Conditions: Gastric Cancer GastroEsophageal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 80
Healthy volunteers: no

Brief summary:
This study evaluates the combination of bavituximab and pembrolizumab in the treatment of gastric and gastroesphogeal cancer. All patients will receive both bavituximab, a drug that is not yet approved by the FDA, and pembrolizumab known as Keytruda.

There is no expanded access program available for the investigational agents per this protocol.

Detailed description:

Arms:
arm 1: Bavituximab 3mg/kg IV weekly in combination with pembrolizumab 200mg IV given once every 3 weeks

Interventions: intervention 1: Bavituximab intervention 2: Pembrolizumab Injection
Intervention descriptions: intervention 1: Bavituximab IV infusion intervention 2: Pembrolizumab IV Infusion

Protocol document:
Prot_000.pdf: 
Oncologie, Inc. 
Clinical Study Protocol 
Bavituximab and Pembrolizumab 
Study ONCG100 
Amendment  4 
Page 1 of 102 
Confidential 
  
 
CLINICAL STUDY PROTOCOL 
ONCG100 
A PHASE 2, MULTICENTER OPEN-LABEL, NON-RANDOMIZED 
STUDY OF BAVITUXIMAB PLUS PEMBROLIZUMAB IN PATIENTS 
WITH ADVANCED GASTRIC OR GASTROESOPHAGEAL CANCER 
WHO HAVE PROGRESSED ON OR AFTER AT LEAST ONE PRIOR 
STANDARD THERAPY 
 
Sponsor: 
Oncologie, Inc. 
400 Totten Pond Road, Suite 120 
Waltham MA 02451 
1-781-907-7810  
Protocol Number: 
ONCG100 
Study Phase: 
2 
IND: 
011947 
Sponsor Contact: 
Susan MacIntyre, RN, BSN 
Executive Director Global Clinical Operations 
Oncologie, Inc. 
400 Totten Pond Road, Suite 120 
Waltham MA 02451 
1-781-907-7810 
Medical Monitor:  
Hagop Youssoufian, MD  
1-617-631-5112 
Version and Date: 
Amendment  4   14 September 2020 
 
Confidentiality Statement 
The information in this document contains commercial information and trade secrets that are 
privileged or confidential and may not be disclosed unless such disclosure is required by applicable 
laws and regulations. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you that is 
indicated as privileged or confidential. 


Oncologie, Inc. 
Clinical Study Protocol 
Bavituximab and Pembrolizumab 
Study ONCG100 
Amendment  4 
Page 2 of 102 
Confidential 
  
 
 
PROTOCOL APPROVAL SIGNATURE PAGE 
 
 
Protocol: 
ONCG100 
 
Title: 
A Phase 2, multicenter open-label, non-randomized study of bavituximab 
plus pembrolizumab in patients with advanced gastric or gastroesophageal 
cancer who have progressed on or after at least one prior standard therapy. 
 
Date: 
 
14 September 2020  
 
Amendment:       
 
4 
 
 
 
 
Reviewed and Approved by: 
 
 
 
 
September 
14, 2020 
 
Name: Hagop Youssoufian, MD 
Title: Interim Chief Medical Officer 
Company: Oncologie, Inc. 
 
Date 
 
 
 
 


 
Amendment 4 
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Confidential 
 
PROTOCOL ACCEPTANCE FORM 
Protocol: 
ONCG100 
 
Title: 
A Phase 2, multicenter open-label, non-randomized study of bavituximab 
plus pembrolizumab in patients with advanced gastric or gastroesophageal 
cancer who have progressed on or after at least one prior standard therapy 
 
Date: 
 
14 September 2020 
 
Amendment: 
 
4 
 
 
I have carefully read this protocol and agree that it contains all the necessary information 
required to conduct this study. I agree to conduct this study as described and according to the 
Declaration of Helsinki, in compliance with Food and Drug Administration (FDA) regulations 
21 CFR Parts 50 and 56, and in conformance with International Council for Harmonization 
(ICH) Guidelines for Good Clinical Practice (CGP) and all applicable regulatory requirements. 
 
 
 
  
Investigator’s Signature 
 Date 
 
 
 
  
Name (printed) 
  
 
 


 
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SYNOPSIS 
Name of Sponsor/Company: Oncologie, Inc. 
Name of Finished Product: Bavituximab 
Name of Active Ingredient: Chimeric Anti-Phosphatidylserine Monoclonal Antibody 
Name of Combination Product: Pembrolizumab, a programmed cell death protein 1 (PD-1) 
Inhibitor 
Title of Study: A Phase 2, multicenter open-label, non-randomized study of bavituximab 
plus pembrolizumab in patients with advanced gastric or gastroesophageal cancer who have 
progressed on or after at least one prior standard therapy 
Number of Study Sites: Approximately 28 
Study centers: This global, multicenter trial will be conducted in the United States (US), 
United Kingdom (UK), South Korea, and Taiwan and other countries as deemed appropriate.  
Studied period (years):  
Date first patient enrolled: Approximately June   2019 
Date last patient completed: Approximately June 2021 
Phase of development: 2 
 
Rationale: 
Oncologie, Inc. is developing bavituximab, a chimeric monoclonal antibody (mAb) that 
inhibits the immunosuppressive effects of phosphatidylserine (PS), for the treatment of 
cancer. PS modulates the tumor microenvironment as a ligand for multiple receptors on 
suppressor cells leading to secretion of immunosuppressive cytokines such as transforming 
growth factor-beta (TGF-) and interleukin-10 (IL-10) from M2-macrophages and myeloid-
derived suppressor cells (MDSCs). PS exposure in the tumor microenvironment prevents 
dendritic cell maturation and inhibits development of tumor-specific cytotoxic T cells. Of 
importance, expression of PS on the external surface of tumors cell acts as an 
immunosuppressive ligand for multiple immune receptors, including TIM/TAM. Nonclinical 
data show that bavituximab blocks PS immunosuppressive signaling, provides specificity for 
innate immune responses, and activates T-cell-driven adaptive immunopathways that 
reactivate a therapeutically effective immune response to the tumor.  
Pembrolizumab is a mAb that acts by blocking the interaction between PD-1 and its ligands, 
programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Molecules 
that disrupt the interaction of PD1/PD-L1, also known as immune check point inhibitors 
(CPI), are emerging as a front-line treatment for several types of cancer. Pembrolizumab is 
approved in the US for the treatment of patients with recurrent locally advanced or metastatic 
gastric or gastroesophageal junction (GEJ) adenocarcinoma after disease progression on or 
after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing 
chemotherapy. 
Although efficacy is notable and can be sustained, many patients fail pembrolizumab 
treatment potentially due to exhaustion of specific T-cells. Exhausted T-cells express elevated 
levels of T cell immunoglobulin and mucin domain 3 (TIM3), as opposed to activated or 
partially activated T-cells. Bavituximab binding to PS interrupts its binding to TIM3, which 


 
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may partially reverse the exhaustion and restore activity to pembrolizumab. Therefore, the 
combination of bavituximab with pembrolizumab may enhance the antitumor immune 
response resulting in increased clinical benefit.  
Given the potential for this combination to enhance antitumor responses, it is being evaluated 
in 2 populations of advanced gastric or GEJ cancer patients: patients that have progressed on 
standard chemotherapy and are naïve to CPI therapy (Group 1); patients that had a confirmed 
partial response (PR) or complete response (CR) to CPI inhibitor alone or in combination 
with chemotherapy, then subsequently progressed following treatment with CPI either alone 
or in combination with chemotherapy (Group 2).  
Study Objectives: 
Study objectives are the same for both Group 1 (CPI naïve) and Group 2 (CPI relapse).    
Primary: 
To assess the safety and tolerability of bavituximab in combination with pembrolizumab in 
patients with advanced gastric/GEJ cancer  
To assess the antitumor activity of the treatment combination based on Response Evaluation 
Criteria in Solid Tumors (RECIST) Guideline version 1.1 (Appendix A) 
Secondary: 
To further characterize the antitumor activity of the treatment combination based on 
additional assessments of clinical benefit 
To evaluate bavituximab concentrations when administered in combination with 
pembrolizumab 
To assess the potential immunogenicity of bavituximab   
Tertiary: 
To evaluate a novel biomarker signature panel and correlate with efficacy outcomes in 
patients treated with bavituximab-pembrolizumab combination 
Study Endpoints: 
Study endpoints are the same for both Group 1 (CPI naïve) and Group 2 (CPI relapse).    
Primary:  
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0, including changes in clinical laboratory 
parameters 
• Objective response rate (ORR) as assessed by the Investigator per RECIST version 
1.1 
Secondary: 
• Duration of response (DoR), disease control rate (DCR) (as defined by ORR and 
stable disease rate at 6 weeks), progression-free survival (PFS), and overall survival 
(OS) 
• Bavituximab concentrations before and after bavituximab infusions   
• Presence of anti-bavituximab antibodies (anti-drug antibodies [ADAs])  


 
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Tertiary: 
• Analysis of tissue to determine percentage of patients with defined genetic signature 
• Preliminary correlation of ORR to genetic signature  
• Status of genomic and immune biomarkers in blood and tissue samples at baseline and 
change from baseline upon treatment 
Study Design: 
This is a Phase 2, multicenter, open-label, non-randomized study with an initial safety 
analysis to assess the safety and tolerability of bavituximab administered in combination with 
pembrolizumab, a PD-1 inhibitor, in patients with advanced gastric or GEJ adenocarcinoma 
who have either progressed on standard chemotherapy and are naïve to CPI therapy 
(Group 1), or have progressed following treatment with CPI either alone or in combination 
with chemotherapy (Group 2).  Approximately 80 patients will be enrolled in the study; a 
minimum of 40 patients will be enrolled in Group 1 and a minimum of 20 patients will be 
enrolled in Group 2.  
Following a minimum of 3 and a maximum of a 10-patient safety run-in with bavituximab 
(3 mg/kg intravenous [IV] weekly) and pembrolizumab (200 mg IV every 3 weeks [Q3W]), 
additional patients will be recruited if the initial doses of the regimen are tolerable. Lower 
doses of bavituximab may be explored if the initial doses are not tolerable. Primary anti-
tumor activity will be documented by Investigator-assessed ORR per RECIST v. 1.1. A total 
of 80 patients will be enrolled. 
The first 3 patients will be evaluated for dose-limiting toxicities (DLTs) for the purpose of 
declaring the tentative recommended dose for expansion (RDE). The Safety Review 
Committee (SRC) will review data from these patients for DLTs at the end of the first 3-week 
cycle:  
• If 0 of 3 patients experiences a DLT on any dose level, the RDE will be tentatively 
declared and further dose expansion will continue. 
• If 1 of 3 patients experiences a DLT on any dose level, that cohort will be expanded to 
6 patients. If 1 of 6 patients experiences a DLT, the RDE will be tentatively declared 
and further dose expansion will continue. 
• If ≥ 2 of 3 or ≥ 2 of 6 patients experience a DLT on Dose Level 0, Dose Level -1 will 
be explored. If ≥ 2 of 3 or ≥ 2 of 6 patients experience a DLT on Dose Level -1, Dose 
Level -2 will be explored. 
• If  2 DLT(s) occur in up to 6 patients at Dose Level -2, further enrollment and dosing 
will be stopped until there is a full review of all available data, including PK, by the 
SRC. 
After a minimum of 3 and a maximum of 10 eligible patients are enrolled and treated for at 
least 1 cycle (3 weeks), the SRC will review data from these patients to determine the RDE. 
In case of DLTs during Cycle 1, de-escalating doses of bavituximab in combination with 
pembrolizumab will be (Table A) as follows: 
Table A: Planned Dose Levels  
Dose Level 
IV Bavituximab (Weekly) 
IV Pembrolizumab (Q3W) 


 
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0 
3 mg/kg 
200 mg 
-1 
2 mg/kg 
200 mg 
-2 
1 mg/kg 
200 mg 
After the DLT observation period, expansion may proceed. The cumulative safety data from 
the initial 3 to10 patients will be evaluated by the SRC, as well as subsequent safety data 
from the expansion population, as deemed appropriate by the SRC. 
Definition of Dose-Limiting Toxicities 
A DLT is defined as any of the AE described below that occurs during the DLT observation 
period and is at least possibly related to bavituximab or pembrolizumab. The Investigator will 
use CTCAE v5.0 guidelines to assign an AE term and severity grade relevant to the DLT. 
A DLT is defined as any of the AEs described below that occurs during the DLT observation 
period and is at least possibly related to bavituximab or pembrolizumab. The Investigator will 
use CTCAE v5.0 guidelines to assign an AE term and severity grade relevant to the DLT. 
Hematological toxicities as follows: 
o Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia: 
▪ Grade 4 thrombocytopenia of any duration 
▪ Grade 3 thrombocytopenia associated with clinically significant 
bleeding 
o  Grade 3 febrile neutropenia 
▪ Grade 3 is defined as ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 
degrees C (100.4 degrees F) for more than 1 hour 
▪ Grade 4 is defined as ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 
degrees C (100.4 degrees F) for more than 1 hour, with life-threatening 
consequences and urgent intervention indicated. 
o Grade 4 lymphocyte decreases lasting > 14 days 
 
Non-hematologic toxicities: 
o Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of anti-emetics or anti-diarrheals per standard of care; Grade 3 
rash without use of corticosteroids or anti-inflammatory agents per standard of care. 
o Any Grade 3 or Grade 4 non-hematologic laboratory value if: 


 
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▪ Clinically significant medical intervention is required to treat the 
subject, or 
▪ The abnormality leads to hospitalization, or the abnormality persists 
for >1 week; the abnormality results in a Drug-induced Liver Injury 
(DILI)  
▪ Exceptions: Clinically nonsignificant, treatable, or reversible 
laboratory abnormalities including liver function tests, uric acid, etc. 
o Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 
o Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1. 
o Missing >25% of planned doses as a result of drug-related AE(s) during the first cycle. 
o Grade 5 toxicity. 
 
Isolated laboratory changes without associated clinical signs or symptoms may not be 
included in this definition. These findings will be discussed and reviewed by the Investigators 
and the Sponsor’s medical monitor. 
Safety data in subsequent cycles will also be monitored on an ongoing basis to determine the 
cumulative incidence of late-onset toxicities. 
Adverse events that are not classified as DLTs by the above definition can be designated as 
DLTs if agreed upon by the Investigators and the Sponsor’s medical monitor. 
Safety data in subsequent cycles will also be monitored on an ongoing basis to determine the 
cumulative incidence of late-onset toxicities. 
Patients who experience a DLT, but in the opinion of the Investigator can be adequately 
monitored for recurrence of the toxicity and are otherwise experiencing clinical benefit, may 
be offered continued treatment with bavituximab and pembrolizumab. 
Dosing will continue until criteria for study treatment discontinuation are met (unacceptable 
toxicity, progressive disease [PD], or withdrawal from the study) or up to a maximum of 
35 cycles. 
Patients will be assessed for tumor response/progression per RECIST version1.1 (Appendix 
A). The initial tumor assessment on study therapy will be conducted 6 weeks after initiation 
of treatment then every 6 weeks until disease progression or another withdrawal criterion is 
met. 
Progressive disease must be confirmed by a second scan 4 weeks after initial PD diagnosis in 
the absence of clearly symptomatic and/or rapidly progressive clinical deterioration or 
requirement for urgent intervention. It is anticipated that most patients will remain on 
treatment during the 4 weeks between scans. 
Number of Patients Planned: Up to 80 patients are planned.  


