must have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
3.1.9 
Female subjects of childbearing potential (Section 6.2) must be willing to use an 
adequate method of contraception as outlined in Section 6.2 – Contraception, for 
the course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
3.1.10 
Male subjects of childbearing potential (Section 6.2) must agree to use an adequate 
method of contraception as outlined in Section 6.2- Contraception, starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
3.2 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
3.2.1 
Is currently participating and receiving study therapy or has participated in 
a study of an investigational agent and received study therapy or used an 
investigational device within 4 weeks of the first dose of treatment. 
3.2.2 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first 
dose of trial treatment. 
3.2.3 
Has a known history of active TB (Bacillus Tuberculosis). 
3.2.4 
Hypersensitivity to pembrolizumab or any of its excipients.  History of 
hypersensitivity to other antibodies can be discussed with the PI to 
determine eligibility.   
3.2.5 
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks 
prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier. 
3.2.6 
Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to a previously administered 
agent. 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 

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Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
3.2.7 
Has experienced an immune-related adverse event requiring 
discontinuation of a prior checkpoint inhibitor. 
3.2.8 
Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin or squamous 
cell carcinoma of the skin that has undergone potentially curative therapy 
or in situ cervical cancer. 
3.2.9 
Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Subjects with previously treated brain 
metastases may participate provided they are stable (without evidence of 
progression by imaging for at least four weeks prior to the first dose of trial 
treatment and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids 
for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
3.2.10 
Has active autoimmune disease that has required systemic treatment in the 
past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, 
or physiologic corticosteroid replacement (such as prednisone 10mg daily or 
its equivalent) for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.  
3.2.11 
Has known history of, or any evidence of active, non-infectious 
pneumonitis. 
3.2.12 
Has an active infection requiring systemic therapy. 
3.2.13 
Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best 
interest of the subject to participate, in the opinion of the treating 
investigator.   
3.2.14 
Has known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial. 
3.2.15 
Is pregnant or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the pre-screening or 
screening visit through 120 days after the last dose of trial treatment. 
3.2.16 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
3.2.17 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., 
HCV RNA [qualitative] is detected). 

Protocol Version 6; 11 November 2019 
 
 
 
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3.2.18 
Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
Patients with a condition requiring systemic treatment with either corticosteroids 
(>10 mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of randomization.  Inhaled or topical steroids and adrenal replacement 
steroid doses < 10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease. 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
4. 
STUDY VISIT SCHEDULE AND PROCEDURES 
4.1 
Screening 
See study table in Section 9 for screening procedures. 
4.2 
Treatment period 
One cycle is 21 days.  Patient will remain on treatment as long as they are obtaining clinical 
benefit with a PR, CR or SD as per RECIST 1.1 criteria, and are without significant toxicity 
requiring treatment discontinuation. 
4.3 
Post-Treatment Tumor Follow-up – Once treatment on protocol has discontinued, no further 
tumor assessments are necessary.  The last obtained CT on protocol will be utilized for response 
assessments. 
4.4 
End-of-Treatment Visit – This will be planned if feasible within 2 weeks of discontinuation of 
therapy. 
4.5 
Long-Term Survival Follow-Up – patients will be followed for survival for 1 year after 
discontinuation of treatment.  Review of medical records or phone calls would be sufficient. 
4.6 
Early Discontinuation of Patients 
Bavituximab and/or pembrolizumab should be discontinued due to significant toxicities if, in 
the opinion of the investigator, they are related to these agents, and continued treatment poses a 
significant risk to the patient. Examples of such toxicities include: 
4.6.1 
Grade 4 immune-mediated toxicities 
4.6.2 
Grade 4 hypersensitivity 
4.6.3 
Grade ≥3 toxicity that recurs or persists > 21 days. 
4.6.4 
Intolerable adverse effects, laboratory abnormality or intercurrent illness that is 
judged by the investigator to be either physically or psychologically detrimental to the 
patient.  

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4.6.5 
Pregnancy.  
4.6.6 
Patient non-compliance.  
4.6.7 
Treatment with other anti-cancer drugs.  
4.6.8 
Confirmed disease progression on therapy.  
4.6.9 
Withdrawal of informed consent (subject’s decision to withdraw for any reason).  
4.6.10 Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness. 
4.6.11 All subjects who discontinue study treatment should comply with protocol specified 
follow-up and survival procedures as outline in section 4.  The ONLY exception to 
this requirement is when a subject withdraws consent for all study procedures in 
writing or loses the ability to consent freely (i.e., is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness); in this case 
they will be deemed off study and no further follow up will be performed.  
4.7 
Study Termination 
The study will be terminated once all patients have been removed from treatment and no further 
follow up for toxicity and survival data is needed.  All data should be collected and reviewed for 
completion prior to study termination. 
5. 
TREATMENT PLAN 
This phase II study will enroll patients who are eligible and those who sign consent will undergo 
screening, including acquisition of fresh tissue for correlative analyses, updated imaging and labs.  
Eligible patients will be enrolled and treated with bavituximab 3 mg/kg IV weekly and pembrolizumab 
200mg IV every 3 weeks.  One cycle is defined to be 21 days.  Patients will be seen for assessments on 
day 1 of each cycle.  Blood will be collected for PK and PD analyses at baseline and during cycles 1 
and 2.  Patients will be re-staged every 3 cycles and treatment will continue until progression, or 
significant toxicity up to 24 months.  Fresh baseline tissue will be collected and repeat tumor biopsy 
will be obtained (if feasible) at a time-point week 4-6 after treatment start for correlative analyses.  This 
on study biopsy should not proceed if tumor is inaccessible or if biopsy is not thought to be in the 
patient’s best interest.  
5.1 
Bavituximab 
Bavituximab is manufactured by Oncologie, in Waltham, MA. 
Bavituximab is supplied as 5 mL of a sterile solution in borosilicate type I glass vials and contains 
120 mg bavituximab (24 mg/mL), 10 mM acetate at pH 5.0, and Water for Injection, United States 
Pharmacopeia.   
Bavituximab will be administered weekly (±2 days) as an IV infusion. Scheduled treatment 
should not be given outside the ±2-day window; such doses will be skipped, and dosing will 
resume at the next scheduled dosing visit. 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 

Protocol Version 6; 11 November 2019 
 
 
 
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required to be recalculated if there is a ≥10% change in weight from Day 1. Prior to each 
bavituximab infusion, the patient may be premedicated with an antihistamine to decrease the risk 
of an infusion reaction. There will otherwise be no modification of dose level or schedule of 
bavituximab treatment at investigator’s discretion.   
DO NOT ADMINISTER TREATMENT AS AN IV PUSH OR BOLUS. 
 
 
 
A pharmacist or designee at the study site will prepare bavituximab to be administered by study 
personnel to patients in accordance with the scheme. Infusion preparation and administration are 
to be performed as follows: 
Using aseptic technique, withdraw the calculated dose volume of bavituximab from the vials 
using a sterile non-siliconized needle and syringe and inject contents of syringe into the normal 
saline container.  Thoroughly mix the infusion container by gentle manual rotation.  Avoid 
shaking or vigorous agitation during preparation and prior to administration.  
 
The IV normal saline container admixed with IP may contain a small amount of intrinsic, 
translucent to white proteinaceous particles.    Administer through a low protein binding 0.2-
micrometer in-line filter (placed as proximal to the patient as practical). Affix the infusion line 
and prime it with infusate before starting the infusion.  The first IV infusion must be administered 
over approximately 90 (±10) minutes. If the first IV infusion is tolerated, subsequent infusions 
may be administered over 60 minutes. Flush the main infusion line with normal saline after 
infusion. 
 