 
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Study Duration: 
Enrollment is planned to occur over approximately 13 months. Treatment and follow-up 
projected will be completed within approximately 6 months thereafter. Anticipated duration 
of the study is at least 21 months. 
Diagnosis and Main Criteria for Inclusion / Exclusion:  
Inclusion Criteria 
For Group 1 only (CPI naïve): 
1. Progressed on and/or after at least 1 prior regimen for metastatic disease which 
includes a fluoropyrimidine and a platinum: 
• Progression within 6 months of prior adjuvant or neoadjuvant chemotherapy will 
be deemed a rapid progressor and thus equivalent to 1 advanced/metastatic disease 
treatment regimen. 
• Changing from IV to oral fluoropyrimidine without noted progression is 
considered only 1 prior regimen. 
• Human epidermal growth factor receptor 2 (HER2)-positive patients must have 
received prior anti-HER2 therapy and demonstrate PD or was ineligible for such 
therapy. 
For Group 2 only (CPI relapse): 
2. Patient achieved stable disease or better in two consecutive scans to PD-1/PD-L1 
inhibition alone or in combination with chemotherapy and relapsed following PD-
1/PD-L1 inhibition either alone or in combination with chemotherapy 
• All patients must be immediate (defined by within 3 months) progressors of 
PD-1/PD-L1 inhibition with no intervening treatment with other agents such as 
chemotherapy alone. 
For both Group 1 and Group 2: 
3. Signed written informed consent obtained prior to performing any study procedure, 
including screening procedures. 
4. Men and women ≥ 18 years old; ≥ 20 years old in South Korea and Taiwan. 
5. Pathologically documented unresectable metastatic or locally advanced gastric or GEJ 
adenocarcinoma:  
• Must be metastatic/unresectable at the time of enrollment into this study. 
6. Willing and able to provide fresh (since most recent progression) formalin-fixed 
paraffin-embedded tissue tumor sample for screening of signature status prior to study 
treatment and PD-L1 status. An archival tissue sample should also be provided, if 
available. 
7. Presence of at least one measurable lesion assessed by the Investigator per RECIST 
version1.1. 
8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. 
9. 
Has adequate organ functions defined as: 
System 
Laboratory valuea 
Hematological 


 
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• Absolute neutrophil count (ANC) 
• 1.5 × 109/L 
• Platelets 
• 100 × 109/L 
• Hemoglobinb 
• ≥ 9.0 g/dL 
Renal 
• Dipstick or routine urinalysis 
o 
For proteinuria  2+ or urine 
protein/creatinine ratio  0.5, 24-hour urine 
must be collected 
• Urine protein < 2 g/24h 
• Creatinine, or 
• ≤ 1.5 × ULN 
• Glomerular filtration rate (GFR) 
•  50 mL/min (see Appendix B) 
Hepatic 
• Total bilirubin 
• ≤ 1.5 × ULN (except for known Gilbert’s 
syndrome) 
• AST/ALT 
• ≤ 2.5 × ULN for patients without liver metastases 
• ≤ 5 × ULN for patients with liver metastases 
Coagulation 
• International normalized ratio (INR) or 
prothrombin time (PT) 
• INR  1.5 × ULN or PT  5 sec above ULN, 
unless the patient is receiving anticoagulant 
therapy, as long as INR or PT is within 
therapeutic range of intended use of 
anticoagulantsc 
• Partial thromboplastin time (PTT) or activated 
partial thromboplastin time (aPTT) 
• PTT or aPTT  5 seconds above ULN, unless the 
patient is receiving anticoagulant therapy, as long 
as PTT or aPTT is within therapeutic range of 
intended use of anticoagulantsc 
a All labs will be performed, and values calculated per local institution standards. 
b Transfusion and/or erythropoietin therapy to increase the patient’s hemoglobin level is not permitted 
within 1 week prior to the baseline hematology profile. 
c Patients on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular 
weight heparin for  14 days. If receiving oral anticoagulant, the patient must have an INR  3.0, no active 
bleeding (that is, no bleeding within 14 days prior to first dose of study therapy), and no pathological 
condition with a high risk of bleeding (for example, tumor involving major vessels or known varices). 
10. Women of childbearing potential must have a negative serum or urine pregnancy test 
within 72 hours prior to start of study treatment. 
11. Women must not be breastfeeding. 
12. Women of childbearing potential defined as not surgically sterile or have not been free 
from menses for ≥2 years, must agree to follow instructions for highly effective 
method(s) of contraception for the duration of treatment with study drug bavituximab 
and pembrolizumab plus 5 months post-treatment completion as described in Section 
4.4 Patients or Partners of Patients of Reproductive Potential for the duration of 
treatment with study drug bavituximab and pembrolizumab plus 5 months post-
treatment completion. 


 
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Males who are sexually active with women of childbearing potential must agree to 
follow instructions for highly effective method(s) of contraception as described in 
Section 4.4 Patients or Partners of Patients of Reproductive Potential for the duration 
of treatment with study treatment plus 90 days post-treatment completion. 
13. Has adequate treatment washout period before the start of study treatment, defined as: 
Major surgery ≥ 4 weeks; radiation therapy with abdominal radiation ≥ 4 weeks and 
have recovered from all radiation-related toxicities, not require corticosteroids and not 
have had radiation pneumonitis; palliative radiation without abdominal radiation  
≥ 2 weeks; chemotherapy ≥ 3 weeks; biologic therapy ≥ 3 weeks. 
Exclusion Criteria 
For Group 1 only (CPI naïve): 
1. 
Prior treatment with any checkpoint inhibitor or other therapies targeting T-cell 
control. 
For Group 2 only (CPI relapse): 
2. 
Primary refractory patients, defined as disease progression at first scan following 
initiation of PD-1/PD-L1 inhibitor treatment, or if best overall response to 
PD-1/PD-L1 inhibition was disease progression 
For both Group 1 and Group 2:  
3. 
Received any form of anti-phosphatidylserine therapies. 
4. 
Known microsatellite instability-high (MSI-H) gastric or GEJ adenocarcinoma 
5. 
Medical history of myocardial infarction within 6 months before registration, 
symptomatic congestive heart failure (CHF) (New York Heart Association Class II to 
IV; Appendix C), troponin levels consistent with myocardial infarction as defined 
according to American College of Cardiologists (ACC) guidelines, unstable angina, or 
serious cardiac arrhythmia requiring treatment. 
6. 
Experienced weight loss >10% over 2 months prior to first dose of study treatment. 
7. 
History of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
8. 
Has known active CNS metastases/and or carcinomatous meningitis,  
Subjects with previously treated brain metastases may participate provided they are 
stable without evidence of progression via imaging for at least four weeks prior to first 
dose of study, and no evidence of neurological symptoms. Carcinomatous meningitis 
is excluded regardless of clinical stability. 
9. 
Known additional malignancy that is progressing or has required active treatment in 
within the past 3 years.  
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded. 
10. An active infection requiring systemic therapy 
11. Known human immunodeficiency virus (HIV) infection or known acute hepatitis B or 
C infection.  


 
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12. Unresolved toxicities from previous cancer treatments (other than alopecia) not yet 
resolved to Grade ≤ 1 or baseline. Grade 2 toxicities may be eligible at the discretion 
of the Investigator after consultation with the Sponsor’s medical monitor. 
13. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator. 
14. Active autoimmune disease or history of chronic recurrent autoimmune disease, 
requiring systemic treatment for the past two years (i.e. Disease modifying agents, 
corticosteroids or immunosuppressive drugs).  
• Replacement therapy (thyroxine, insulin, or physiological corticosteroid 
replacement for either adrenal or pituitary insufficiency) is not considered a 
form of systemic treatment. 
15. History of hypersensitivity to pembrolizumab and/or any of its excipients that in the 
opinion of the investigator suggests a high risk for a severe hypersensitivity reaction 
while on treatment.  
16. History of infusion reactions to any component/excipient of bavituximab. 
17. History of hypersensitivity to mAbs that in the opinion of the investigator suggests a 
high risk for a severe hypersensitivity reaction while on treatment. 
18. Systemic steroid therapy (>10 mg daily prednisone or equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment 
(note: topical, inhaled, nasal and ophthalmic steroids are permitted). 
19. Has received a live vaccine within 30 days prior to first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, 
rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin 
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(e.g., FluMist®) are live attenuated vaccines and are not allowed. 
20. Prior organ transplantation including allogeneic or autologous stem-cell 
transplantation. 
21. Currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
treatment. 
Note:  Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent. 
22. Receipt of treatment with immunotherapy, biological therapies, or therapeutic doses of 
hormonal therapies within 3 weeks of scheduled C1D1 dosing. 
23. Known psychiatric, substance abuse disorder, or geographical travel limitations that 
would interfere with participant’s ability to cooperate with the requirements of the 
study. 


 
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24. Pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 5 months after 
the last dose of study treatment. 
 
Investigational Medicinal Product (IMP), Dose, and Mode of Administration:  
Bavituximab is supplied as a sterile, preservative-free solution with a composition of 
bavituximab, in 10 mM acetate, pH 5.0. It is provided in borosilicate Type 1 glass vials 120 
mg/5mL (24 mg/mL) stored at 2°C to 8°C.  
Dosage is calculated at 0.125 mL/kg body weight and diluted with normal saline to a volume 
of no less than 100 mL. Administer as IV with in-line 0.2 m filter over 90 minutes once 
weekly. After the 1st infusion, in the absence of Grade 2 or greater hypersensitivity reactions, 
the infusion time will be reduced to 60 minutes. After the 2nd infusion, in the absence of Grade 
2 or greater hypersensitivity reactions, the infusion time will be reduced to 30 minutes. 
Pembrolizumab will be administered as 200 mg IV on Day 1 Q3W. Refer to pembrolizumab 
administration section for more details.  
The doses of bavituximab will be adjusted or interrupted as appropriate based on treatment 
modifications defined in the protocol. 
No dose reductions of pembrolizumab are permitted. Doses will be withheld as appropriate 
based on treatment modifications defined in the protocol. 
Duration of Treatment:  
Treatment may be continued until one of the following criteria applies: 
• Progressive disease (PD): In patients with PD, a confirmatory scan will be performed 
at least 4 weeks later to confirm PD prior to removing the patient from study 
treatment. 
• Intervening illness that prevents further administration of treatment. 
• Unacceptable AEs. 
• The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication. 
Discontinuation from study treatment will occur prior to introduction of the new 
agent. 
• Significant patient non-compliance with the protocol. 
• Received 35 cycles of pembrolizumab.  
• Pregnancy. 
• Patient decision to withdraw from the study. 
• Investigator decision to withdraw the patient from the study. 
• Patient is lost to follow up. 
• Sponsor decision to end the study. 


 
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Pharmacokinetics of bavituximab: Peripheral venous blood (4 mL) will be collected from 
all patients during Cycle 1 on Days 1 and 15 within 24 hours prior to bavituximab infusion, 
and at 1 hour (± 30 minutes) after the end of bavituximab infusion. Samples are also collected 
within 24 hours prior to bavituximab infusion on Cycle 2 Days 1 and 15, and Day 1 of Cycles 
3, 4, and 6 for quantitation of bavituximab. 
Biomarkers:  
Peripheral blood and tumor tissue will be collected for biomarker analysis. Tissue will be 
obtained prior to therapy (mandatory fresh tumor biopsy and, if available, archival sample) 
and this tissue will be used to measure potential tissue-based predictive biomarkers. Those 
biomarkers include immunohistochemistry (IHC) as well as RNA signatures. Residual 
sample material available after completion of the designated analyses may be used in the 
future for identification of predictive markers or to enhance understanding of disease biology 
unless prohibited by local laws or regulations. Samples will be de-identified to ensure patient 
privacy. Serum will be collected at baseline and at timepoints post treatment as specified in 
the protocol to assess circulating pharmacodynamic biomarkers. 
Statistical Methods: 
The trial will evaluate safety and efficacy of the bavituximab-pembrolizumab combination in 
a disease setting in which pembrolizumab has shown promising but modest activity. The 
hypothesis to be evaluated is whether the bavituximab-pembrolizumab combination will yield 
an ORR superior to historical ORR of pembrolizumab in the 2nd-line setting in patients who 
have not previously been exposed to an anti-PD-1 or anti-PD-L1 agent. 
Sample Size: 
The primary efficacy objective of this Phase 2 study is the evaluation of ORR of bavituximab 
in combination with pembrolizumab in patients with advanced gastric or GEJ cancer. The 
overall sample size of 80 patients was chosen to yield adequate information regarding 
efficacy at the recommended dose and to allow an initial correlation of the preliminary 
efficacy with biomarker profiles. This includes patients enrolled in both Group 1 and 
Group 2. Both 2nd and 3rd line patients will be enrolled with no cap on either line of treatment 
of patients. The 2nd line cohort will have 72% to 86% power to show that the lower bound of 
the 80% CI is greater than 15% for 30-50 patients is the with a true ORR of 30%, and the 3rd 
line cohort will have 67% to 78% power to show that the lower bound of the 80% CI is 
greater than 6% for 30-50 patients is the with a true ORR of 15%.   
For Group 1 (CPI naïve),approximately 40 patients are needed to show a statistical 
superiority of bavituximab-pembrolizumab with 80% statistical power at one-sided type I 
error rate of α=0.10. For the CPI-relpase patient population, the n was set to 20 patients for 
the initial assessment of safety, tolerability and initial antitumor activity.  See the statistical 
section of the protocol for further detail. 
Criteria for Evaluation: 
Safety  
All patients who receive at least 1 dose of study treatment will be included in the safety 
analyses (safety analysis set). DLT evaluable set will be included for the first 3 patients up to 


 
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a maximum of 10 patients who have received at least 1 dose and completed 1 full cycle 
follow up or experienced a DLT. 
The safety and tolerability of study treatment will be evaluated based on AEs (incidence and 
severity), performance status, physical examinations, vital sign measurements, standard 
clinical laboratory safety evaluations. Laboratory abnormalities and AEs will be graded 
according to CTCAE v5.0. Immune-related reactions (IRRs) may occur with bavituximab 
and/or pembrolizumab. Detailed guidance for the handling of IRRs will be presented in the 
protocol. 
Pharmacokinetics 
Serum concentrations for bavituximab will be listed and summarized using descriptive 
statistics by cohort at each time point.   
Immunogenicity 
The immunogenicity of bavituximab (ADA formation) will be investigated during the course 
of the study. 
Efficacy 
Efficacy analysis will be performed on the full analysis set, and per protocol analysis set, 
including predefined biomarker subgroups (as below). Radiological and clinical tumor 
assessments will be evaluated based on RECIST version1.1. For patients with PD, a 
confirmatory scan will be performed at least 4 weeks later to confirm PD prior to removing 
the patient from study treatment. This confirmatory scan is recommended but not required, it 
is at the discretion of the treating physician. 
Statistical Methods: 
Tabular summaries of data will be descriptive in nature (i.e., number of patients [n], mean, 
standard deviation, median, minimum and maximum for continuous variables and n and 
percent for categorical variables). A more detailed description of analysis methods will be 
provided in the statistical analysis plan (SAP) to be completed prior to the clinical database 
lock. 