NOTE: Bavituximab should only be administered in settings in which emergency resuscitative 
equipment and personnel trained in the management of anaphylaxis are immediately available to 
treat systemic hypersensitivity reactions. Systemic hypersensitivity 
  
5.1.1 
Bavituximab Treatment Dose Adjustment and Dose Delay 
The total dose is only required to be recalculated if there is a ≥10% change in weight 
from Day 1. If a patient experiences an AE due to bavituximab requiring treatment 
interruption, a treatment delay of up to one cycle is permitted. If the patient experiences 
an AE that is clearly related to other therapy requiring its delay or discontinuation, 
bavituximab treatment should continue weekly as scheduled in patients receiving 

Protocol Version 6; 11 November 2019 
 
 
 
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combination therapy. In the absence of toxicity, no scheduled treatment should be given 
more than 2 days late; such doses will be skipped, and dosing will resume at the next 
scheduled dosing visit.  If there are bavituximab related adverse events which are limiting 
to further therapy, at investigator’s discretion patients may be treated at a -1 dose level of 
1mg/kg. 
5.1.2 
Storage of Study Treatments 
Bavituximab is stored at 2°C to 8°C. Sites should monitor temperature conditions and 
report any temperature excursions. Once diluted, bavituximab should be stored at room 
temperature and infused within 8 hours. The infusion must be completed within 8 hours 
of dilution. 
Bavituximab must be stored in a secure area and administered only to patients entered 
into the clinical study in accordance with the conditions specified in the protocol. 
Bavituximab will be managed by a pharmacist or designee at the site.  
The pharmacist or designee must keep an accurate accounting of the number of 
investigational units received from Oncologie, dispensed to patients, and returned to the 
Oncologie or representative (or destroyed at the site) during and at the completion of the 
study. Standard operating procedures (SOPs) must be in place to control the use of the 
study drug. Bavituximab must be dispensed only by an appropriately qualified person 
and is to be used in accordance with the protocol in patients who are under the direct 
supervision of the investigator. 
All used vials may be stored under ambient conditions for accountability purposes. All 
unused study treatments should be saved, accounted for, and processed after 
consulting with Oncologie. 
The treatment to be used in this trial is outlined below in Table 1. 
 
Table 1  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Bavituximab 
3 mg/kg 
weekly 
IV infusion 
Weekly of a 21 day 
cycle 
Experimental 
 
Trial treatment must begin within 2 weeks (14 days) to the date of registration.   
Dose Selection/Modification 

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5.2.1 
Pembrolizumab Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 2.5.2. 
Details on preparation and administration of pembrolizumab (MK-3475) are provided 
in the Pharmacy Manual.   
5.2.2 
Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs as per 3 below. See Section 5.6 for supportive care guidelines, 
including use of corticosteroids. 
 
Table 3. Pembrolizumab Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treat
ment 
For 
Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
T1DM 
or  
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus or 
Grade 3-4 hyperglycemia 
Resume pembrolizumab when patients are 
clinically and metabolically stable 

Protocol Version 6; 11 November 2019 
 
 
 
20 
 
 
Toxicity 
Hold 
Treat
ment 
For 
Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
onset) or 
Hyperglycemia 
associated with evidence of beta 
cell failure 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab 
can be continued while 
endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is instituted 
Therapy with pembrolizumab can be continued 
while thyroid replacement therapy is instituted 
 
Infusion 
Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops 
despite adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Permanently discontinue 
Permanently discontinue 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 

Protocol Version 6; 11 November 2019 
 
 
 
21 
 
 
Toxicity 
Hold 
Treat
ment 
For 
Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
All Other Drug-
Related Toxicityc 
3 or 
Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening 
event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original 
infusion rate   (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the 
subject should be premedicated  for the next scheduled dose; Refer to Error! Reference source not found. – 
Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has 
been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
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 back on study therapy 
within 3 weeks of the scheduled interruption, unless otherwise discussed with the PI. 
The reason for interruption should be documented in the patient's study record. 
5.2.3 
Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 9.0).  Trial treatment may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons. 

Protocol Version 6; 11 November 2019 
 
 
 
22 
 
 
All trial treatments will be administered on an outpatient basis. 
On the days both agents are to be administered,, bavituximab will be infused prior to 
pembrolizumab.  Pembrolizumab 200 mg will be administered as a 30 minute IV 
infusion every 3 weeks.  Sites should make every effort to target infusion timing to be 
as close to 30 minutes as possible.  However, given the variability of infusion pumps 
from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion 
time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
5.2.4 
Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the 
treatment administered. 
5.2 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the PI.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician.  
5.3.1 
Acceptable Concomitant Medications 
All treatments that the 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 medication will be recorded on the case 
report form (CRF) including all prescription, over-the-counter (OTC), herbal 
supplements, and IV medications and fluids.  If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be included on 
the CRF. 
All concomitant medications received within 28 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs as defined in Section 7.2. 
5.3.2 
Prohibited Concomitant Medications 

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Subjects are prohibited from receiving the following therapies during the Screening 
and Treatment Phase (including retreatment for post-complete response relapse) of 
this trial: 
5.3.2.1 
Antineoplastic systemic chemotherapy or biological therapy  
5.3.2.2 
Immunotherapy not specified in this protocol 
5.3.2.3 
Chemotherapy not specified in this protocol 
5.3.2.4 
Investigational agents other than pembrolizumab and bavituximab 
5.3.2.5 
Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.   
Live vaccines within 30 days prior to the first dose of trial treatment, while 
participating in the trial, and 30 days after the last dose of pembrolizumab.  Examples 
of live vaccines include, 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.  The use of 
physiologic doses of corticosteroids may be approved after consultation with 
Merck and/or Oncologie. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.3 
Rescue Medications & Supportive Care 
5.4.1 
Supportive Care Guidelines and Dose Modifications 
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 

Protocol Version 6; 11 November 2019 
 
 
 
24 
 
 
decreased. For each disorder, attempts should be made to rule out other causes such 
as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.  
Note:  If after the evaluation the event is determined not to be related, the 
investigator does not need to follow the treatment guidance (as outlined below). 
Refer to Section 5.2.1 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. 
5.4.1.1 Pneumonitis 
 
a. 
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. 
b. 
For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
c. 
Add prophylactic antibiotics for opportunistic infections in the case 
of prolonged steroid administration. 
5.4.1.2 Diarrhea/Colitis 
a. 
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). 
b. 
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. 
c. 
For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
d. 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids.   
e. 
When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
5.4.1.3 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 

Protocol Version 6; 11 November 2019 
 
 
 
25 
 
 
a. 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
b. 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
5.4.1.4 Hypophysitis 
a. 
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. 
b. 
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. 
5.4.1.5 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. 
a. 
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 liothyroinine, is indicated per standard of care. 
b. 
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. 
5.4.1.6 Hepatic 
a. 
For Grade 2 events, monitor liver function tests more frequently 
until returned to baseline values (consider weekly). 
Treat with IV or oral corticosteroids 
b. 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 
to 48 hours.  

Protocol Version 6; 11 November 2019 
 
 
 
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c. 
When symptoms improve to Grade 1 or less, a steroid taper should 
be started and continued over no less than 4 weeks. 
5.4.1.7 Renal Failure or Nephritis 
a. 
For Grade 2 events, treat with corticosteroids. 
b. 
For Grade 3-4 events, treat with systemic corticosteroids. 
c. 
When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
5.4.1.8 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. 
Error! Reference source not found. below shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab (MK-3475). 
Table 2 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 

Protocol Version 6; 11 November 2019 
 
 
 
27 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g., from 
100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
No subsequent dosing 

Protocol Version 6; 11 November 2019 
 
 
 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
 
6. 
DIET/ACTIVITY/OTHER CONSIDERATIONS 
6.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
6.2 
Contraception 
Pembrolizumab and bavituximab may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab or bavtuximab 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).   

Protocol Version 6; 11 November 2019 
 
 
 
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6.2.1 Female subjects will be considered of non-reproductive potential if they are 
either:  
6.2.1.1 
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  
6.2.1.2 
have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks 
prior to screening;  
OR  
6.2.1.3 
has a congenital or acquired condition that prevents childbearing. 
6.2.2 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:   
6.2.2.1 
practice abstinencefrom heterosexual activity;  
OR  
6.2.2.2 
use (or have their partner use) acceptable contraception during 
heterosexual activity.   
6.2.3 Acceptable methods of contraception are 
6.2.3.1 
Single method (one of the following is acceptable): 
a. 
intrauterine device (IUD) 
b. 
vasectomy of a female subject’s male partner  
c. 
contraceptive rod implanted into the skin 
d. 
For men of reproductive potential who may participate in the study, 
condoms with spermicide, if properly used, are generally considered 
a reliable form of contraception. 
6.2.3.2 
Combination method (requires use of two of the following): 
a. 
diaphragm with spermicide (cannot be used in conjunction with 
cervical cap/spermicide) 
a. 
cervical cap with spermicide (nulliparous women only)   
b. 
contraceptive sponge (nulliparous women only)  

Protocol Version 6; 11 November 2019 
 
 
 
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c. 
male condom or female condom (cannot be used together) 
d. 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin 
pill or progestin-only pill), contraceptive skin patch, vaginal 
contraceptive ring, or subcutaneous contraceptive injection  
NOTE:  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.  
NOTE:  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 (or 14 days prior to the initiation of study medication for 
oral contraception) throughout the study period up to 120 days after the last dose of trial therapy.  If 
there is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
6.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and 
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 the Sponsor, Oncologie and to 
Merck without delay and within 24 hours to the Sponsor and within 2 working days to Oncologie 
and 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 investigator will notify the patient’s physician that the patient was participating in a clinical 
trial and follow the progress of the pregnancy. 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 notify the sponsors. 
6.4 
Use in Nursing Women 
It is unknown whether pembrolizumab or bavituximab are 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. 