 
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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE ......................................................................2 
PROTOCOL ACCEPTANCE FORM .........................................................................................3 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ............................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................21 
1. 
INTRODUCTION ..............................................................................................................26 
1.1. Overview of Bavituximab ...............................................................................................26 
1.1.1. Nonclinical Experience with Bavituximab ..........................................................27 
1.1.2. Clinical Experience with Bavituximab ................................................................27 
1.1.3. Rationale for Study and Starting Dose of Bavituximab ......................................28 
1.2. Overview of Pembrolizumab ...........................................................................................28 
1.2.1. Pharmaceutical and Therapeutic Background .....................................................29 
1.2.2. Non-clinical and Clinical Trials ..........................................................................29 
1.2.3. Justification for Dose ...........................................................................................30 
1.3. Rationale for Combining Bavituximab with Pembrolizumab .........................................31 
1.4. Benefit-Risk Assessment .................................................................................................32 
2. 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................33 
3. 
INVESTIGATIONAL PLAN ............................................................................................34 
3.1. Overall Study Design ......................................................................................................34 
3.2. Study Duration .................................................................................................................35 
4. 
STUDY POPULATION .....................................................................................................36 
4.1. Number of Patients ..........................................................................................................36 
4.2. Patient Inclusion Criteria .................................................................................................36 
4.3. Patient Exclusion Criteria ................................................................................................38 
4.4. Patients or Partners of Patients of Reproductive Potential ..............................................40 
4.5. Waivers of Inclusion/Exclusion Criteria .........................................................................41 
4.6. Criteria for Treatment Discontinuation ...........................................................................41 
5. 
DESCRIPTION OF STUDY TREATMENT ..................................................................43 
5.1. Doses and Schedule of Administration ...........................................................................43 
5.2. Description of Bavituximab ............................................................................................44 
5.3. Description of Pembrolizumab ........................................................................................44 
5.4. Method of Assigning Patients to Treatment Groups .......................................................44 
5.5. Preparation and Administration of Study Treatment .......................................................44 
5.5.1. Bavituximab ........................................................................................................44 
5.5.2. Pembrolizumab ....................................................................................................45 
5.6. DLT Dose De-escalation/Modification ...........................................................................45 
5.6.1. Definition of Dose-Limiting Toxicities ...............................................................46 
5.7. Dose Modification Guidelines .........................................................................................48 


 
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5.8. Treatment Compliance ....................................................................................................48 
5.9. Study Drug Accountability ..............................................................................................48 
5.10. Concomitant Medications ...........................................................................................49 
5.11. Premedication for Infusion Reactions ........................................................................49 
5.12. Corticosteroid Use ......................................................................................................49 
5.13. Hematopoietic Growth Factor and Blood Products ....................................................49 
5.14. Prohibited Therapies ...................................................................................................49 
5.15. Treatment of Overdose ...............................................................................................50 
6. 
MONITORING AND MANAGEMENT OF EXPECTED OR POTENTIAL 
TREATMENT-RELATED TOXICITY .................................................................52 
6.1. Patient Monitoring ...........................................................................................................52 
6.2. Management of Infusion Reactions – Bavituximab and Pembrolizumab .......................52 
6.3. Bavituximab Expected or Potential Treatment-related Toxicities ..................................56 
6.3.1. Management of Thromboembolic Events ...........................................................56 
6.3.2. Management of Other Adverse Events ................................................................56 
6.4. Dose modification and toxicity management for immune-related AEs 
associated with pembrolizumab ...............................................................................56 
7. 
STUDY ASSESSMENTS ...................................................................................................62 
7.1. Summary of Assessments ................................................................................................67 
7.1.1. Screening .............................................................................................................67 
7.1.2. Treatment Phase ..................................................................................................68 
7.1.3. Post – Treatment Follow-up Phase ......................................................................69 
7.1.3.1. End of Treatment .......................................................................................69 
7.1.3.2. 30-Day Safety Follow-Up Visit .................................................................69 
7.1.3.3. Survival Follow-up ....................................................................................69 
7.1.4. Beginning and End of the Trial ...........................................................................69 
7.1.5. Informed Consent ................................................................................................69 
7.1.6. Ethical Review .....................................................................................................70 
7.1.7. Adverse Event Assessment ..................................................................................70 
7.1.8. Inclusion/Exclusion Criteria ................................................................................70 
7.1.9. Demographic/Medical History/Prior Treatments ................................................70 
7.1.10. Vital Signs ...........................................................................................................71 
7.1.11. Weight and Height ...............................................................................................71 
7.1.12. Full Physical Examination ...................................................................................71 
7.1.13. Directed Physical Exam ......................................................................................71 
7.1.14. ECOG Performance Status ..................................................................................71 
7.1.15. 12-Lead Electrocardiogram .................................................................................71 
7.1.16. Laboratory Assessments ......................................................................................71 
7.1.17. Pregnancy Test ....................................................................................................72 
7.2. Efficacy Assessments ......................................................................................................73 
7.2.1. Tumor Assessments .............................................................................................73 
7.2.1.1. Baseline Tumor Imaging............................................................................73 
7.2.1.2. Tumor Imaging During Trial .....................................................................73 
7.2.1.3. Timing of Repeat Imaging .........................................................................74 
7.3. Immunogenicity Assessments .........................................................................................74 


 
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7.3.1. Antidrug Antibody Assessments .........................................................................74 
7.4. Pharmacokinetic Assessments .........................................................................................74 
7.4.1. Blood Sample Collection .....................................................................................74 
7.4.2. Sample Analysis ..................................................................................................75 
7.5. Biomarker Assessments ...................................................................................................75 
7.5.1. Tumor Biopsies ...................................................................................................75 
7.5.2. Biomarker Blood Samples ...................................................................................76 
8. 
ADVERSE EVENT MANAGEMENT .............................................................................76 
8.1. Definition of Adverse Events ..........................................................................................76 
8.1.1. Adverse Event (AE) ............................................................................................76 
8.1.2. Serious Adverse Event (SAE) .............................................................................76 
8.2. Clarifications to Serious Adverse Event Reporting .........................................................76 
8.3. Assessment of Causality ..................................................................................................77 
8.4. Assessment of Severity ....................................................................................................78 
8.5. Pregnancy or Drug Exposure during Pregnancy .............................................................78 
8.6. Laboratory Abnormalities ...............................................................................................79 
8.7. Reporting Adverse Events ...............................................................................................79 
8.8. Adverse Events of Special Interest (Immediately Reportable to the Sponsor) ...............80 
9. 
STATISTICS ......................................................................................................................81 
9.1. Sample Size .....................................................................................................................81 
9.2. Analysis Populations .......................................................................................................82 
9.3. Statistical Analyses ..........................................................................................................83 
9.3.1. Safety Analyses ...................................................................................................83 
9.3.2. Pharmacokinetic/Pharmacodynamic Analyses ....................................................84 
9.3.3. Efficacy Analyses ................................................................................................84 
9.3.4. Primary Analysis .................................................................................................84 
9.3.5. Other Analyses ....................................................................................................85 
9.3.5.1. Patient Characteristics ................................................................................85 
9.3.5.2. Poststudy-Treatment-Discontinuation Therapy .........................................85 
9.3.5.3. Treatment Compliance ...............................................................................85 
9.3.5.4. Interim Analysis .........................................................................................85 
9.4. Statistical Methods ..........................................................................................................86 
10. 
STUDY ADMINISTRATION ...........................................................................................87 
10.1. Regulatory and Ethical Considerations ......................................................................87 
10.1.1. Regulatory Authority Approvals .........................................................................87 
10.1.2. Institutional Review Board/Ethics Committees ..................................................87 
10.2. Confidentiality of Information ....................................................................................88 
10.3. Patient Informed Consent ...........................................................................................88 
10.4. Study Monitoring ........................................................................................................88 
10.5. Electronic Case Report Form (eCRF) .........................................................................89 
10.6. Study Termination and Site Closure ...........................................................................89 
10.7. Modification of the Study Protocol ............................................................................90 
10.8. Retention of Study Documents ...................................................................................90 
10.9. Clinical Study Report .................................................................................................90 


 
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10.10. 
Study Publication .....................................................................................................91 
10.11. 
Quality Assurance Audits .........................................................................................91 
11. 
REFERENCES ...................................................................................................................92 
12 
APPENDICES ....................................................................................................................95 
 


 
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LIST OF TABLES 
Table 1: 
Doses and Schedule of Administration .......................................................................43 
Table 2: 
Dose Interruption for Dose-Limiting Toxicity During the DLT Observation 
Period ..........................................................................................................................45 
Table 3: 
Planned Dose Levels ...................................................................................................46 
Table 4: 
Definition of Infusion-Related Reactions (IRRs) .......................................................53 
Table 5: 
Management of IRRs Induced by Bavituximab or Pembrolizumab ...........................54 
Table 6: 
Bavituximab Dose Reductions for Treatment-Related Adverse Events .....................56 
Table 7: 
Management of Potential Pembrolizumab Toxicities .................................................58 
Table 8: 
Schedule of Assessments ............................................................................................63 
Table 9: 
Pharmacokinetic/Pharmacodynamic/Biomarker Blood Sample Specific 
Collections – Collection Times ..................................................................................66 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations are used in this study protocol. 
Abbreviations and Definitions of Terms 
Abbreviation or Specialist Term 
Explanation 
ACC 
American College of Cardiologists 
ADA 
Antidrug antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve  
BCG 
Bacille Calmette-Guerin 
β2-GP1 
β2-glycoprotein 1  
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CD8 
Cluster of differentiation 8, a co-receptor for the T-cell 
receptor 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CK 
Creatine kinase 
Cmax 
Maximum concentration 
CMP 
Complete metabolic panel 
CNS 
Central Nervous System  
COPD 
Chronic obstructive pulmonary disease 
CR 
Complete response 
CT 
Computerized tomography (scan) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-Lymphocyte Associated Protein 4 


 
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Abbreviation or Specialist Term 
Explanation 
Ctrough 
Lowest dose concentration prior to the next dose  
DCR 
Disease control rate 
DILI 
Drug-induced Liver Injury 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EOI 
End of infusion 
EOT 
End of treatment 
FoxP3 
Forkhead box p3, a marker for regulatory T-cells 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
3G4 
Mouse IgG3 mAb that specifically targets anionic 
phospholipids  
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal junction 
GFR 
Glomerular filtration rate  
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HER2 
Human epidermal growth factor receptor 2 
HGB 
Hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
HR 
Heart rate or Hazard Ratio 


 
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Abbreviation or Specialist Term 
Explanation 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IgG1 
immunoglobulin gamma 1-kappa (IgG1)κ 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IUD 
Intrauterine device 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LMWH 
Low-molecular-weight heparin 
mAb 
Monoclonal antibody 
mch1N11 
Mouse chimeric 1N11 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDSC 
Myeloid-derived suppressor cell 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MSI-H 
High microsatellite instability 
N 
Number 
NCI  
National Cancer Institute  
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease OR pharmacodynamics 
PD-1 
Programmed cell death protein 1 


 
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Abbreviation or Specialist Term 
Explanation 
PD-L1 
Programmed death-ligand 1 
PD-L2 
Programmed death-ligand 2 
PE 
Physical exam 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Prescribing Information 
PK 
Pharmacokinetics 
PLT 
Platelets 
PO 
Orally 
PR 
Partial response 
PS 
Phosphatidylserine OR Performance Status 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Q3W 
Every 3 weeks 
RBC 
Red blood cells 
RDE 
Recommended dose for expansion 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SOC 
System organ class 
SRC 
Safety Review Committee 
SUSAR 
Serious Unexpected serious adverse reaction 
T 
Temperature  
TAM 
Tumor-associated macrophages 
T Cell 
T lymphocyte  
TGF-ß 
Transforming growth factor-beta 
TIL 
Tumor infiltrating lymphocytes 
TIM3 
T cell immunoglobulin and mucin domain 3 
TMDD 
Target-mediated drug disposition 


 
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Abbreviation or Specialist Term 
Explanation 
TNBC 
Triple negative breast cancer 
TNF-α 
Tumor necrosis factor-alpha 
T-regs 
Regulatory T-cells 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
ZAP70 
Zeta-chain-associated protein kinase 


 
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1. 
INTRODUCTION 
1.1. 
Overview of Bavituximab 
Oncologie, Inc. is developing bavituximab as an immunomodulatory drug for the treatment of 
cancer. 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). 
In normal non-tumorigenic cells, PS is segregated to the inner leaflet of the plasma membrane. 
Conditions that induce cellular stress, including normal cell death, immune phagocytic cell 
clearance, oxygen radicals, hypoxia, irradiation, and chemotherapy, cause a shift resulting in the 
externalization of PS to the outer leaflet of the plasma membrane. Exposed PS is recognized and 
bound by PS receptors on immune cells where it induces and maintains immune suppression. 
This relocation also occurs in tumor cells, exosomes, and vascular endothelial cells inducing 
non-inflammatory signals via multiple receptors which contribute to the immunosuppression of 
the tumor microenvironment, including binding to TIM/TAM receptors. Phosphatidylserine-
targeting agents block PS-mediated immunosuppression by multifocal reprograming of the 
immune cells in the tumor microenvironment to support immune reactivation. Antibody-
mediated PS blockade reduces the levels of myeloid-derived suppressor cells (MDSCs), 
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, and induces potent adaptive antitumor T-cell 
immunity. In vitro 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 
mouse cancer models, the bavituximab surrogate antibody mch1N11 as a single agent reduced 
tumor growth and prolonged survival. In addition, the anti-tumor effects of mch1N11 were 
enhanced by co-administration of checkpoint inhibitors (anti- Cytotoxic T-Lymphocyte Associated 
Protein 4 (CTLA4) and anti-PD-1/L1), as well as chemotherapy or radiation (Yin et al., 2013a; 
Yin et al., 2013b). 
Bavituximab is an attractive immunotherapeutic approach to treating cancer, because its primary 
mechanism of action involves modulating the tumor microenvironment from a primarily 
immunosuppressive, angiogenesis-promoting state (with infiltrating 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). 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, thus allowing tumor growth and 
progression. Exposing PS on the external surface of the cell provides a rich source of ligand for 
multiple immune receptors expressed on immune cells present in the microenvironment, 
including PS binding to T cell immunoglobulin and mucin domain 3 (TIM3) receptors.  
Nonclinical data suggest that bavituximab and pembrolizumab can be co-administered 
effectively as demonstrated in murine models for melanoma and triple negative breast cancer. 
Combining PS-targeting antibody mch1N11 with a single dose of radiotherapy and anti-
programmed cell death protein 1 (PD-1) blocking antibody, a triple therapy combination, to treat 