Protocol Version 6; 11 November 2019 
 
 
 
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7. 
ADVERSE EVENT REPORTING 
7.1 
Adverse Events 
7.1.1 
Adverse Event Reporting – 
All AEs from first dose (including premedication) until 30 days after the last 
administration of study treatment will be recorded on CRFs. Whenever possible, 
medical diagnoses should be captured instead of symptoms to prevent reporting more 
than one AE for a single event.  A medical procedure is not considered an AE. 
Deaths are not be recorded as an event and are instead to be recorded as the outcome 
of an event. The condition that resulted in the death is to be recorded as the event.  
Abnormal laboratory values that are clinically significant in the investigator’s 
judgment will be recorded as AEs if there is not a related medical diagnosis.  Severity 
(National Cancer Institute Common Terminology Criteria for Adverse Events 
[CTCAE] Version 50.3), relationship to study therapy, and any treatments given will 
be noted on the CRF. All related AEs must be followed until resolution or until the 
event is deemed stable or irreversible. All SAEs, regardless of relationship, should be 
followed until an outcome of the SAE can be documented. For patients discontinuing 
the study prematurely, all unrelated AEs are to be followed for 30 days after the last 
administration of study therapy, and all related AEs and SAEs are be followed as 
defined above. Cancer progression or cancer-related death will be considered a study 
endpoint and not an AE. Hospitalization for elective procedures or for protocol 
compliance is not considered an SAE.  Relationship of an AE to the study drug is to 
be evaluated using the guidelines above. 
7.1.2 
Serious Adverse Event Reporting 
All SAEs and pregnancies that occur between the first dose of study drug and 30 days 
after the last dose of study drug, whether or not considered related to the study drug, 
must be reported. In addition, SAEs occurring at any time that are attributable to 
study drug must be reported.  
7.1.2.1 
The SAE report should include  
a. 
date and time of onset 
b. 
description of event 
c. 
severity (CTCAE Version 4.0.3), duration 
d. 
outcome 
e. 
etiology 
f. 
relationship to study drug 

Protocol Version 6; 11 November 2019 
 
 
 
32 
 
 
g. 
action taken 
h. 
other relevant details should be documented on these forms as 
available.  
i. 
SAEs related to other therapy or treatment must be reported as per 
local requirements. 
7.1.2.2 
Patients 
Patients may be hospitalized for observation following study drug administration. 
Planned hospitalization (e.g., for observation, protocol compliance, elective 
procedures, social reasons) will not be considered an SAE; however, any AE that 
prolongs hospitalization will be considered an SAE. 
7.1.2.3 
Investigator  
a. 
The investigator must also report SAEs to the IRB in accordance 
with local requirements.  
b. 
The investigator must maintain documentation of all 
communications with the IRB.  
c. 
The lead investigator will expedite the reporting of suspected 
unexpected serious adverse reactions to concerned regulatory 
authorities, ethics committees, and investigators in accordance with 
all relevant laws and regulations governing the reporting of adverse 
drug reactions from clinical trials. 
d. 
Investigators are required to report to Merck and Oncologie Drug 
Safety any SUSAR (Suspected Unexpected Serious Adverse 
Reaction) as soon as possible.   
7.1.2.4 
SUSAR  
A SUSAR is any sign, symptom or medical condition that emerges during 
bavituximab treatment or during a post-treatment follow-up period that (1) was not 
present at the start of bavituximab treatment and it is not a chronic condition that is 
part of the patient’s medical history, OR (2) was present at the start of bavituximab 
treatment or as part of the patient’s medical history but worsened in severity and/or 
frequency during therapy, AND that meets any of the following regulatory serious 
criteria: 
a. 
Results in death  
b. 
Is life-threatening  
c. 
Requires or prolongs inpatient hospitalization  
d. 
Is disabling  
e. 
Is a congenital anomaly/birth defect  

Protocol Version 6; 11 November 2019 
 
 
 
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f. 
Is medically significant or requires medical or surgical intervention 
to prevent one of the outcomes listed above. 
All SUSARs are to be recorded on a MedWatch 3500A Form and emailed to: 
AND: 
 
AND: 
Sites local Institutional Review Boards (IRB); reporting must occur within the timeframe 
required by the site IRB. 
7.1.3 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report must include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
7.1.3.1 
Treatment regimen (dosing frequency, combination therapy) 
7.1.3.2 
Protocol description (and number, if assigned) 
7.1.3.2 
Description of event, severity, treatment, and outcome, if known 
7.1.3.3 
Supportive laboratory results and diagnostics (as applicable) 
7.1.3.4 
Investigator’s assessment of the relationship of the adverse event to 
each investigational product and suspect medication 
Additional information may be added to a previously submitted report by any of the 
following methods: 
7.1.3.5 
Adding to the original MedWatch 3500A report and submitting it as 
follow-up 
7.1.3.6 
Adding supplemental summary information and submitting it as 
follow-up with the original MedWatch 3500A form  
7.1.3.7 
Summarizing new information and faxing it with a cover letter 
including patient identifiers (i.e. D.O.B. initial, patient number), 
protocol description and number, if assigned, suspect drug, brief 
adverse event description, and notation that additional or follow-up 
information is being submitted (The patient identifiers are important 
so that the new information is added to the correct initial report) 
Occasionally Oncologie may contact the reporter for additional information, 
clarification, or current status of the patient for whom and adverse event was 
reported.  
7.1.4 
Assessing Causality 

Protocol Version 6; 11 November 2019 
 
 
 
34 
 
 
Investigators are required to assess whether there is a reasonable possibility that 
bavituximab caused or contributed to an adverse event.  The following general 
guidance may be used. 
7.1.4.1 
Yes 
If the temporal relationship of the clinical event to bavituximab or pembrolizumab 
administration makes a causal relationship possible, and other drugs, therapeutic 
interventions or underlying conditions do not provide a sufficient explanation for the 
observed event. 
7.1.4.2 
No 
If the temporal relationship of the clinical event to bavituximab or pembrolizumab 
administration makes a causal relationship unlikely, or other drugs, therapeutic 
interventions or underlying conditions provide a sufficient explanation for the 
observed event. 
7.1.5 
Safety Reporting Requirements for IND Holders 
In accordance with 21 CFR 212.32, investigator-investigators of studies conducted 
under an IND must comply with following safety reporting requirements:  
7.1.5.1 
Expedited IND Safety Reports 
a. 
7 Calendar-Day Telephone or Fax Report 
The Investigators required to notify the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the 
investigator to be possibly related to the use of bavituximab.  An 
unexpected adverse event is one that is not already described in the 
Investigator Brochure.  Such reports are to be telephoned or faxed 
to the FDA and Oncologie within 7 calendar days of first learning 
of the event.  Each telephone call or fax transmission (see fax 
number below) should be directed to the FDA new drug review 
division in the Center for Drug Evaluation and Research or in the 
product review division for the Center for Biologics Evaluation and 
Research, whichever is responsible for the review of the IND. 
b. 
15 Calendar-Day Written Report 
The Investigators also required to notify the FDA and all 
participating investigators, in a written IND Safety Report, of any 
serious, unexpected AE that is considered possibly related to the use 

Protocol Version 6; 11 November 2019 
 
 
 
35 
 
 
of bavituximab.  An unexpected adverse event is one that is not 
already described in the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar 
Events in accordance with regulation 21 CFR § 312.32.  All safety 
reports previously filed with the IND concerning similar events 
should be analyzed.  The new report should contain comments on 
the significance of the new event in light of the previous, similar 
reports.   
Written IND safety reports with Analysis of Similar Events are to 
be submitted to the FDA, Oncologie Drug Safety, and all 
participating investigators within 15 calendar days of first learning 
of the event.  The FDA prefers these reports on a MedWatch 3500A 
Form but alternative formats are acceptable (e.g. summary letter). 
7.1.5.2 
FDA fax number for IND Safety Reports: 
a. 
1 (800) FDA - 0178 
b. 
All written IND Safety Reports submitted to the FDA by the 
Investigator must also be emailed to:  
Oncologie  
 
 
North America 
Safety Reporting Email Fax 
 
 
AND 
AND 
Sites local Institutional Review Boards (IRB); reporting must occur 
within the timeframe required by the site IRB.For questions related to 
safety reporting, contact: 
All SAEs, whether related or unrelated to bavituximab, pembrolizumab, 
and all pregnancies must be reported to the within 24 hours of 
knowledge of the event for reporting to Peregrine, Merck, and the FDA ( 
as applicable, by the investigator or designee). 