 
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mice bearing PD-1 resistant melanoma, results in almost complete tumor elimination and leads to 
statistically significant prolonged survival (Giese et al., 2018). 
Gray et al. (2016) demonstrated that immune-competent mice implanted with triple negative 
breast cancer (TNBC) cell lines and treated with a combination of the PS-targeting antibody 
mch1N11 and anti-PD-1 antibody therapy had significantly greater inhibitory tumor growth 
activity and significantly increased overall survival compared with either single treatment alone, 
and is capable of causing complete tumor regression. Additionally, mice treated with the 
combination experienced complete tumor regression, demonstrated increased splenic IFNγ 
production and enhanced number of tumor infiltrating lymphocytes (TILs). Furthermore, on 
TNBC re-challenge those treated with the combinations were capable of mounting a durable 
immune response that suppressed tumor growth. 
Bavituximab has been administered to 800 patients in early and late phase studies. Initial 
indication of activity for bavituximab as monotherapy or in combination with chemotherapy is 
noted in phase 2 trials for breast cancer, non-small cell lung cancer (NSCLC) and pancreatic 
cancer. A Phase 3 advanced NSCLC trial, SUNRISE, was completed.  The primary endpoint of 
improved overall survival (OS) in bavituximab plus docetaxel versus docetaxel plus placebo was 
not met. However, subgroup analysis indicated that patients who progressed on study treatment 
with bavituximab plus docetaxel and went onto a checkpoint inhibitor showed significantly 
improved OS compared to a similar group of patients with progressive disease (PD) post 
docetaxel plus placebo who went onto receive a checkpoint inhibitor.  
1.1.1. 
Nonclinical Experience with Bavituximab 
In nonclinical studies, no target organs of toxicity were identified in rats and monkeys receiving 
doses of bavituximab of up to 100 mg/kg. Incidental minimal histological findings were noted in 
heart and lungs in high-dose monkeys and included left ventricular thrombus, right ventricular 
subendocardial fibrosis and arteriopathy, and fibrosis in the lung. In rats, subendocardial 
inflammation was noted in the high-dose group. Bavituximab has been associated with 
immunogenicity in rats and monkeys. A dose-related prolongation of aPTT in rats and of aPTT 
and PT in monkeys has been demonstrated to be an in vitro phenomenon due to inhibition of 
phospholipid-dependent coagulation assays. Bavituximab up to 100 mg/kg did not affect time-to-
healing in dermal healing rodent models. 
Refer to the bavituximab Investigator’s Brochure (IB) for detailed nonclinical data. 
1.1.2. 
Clinical Experience with Bavituximab 
Phase 1 (single agent, safety, and pharmacokinetic [PK]) and Phase 1b (safety, tolerability, and 
PK) studies of bavituximab in combination with chemotherapy have been completed in patients 
with advanced cancer. Several Phase 2 studies of bavituximab with chemotherapy have been 
completed, including safety and efficacy studies in patients with locally or advanced metastatic 
cancers. These studies include patients with NSCLC, previously treated or untreated non-
squamous NSCLC, breast cancer, and previously untreated Stage 4 pancreatic cancer. A Phase 3 
clinical trial to evaluate the efficacy and safety of bavituximab when given with docetaxel in 
patients with previously treated Stage 3b/4 non-squamous NSCLC was discontinued following a 
pre-specified interim analysis. Addition of bavituximab to docetaxel did not improve OS in 
previously treated advanced NSCLC. Subset analyses suggested possible benefit in high β2GP1 


 
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cases and those subsequently receiving immune checkpoint inhibitors. Current development of 
bavituximab is focused on the combination of bavituximab with other therapeutic approaches 
including radiation and immunotherapies.  
Across all studies, the profile of serious adverse events (SAEs) in subjects receiving bavituximab 
in combination with chemotherapy or an antiviral was similar to those receiving chemotherapy 
alone. The most common SAEs were febrile neutropenia (4.6%), neutropenia (4.0%), pneumonia 
(2.7%), and pulmonary embolism (2.0%), anemia (1.6%), pyrexia (1.6%), dyspnea (1.1%), deep 
vein thrombosis (1.3%), asthenia (1.2%), diarrhea (1.0%), fatigue (1.0%), and sepsis (1.0%). The 
only events that occurred at a meaningfully higher frequency (increase by >1.0%) in subjects 
receiving bavituximab in combination with chemotherapy compared to those receiving 
chemotherapy alone were febrile neutropenia, neutropenia, and anemia. These events were not 
observed in the small group of patients receiving bavituximab monotherapy. 
Infusion reactions and similar events (e.g. hypersensitivity reactions and anaphylaxis) have 
occurred in association with bavituximab administration and are a known class effect of chimeric 
mAbs. These types of reactions have occurred more commonly in oncology studies in which 
chemotherapy is also administered, but have also occurred in monotherapy studies in both the 
antiviral and oncology programs. The highest incidence was in Study PPHM 0704, a study 
conducted in the Republic of Georgia in which patients with advanced breast cancer also 
received docetaxel therapy. All reactions in that study were mild or moderate in severity, and 
patients were able to continue to receive bavituximab without an apparent increase (or decrease) 
in the frequency or severity of the reactions. It is unclear what impact, if any, that the 
concomitant chemotherapy, patient characteristics, or environment had on the frequency of 
events in this study.  
Grade 3 infusion reactions have occurred in other studies, resulting in discontinuation of patients 
from treatment with bavituximab. Infusion reactions have occurred both with and without 
premedication, and it is unclear whether the type of co-administered chemotherapy or 
premedication with steroids and antihistamines impacts the frequency or severity of infusion 
reactions. Reports of infusion reactions will continue to be monitored.  
Refer to the bavituximab IB for detailed clinical data. 
1.1.3. 
 Rationale for Study and Starting Dose of Bavituximab 
The approved dose and schedule of pembrolizumab will be used in this trial in combination with 
the recommended dose of bavituximab for Phase 2 and Phase 3 development. No overlapping 
toxicities are expected, and the Safety Review Committee (SRC) will review emerging data 
during the conduct of the trial.   
1.2. 
Overview of Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
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indications. For more details on specific indications and background information, refer to the 
Investigator’s Brochure/approved labeling for pembrolizumab. 
1.2.1. 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma [Dudley et al., 2005; Hunder et al., 2008]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald et al., 2005; Okazaki et al., 2001]. 
The structure of murine PD-1 has been resolved [Zhang et al., 2004]. PD-1 and its family members 
are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch 
motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), 
and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling 
cascade [Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 2009]. 
The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct from, 
that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins [Parry 
et al., 2005; Francisco, 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive target 
for therapeutic intervention in gastric and gastroesophageal junction (GEJ) adenocarcinoma.  
1.2.2. 
Non-clinical and Clinical Trials 
 
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to 
tumor rejection, either as a monotherapy or in combination with other treatment modalities 
[Hirano, 2005; Blank, 2004;Weber, 2010; Strome, 2003; Spranger, 2014; Curran, 2010; Pilon, 
2010].  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor responses 
in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia 
and colorectal carcinoma [Strome, 2003; Curran, 2010; Pilon, 2010; Nomi, 2007; Zhang, 2004].  
In such studies, tumor infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin 


 
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expression were observed, indicating that the mechanism underlying the antitumor activity of PD-
1 checkpoint inhibition involved local infiltration and activation of effector T cell function in vivo 
[Curran, 2010]. Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as 
a monotherapy, as well as in combination with chemotherapy, in syngeneic mouse tumor models 
(see the Investigator’s Brochure [IB]). 
1.2.3. 
Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied. Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics, and given that fixed-dose has advantages of reduced dosing complexity 


 
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and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
 
1.3. 
Rationale for Combining Bavituximab with Pembrolizumab 
Pembrolizumab was recently approved in the US and other countries for later line treatment of 
recurrent or advanced gastric or GEJ adenocarcinoma based on the KEYNOTE 059 in which 
patients received 200 mg pembrolizumab intravenously (IV) every 3 weeks until disease 
progression, Investigator or patient decision to withdraw, or unacceptable toxicity. A total of 259 
patients were enrolled; most were male (198 [76.4%]) and white (200 [77.2%]). The median 
(range) age was 62 (24-89) years. Objective response rate (ORR) was 11.6% (95%CI, 8.0%-
16.1%; 30 of 259 patients), with complete response (CR) in 2.3% (95%CI, 0.9%-5.0%; 6 of 259 
patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months. ORR and median 
(range) response duration were 15.5% (95%CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ 
to 17.3+) months, and 6.4% (95%CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) 
months in patients with PD-L1–positive and PD-L1–negative tumors, respectively. Forty-six 
patients (17.8%) experienced 1 or more Grade 3 to 5 treatment-related adverse events (AEs). 
Based on these results, albeit positive for gastric cancer patients but still suboptimal in this 
aggressive disease, and pembrolizumab’s manageable safety profile, pembrolizumab will be a 
rationale combination for the treatment of gastric cancer.  In addition, KEYNOTE 061 
pembrolizumab versus paclitaxel, pembrolizumab did not significantly improve overall survival 
compared with paclitaxel as second-line therapy for advanced gastric or gastro-esophageal 
junction cancer with PD-L1 CPS of 1 or higher, although a better safety profile than paclitaxel 
was identified.   Median overall survival was 9·1 months (95% CI 6·2 –10·7) with 
pembrolizumab and 8·3 months (7·6 –9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66 –
1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4 –2·0) 
with pembrolizumab and 4·1 months (3·1 –4·2) with paclitaxel (HR 1·27, 95% CI 1·03 –
1·57). The ORR in these patients was 13.3% (95% CI, 8.2-20.0), including a complete response 
(CR) rate of 1.4% and a partial response (PR) rate of 11.9%. 
Pembrolizumab has received accelerated approval for the treatment of 3rd-line (plus) gastric/GEJ 
cancer. However, the ORR was 11.6% (95% CI, 8.0%, 16.1%), implying that the majority of 
such patients fail to derive sufficient benefit from pembrolizumab monotherapy. In experimental 
mouse cancer models, the bavituximab surrogate antibody used in combination with an anti-
PD-1/L1 antibody demonstrated enhanced tumor control. Bavituximab has also demonstrated a 
tolerable safety profile. Thus, little to no overlapping toxicities are anticipated. The SUNRISE 
subgroup analysis indicated that patients who progressed on study treatment with bavituximab 
plus docetaxel and went onto a checkpoint inhibitor showed significantly improved OS. These 
data in combination with the preclinical data suggest that bavituximab may restimulate T cells or 
render exhausted T cells susceptible to checkpoint inhibition. Therefore, we hypothesize the 
addition of bavituximab to pembrolizumab may enhance the antitumor immune response and 
eventually potentiate the activity of the antibody that is already targeting checkpoint inhibition, 
resulting in increased clinical benefit. 
Given the potential for this combination to enhance antitumor responses, it is being evaluated in 
2 populations of advanced gastric or GEJ cancer patients: CPI naïve patients that have 


 
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progressed on standard chemotherapy and are naïve to CPI therapy; and CPI relapse patients that 
had a confirmed PR or CR then subsequently progressed following treatment with CPI either 
alone or in combination with chemotherapy. 
1.4. 
Benefit-Risk Assessment 
Clinical trials in cancer are designed to assess new therapeutic strategies that may provide greater 
benefit, less toxicity or both than those of existing therapies. This trial is an initial attempt to 
understand the activity and safety profile of an approved agent for gastric/GEJ cancer when used 
in combination with an experimental agent that has shown promise in preclinical testing. 
However, subjects enrolled in clinical trials cannot expect to receive direct benefit from this 
proposed combination.  
Common AEs observed with anti PD-1/PD-L1 agents include diarrhea/colitis, 
pneumonitis/interstitial lung disease (ILD), hepatitis and increases in transaminases, 
endocrinopathies (hypo- and hyper-thyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and Type 1 diabetes mellitus), myocarditis, nephritis and increases 
in serum creatinine, dermatitis/rash and pruritus, neuromuscular toxicity such as myasthenia 
gravis and Guillain-Barré, and pancreatitis.  
Emerging safety data from bavituximab trials, indicates that the overall safety profile appears to 
be acceptable and consistent across studies. Combination therapy, particularly with docetaxel, 
did not substantially increase the AE risks. Sporadic infusion reactions have occurred, and it is 
not clear if corticosteroid premedication mitigates this risk. Refer to the bavituximab IB for 
additional details. 
No patients have been treated with bavituximab and immune checkpoint inhibitors to date in 
Oncologie-sponsored trials. Overall, the potential additional benefits of the combination of 
bavituximab and pembrolizumab therapy are likely to outweigh the risks. 
 


 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
For both Group 1 and Group 2: 
Primary Objectives 
Primary Endpoints 
• To assess the safety and tolerability of 
bavituximab in combination with 
pembrolizumab in patients with 
advanced gastric/GEJ cancer 
• To assess the antitumor activity of the 
treatment combination based on 
Response Evaluation Criteria in Solid 
Tumors (RECIST) version1.1 
(Appendix A) 
• Incidence and severity of AEs and SAEs 
graded according to the National Cancer 
Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0, 
including changes in clinical laboratory 
parameters 
• Objective response rate (ORR) as assessed 
by the Investigator per RECIST version1.1 
Secondary Objectives 
Secondary Endpoints 
• To further characterize the antitumor 
activity of the treatment combination 
based on additional assessments of 
clinical benefit 
• To evaluate bavituximab 
concentrations when administered in 
combination with pembrolizumab 
• To assess the potential 
immunogenicity of bavituximab   
• Duration of response (DoR), disease control 
rate (DCR) (as defined by ORR and stable 
disease rate at 6 weeks), progression-free 
survival (PFS), and OS 
• Bavituxiamb concentrations before and after 
bavituximab infusions 
• Presence of anti-bavituximab antibodies 
(anti-drug antibodies [ADAs])  
Tertiary Objective 
Tertiary Endpoints 
• To evaluate a novel biomarker 
signature panel and correlate with 
efficacy outcomes in patients treated 
with bavituximab-pembrolizumab 
combination 
• Analysis of tissue to determine percentage 
of patients with defined genetic signature 
• Preliminary correlation of ORR to genetic 
signature 
• Status of genomic and immune biomarkers 
in blood and tissue samples at baseline and 
change from baseline upon treatment 
 


 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 2, multicenter, open-label, non-randomized study with an initial safety analysis to 
assess the safety and tolerability of bavituximab administered in combination with 
pembrolizumab, a PD-1 inhibitor, in patients with advanced gastric or GEJ adenocarcinoma who 
have either progressed on standard chemotherapy and are naïve to CPI therapy (Group 1), or had 
a confirmed PR or CR then subsequently progressed following treatment with CPI either alone or 
in combination with chemotherapy (Group 2).   
Following a minimum of 3 and a maximum of 10 patient safety run-in with bavituximab 
(3 mg/kg IV weekly) and pembrolizumab (200 mg IV every 3 weeks [Q3W]), additional patients 
will be recruited if the initial doses of the regimen are tolerable. Lower doses of bavituximab 
may be explored if the initial doses are not tolerable. Primary anti-tumor activity will be 
documented by Investigator-assessed objective response per RECIST 1.1. Approximately  80 
patients will be enrolled in the study, a minimum of 40 patients will be enrolled in Group 1 and a 
minimum of 20 patients will be enrolled in Group 2.  
The first 3 patients will be evaluated for dose-limiting toxicities (DLTs) for the purpose of 
declaring the tentative RDE. The SRC will review data from these patients for DLTs at the end 
of the first 3-week cycle.  
After a minimum of 3 and maximum of 10 eligible patients are enrolled and treated for at least 
1 cycle (3 weeks), the SRC will review data from these patients to determine the recommended 
dose for expansion (RDE). In case of DLTs, de-escalating doses of bavituximab in combination 
with pembrolizumab will be assessed (see Section 5.6). After the DLT observation period, 
expansion may proceed. The cumulative safety data from the initial 3 to 10 patients will be 
evaluated by the SRC, as well as subsequent safety data from the expansion population, as 
deemed appropriate by the SRC.  
Once the RDE of the combination of bavituximab and pembrolizumab has been confirmed, 
additional patients, for a total of 80 across both groups, will be enrolled in the expansion and 
assessed for preliminary efficacy and pharmacodynamic effects, as well as safety and 
tolerability. Patients will be evaluated regularly for safety and efficacy according to the Schedule 
of Assessments (Table 8). 
Safety data will be monitored throughout the course of the study including but not limited to; 
reviewing trends in safety data, laboratory analytes, and AEs including monitoring of adverse 
events of special interest (AESIs).  
The SRC, comprised of a medical monitor, statistician, the primary Investigator, and ad hoc SRC 
members, as needed, will be responsible for review of safety data. The SRC will convene 
regularly to review data to assess DLTs, and will convene at least yearly to review all safety 
data.  
Additional formal meetings for the SRC will occur  
(a) when a total of 10 patients have received at least one dose of study therapy and followed 
for 3 months after the 10th subject patient receives the first dose of study therapy and  


 
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(b) when a total of 40 patients have received at least one dose of study therapy and followed 
for 3 months after the 40th patient receives the first dose of study therapy   
Special attention will be paid for later-onset DLT-like toxicities.  
Patients will be assessed for tumor response/progression per RECIST version1.1 (Appendix A). 
The initial tumor assessment on study therapy will be conducted 6 weeks after initiation of 
treatment for, then every 6 weeks until disease progression or another withdrawal criterion is 
met. 
An End-of-Treatment Visit will be performed at the time of treatment discontinuation followed 
by a Safety Follow-Up Visit 30 days after the end of treatment. 
3.2. 
Study Duration 
Enrollment is planned to occur over approximately 13 months. Treatment and follow-up 
projected will be completed within approximately 6 months thereafter. The total anticipated 
duration of the study is at least 21 months. 


 
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4. 
STUDY POPULATION 
4.1. 
Number of Patients 
Up to approximately 80 patients are planned for inclusion in this study. A minimum of 
40 patients will be enrolled in Group 1 and a minimum of 20 patients will be enrolled in 
Group 2. 
4.2. 
Patient Inclusion Criteria 
Patients must meet all the following inclusion criteria to be enrolled.  
For Group 1 only (CPI naïve):  
1. Progressed on and/or after at least 1 prior regimen for metastatic disease which includes a 
fluoropyrimidine and a platinum therapy: 
• Progression within 6 months of prior adjuvant or neoadjuvant chemotherapy will be 
deemed a rapid progressor and thus, equivalent to 1 advanced/metastatic disease 
treatment regimen. 
• Changing from IV to oral fluoropyrimidine without noted progression is considered 
only 1 prior regimen. 
• Human epidermal growth factor receptor 2 (HER2)-positive patients must have 
received prior anti-HER2 therapy and demonstrate PD or was ineligible for such 
therapy. 
For Group 2 only (CPI relapse): 
2. Patient achieved stable disease or better in two consecutive scans to PD-1/PD-L1 inhibition 
alone or in combination with chemotherapy and relapsed following PD-1/PD-L1 inhibition 
either alone or in combination with chemotherapy 
• All patients must be immediate (defined by within 3 months) progressors of 
PD-1/PD-L1 inhibition with no intervening treatment with other agents such as 
chemotherapy alone.   
For both Group 1 and Group 2: 
3. Signed written informed consent obtained prior to performing any study procedure, including 
screening procedures. 
4. Men and women ≥ 18 years old; ≥ 20 years old in South Korea and Taiwan. 
5. Pathologically documented unresectable metastatic or locally advanced gastric or GEJ 
adenocarcinoma  
• Must be metastatic/unresectable at the time of enrollment into this study 
6. Willing and able to provide fresh (since most recent progression) formalin-fixed paraffin-
embedded tissue tumor sample for screening of signature status prior to study treatment and 
to measure PD-1 status. An archival tissue sample should also be provided, if available. 


 
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7. Presence of at least one measurable lesion assessed by the Investigator per RECIST version 
1.1. 
8. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. 
9. Has adequate organ functions defined as: 
System 
Laboratory valuea 
Hematological 
• Absolute neutrophil count (ANC) 
• 1.5 × 109/L 
• Platelets 
• 100 × 109/L 
• Hemoglobinb 
• ≥ 9.0 g/dL 
Renal 
• Dipstick or routine urinalysis 
o 
For proteinuria  2+ or urine 
protein/creatinine ratio  0.5, 24-hour 
urine must be collected 
• urine protein < 2 g/24 h 
• Creatinine, or 
• ≤ 1.5 × upper limit of normal (ULN) 
• Glomerular filtration rate (GFR) 
•  50 mL/min (see Appendix B) 
Hepatic 
• Total bilirubin 
• ≤ 1.5 × ULN (except for known Gilbert’s 
syndrome) 
• Aspartate transaminase (AST)/ alanine 
transaminase (ALT) 
• ≤ 2.5 × ULN for patients without liver 
metastases 
• ≤ 5 × ULN for patients with liver metastases 
Coagulation 
• International normalized ratio (INR) or 
prothrombin time (PT) 
• INR  1.5 × ULN or PT  5 sec above ULN, 
unless the patient is receiving anticoagulant 
therapy, as long as INR or PT is within 
therapeutic range of intended use of 
anticoagulantsc 
• Partial thromboplastin time (PTT) or activated 
partial thromboplastin time (aPTT) 
• PTT or aPTT  5 seconds above ULN, unless 
the patient is receiving anticoagulant therapy, 
as long as PTT or aPTT is within therapeutic 
range of intended use of anticoagulantsc 
a All labs will be performed, and values calculated per local institution standards. 
b Transfusion and/or erythropoietin therapy to increase the patient’s hemoglobin level is not permitted 
within 1 week prior to the baseline hematology profile. 
c Patients on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular 
weight heparin for  14 days. If receiving oral anticoagulant, the patient must have an INR  3.0, no 
active bleeding (that is, no bleeding within 14 days prior to first dose of study therapy), and no 
pathological condition with a high risk of bleeding (for example, tumor involving major vessels or 
known varices). 
 
10. Women of childbearing potential must have a negative serum or urine pregnancy test within 
72 hours prior to start of study treatment. 


 
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11. Women must not be breastfeeding. 
12. Women of childbearing potential defined as not surgically sterile or have not been free from 
menses for ≥ 2 years, must agree to follow instructions for highly effective method(s) of 
contraception as described in Section 4.4 Patients or Partners of Patients of Reproductive 
Potential for the duration of treatment with study drug bavituximab and pembrolizumab plus 
5 months post-treatment completion.   
Males who are sexually active with women of childbearing potential must agree to follow 
instructions for highly effective method(s) of contraception as described in Section 4.4 s or 
Partners of Patients of Reproductive Potential for the duration of treatment with study 
treatment plus 90 days post-treatment completion. 
13. Has adequate treatment washout period before start of study treatment, defined as: 
• Major surgery ≥ 4 weeks; radiation therapy with abdominal radiation ≥ 4 weeks and 
have recovered from all radiation-related toxicities, not require corticosteroids and 
not have had radiation pneumonitis; palliative radiation without abdominal radiation  
≥ 2 weeks; chemotherapy ≥ 3 weeks; biologic therapy ≥ 3 weeks. 
4.3. 
Patient Exclusion Criteria 
Patients who meet any of the following criteria may not be enrolled.  
For Group 1 only: 
1. Prior treatment with any checkpoint inhibitor or other therapies targeting T-cell control. 
For Group 2 only: 
2. Primary refractory patients, defined as disease progression at first scan following initiation of 
PD-1/PD-L1 inhibitor treatment, or if best overall response to PD-1/PD-L1 inhibition was 
disease progression. 
For both Group 1 and Group 2: 
3. Received any form of anti-phosphatidylserine therapies. 
4. Known MSI-H gastric or GEJ adenocarcinoma 
5. Medical history of myocardial infarction within 6 months before registration, symptomatic 
congestive heart failure (CHF) (New York Heart Association Class II to IV; Appendix C), 
troponin levels consistent with myocardial infarction as defined according to American 
College of Cardiologists (ACC) guidelines, unstable angina, or serious cardiac arrhythmia 
requiring treatment. 
6. Experienced weight loss >10% over 2 months prior to first dose of study treatment. 
7. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 
8. Known active CNS metastases and/or carcinomatous meningitis. Subjects with previously 
treated brain metastases may participate provided they are stable without evidence of 
progression via imaging for at least four weeks prior to first dose of study, and no evidence of 
neurological symptoms. Carcinomatous meningitis is excluded regardless of clinical stability. 


 
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9. Known additional malignancy that is progressing or has required active treatment in within 
the past 3 years.  
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone 
potentially curative therapy are not excluded. 
 
10. Active infection requiring systemic therapy. 
11. Known human immunodeficiency virus (HIV) infection, or known acute hepatitis B or C 
infection. 
12. Unresolved toxicities from previous cancer treatments (other than alopecia) not yet resolved 
to Grade ≤ 1 or baseline. Grade 2 toxicities may be eligible at the discretion of the 
Investigator after consultation with the Sponsor’s medical monitor. 
13. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the participant's participation for the full 
duration of the study, or is not in the best interest of the participant to participate, in the 
opinion of the treating investigator. 
14. Active autoimmune disease or history of chronic recurrent autoimmune disease, requiring 
systemic treatment for the past two years (i.e., disease modifying agents, corticosteroids, or 
immunosuppressive drugs).  
• Replacement therapy (thyroxine, insulin, or physiological corticosteroid 
replacement for either adrenal or pituitary insufficiency) is not considered a form 
of systemic treatment. 
15.  History of hypersensitivity to pembrolizumab and/or any of its excipients that in the opinion 
of the investigator suggests a high risk for a severe hypersensitivity reaction while on 
treatment. 
16. History of infusion reactions to any component/excipient of bavituximab. 
17.  History of a hypersensitivity to mAbs that in the opinion of the investigator suggests a high 
risk for a severe hypersensitivity reaction while on treatment. 
18. Systemic glucocorticoid therapy (>10 mg daily prednisone or equivalent) or any other form 
of immunosuppressive therapy within 7 days prior to the first dose of study treatment (note: 
topical, inhaled, nasal and ophthalmic steroids are permitted). 
19. Received a live vaccine within 30 days prior to the first dose of study drug. Examples of live 
vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed. 
 
20. Prior organ transplantation including allogeneic or autologous stem-cell transplantation. 


 
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21. Currently participating in or has participated in a study of an investigational agent or has used 
an investigational device within 4 weeks prior to the first dose of study treatment. 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational 
agent. 
22. Receipt of treatment with immunotherapy, biological therapies, or therapeutic doses of 
hormonal therapies within 3 weeks of scheduled C1D1 dosing. 
23. Known psychiatric, substance abuse disorder, or geographical travel limitations that would 
interfere participant’s ability to cooperate with the requirements of the study. 
24. Pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through 5 months after the last dose of 
study treatment. 
 
4.4. 
Patients or Partners of Patients of Reproductive Potential 
Pregnancy is an exclusion criterion and women of childbearing potential must not be considering 
getting pregnant during the study. 
It is unknown whether bavituximab or pembrolizumab is excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment. 
 
 Female patients of childbearing potential must have a negative serum or urine pregnancy test 
within 72 hours prior to start of study treatment. A serum or urine pregnancy test will be 
performed at the End-of-Treatment (EOT) Visit. 
To be considered of non-childbearing potential, a female patient must meet at least one of the 
following criteria: 
• Postmenopausal (i.e., amenorrheic for ≥ 2 years) AND a follicle-stimulating hormone 
(FSH) value within the institution’s post-menopausal range at screening 
• Hysterectomy OR bilateral oophorectomy 
• Tubal ligation at least 5 years prior to screening with no subsequent pregnancies 
Fertile female patients must practice a highly effective method of contraception during treatment 
and for 5 months following the last dose of study treatment. Highly effective contraception 
includes: 
• an intrauterine device (IUD; alone or in combination with other birth control) 
• bilateral tubal occlusion  
• vasectomized partner (provided that partner is the sole sexual partner of the woman of 
childbearing potential study participant and that the vasectomized partner has received 
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• sexual abstinence as defined as complete abstinence, acceptable only when it is the usual 
and preferred lifestyle of the patient; periodic abstinence (e.g., calendar, symptothermal, 
post-ovulation methods) is not acceptable 
• Combination of any 2 of the following (a + b or a + c or b + c) 
a) Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
< 1%) (e.g., hormone vaginal ring or transdermal hormone contraception) 
b) Placement of an intrauterine device or intrauterine system 
c) Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault cap) with spermicidal foam/gel/cream/vaginal suppository. 
Male patients with a female partner of childbearing potential must have either had a prior 
vasectomy with medical assessment of the surgical success or agree to double-barrier methods of 
contraception during treatment, and for 90 days after the last dose of either study treatment to 
allow for clearance of any altered sperm.  
Patients will be instructed to notify the Investigator if pregnancy is discovered either during or 
within 5 months of the last dose of study treatment.  
4.5. 
Waivers of Inclusion/Exclusion Criteria 
No waivers of these inclusion or exclusion criteria will be granted by the Investigator and the 
Sponsor or its designee for any patient enrolling into the study.  
No deviations from the protocol should be initiated without prior discussion with Sponsor and 
written Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval of an 
appropriate amendment, except when necessary to eliminate immediate hazards to the subjects. 
4.6. 
Criteria for Treatment Discontinuation 
Patients may withdraw voluntarily from participation in the study or from study treatment at any 
time and for any reason. A patient’s participation in the study may terminate at his/her request or 
on the basis of the Investigator’s clinical judgment. The reason for patient withdrawal will be 
documented in the source data and noted on the electronic case report form (eCRF). 
At a minimum, all patients who discontinue study treatment, including those who refuse to return 
for a final visit, will be contacted for safety evaluations at the 30-Day Safety Follow-up visit.  
If such withdrawal occurs, or if the patient fails to return for visits, the Investigator must 
determine the primary reason for a patient’s withdrawal from the study and record the 
information on the eCRF. If the reason for withdrawal is an AE, monitoring should continue 
until the outcome is evident. The specific event or test result(s) must be recorded in the eCRF. At 
the discretion of the Sponsor, patients may also be removed from the study. 
It should be clearly documented in the source data whether patients withdrew their consent and 
will not enter the follow-up phase, or if patients withdrew their consent for study treatment but 
will continue further participation in the study. If patients withdraw consent for the survival 
follow-up phase, the study site is still obligated to follow the patient’s survival status through 
publicly available forms of information (i.e. death registries). 