Protocol Version 6; 11 November 2019 
 
 
 
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7.1.5.3 
IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Investigatorhall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the 
progress of the investigation.  Please refer to Code of Federal Regulations, 21 CFR § 
312.32 for a list of the elements required for the annual report.  All IND annual 
reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Oncologie.  Copies of such reports should be mailed to 
 
7.2 
Assessing and Recording Adverse Events – Merck 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events 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 

Protocol Version 6; 11 November 2019 
 
 
 
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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. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets.  The reporting 
timeframe for adverse events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for 
outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. [Please delete this section if N/A]. 
7.2.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and 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 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 the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck 

Protocol Version 6; 11 November 2019 
 
 
 
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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 the Sponsor and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 
Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 
Serious Adverse Events 
a. 
A serious adverse event is any adverse event occurring at any dose 
or during any use of Merck’s product that: 
b. 
Results in death; 
c. 
Is life threatening; 
d. 
Results in persistent or significant disability/incapacity; 
e. 
Results in or prolongs an existing inpatient hospitalization; 
f. 
Is a congenital anomaly/birth defect; 
g. 
Is another important medical event;  
Note:  In addition to the above criteria, adverse events meeting either of 
the below criteria, although not serious per ICH definition, are reportable 
to the Merck in the same timeframe as SAEs to meet certain local 
requirements. Therefore, these events are considered serious by Merck 
for collection purposes. 

Protocol Version 6; 11 November 2019 
 
 
 
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h. 
Is a new cancer (that is not a condition of the study); 
i. 
Is associated with an overdose. 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 for additional details) [Note: this portion in blue text 
only applies to trials capturing Disease Progression as primary or secondary endpoint 
(PFS or ORR) – please delete if N/A]. that occurs to any subject must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
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 serious adverse 
event, or follow up to a serious adverse event, including death due to any cause other 
than progression of the cancer under study (reference Section 7.2.3.3 for additional 
details), [Note: this portion in blue text only applies to trials capturing Disease 
Progression as primary or secondary endpoint (PFS or ORR) – please delete if N/A]. 
whether or not related to the Merck product, must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety. 
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 specified in the paragraph above, or at any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the 
Sponsor and 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:  +1-215-993-1220 
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 

Protocol Version 6; 11 November 2019 
 
 
 
40 
 
 
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 
993-1220) at the time of submission to FDA. 
7.2.3.2 
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 the Sponsor and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 
993-1220). 
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 the Sponsor and within 2 working days to Merck 
Global Safety if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
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 the Sponsor and within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
a. 
an overdose of Merck product, as defined in Section 7.2.1 - 
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.  
b. 
2.  an elevated AST or ALT lab value that is greater than or equal to 
3X the upper limit of normal and an elevated total bilirubin lab 
value that is greater than or equal to 2X the upper limit of normal 
and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
*Note: These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of 
abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology.  

Protocol Version 6; 11 November 2019 
 
 
 
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7.2.3.3 
Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as 
described in Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor 
and to Merck, unless there is evidence suggesting a causal relationship between the 
drug and the event. Any such event will be submitted to the Sponsor within 24 hours 
and to Merck Global Safety within 2 working days either by electronic or paper 
media. 
Specifically, the suspected/actual events covered in this exception include any event 
that is disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety 
data to ensure the safety of the subjects in the trial. Any suspected endpoint which 
upon review is not progression of the cancer under study will be forwarded to Merck 
Global Safety as a SAE within 2 working days of determination that the event is not 
progression of the cancer under study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be 
considered a SAE. 
7.2.4 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events 
according to the NCI Common Terminology for Adverse Events (CTCAE), version 
4.0. Any adverse event which changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the adverse event case report 
forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness. 
  
Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as 
to: 
V4.0 CTCAE Grading 
 
Grade 1 
Mild; asymptomatic or mid 
symptoms; clinical or diagnostic 
observations only; intervention not 
indicated 

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Grade 2 
Moderate; minimal, local or 
noninvasive intervention indicated; 
limiting age-appropriate instrumental 
ADL. 
Grade 3 
Severe or medically significant but 
not immediately life-threatening; 
hospitalization or prolongation or 
hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4 
Life threatening consequences; 
urgent intervention indicated. 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any 
adverse event occurring at any dose 
or during any use of Merck or 
Oncologie product that: 
†Results in death; or 
 
†Is life threatening; 
or places the subject, in the view of 
the investigator, at immediate risk of 
death from the event as it occurred 
Note:  This does not include an adverse event that, had it occurred in a more 
severe form, might have caused death; or 
†Results in a persistent or 
significant disability/incapacity 
substantial disruption of one’s ability 
to conduct normal life functions; or 
†Results in or prolongs an 
existing inpatient hospitalization 
hospitalization is defined as an 
inpatient admission, regardless of 
length of stay, even if the 
hospitalization is a precautionary 
measure for continued observation. 
Note:  Hospitalization for an elective procedure to treat a pre-existing 
condition that has not worsened is not a serious adverse event. 
Note:  A pre-existing condition is a clinical condition that is diagnosed prior to 
the use of a Merck product and is documented in the patient’s medical 
history; or 
†Is a congenital anomaly/birth 
defect 
(in offspring of subject taking the 
product regardless of time to 
diagnosis);or 

Protocol Version 6; 11 November 2019 
 
 
 
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Is a new cancer 
(that is not a condition of the study) 
(although not serious per ICH 
definition, is reportable to the PI 
within 24 hours and to Merck and 
Oncologie within 2 working days to 
meet certain local requirements); or 
Is an overdose  
(whether accidental or intentional).   
Any adverse event associated with 
an overdose is considered a serious 
adverse event for collection 
purposes. An overdose that is not 
associated with an adverse event is 
considered a non-serious event of 
clinical interest and must be reported 
within 24 hours to the PI and to 
Merck and Oncologie within 2 
working days. 
Other important medical events 
that may not result in death, not be 
life threatening, or not require 
hospitalization may be considered a 
serious adverse event when, based 
upon appropriate medical judgment, 
the event may jeopardize the subject 
and may require medical or surgical 
intervention to prevent one of the 
outcomes listed previously 
(designated above by a †). 
Duration Record 
the start and stop dates of the 
adverse event. If less than 1 day, 
indicate the appropriate length of 
time and units 
Action Taken 
Did the adverse event cause Merck 
or Oncologie product to be 
discontinued? 

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Relationship to Merck/Oncologie 
Product 
Did Merck or Oncologie product 
cause the adverse event? The 
determination of the likelihood that 
the Merck or Oncologie product 
caused the adverse event will be 
provided by an investigator who is a 
qualified physician. The investigator’s 
signed/dated initials on the source 
document or worksheet that supports 
the causality noted on the AE form, 
ensures that a medically qualified 
assessment of causality was done. 
This initialed document must be 
retained for the required regulatory 
time frame. The criteria below are 
intended as reference guidelines to 
assist the investigator in assessing 
the likelihood of a relationship 
between the test drug and the 
adverse event based upon the 
available information. 
The following components are to be used to assess the relationship between 
Merck product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely 
Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject 
was actually exposed to Merck or 
Oncologie product such as: reliable 
history, acceptable compliance 
assessment (pill count, diary, etc.), 
expected pharmacologic effect, or 
measurement of drug/metabolite in 
bodily specimen? 
Time Course 
Did the AE follow in a reasonable 
temporal sequence from 
administration of Merck or Oncologie 
product? 
Time of Onset 
Is the time of onset of the AE 
compatible with a drug-induced effect 
(applies to trials with investigational 
medicinal product)? 

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Likely Cause 
Is the AE not reasonably explained 
by another etiology such as 
underlying disease, other 
drug(s)/vaccine(s), or other host or 
environmental factors 
Relationship 
The following components are to be 
used to assess the relationship 
between the test drug and the AE: 
(continued) 
 
to Merck or Oncologie Product 
Dechallenge 
Was Merck or Oncologie product 
discontinued or 
dose/exposure/frequency reduced? 
If yes, 
did the AE resolve or improve? 
If yes, 
this is a positive dechallenge. 
If no, 
this is a negative dechallenge. 
Note:  This criterion is not applicable if:  
1) the AE resulted in death or permanent disability;  
2) the AE resolved/improved despite continuation of the 
Sponsor’s product; or  
3) the trial is a single-dose drug trial); or  
4) Sponsor’s product(s) is/are only used one time. 
Rechallenge 
Was the subject re-exposed to Merck 
or Oncologie product in this study? 
If yes, 
did the AE recur or worsen? 
If yes, 
this is a positive rechallenge. 
If no, 
this is a negative rechallenge. 
Note:  This criterion is not applicable if:  
1) the initial AE resulted in death or permanent disability, or  
2) the trial is a single-dose drug trial); or  
3) Sponsor’s product(s) is/are used only one time. 

Protocol Version 6; 11 November 2019 
 
 
 
46 
 
 
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT 
WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY 
MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE 
SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL. 
Consistency with Trial Treatment 
Profile 
Is the clinical/pathological 
presentation of the AE consistent 
with previous knowledge regarding 
Merck product or drug class 
pharmacology or toxicology? 
Note:  The assessment of relationship will be reported on the case report 
forms /worksheets by an investigator who is a qualified physician according 
to his/her best clinical judgment, including consideration of the above 
elements. 
Record one of the following: 
Use the following scale of criteria as guidance (not all criteria must be present 
to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship.  
There is evidence of exposure to 
Merck or Oncologie product.   
The temporal sequence of the AE 
onset relative to the administration of 
Merck product is reasonable.   
The AE is more likely explained by 
Merck product than by another 
cause. 

Protocol Version 6; 11 November 2019 
 
 
 
47 
 
 
No, there is not a reasonable 
possibility of Merck product 
relationship. 
Subject did not receive the Merck or 
Oncologie product  
OR  
temporal sequence of the AE onset 
relative to administration of Merck or 
Oncologie product is not reasonable  
OR  
the AE is more likely explained by 
another cause than the Merck or 
Oncologie product.  
(Also, entered for a subject with 
overdose without an associated AE.) 
  
8. 
LABORATORY EVALUATIONS 
8.1 
Efficacy Measures 
Patients will be re-staged every 3 cycles and treatment will continue until progression, or significant 
toxicity up to 24 months.  Staging assessments will include cross-section imaging with either MRI 
head and neck or CT head and neck with contrast, and CT chest/abdomen with contrast.    
8.2 
The Following Laboratory Parameters Will Be Assessed: 
Hematology: complete blood count (red blood cell count, white blood cell count, hemoglobin, 
hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular 
hemoglobin concentration) with differentials, and platelets,  
Chemistry: AST, ALT, gamma-glutamyl transpeptidase, alkaline phosphatase, lactate 
dehydrogenase, creatinine, blood urea nitrogen, serum bilirubin (serum total and direct bilirubin at 
screening, direct bilirubin subsequently only if serum total bilirubin is elevated), total protein, 
albumin, glucose, uric acid, magnesium, phosphate, amylase, lipase, electrolytes (sodium, 
potassium, chloride, calcium, and bicarbonate), thyroid function tests (thyroid stimulating hormone 
[TSH] reflex to free triiodothyronine and free thyronine if abnormal TSH result). 
Urinalysis:  specific gravity, pH, dipstick for blood, glucose, protein, and microscopy for cells and 
casts. 
Pregnancy testing for women of childbearing potential - See section 3.1.8 
Other safety evaluations will be made based on regular vital signs assessments (heart rate, systolic 
and diastolic blood pressure, oxygenation at rest and walking, weight) and physical examinations. 

Protocol Version 6; 11 November 2019 
 
 
 
48 
 
 
8.3 
Correlative Studies - Please see lab manual for full details regarding collection and 
processing. 
Exploratory correlatives are planned in order to determine biomarkers that may be 
related to response to therapy.  Blood will be collected at baseline, during each cycle 
and at the end of the study. The blood samples from the baseline, cycles 2, 4, and the 
end of the study will be used for DNA extraction and biomarker discovery analyses 
(mutation- and methylation-specific). The blood samples at cycles 1 and 3 will be 
preserved in case of any issues or with blood samples at cycles 2 and 4. Fresh biopsy 
tissue will be obtained at the baseline and if feasible at the end of the study.  Fresh 
biopsy tissue will be used for DNA and RNA extraction. The following correlative 
studies will be performed:  
8.3.1 
H&E staining will be performed on each tumor samples to define the tumor 
histology. This will be performed at the University of Maryland Pathology 
Department under the direction of Dr. John Papadimitriou. 
 
8.3.2 
Immunohistochemical analysis of PD-L1 protein expression will be performed on 
primary tumor samples at the baseline and the end of the study.   
 
8.3.3 
HPV status will be obtained as per clinical standard.  If this data is available in the 
medical record repeat testing is not necessary. 
 
8.3.4 
The somatic genomic analysis will be performed using AmpliSeq platform on 
primary tumor tissues collected at the baseline and the end of the study, as well as 
on the blood samples collected at the baseline, cycles 2, 4, and the end of the study. 
DNA from plasma will be used for such AmpliSeq analysis. DNA from lymphocytes 
collected at the baseline will be used as a somatic control for mutation detection. 
Tumor and blood samples will be compared at the baseline and the end of the study 
to define the blood-based detection specificity and sensitivity. Overall, 7 samples 
per patient will be used for AmpliSeq analysis.  
 
8.3.5 
DNA methylation analysis of primary samples will be performed on tumor samples 
at the baseline and the end of the study using DNA methylation array 850K 
(Illumina) to define DNA methylation-based biomarkers. All DNA samples will be 
bisulfite-converted before the analysis. For this reason, the extracted DNA from 
n=15 normal mucosa of non-cancer patients matched by the age, gender and 
smoking status (available from Otolaryngology tissue bank) will be used as non-
cancer controls. The panel of 10 hypermethylated DNA sites (including 4 well-
characterized and 6 patient-unique signals) for each patient will be developed for 
each patient.  

Protocol Version 6; 11 November 2019 
 
 
 
49 
 
 
 
8.3.6 
Ten hypermethylated DNA sites (developed for each patient) will be used for the 
design of droplet digital PCR (ddPCR) primers and probes assays. Plasma DNA at 
the baseline, cycles 2, 4, and the end of the study will be used as a template for 
ddPCR. All DNA samples will be bisulfite-converted before the analysis. The 
sensitivity and specificity of the developed ddPCR assay, as well as their ability to 
trace the treatment response, will be evaluated on this step. 
 
8.3.7 
Gene expression analysis landscape of tumors tissues before and after treatment 
will be evaluated on the primary samples at the baseline and the end of the study 
using low-throughput RNA-Seq analysis. For this reason, the extracted RNA from 
n=15 normal mucosa of non-cancer patients matched by the age, gender and 
smoking status (available from Otolaryngology tissue bank) will be used as non-
cancer controls. Pathway analysis will be performed for each patient using the 
panel of differentially expressed genes relative to controls. This will allow defining 
the treatment response on the gene expression level. The gene expression will also 
be correlated with DNA methylation landscape to evaluate which of the cancer-
related changes are triggered by epigenetic changes common for cancers. 
 
8.3.8 
The analysis of immune cell infiltration and cell repertoire will be performed for 
each sample using gene expression analysis of immune markers, as well as other 
immune-related and cell type-specific genes.  
 
8.3.9 
Immunohistochemical staining of immune markers (especially one detected on the 
RNA level) will be performed. 
 
 
9. 
STUDY CALENDAR 
Baseline laboratory and exam evaluations are to be conducted within 10 days prior to start of protocol 
therapy.  Scans and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the 
patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.   
With the exception of screening evaluations, all time points on study have leeway of plus or minus 3 
days. 
 