 
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Treatment may be continued until one of the following criteria applies: 
• Progressive disease (PD): In patients with PD, a confirmatory scan should be performed 
at least 4 weeks later to confirm PD prior to removing the patient from study treatment. 
The confirmatory scan is recommended but not required, it is at the discretion of the 
treating physician 
• Intervening illness that prevents further administration of treatment. 
• Recurrent Grade 2 pneumonitis 
• Unacceptable AE(s). 
• The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication. Discontinuation 
from study treatment will occur prior to introduction of the new agent. 
• Significant patient non-compliance with the protocol. 
• Completion of 35 cycles (approximately 2 years) with pembrolizumab.  
o Note: The number of treatments is calculated starting with the first dose of 
pembrolizumab. 
• Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 24 
weeks), beyond the date when the initial CR was declared.  
• Pregnancy. 
• Patient decision to withdraw from the study. 
• Investigator decision to withdraw the patient from the study. 
• Patient is lost to follow up. 
• Sponsor decision to end the study. 
 


 
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5. 
DESCRIPTION OF STUDY TREATMENT 
5.1. 
Doses and Schedule of Administration 
Table 1: 
Doses and Schedule of Administration 
Study 
Treatment 
Name 
Dosage 
Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Regimen/Tre
atment 
Period/Vacci
nation 
Regimen 
Sourcing 
Pembrolizumab  Solution for 
infusion 
100 mg/vial 
200 mg Q3W 
IV infusion 
Day 1 of 
each 3-week 
cycle 
Sponsor 
Bavituximab 
Solution for 
infusion 
120 mg/vial 
3 mg/kg* 
IV infusion 
Days 1,8,15 
of each 3-
week cycle 
Sponsor 
*The first 3-10 patients will receive 3mg/kg bavituximab, unless DLTs require de-escalation (see Section 5.6). 
On days when both pembrolizumab and bavituximab are administered, pembrolizumab will be 
administered first. After a window of at least 60 minutes, bavituximab will be administered.   In 
the absence of Grade 2 or greater hypersensitivity reactions, the window of time between the two 
infusion may be reduced to 30 minutes after the first two cycles. 
Dose escalations from starting dose are not allowed for bavituximab or pembrolizumab 
Bavituximab must occur within a 3 day window of the scheduled treatment. Outside a 3 day 
window, such doses will be skipped and dosing will resume at the next scheduled time.   A 
missed dose due to holiday, bad weather, or other unforeseen circumstances will not be not 
counted as a protocol deviation. 
A delay of a pembrolizumab dose due to holiday, weekend, bad weather, or other unforeseen 
circumstances will be permitted for a maximum of 7 days.  Outside of a 7 day delay, the dose 
will be skipped and resumed at the next scheduled time. 
The safety outcome of the run-in phase will determine the RDE for subsequent patients. 
Bavituximab dose may be reduced pending DLT analysis of the first 3 to 10 patients (See 
Section 5.6).  
Patients enrolled in the safety run- in phase the dose of bavituximab will be adjusted or 
interrupted as appropriate; see Section 5.6 
Patients enrolled in the expansion phase (once RDE is determined) may not have a reduction in 
the dose of bavituximab.  The dose of bavituximab will be interrupted as appropriate, see Section 
5.7 and Table 6. 
No dose reductions of pembrolizumab are permitted. Doses will be withheld as appropriate based 
on treatment modifications defined in Table 7. 


 
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Administration of bavituximab and pembrolizumab will be performed in a setting with 
emergency medical facilities and staff who are trained to monitor for and respond to medical 
emergencies. 
If continued treatment with bavituximab is contraindicated due to AEs, the patient may continue 
treatment with pembrolizumab after consultation with the medical monitor. If continued 
treatment with pembrolizumab is contraindicated due to AEs, bavituximab administration may 
continue upon consultation with the medical monitor. 
5.2. 
Description of Bavituximab 
Bavituximab is a chimeric (human/mouse) version derived from the original murine PS-targeting 
mAb 3G4. It is a genetically engineered immunoglobulin gamma 1-kappa (IgG1)κ consisting of 
human IgG1κ constant regions linked by recombinant deoxyribonucleic acid (DNA) techniques 
to murine 3G4 variable regions. 
Bavituximab is supplied as a sterile, preservative-free solution with a composition of 
bavituximab, in 10 mM acetate, pH 5.0. It is provided in borosilicate Type 1 glass vials and 
stored at 2°C to 8°C containing 120 mg/5mL (24mg/mL). 
Vials containing bavituximab drug product will be labeled according to national regulations for 
investigational products. 
5.3. 
Description of Pembrolizumab 
Pembrolizumab is a PD-1 blocking antibody. 
Pembrolizumab is supplied as 100 mg/4 mL (25 mg/mL) solution in a single-dose vial. 
Pembrolizumab vials should not be used beyond the expiration date provided by the 
manufacturer. Each vial is intended for single use only. Vial contents should not be frozen or 
shaken and should be protected from direct sunlight. 
5.4. 
Method of Assigning Patients to Treatment Groups 
Patients will be enrolled through an interactive web response system (IWRS).  
5.5. 
Preparation and Administration of Study Treatment 
5.5.1. 
Bavituximab 
The Investigator or designee will be responsible for administering the appropriate dose of IV 
bavituximab to all patients. Bavituximab must be stored at 2°C to 8°C in its original package.  
Infusion reactions have occurred both with and without premedication, and it is unclear whether 
the type of co-administered chemotherapy or premedication with steroids and antihistamines 
impacts the frequency or severity of infusion reactions. Reports of infusion reactions will 
continue to be monitored. Prior to each bavituximab infusion, the patient should be premedicated 
with an antihistamine to decrease the risk of an infusion reaction. A recommended regimen is 50 
mg diphenhydramine IV and 325 mg acetaminophen orally (PO) administered 1.5 hours (± 30 
minutes) prior to infusion. See Section 6.2 for full recommendations for IRRs. The regimen, 
dosages, and timing of the premedications can be adjusted at the Investigator’s discretion.  


 
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The bavituximab dosage is calculated at 0.125 mL/kg body weight and diluted with normal 
saline to a volume of no less than 100 mL. The total dose will not be recalculated based on body 
weight unless there is a ≥ 10% change in weight from Day 1. Administer as IV with in-line 
0.2 m filter over 90 minutes once weekly. After the 1st infusion, in the absence of Grade 2 or 
greater hypersensitivity reactions, the infusion time will be reduced to 60 minutes. After a 2nd 
infusion, in the absence of Grade 2 or greater hypersensitivity reactions, the infusion time will be 
reduced to 30 minutes. 
The individual bavituximab infusion will be prepared under aseptic conditions and administered 
at the study site, according to the directions of the Sponsor, which will be provided in a 
Pharmacy Manual. In general, a vial of bavituximab must be used as soon as possible after 
reaching room temperature. Any solution remaining in the vial must be discarded. After dilution 
for infusion, administration of bavituximab should take place as soon as possible. Maximum 
allowed storage times and conditions will be detailed in the Pharmacy Manual. 
Bavituximab is administered as an infusion. Bavituximab should not be administered as an IV 
push or bolus. 
5.5.2. 
Pembrolizumab 
Pembrolizumab will be administered using IV infusion on Day 1 of each 3-week treatment cycle 
after all procedures and assessments have been completed. Bavituximab compound to be 
administered post administration of pembrolizumab. 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes (-5 min/+10 min).This is an open-
label study; study treatments will not be blinded. 
5.6. 
DLT Dose De-escalation/Modification  
Patients who complete the DLT observation period without a DLT will continue study treatment 
until a criterion for discontinuation is met (Section 4.6). See Section 5.7 for information about 
administration of bavituximab dose modifications for patients who continue on study treatment 
after they complete the DLT observation period.  
If the patient experiences a DLT during the DLT observation period (see Section 3.1), dosing of 
bavituximab and pembrolizumab must be interrupted, as shown in Table 2. If a DLT resolves to 
Grade  1, dosing may be resumed at the next available reduced dose level for bavituximab or 
the same dose for pembrolizumab if agreed to by the Investigator and the Sponsor’s medical 
monitor. If the patient was on the lowest dose level of bavituximab when the DLT occurred, they 
must be discontinued from the study. No intra-patient dose re-escalation is allowed after a dose 
reduction. 
Table 2: 
Dose Interruption for Dose-Limiting Toxicity During the DLT Observation Period  
DLT is at least possibly 
related to: 
Bavituximab Dosing 
Pembrolizumab Dosing 
Bavituximab 
Hold dose/reduce 
Administer 


 
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Pembrolizumab 
Administer 
Hold dose 
Bavituximab and 
Pembrolizumab  
Hold dose/reduce 
Hold dose 
A patient will be considered evaluable for DLTs if he or she (1) receives at least one dose of 
either study treatment and completes the DLT observation period or (2) discontinues because of 
a DLT. A patient will be considered nonevaluable for DLTs if he or she discontinues during the 
DLT observation period for a reason other than a DLT; patients who are not evaluable for DLTs 
will be replaced.  
The first 3 patients will be evaluated for DLTs for the purpose of declaring the tentative RDE. 
The SRC will review these patients for DLTs at the end of the first 3-week cycle: 
• If 0 of 3 patients experiences a DLT on any dose level, the RDE will be tentatively 
declared and further dose expansion will continue. 
• If 1of 3 patients experiences a DLT on any dose level, that cohort will be expanded to 
6 patients. If 1 of 6 patients experiences a DLT, the RDE will be tentatively declared and 
further dose expansion will continue. 
• If ≥ 2 of 3 or ≥ 2 of 6 patients experience a DLT on Dose Level 0, Dose Level -1 will be 
explored. If ≥ 2 of 3 or ≥ 2 of 6 patients experience a DLT on Dose Level -1, Dose 
Level -2 will be explored.  
• If  2 DLT(s) occur in up to 6 patients at Dose Level -2, further enrollment and dosing 
will be stopped until there is a full review of all available data, including PK, by the SRC. 
Table 3: 
Planned Dose Levels  
Dose Level 
IV Bavituximab (Weekly) 
IV Pembrolizumab (Q3W) 
0 
3 mg/kg 
200 mg 
-1 
2 mg/kg 
200 mg 
-2 
      1 mg/kg 
200 mg 
The SRC may decide to meet at any time to evaluate a dosing cohort if a safety signal arises or 
other data become available to justify re-evaluation of the dosing cohort before it is fully 
enrolled.  
Patients who are lost to follow up or withdraw consent for study participation prior to receiving 
study treatment or who withdraw prior to completing Cycle 1 for reasons other than DLT may be 
replaced. Approximately ten patients will be evaluated for safety by SRC, even if no DLTs have 
been identified to ensure early safety monitoring of the combination. 
5.6.1. 
Definition of Dose-Limiting Toxicities 
A DLT is defined as any of the AEs described below that occurs during the DLT observation 
period and is at least possibly related to bavituximab or pembrolizumab. The Investigator will 
use CTCAE v5.0 guidelines to assign an AE term and severity grade relevant to the DLT. 
Hematological toxicities as follows: 
o Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia: 


 
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▪ Grade 4 thrombocytopenia of any duration 
▪ Grade 3 thrombocytopenia associated with clinically significant bleeding 
o  Grade 3 febrile neutropenia 
▪ Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than 1 hour 
▪ Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than 1 hour, with life-threatening consequences 
and urgent intervention indicated. 
o Grade 4 lymphocyte decreases lasting > 14 days 
 
Non-hematologic toxicities: 
o Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤ 3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of anti-emetics or anti-diarrheals per standard of care; Grade 3 rash 
without use of corticosteroids or anti-inflammatory agents per standard of care. 
o Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
▪ Clinically significant medical intervention is required to treat the subject, 
or 
▪ The abnormality leads to hospitalization, or the abnormality persists for 
>1 week; the abnormality results in a Drug-induced Liver Injury (DILI)  
▪ Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc. 
o Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 
o Any treatment-related toxicity that causes the participant to discontinue treatment during 
Cycle 1. 
o Missing >25% of planned doses as a result of drug-related AE(s) during the first cycle. 
o Grade 5 toxicity. 
 
Isolated laboratory changes without associated clinical signs or symptoms may not be included 
in this definition. These findings will be discussed and reviewed by the Investigators and the 
Sponsor’s medical monitor. 
Safety data in subsequent cycles will also be monitored on an ongoing basis to determine the 
cumulative incidence of late-onset toxicities. 


 
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Patients who experience a DLT, but in the opinion of the Investigator can be adequately 
monitored for recurrence of the toxicity and are otherwise experiencing clinical benefit, may be 
offered continued treatment with bavituximab and pembrolizumab. 
Dosing will continue until criteria for study treatment discontinuation are met (unacceptable 
toxicity, PD, or withdrawal from the study) or up to a maximum of 35 cycles.  
5.7. 
Dose Modification Guidelines 
CTCAE v5.0 must be used to grade the severity of AEs. 
If appropriate, the Investigator may attribute each toxicity event to either bavituximab or 
pembrolizumab alone or in combination. 
Bavituximab Dose Reductions: Once RDE derived from the DLT observation period is 
established, bavituximab doses may not be reduced.  
Bavituximab Dose Interruptions: Treatment with bavituximab may be interrupted for up to 
21 days (1 cycle) for toxicity or reasons unrelated to toxicity. If bavituximab is withheld because 
of AEs for  21 days, then the patient will be discontinued from bavituximab. If, in the judgment 
of the Investigator, the patient is likely to derive clinical benefit from bavituximab after a hold of 
 21 days, study drug may be restarted with the approval of the medical monitor.  
Recommendations for bavituximab dose modifications for the management of specific AEs are 
presented in Section 6.3. 
Pembrolizumab Dose Reductions: Dose reductions of pembrolizumab are not permitted. 
Pembrolizumab Dose Interruptions: Treatment with pembrolizumab may be temporarily 
suspended for up to 12 weeks (3 cycles) beyond the last dose to allow for resolution of immune-
related AEs and tapering of corticosteroids.  
If a patient must be tapered off steroids used to treat AEs, pembrolizumab may be withheld for 
up to 12 weeks from the last dose until steroids are discontinued or reduced to prednisone dose 
equivalent  10 mg/day. The acceptable length of interruption will depend on an agreement 
between the Investigator and the medical monitor. 
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be allowed 
with medical monitor approval. The acceptable length of interruption will depend on agreement 
between the Investigator and the medical monitor. 
5.8. 
Treatment Compliance 
The study treatments will be administered to subjects at the study site, under the supervision of 
the Investigator or designee in accordance with the protocol. Compliance with schedule infusions 
during study visits will be recorded on the CRF. 
5.9. 
Study Drug Accountability  
Study personnel will maintain accurate records of study treatment shipments/receipts and 
administration. The site is responsible for the return or destruction of study treatment as required.  