 
 

Protocol Version 6; 11 November 2019 
 
 
 
50 
 
 
 
Pre-
Study 
 
3 week cycles (repeat) 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
EOS 
Follow 
up 
Pembrolizumab 1 
 
X 
X 
X 
X 
 
 
Bavituximab7 
 
X 
X 
X 
X 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
History & 
Physical2 
X 
X 
X 
X 
X 
 
 
Concurrent  
Meds 
X 
X 
X 
X 
X 
 
 
CBC and  
Chemistry3 
X 
X 
 
X 
 
 
 
Research 
Bloods 4 
X 
X 
X 
X 
X 
X 
 
β-HCG8 
X 
 
 
 
 
 
 
AE assessment 
X 
X 
X 
X 
X 
 
X 
CT or MRI for 
Tumor 
Assessment 5 
X5* 
 
 
 
X5 
 
 
Tumor Biopsy6 
X 
 
 
 
X 
 
 
Review of 
medical records, 
telephone 
contact for 
recurrence-free 
and overall 
survival 
 
 
 
 
 
 
Every 3 
months 
up to 1 
year 
 
1. 200 mg IV day 1 of each cycle up to 24 months while on study 
2. History to be collected only at baseline; physical, includes interval history, prior treatment and radiation 
exposure, vital signs, (heart rate, systolic and diastolic blood pressure, oxygenation at rest and walking, 
height, weight, and performance status.  Height is only required at baseline. 
3. Complete blood count and differential, and comprehensive metabolic panel, NOTE -TSH, Free T4 once 
every 4 weeks. 
4. Amount is detailed in laboratory manual. 
5. Tumor assessment includes radiologic assessment for RECISTv1.1 evaluation. Repeat radiologic 
assessment at week 9 and every 9 weeks thereafter while patient continues to receive study therapy. 
6. Tumor biopsy to be obtained after cycle 4 if feasible.  Archival tissue will be collected at baseline if pre-
study biopsy is not feasible at the discretion of the PI. 
7 Bavituximab is dosed weekly 
8 See section 3.1.8 
10. 
MEASUREMENT OF EFFECT 

Protocol Version 6; 11 November 2019 
 
 
 
51 
 
 
Antitumor Effect – Solid Tumors 
On this study, planned radiologic evaluations will be performed at baseline (within 4 weeks prior to 
starting study therapy) and then every 3 cycles.  Confirmatory scans should be obtained not less than 4 
weeks following initial documentation of objective response, and will typically be obtained at the time 
of the next planned evaluation. 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) guideline[Clin 
Cancer Res. 2009 Dec 1;15(23):7412-20] , Changes in the longest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECISTv1.1 criteria. 
Accumulating evidence indicates that the emergence of objective responses to agents that activate anti-
tumor immune responses may follow delayed kinetics of weeks or months, and can be preceded by 
initial apparent radiological progression, or the appearance of new lesions or some enlarging lesions 
while certain target lesions are regressing (“mixed response”). It is thus reasonable, in the absence of 
clinical deterioration, to continue to treat these subjects until radiologic progression is both confirmed 
and found to have worsened at a subsequent imaging evaluation. Evidence of PD will be based on a 
comparison with baseline (or nadir) scans, in which there is either an increase of 20% or more in the 
sum of the longest diameters (SLD) of target lesions taking as reference the smallest sum of the 
longest diameters (nadir) recorded since starting pembrolizumab/bavituximab treatment, and/or 
unequivocal progression of non-target lesions, with or without the development of 1 or more new 
lesions.  PD should be confirmed by repeat scans at the next scheduled imaging evaluation 8 weeks 
later (but no sooner than 4 weeks). 
Subjects with PD should be managed in the study as per Section 4.  
10.1 
Definitions 
10.1.1 
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment on 
protocol. 
10.1.2 
Evaluable for objective response 
For each, only those patients who have measurable disease present at baseline, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of the first cycle of either therapy will also be 
considered evaluable.) 

Protocol Version 6; 11 November 2019 
 
 
 
52 
 
 
10.1.3 
Evaluable Non-Target Disease Response   
Patients who have lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
10.2 
Disease Parameters 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements.  Measurable 
disease is defined by the presence of at least one measurable lesion. 
10.2.1 
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 by chest x-ray or as >10 
mm with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area are not 
considered measurable unless there has been demonstrated progression in the lesion. 
10.2.2 
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be 
measured and followed. 
10.2.3 
Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 
mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitic involvement of the skin or lung, 
inflammatory breast disease, and abdominal masses/abdominal organomegaly (not 
followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 

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53 
 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
10.2.4 
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), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum 
diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
10.2.5 
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
10.3 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 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
10.3.1 
Clinical lesions 

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54 
 
 
Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
10.3.2 
Chest x-ray  
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
10.3.3 
Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved in 
MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with CT, 
the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECISTv1.1 guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
10.3.4 
PET-CT 
At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST v1.1 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST v1.1 
measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT 

Protocol Version 6; 11 November 2019 
 
 
 
55 
 
 
introduces additional data which may bias an investigator if it is not routinely or 
serially performed.   
10.3.5 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
10.3.6 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised.  
However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
10.3.7 
Tumor markers 
Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in 
recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
10.3.8 
Cytology, Histology   
These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 

Protocol Version 6; 11 November 2019 
 
 
 
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10.3.9 
FDG-PET 
While FDG-PET response assessments related to NSCLC management and to 
immunotherapy need additional study, it is sometimes reasonable to incorporate the 
use of FDG-PET scanning to complement CT scanning in assessment of tumor 
progression (particularly possible 'new' disease) or regression (evaluation of potential 
CR).  Lesions can be assessed on FDG-PET imaging according to the following 
algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image. 
10.4 Response Criteria 
10.4.1 
Evaluation of Target Lesions 
10.4.1.1 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm. 
10.4.1.2 
Partial Response (PR)  
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
10.4.1.3 
Progressive Disease (PD): 
 

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57 
 
 
At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions). 
10.4.1.4 
Stable Disease (SD) 
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
10.4.2 
Special notes on the assessment of target lesions 
10.4.2.1 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded and should be measured in the same anatomical plane as the 
baseline examination, even if the nodes regress to below 10mm on study.  This 
means that when lymph nodes are included as target lesions, the ‘sum’ of lesions may 
not be zero even if complete response criteria are met, since a normal lymph node is 
defined as having a short axis of < 10 mm. 
10.4.2.2 
Target lesions that become ‘too small to measure’ 
All lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 
2mm).  If the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5mm.  When such a lesion becomes difficult to assign an 
exact measurement, it is recommended to:  If it is in the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm.  
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned (note: in case of a lymph node believed to 
be present and faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well).  This default value is derived from the 5 
mm CT slice thickness (but should not be changed with varying CT slice thickness). 
10.4.2.3 
Lesions that split or coalesce on treatment 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have 

Protocol Version 6; 11 November 2019 
 
 
 
58 
 
 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
10.4.3 
Evaluation of Non-Target Lesions 
10.4.3.1 
Complete Response (CR): 
 
Disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
10.4.3.2 
Non-CR/Non-PD: 
 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
10.4.3.3 
Progressive Disease (PD): 
 
Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion 
increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).  When the patient also has measurable disease:  To achieve 
‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status.  When the patients has only non-measurable disease:  To achieve 
‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening such that the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in the 
size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  Because worsening in non-target disease cannot be 
easily quantified (by definition: if all lesions are non-measurable) a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-measurable disease 

Protocol Version 6; 11 November 2019 
 
 
 
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is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e., an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described 
in protocols as ‘sufficient to require a change in therapy’.  If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that 
point. 
10.4.4 
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 Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 

Protocol Version 6; 11 November 2019 
 
 
 
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Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Patients 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. 
 
10.5 Duration of Response 
10.5.1 
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). 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented. 
 
10.5.2 
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, including the baseline measurements.  
10.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 

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11. 
STATISTICAL CONSIDERATIONS 
The primary outcome of this study is overall response rate (CR+PR via RECIST 1.1).  We will use a 
Simon’s optimal 2-stage design with 80% power and 5% one-sided type-I error to compare the null 
hypothesis of ORR=5% vs. the alternative of ORR=20%.  The first stage will enroll 10 patients, and if 
1 or more responses are observed an additional 19 patients will be enrolled.  If at least 4 responses are 
observed out of the 29 patients, the null hypothesis will be rejected 
Safety Monitoring: We will monitor adverse events (AEs) throughout the study. If it appears that the 
risk of a serious AE is excessive, we will evaluate the treatment regimen and either modify the 
treatment plan or consider stopping the study. The risk of a serious AE (or DLT as defined above) is 
excessive if the risk is greater than 25%. Our stopping criterion corresponds to our determining that 
there is 75% or greater probability that the risk of a DLT exceeds 25%. Experience with single-agent 
anti-PD1 therapy suggests that the risk of a serious AE is between 15% and 20% but may be higher 
with the combination. We characterize this estimate with uncertainty using a beta distribution with 
parameters 2 and 8. This distribution has mean 0.2 and 90% probability that the risk is between 4% 
and 43%. The following table shows the stopping boundaries for safety monitoring. 
 