 
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5.10. 
Concomitant Medications 
Patients are allowed to continue the medications that they are taking at baseline. Patients may 
also receive concomitant medications that are medically indicated as standard care for the 
treatment of symptoms and intercurrent illnesses. Medications to treat concomitant diseases, e.g., 
diabetes, hypertension, and chronic obstructive pulmonary disease (COPD) are allowed. Patients 
may also receive therapy to mitigate side effects of the study medication as clinically indicated, 
as well as best supportive care as per institutional guidelines. This may include, e.g., 
anti-emetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, antihistamines, 
analgesics, antibiotics, and other medications intended to treat symptoms. The Investigator 
should instruct the patient not to take any additional medications (including over-the-counter 
products) during the study without prior consultation.  
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of study treatment should be recorded for 
SAEs and AESIs, 
5.11. 
Premedication for Infusion Reactions 
Routine premedication (e.g., diphenhydramine and acetaminophen) is required prior to infusion 
of bavituximab (Section 5.5.1). Management of infusion-related reactions is described in 
Section 6.2. 
5.12. 
Corticosteroid Use 
Systemic corticosteroids and tumor TNF-α inhibitors may attenuate potential beneficial 
immunologic effects of treatment with bavituximab and pembrolizumab but may be administered 
at the discretion of the treating physician. If feasible, alternatives to corticosteroids should be 
considered. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. Megestrol 
administered as an appetite stimulant is acceptable while the patient is enrolled in the study. 
5.13. 
Hematopoietic Growth Factor and Blood Products 
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for treatment 
of cytopenias should be administered according to institutional guidelines. Prophylactic use of 
these agents is not permitted. 
Transfusion thresholds for blood product support will be in accordance with institutional 
guidelines. 
5.14. 
Prohibited Therapies 
Listed below are specific restrictions for concomitant therapy or vaccination during the course of 
the study: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 


 
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• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• 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 study treatment, while participating 
in the study, and for 4 months following the last dose of either pembrolizumab or 
bavituximab, whichever is later. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
that is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Medical Monitor  
 
Note: Inhaled steroids are allowed for management of asthma.  
 
Participants who, in the assessment of the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  
5.15. 
Treatment of Overdose 
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
≥5 times the indicated dose.   
For this study and overdose of bavituximab will be defined as any dose of 15mg/kg or ≥5 times 
the indicated dose.   
No specific information is available on the treatment of overdose of bavituximab or 
pembrolizumab. In the event of overdose, the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
In the event of a known or suspected overdose, the patient should be monitored with appropriate 
hematology and clinical chemistry and should receive supportive therapy, as necessary. Please 
also refer to Section 6.3 for guidelines on the management of potential study treatment-related 
toxicities. 
Decisions regarding dose interruptions or modifications for bavituximab and/or pembrolizumab 
(interruptions only) in the case of a suspected overdose will be made by the Investigator in 
consultation with the medical monitor based on the clinical evaluation of the patient. 


 
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A plasma sample for PK analysis may be requested by the medical monitor or Sponsor on a case-
by-case basis. This plasma sample should be collected as soon as possible, but within 10 days 
from the date of the last dose of on-study dosing. 
Information regarding the quantity of the excess dose as well as the duration of the overdosing 
should be documented in the appropriate eCRF. 


 
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6. 
MONITORING AND MANAGEMENT OF EXPECTED OR 
POTENTIAL TREATMENT-RELATED TOXICITY 
6.1. 
Patient Monitoring 
Staff administering study drug are required to closely monitor all patients for possible systemic 
hypersensitivity reactions (e.g., generalized exanthema, urticaria, paraesthesia, 
bronchoconstriction, palpitations) during and after the first infusion of both study drugs. 
All systemic hypersensitivity manifestations will be captured on the appropriate eCRF page(s) 
and identified as being due to a hypersensitivity reaction. 
6.2. 
Management of Infusion Reactions – Bavituximab and 
Pembrolizumab 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or another H2 receptor 
antagonist, as per standard practice.  
Precautions for anaphylaxis should be observed during both bavituximab and pembrolizumab 
administration. Vital signs should be measured as outlined in Section 7.1.10 during both 
bavituximab and pembrolizumab infusions. All supportive measures consistent with optimal 
patient care will be provided throughout the study according to institution standards. Emergency 
resuscitation equipment and medications should be readily available. Additional supportive 
measures should also be available and may include, but are not limited to, epinephrine, 
antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, 
diphenhydramine, and acetaminophen (paracetamol). 
Infusion-related reactions (IRRs) will be defined according to Table 4. 


 
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Table 4: 
Definition of Infusion-Related Reactions (IRRs) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, 
IV fluids); prophylactic 
medications indicated for 
≤ 24 hours 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication, brief interruption of 
infusion, or both); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for clinical sequelae 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Abbreviations: IRR=infusion-related reaction; IV=intravenous; NSAIDs=non-steroidal anti-inflammatory 
drugs. 
Note: An acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal 
antibodies or other biological agents). Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. Signs/symptoms may include: 
allergic reaction/hypersensitivity (including drug fever); arthralgia (joint pain); bronchospasm; cough; dizziness; 
dyspthatnea (shortness of breath); fatigue (asthenia, lethargy, malaise); headache; hypertension; hypotension; 
myalgia (muscle pain); nausea; pruritis/itching; rash/desquamation; rigors/chills; sweating (diaphoresis); 
tachycardia; tumor pain (onset or exacerbation of tumor pain due to treatment); urticaria (hives, welts, wheals); 
vomiting. 
 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Dose modification and toxicity management guidelines on bavituximab and pembrolizumab 
associated infusion reaction are provided in Table 5. 
 


Oncologie, Inc. 
Clinical Study Protocol 
Bavituximab and Pembrolizumab 
Study ONCG100 
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Table 5: 
Management of IRRs Induced by Bavituximab or Pembrolizumab 
NCI CTCAE v5.0 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 patient 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 hours 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include, but is not limited to: 
-IV fluids 
-Antihistamines 
-NSAIDs 
-Acetaminophen 
-Narcotics 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the Investigator. 
If symptoms resolve within one hour of 
stopping treatment infusion, the infusion may 
be restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr). Otherwise, 
dosing will be held until symptoms resolve and 
the patient should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Patient may be premedicated 
1.5 hours (± 30 minutes) prior to 
infusion of pembrolizumab with: 
-Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine). 
-Acetaminophen 500-1000 mg PO 
(or equivalent dose of antipyretic). 


 
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Grade 3 or 4:  
Grade 3: Prolonged (i.e., not rapidly 
responsive to symptomatic medication 
and/or brief interruption of infusion); 
recurrence of symptoms following initial 
improvement; hospitalization indicated for 
other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include, but is not limited to: 
-IV fluids 
-Antihistamines 
-NSAIDs 
-Acetaminophen 
-Narcotics 
-Oxygen 
-Pressors 
-Corticosteroids 
-Epinephrine** 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the Investigator. 
Hospitalization may be indicated.  
** in cases of anaphylaxis, epinephrine 
should be used immediately.  
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of study 
treatment. 
 


 
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6.3. 
Bavituximab Expected or Potential Treatment-related Toxicities 
6.3.1. 
Management of Thromboembolic Events 
Very high doses of bavituximab (100 mg/kg) in animals have been associated with evidence of 
minimal to mild thrombi (see bavituximab IB). Although it is known that tumor disease causes 
thromboembolic events, it is unknown whether treatment with bavituximab in the doses utilized 
in this study poses an increased risk of thrombosis in humans. Therefore, the Investigator should 
maintain a high degree of vigilance for thrombotic events in study patients.  
Should thrombotic or thromboembolic events be suspected at any time after the start of 
bavituximab treatment, whether on the basis of clinical signs or symptoms, abnormalities of 
platelets, aPTT, PT, or d-dimer results, or some combination of abnormalities and/or clinical 
findings, additional diagnostic and/or therapeutic measures should be undertaken without delay. 
Evaluation and management of such events should include Doppler examination and 
consideration of additional coagulation studies, imaging studies as appropriate, as well as 
consideration of treatment with low-molecular-weight heparin (LMWH) and/or transfusion of 
blood products as appropriate. Events that meet seriousness criteria should be reported to and 
discussed with the medical monitor (as with any other SAEs). 
6.3.2. 
Management of Other Adverse Events 
For dose modifications of bavituximab based on the occurrence of related AEs, see Table 6. 
Table 6: 
Bavituximab Dose Reductions for Treatment-Related Adverse Events 
Severity of 
Event 
Dose Adjustment for Bavituximab 
Grade 1 
Maintain bavituximab dose level and provide treatment to control symptoms, if 
applicable. 
Grade 2 
(tolerable) 
Maintain bavituximab dose level and provide treatment to control symptoms, if 
applicable. 
Grade 2 
(intolerable) 
Hold administration of bavituximab until the AE recovers to Grade 0-1 or to 
pretreatment baseline AE level, whichever is more abnormal. Then, resume treatment. 
Grade 3 
Hold administration of bavituximab until the AE recovers to Grade 0-1 or to 
pretreatment baseline AE level, whichever is more abnormal.  
Grade 4 
Discontinue 
Abbreviations: AE = adverse event. 
6.4. 
 Dose modification and toxicity management for immune-related 
AEs associated with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 


 
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Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 7.  
 
 
 
 
 
 


 
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Table 7: 
Management of Potential Pembrolizumab Toxicities 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
Monitor participants for signs and 
symptoms of pneumonitis 
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
Monitor participants for signs and 
symptoms of enterocolitis (i.e., diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (i.e., peritoneal signs and 
ileus). 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy 
to rule out colitis.  
Participants with diarrhea/colitis should 
be advised to drink liberal quantities of 
clear fluids.  If sufficient oral fluid 
intake is not feasible, fluid and 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 


 
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electrolytes should be substituted via IV 
infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable) 
Grade 3 or 4  
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycemi
a 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure 
Withhold 
Initiate insulin replacement 
therapy for participants with 
T1DM  
Administer anti-hyperglycemic 
in participants with 
hyperglycemia  
 
Monitor participants for hyperglycemia 
or other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.   
 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidi
sm  
Grade 2 
Continue  
Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidis
m 
Grade 2-4 
Continue  
Initiate thyroid replacement 
hormones (e.g., levothyroxine 
Monitor for signs and symptoms of 
thyroid disorders.  


 
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or liothyroinine) per standard of 
care 
 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury  
Grade 2 
Withhold  
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
Based on type and severity of 
AE administer corticosteroids  
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis, 
Stevens-
Johnson 
Syndrome and 
toxic epidermal 
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Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
1Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM).   
 
The Investigator should consider the benefit−risk balance a given patient may be experiencing prior to further administration of 
pembrolizumab. In patients who have met the criteria for permanent discontinuation, resumption of pembrolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the immune-related event. Patients can be re-challenged with 
pembrolizumab only after approval has been documented by both the Investigator (or an appropriate delegate) and the medical 
monitor. 
 
 
 
 
 
 


 
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7. 
STUDY ASSESSMENTS 
The procedures and assessments that will be conducted during this study are described in this 
section and summarized in the Schedule of Assessments (Table 8). Study assessments are 
identical for patients enrolled in Group 1 and Group 2. Detailed instructions regarding all 
laboratory procedures, including collection and handling of samples, will be included in the 
study Laboratory Manual provided by the Sponsor. 
Pharmacokinetic, pharmacodynamic, and ADA assessments are presented in Table 9.  
Written informed consent must be granted by each patient prior to the initiation of any study 
procedure or assessment (other than those considered standard of care). 
 


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Table 8: 
Schedule of Assessments 
Procedure or Assessment 
Screening  
Cycle 1 (21 days)a 
Day in Cycle 
Cycle 2 (21 days)a 
Day in Cycle 
± 1 day 
Cycle 3 (21 days)a 
Day in Cycle 
± 1 day 
Cycle 4 and 
Subsequent 
Cyclesa 
± 3 days 
EOT 
Visitb 
Safety 
FU Visit 
30 
± 3 days 
Survival 
FU 
Every 
12 wks 
Days -28 
to -1 
1 3 
days 
8 3 
days 
153 
days 
1 3 
days 
8 3 
days 
153 
days 
1 3 
days 
8 3 
days 
153 
days 
Optional Future Tissue Study 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Tissue Biopsy 
Xc 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ Signs and 
Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Cancer Treatment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Meds Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Directed Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Review of AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital SignsP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body Weight/Height  
(Height at screening only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG PSe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Bavituximab 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
(Day 1,8,15) 
 
 
 
Administer Pembrolizumab 
 
X 
 
 
X 
 
 
X 
 
 
X (Day 1) 
 
 
 
PK/PDf 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
ADAf 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Biomarker Blood Samplef 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
Hematologyg,h 
X 
X 
 
 
X 
 
 
X 
 
 
X (Day 1) 
X 
X 
 


 
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Procedure or Assessment 
Screening  
Cycle 1 (21 days)a 
Day in Cycle 
Cycle 2 (21 days)a 
Day in Cycle 
± 1 day 
Cycle 3 (21 days)a 
Day in Cycle 
± 1 day 
Cycle 4 and 
Subsequent 
Cyclesa 
± 3 days 
EOT 
Visitb 
Safety 
FU Visit 
30 
± 3 days 
Survival 
FU 
Every 
12 wks 
Days -28 
to -1 
1 3 
days 
8 3 
days 
153 
days 
1 3 
days 
8 3 
days 
153 
days 
1 3 
days 
8 3 
days 
153 
days 
Coagulationg,i 
X 
X 
 
 
X 
 
 
X 
 
 
X (Day 1) 
 
 
 
Clinical Chemistryg,j 
X 
X 
 
 
X 
 
 
X 
 
 
X (Day 1) 
X 
X 
 
Thyroid Panel]i 
X 
 
 
 
 
 
 
X 
 
 
X (Day 1 
every other 
cycle) 
 
X 
 
Urinalysisg,k 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testl 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Tumor Imagingm,n 
X 
 
 
 
 
 
 
X 
 
 
 
Xo 
 
 
Post-study Anti-cancer Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: ADA=antidrug antibody, AE=adverse event, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, FU=follow-up; 
Meds=medications, PK=pharmacokinetic, PS=performance status, Q3W=every 3 weeks, SAE=serious adverse event, TSH=thyroid-stimulating hormone, 
W=weeks. 
a 
Unless otherwise specified, assessments/procedures are to be performed prior to dose administration on Day 1 of each cycle. 
b 
Patients who discontinue both study treatments should be scheduled for an EOT visit within 15 days following the last dose date of study treatment.  
c 
 Baseline tumor tissue will be collected prior to enrollment on study for exploratory biomarker and PDL1 status (see study manual for details) 
d 
An optional biopsy is also requested at the time of discontinuation for PD. 
e 
Screening ECOG should be performed within 72 hours prior to first dose of treatment.  
f 
Refer to Table 9 for details on PK, ADA and biomarker blood sample scheduling.  
g 
Laboratory Screening Tests should be performed within 72 hours prior to first dose of treatment. For all subjects, unresolved abnormal labs resulting in drug-
related AEs should be followed until resolution.  
h 
CBC w/differentials will be collected and assessed within 72 hours of Day 1 of each cycle prior to dosing.  
i 
T3 (free or total), T4 (free or total), and TSH will be collected and assayed prior to C1D1, C3D1, and every other cycle thereafter (e.g., C5D1, C7D1, etc.).  
j 
Chemistry will be collected within 72 hours of Day 1 of each cycle prior to dosing.  
k 
Urinalysis is conducted post screening every other cycle as clinically indicated. 
l 
For women of reproductive potential, a negative pregnancy test should be performed within 72 hours prior to first dose of trial treatment. Pregnancy tests 
(serum and/or urine tests) should be repeated prior to dosing on Day 1 of every cycle in the UK.  In all other countries pregnancy tests should be repeated as 
required by local guidelines.  
m 
Tumor imaging at screening: Imaging will be performed within 28 days prior to the first dose of trial treatment. For all subjects, already available imaging 
scans performed as part of routine clinical management are acceptable if they are of diagnostic quality and performed within the acceptable timeframe. 