Number of patients 
experiencing a DLT 
4 
5 
6 
7 
8 
9 
10 
11 
Number of patients 
treated 
4 - 6 
7 - 9 
10 - 13 
14 - 17 
18 - 20 
21 - 24 
25 - 27 
28 - 29 
 
Estimates of the operating characteristics for this stopping rule, as estimated from 5,000 simulations 
for each scenario, are as follows. 
 
11.1 
Data Analysis 
We will summarize the response experience of the patients with percentages and 
confidence intervals. (We will not adjust for the interim analysis when computing the 
confidence intervals.) We will define overall survival as the time from the start of 
treatment until death from any cause. Patients who leave the study and whose survival 
status we cannot determine will be censored at the last date they were known to be alive. 
Progression-free survival will be the time from the start of treatment until disease 
progression or death from any cause. Patients who start non-protocol therapy in the 
Risk of DLT 
0.10 
0.15 
0.20 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
Chance of declaring the 
combination too toxic 
1.2 
4.8 
14.2 
31.2 
51.7 
71.5 
86.9 
94.9 
98.3 
Average sample size 
28.8 
28.1 
26.6 
24.0 
20.8 
17.2 
13.7 
11.1 
9.1 

Protocol Version 6; 11 November 2019 
 
 
 
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absence of disease progression will be considered to have progressed on the date the new 
therapy begins. If the patient is lost to follow up, the patient’s time to progression will be 
censored at the last date they were known to be alive and disease free. Duration of 
response will be defined as the time from the first known response until disease 
progression, with death not related to disease censoring this endpoint. All failure-time 
endpoints will be analyzed with appropriate statistical methods for censored data. We 
will estimate the distributions of times until the events by the method of Kaplan and 
Meier. We will fit the proportional hazards model to learn about associations of patient or 
tumor characteristics with failure-time endpoints. Data displays will include summary 
statistics and confidence intervals. 
 
Correlative analyses (e.g., laboratory correlates of response, such as PD-L1 expression, 
presence of TILs, and changes in immune markers) will be exploratory  
 
Safety Analysis 
All patients who receive any study treatment will be included in final summaries of safety data. 
Summaries of AEs and other safety parameters will be provided as appropriate. Summary 
tables for extent of exposure to study treatment will also be provided.  
11.2 Interim Analysis  
The first stage will enroll 10 patients, and if 1 or more responses are observed an additional 19 
patients will be enrolled. After the first 6 patients are accrued, the regimen will be evaluated for 
toxicity.  If 2 or more patients experience a DLT, the study will be halted for excess toxicity. 
12. 
ADMINISTRATIVE ITEMS 
This protocol is to be conducted in accordance with the International Conference on Harmonisation 
(ICH) Guideline on Good Clinical Practice (GCP) and any other applicable regulatory requirements, 
such as national legislation, European Union (EU) Directives, and Title 21 of the US Code of Federal 
Regulations (CFR), as well as with the Investigator’s (or designee’s) SOPs. 
This clinical trial will be registered on the “clinicaltrials.gov” clinical trial registry website and any 
additional national clinical trial registries, as applicable. 
Safety reporting will be conducted by and through the holder of the IND to Oncologie. 
Before the start of this study and the shipment of investigational agent to the main site, the following 
documents must be on file at Oncologie, Inc. 
a. 
U.S. Food and Drug Administration (FDA) Form 1572, signed by 
the Principal Investigator 

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b. 
The names of any sub-investigators must appear on this form. 
Investigators must also complete all regulatory documentation as 
required by local regulations 
c. 
Current curricula vitae and license of the Principal Investigator 
d. 
Final Protocol 
e. 
A signed and dated investigator brochure acceptance form 
f. 
Written documentation of IRB approval of protocol (identified by 
title and date of approval) for each site 
g. 
Written documentation from the FDA assigning an IND number to 
the trial and the approval to begin the study 
h. 
A signed Confidentiality Agreement  
i. 
A signed Clinical Trial Agreement for each site  
j. 
A letter of cross-reference to the Oncologie Pharmaceuticals IND 
The following data and materials are required by Oncologie before a study can be considered 
complete or terminated: 
a. 
Copies of protocol amendments and IRB approval/notification, if 
appropriate 
b. 
Copies of the IRB final report, documentation of submission to the 
IRB and to the FDA. 
c. 
A summary of the study prepared by the Principal Investigator 
(Study report, manuscript and/or abstract) 
d. 
All regulatory documents (e.g., updated curriculum vitae for each 
Principal Investigator, updated U.S. FDA Form 1572 for each site) 
12.1 Ethics 
The trial will be conducted in accordance with the Declaration of Helsinki for biomedical 
research involving human subjects and with local regulatory requirements. 
12.2 Ethical Principles 
The study is based on adequately performed laboratory and animal experimentation. The study 
will be conducted under a protocol reviewed by an IRB. The study is to be conducted by 
scientifically and medically qualified persons. The benefits of the study are in proportion to the 
risks. The rights and welfare of the patients will be respected. The physicians conducting the 
study will ensure that the hazards do not outweigh the potential benefits. The results to be 
reported will be accurate. Patients will give their informed consent and will be competent to do 
so and not under duress. The study will comply with the ethical principles in Title 21 of the US 
CFR and other country-specific requirements. 

Protocol Version 6; 11 November 2019 
 
 
 
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12.3 Compliance with Informed Consent Regulations 
This study will be conducted in full compliance with informed consent regulations in US 21 
CFR Part 50 or with other applicable regulations. The ICF must be reviewed and approved by 
the Investigator prior to initiation of the study. The ICF must contain a full explanation of the 
possible advantages, risks, alternate treatment options, and availability of treatment in the case 
of injury, in accordance with the applicable regulations. The ICF should also indicate that, by 
signature, the patient (or legal guardian where appropriate) permits access to relevant medical 
records by the Investigator and by representatives of the agency.  
The investigator is responsible for obtaining written consent from potential patients prior to 
performing any screening tests or assessments required by the protocol. A copy of the signed 
ICF will be given to the patient and the original retained by the investigator with other study 
documentation maintained at the site.  
No investigator may involve a human being as a subject in research unless the investigator has 
obtained the legally effective informed consent of the patient or the patient’s legally authorized 
representative. An investigator may seek such consent only under circumstances that provide 
the prospective patient or the representative sufficient opportunity to consider whether to 
participate and that minimize the possibility of coercion or undue influence. The information 
given to the patient or the representative must be in a language understandable to the patient or 
the representative. No informed consent, whether oral or written, may include any exculpatory 
language through which the patient or the representative is made to waive or appear to waive 
any of the patient’s legal rights, or releases or appears to release the investigator, the institution, 
the Investigator, or its agents from liability for negligence.  
Each patient must sign the ICF before any screening assessments specific to this study can be 
initiated. The signed ICF must remain in the patient’s file and must be available for verification 
by a representative of the Investigator. 
12.4 Compliance with IRB Regulations 
This study will be conducted in full compliance with the IRB regulations in 21 CFR Part 56 and 
other applicable regulations. This protocol will not be initiated unless it and the ICF have been 
reviewed and approved by, and remains open to continuing review by, an appropriate IRB. The 
IRB shall review and have the authority to approve, require modification in (to secure 
approval), or disapprove the protocol. The IRB shall notify the investigator and the institution 
in writing of its decision, and the Letter of Approval from the IEC/IRB must contain specific 
identification of the documents approved. The IRB shall require that the information given to 
patients as part of the informed consent is in accordance with 21 CFR Part 50.25 and/or other 
applicable regulations. Copies of all reports to and correspondence between the investigator and 

Protocol Version 6; 11 November 2019 
 
 
 
65 
 
 
the IRB must be provided to the Investigator. At the completion or early termination of the trial, 
a final report should be made to the IRB by the investigator within the legal timelines. 
The investigator is obligated to maintain an IRB correspondence file and to make this file 
available for review by the Investigator’s representatives as part of the trial monitoring process. 
12.5 Patient Confidentiality and Privacy 
The investigator must ensure that patient confidentiality is maintained. Patients should not be 
identified by name on any documents submitted to the Investigator or during verbal 
communications. Patients will be identified only by an appropriate identifier and a patient 
number assigned as specified in the protocol.  
Permission for direct access to patient data will be sought in writing for the patient by the 
investigator as part of the informed consent procedure. The patient will be informed that all 
clinical information is confidential, but that the Investigator or designee, the IRB, and 
regulatory authorities may need to inspect the portion of these records that is related to the 
study. The Investigator may review the records for monitoring and audit purposes. 
Written authorization (US sites) and other documentation in accordance with the relevant 
country and local privacy requirements (where applicable) is to be obtained from each patient 
prior to enrollment into the study, and/or from the patient’s legally authorized representative in 
accordance with the applicable privacy requirements (e.g., the Health Insurance Portability and 
Accountability Act Standards for Privacy of Individually Identifiable Health Information 
(“HIPAA”). 
In accordance with HIPAA requirements, additional purposes of this study include the 
following: 
a. 
to publish anonymous patient data from the study; and  
b. 
to create and maintain a data repository 
12.6 Trial Conduct 
This trial will be conducted in compliance with the protocol approved by the IRB and by the 
Competent Authorities (CA), as applicable, and according to GCP standards. No modification 
to the protocol will be implemented without the prior review and approval of the IRB and/or 
CA except where it may be necessary to eliminate an immediate hazard to a research subject. In 
such case, the modification will be reported to the IRB and/or CA as soon as possible. 
All study drug of bavituximab required for completion of this study will be provided by 
Oncologie. and (other compound company if needed) (unless otherwise noted).  The recipient 

Protocol Version 6; 11 November 2019 
 
 
 
66 
 
 
will acknowledge receipt of the study drug by returning the drug receipt form indicating 
shipment content and condition.  Damaged supplies will be replaced. 
Study drug accountability records should be maintained by the site in accordance with the FDA 
regulations. 
The original drug supply request will be submitted to Peregrine along with the form “Approval 
for Drug Re-Supply”, indicating which personnel will be able to submit drug re-supply 
requests. 
Drug re-supply requests for Bavituximab will be directly submitted to Oncologie from the site. 
Drug re-supply requests for (other compound) will be directly submitted to (other 
pharmaceutical company) from the site. 
At the time of study closure, unused, used and expired study drug will be destroyed at the site 
per Institutional SOPs. For bavituximab, if site SOPs are not available, drug may be returned 
using the Agent Return Form. 
12.7 Changes to the Protocol 
The investigator must not implement any modifications or changes to the protocol without 
approval by the Investigator and prior review and documented approval/favorable opinion from 
the IRB of a protocol amendment, except where necessary to eliminate immediate hazards to 
study patients, or when the changes involve only logistical or administrative aspects of the 
study (e.g., change in monitors, change of telephone numbers).  
Agreement from the investigator must be obtained for all protocol amendments and 
amendments to the ICF. The IRB must be informed of all substantial amendments and give 
approval. The investigator must send a copy of the approval letter from the IRB to the 
Investigator.  
If applicable, approval of the CA must also be obtained prior to implementing a protocol 
amendment. Other local approvals may also be required. 
12.8 Study Documentation 
Documents that must be provided to the Investigator prior to study initiation are as follows: 
Medical license, signed and dated current curriculum vitae, and financial disclosure forms for 
investigators; Food and Drug Administration Form 1572; and any other forms required by local 
authorities. 
Signed and dated Investigator Agreement. 

Protocol Version 6; 11 November 2019 
 
 
 
67 
 
 
Assurance that an IRB that complies with applicable regulatory requirements has reviewed and 
approved the protocol. The required documentation will consist of the name and address of the 
IRB and a current list of IRB members.  
A copy of the formal written notification to the investigator regarding approval of the protocol 
and ICF by the IRB. The written notification is to be signed by the chairman or authorized 
designee and must identify the specific protocol. In cases where an IRB member has a known 
conflict of interest, abstention of that individual from voting should be documented; an 
investigator (or sub-investigator) may be a member of the IRB, but may not vote on any 
research in which he or she is involved. 
A copy of the IRB-approved ICF and other adjunctive materials (e.g., advertising) to be used 
for the study, including written documentation of IRB approval of these items. The IRB will 
determine if the ICF requires revision. The investigator should also comply with the IRB 
procedures for reporting any other safety information.  
In addition to the documents required prior to the study, other documentation may be required 
during the course of the study. 
The investigator will promptly report to the IRB all changes in research activity and all 
unanticipated problems involving risks and will not make any changes in the research without 
IRB approval, except where necessary to eliminate immediate hazards to human subjects. 
Those amendments that involve no more than minimal risk or minor changes in previously 
approved research only require submission to the IRB. Protocol modifications will be reported 
as required by the IRB. Major amendments require approval of the full IRB committee and 
must be submitted to the agency/licensing authority by the Investigator before implementation, 
except in an emergency situation.  Documentation of all study amendment activity should be 
forwarded to the Investigator. The investigator must also provide updates to the IRB at least 
yearly on the progress of the investigation. 
Continuing IRB review should be documented by a letter from the IRB, which should be 
forwarded to the Investigator. Notification to the IRB by the investigator within 3 months after 
completion, termination, or discontinuation of the study at the specific study center must be 
documented. 
12.9 Case Report Forms 
Patient medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. 

Protocol Version 6; 11 November 2019 
 
 
 
68 
 
 
Upon the patient’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare.  This 
medical information must be made available to Oncologie and authorized representatives of 
Oncologie, upon request, for source verification of study documentation.   
Data generated by this study must be available for inspection upon request by representatives of 
the U.S. FDA, local health authorities, Oncologie, Inc., and their authorized representative(s), 
collaborators and licensees, and the IRB for each study site, if appropriate. 
All information will be collected on study-specific case report forms in CRMS by the study 
staff.  
The completed forms will be forwarded for central review and inclusion in the study dataset 
with relevant source documentation as outlined in the case report forms. The data submission 
schedule is as follows: 
At the time of registration:  
a. 
Registration Form 
b. 
Informed Consent Form (signed by the subject) 
c. 
Eligibility Checklist 
d. 
Source documents related to eligibility and randomization 
Within 2 weeks after registration: 
a. 
Baseline study case report forms 
b. 
Pertinent source documents 
Within 2 weeks after final dose of study medication: 
a. 
On study case report forms 
b. 
Pertinent source documents 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all 
study related documents. The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).  
12.10 Quality Management and Data Management 
 
Data monitoring of this protocol will occur on a regular basis with the frequency dependent on 
the rate of subject accrual and the progress of the study.  The protocol will be monitored 
internally (University of Maryland Greenebaum Comprehensive Cancer Center) by the 

Protocol Version 6; 11 November 2019 
 
 
 
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Principal Investigator. Clinical data will be entered into the Oncore® database by the 
designated data manager at the University of Maryland Marlene and Stewart Greenebaum 
Cancer Center (UMGCC). CRSS implemented Oncore® as its clinical research database in 
FY2006. Oncore is equipped for HIPAA-compliant internet-based entry of protocol tracking 
and review information, houses accrual and demographic information for patients enrolled in 
clinical trials, offers customizable study calendars and case report forms, and contains invoicing 
data for clinical trials and summaries of external and internal adverse events. Oncore® easily 
generates accrual information for IRB annual reports, NCI-required Summary 4 reports, 
agendas for scientific review and DSMB meetings, and reports about adverse events. Using the 
internet, physicians and nursing staff can access Oncore® to download current versions of 
protocols, consents, and other protocol-related documents. Such access eliminates the need to 
maintain and track paper copies when a patient is waiting in a clinic. Oncore’s® study 
calendars are linked to an invoice-generating financial module, allowing for seamless 
communication between research and billing staff. One-half of an FTE in the Cancer Center is 
dedicated to the overall management, quality control, and staff education in relation to 
Oncore®. Opening and accruing protocols at UMGCC are listed on the UMGCC website on the 
Internet via an Oncore interface, along with summaries for referring physicians and patients. 
All study data will be collected by the Research team at each and every study visit and recorded 
in the research record. This data will then be entered in to the study database in a timely 
fashion.All source documents will be obtained and retained along with any study forms, and 
placed into the patient’s research folder. 
 
13. 
DATA SAFETY AND MONITORING BOARD (DSMB) 
Local DSMB oversight will be conducted in accordance with performance site guidelines. The 
Greenebaum Comprehensive Cancer Center DSMB will also provide trial oversight per its standard 
operating procedures. 
 
 

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