 
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n 
The first on-study tumor imaging will be performed 6 weeks (±7 days) after initiation of treatment and then every 6 weeks (±7 days) thereafter (or more 
frequently if clinically indicated). Timing of imaging follows calendar days and should not be adjusted due to dose interruptions. The same imaging 
technique, acquisition, and processing parameters for a subject should be used throughout the trial. 
o 
Subjects without confirmed PD who discontinue treatment will have imaging performed at the time study treatment is discontinued (i.e. date of 
discontinuation ± 4-week window). If a scan was obtained within 4 weeks prior to discontinuation of treatment, then imaging at treatment discontinuation is 
not required. Continue to monitor disease status as indicated in Section 7.2.1.3.  
P 
Vital signs will be captured approximately 30 minutes prior to pembrolizumab; 30 minutes prior to bavituximab administration and within 60 minutes post 
bavituxumab 
 
 
 


 
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Table 9: Pharmacokinetic/Pharmacodynamic/Biomarker Blood Sample Specific Collections – 
Collection Times 
 
 
Bavituximaba 
Biomarker 
Blood 
Sample 
 
Visit 
Time Point 
PK/PD 
ADA 
Window 
Cycle 1 Day 1 
Prior to dosingb 
X 
X 
X 
Within 24 hours prior to bavituximab 
administration 
Cycle 1 Day 1 
1 hour post 
EOIc 
X 
 
 
+/-30 minutes post bavituximab infusion  
Cycle 1 Day 15 
Prior to dosingb 
X 
 
X 
Within 24 hours prior to bavituximab 
administration  
Cycle 1 Day 15 
1 hour post 
EOIc 
X 
 
 
+/-30 minutes post bavituximab infusion  
Cycle 2 Day 1 
Prior to dosingb 
X 
X 
X 
Within 24 hours prior to bavituximab 
administration 
Cycle 2 Day 15 
Prior to dosingb 
X 
 
X 
Within 24 hours prior to bavituximab 
administration 
Cycle 3 Day 1 
Prior to dosingb 
X 
 
 
Within 24 hours prior to bavituximab 
administration 
Cycle 4 Day 1 
Prior to dosingb 
X 
X 
 
Within 24 hours prior to bavituximab 
administration 
Cycle 6 Day 1 
Prior to dosingb 
X 
 
 
Within 24 hours prior to bavituximab 
administration 
30-day Follow-up 
Follow-up 
 
X 
X 
Any time during the Safety Follow-up Visit 
Abbreviations: EOI = end of infusion; ADA=antidrug antibody; PK = pharmacokinetics. 
a In the event of an infusion-related reaction (IRR), blood samples will be collected for both PK and ADA at the 
following time points: (i) as soon as possible after the onset of the IRR, (ii) at the resolution of the IRR, and (iii) 
30 days (±3 days) following the IRR. 
b 
Pre-dose PK samples are collected within 24 hours prior to infusion of bavituximab. 
c 
Post-dose PK samples are collected 1 hour (+/-30 minutes) post bavituximab infusion  


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7.1. 
Summary of Assessments 
7.1.1. 
Screening 
All screening procedures must be performed within 28 days prior to first treatment (C1D1), 
unless otherwise stated. The screening procedures include the following (See Table 8 above for 
the list of assessments to be performed.): 
Informed Consent 
Informed consent may be obtained any time prior to screening procedures being performed.  
Screening procedures performed as standard of care prior to informed consent need not be 
repeated if they were done within protocol defined windows.  These are the anticipated consents 
to be used in the trial.   However individual IRBs/ECs may require additional consent. 
1) General Informed Consent: To consent patients for all study procedures 
2) Optional Future Tissue Study Informed Consent: To obtain consent to use tumor 
tissue for possible future tissue study. 
Eligibility Checklist (Inclusion/Exclusion) 
In order to determine and confirm the eligibility of the patient, all screening procedures must be 
documented and completed. 
Patient Demographics and other Baseline Characteristics 
The data that will be collected on patient characteristics at screening includes: 
Demographic (name, age), sex, race/ethnicity; 
Diagnosis, and extent of cancer;  
Pertinent medical history; 
Prior cancer treatment; 
AEs related to study procedures 
All medications taken within 30 days before first treatment. If there are any changes, medications 
are to be updated on a continual basis. 
Furthermore, the following assessments will be performed: 
Vital signs (BP, HR, T, RR); 
Concomitant medications; 
Height and weight; 
Physical examination (PE); 
ECOG PS; 
Laboratory evaluations (complete metabolic panel [CMP], complete blood count [CBC], PT/INR 
and PTT/aPTT, thyroid panel);  
12-lead electrocardiogram (ECG);  


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Radiological assessments (RECIST version1.1) (computed tomography [CT] - 
chest/abdomen/pelvis or magnetic resonance imaging [MRI] – abdomen/pelvis). Chest CT will 
be performed at baseline only. During the treatment phase, a chest CT will be performed as 
clinically indicated; 
Urinalysis; 
Urine or serum pregnancy test (women of childbearing potential only). 
Pre-Treatment - Biomarker Tissue Biopsy (Required) 
After obtaining informed consent, the fresh tumor biopsy must be obtained prior to initial 
treatment (C1D1), and can be since progression of last treatment. Archival formalin fixed 
paraffin embedded tumor tissue is requested from any early tissue sample for same disease, as 
well. 
7.1.2. 
Treatment Phase 
Study Treatment 
Patients will be treated with bavituximab (3 mg/kg IV weekly) and pembrolizumab (200 mg IV 
Q3W). Patients will be treated until disease progression, unacceptable toxicity, death, or 
discontinuation from the study treatment due to any other reason. For details of assessment, refer 
to Table 8. 
Additional Treatment Phase Assessments will be performed: 
Vital signs (BP, HR, T, RR); 
AEs / Concomitant medications; 
Weight; 
PE; 
ECOG PS; 
Laboratory evaluations (Day 1 of every cycle: CMP, CBC, PT/INR and aPTT; Day 1 of every 
other cycle: thyroid panel and urinalysis as clinically indicated) 
Radiological assessments (RECIST 1.1) (CT - chest/abdomen/pelvis or MRI – abdomen/pelvis). 
During the treatment phase, a Chest CT will be performed as clinically indicated. 
Urine or serum pregnancy test (women of childbearing potential only). 
Biomarker Blood Collection 
Biomarker blood samples will be collected, during treatment, and at the 30 day follow up visit. 
This procedure is for research and will not be used to make medical decisions regarding the 
patient’s treatment.  
 


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7.1.3. 
Post – Treatment Follow-up Phase 
7.1.3.1. 
End of Treatment  
Patients who discontinue both study treatments should be scheduled for an EOT visit within 
15 days following the last dose date of study treatment, at which time all the assessments listed 
for the EOT visit will be performed. For details of the assessment, see Table 8.  
An optional fresh tumor biopsy is requested for patients who discontinue due to PD 
At a minimum, all patients who discontinue study treatment, including those who refuse to return 
for a final visit, will be contacted for study evaluations during the 30 days following the last dose 
date of study treatment. 
 
7.1.3.2. 
30-Day Safety Follow-Up Visit 
All patients will be followed up for safety up to 30 days after last dose of study drug 
(bavituximab and pembrolizumab) treatment. Patients whose treatment is interrupted or 
permanently discontinued due to an AE, including abnormal laboratory value, must be followed 
until resolution or stabilization of the event, whichever comes first. 
The Investigator will review all new anti-cancer therapy initiated after the last dose of trial 
treatment. If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial 
treatment, the 30-day Safety Follow-up Visit must occur before the first dose of the new therapy. 
Once new anti-cancer therapy has been initiated the subject will move into survival follow-up. 
7.1.3.3. 
Survival Follow-up 
Patients will be followed for survival every 12 weeks after the 30-Day Safety Follow-up Visit. 
Telephone contacts will be documented every 12 weeks to confirm survival, withdrawal of 
consent, lost to follow-up or to notify patient of the end of the study, whichever occurs first.  
At least 3 documented attempts should be made to contact the patient before the patient is 
considered lost to follow-up.  
If patients withdraw consent for the survival follow-up phase, the study site is still obligated to 
follow the  patient’s survival status through publicly available forms of information (i.e. death 
registries). 
7.1.4. 
Beginning and End of the Trial 
The study begins when the first patient signs the informed consent. The end of the study may be 
designated as a maximum of 12 months from the last patient receiving the last dose of study 
therapy or the time point when all patients have discontinued the study, whichever is sooner.  
7.1.5. 
Informed Consent  
The investigator or qualified designee must obtain documented consent from each potential 
patient or each patient’s legally acceptable representative prior to participating in a clinical trial.  
Consent must be documented by the patient’s dated signature on a consent form along with the 
dated signature of the person conducting the consent discussion.   


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A copy of the signed and dated consent form should be given to the patient prior to trial 
participation.   
The Investigator is responsible for:  
• ensuring that the patient understands the potential risks and benefits of participating in 
the study  
• ensuring that informed consent is given by each patient or legal representative. This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any study procedures and prior to the administration of study treatment.  
• answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the trial.  
7.1.6. 
Ethical Review  
Documentation of IEC/IRB approval of the protocol, ICF and any other patient materials must be 
provided to Oncologie, Inc. or its representative before the study may begin at the investigative 
site(s). Oncologie, Inc. or its representatives must approve the ICF, including any changes made 
by the IEC/IRBs, before it is used at the investigative site(s). All ICFs must be compliant with 
the International Council for Harmonisation (ICH) guideline for GCP) and local regulations. 
7.1.7. 
Adverse Event Assessment 
The Investigator has the responsibility for assessing the safety of the patients and for compliance 
with the protocol to ensure study integrity. Patients will be monitored for AEs during study 
participation (beginning after informed consent is signed) and until 30  days after the last dose of 
study treatment. Any ongoing SAEs will be followed until resolution or stabilization. AEs and 
laboratory abnormalities will be graded according to the CTCAE v5.0 grading system and 
recorded on the eCRF. 
Complete details for monitoring AEs, including the definition of drug-related AEs, are provided 
in Section 8. 
7.1.8. 
Inclusion/Exclusion Criteria 
All inclusion/exclusion criteria will be reviewed by the Investigator or qualified designee to 
ensure that the subject qualifies for the trial. 
7.1.9. 
Demographic/Medical History/Prior Treatments 
Patient demographics and significant medical history including prior treatments will be recorded 
by the Investigator or qualified designee. Medical history will include all active conditions and 
any condition diagnosed within the last 10 years that are considered clinically significant by the 
Investigator. Details regarding the patient’s gastric or GEJ adenocarcinoma will be recorded 
separately and NOT listed as medical history.   
If patient has lost at least 15 pounds over the three months prior to screening, “weight loss” 
should be considered an active condition and noted in Medical History. Autoimmune disorders, 
regardless of onset date, should be recorded.  


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7.1.10. 
Vital Signs 
The Investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of bavituximab and again prior to administration of each dose of 
pembrolizumab,  and at treatment discontinuation. Vital signs should include temperature, pulse, 
respiratory rate, weight and blood pressure. Height will be measured at screening only.  
Vital signs will be captured approximately 30 minutes prior to pembrolizumab; 30 minutes prior 
to bavituximab administration and within 60 minutes post bavituxumab 
7.1.11. 
Weight and Height 
Height will be measured only during screening. Weight will be measured at Day 1 of each cycle. 
The patient should be in light indoor clothes.  
7.1.12. 
Full Physical Examination 
Physical examinations will include an assessment of all the major body systems. A complete 
physical examination will be performed at the time points specified in Table 8. Clinically 
significant abnormal findings noted during screening period should be recorded as medical 
history.  
7.1.13. 
Directed Physical Exam 
For cycles that do not require a full physical exam per Table 8, the Investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to dosing on Day 1 
of each treatment cycle. New clinically significant abnormal findings should be recorded as AEs. 
7.1.14. 
ECOG Performance Status 
ECOG performance status will be assessed at the time points specified in Table 8. Care will be 
taken to accurately score performance status, especially during screening for study eligibility 
purposes. Additional consideration should be given to borderline ECOG performance status to 
avoid enrolling patients with significant impairment. 
7.1.15. 
12-Lead Electrocardiogram 
A standard 12-lead ECG will be performed using local standard procedures once at screening. 
Clinically significant abnormal findings should be recorded as medical history. Additional time 
points may be performed as clinically necessary. 
7.1.16. 
Laboratory Assessments 
Blood and urine samples will be collected at the time points specified in Table 8. Screening 
results for study eligibility should be performed within 72 hours prior to first dose of treatment. 
Additional clinical laboratory tests can be obtained at any time during the study at the 
Investigator’s discretion. Local laboratories will perform the assessments. 
All blood and urine collections for clinical laboratory tests occurring on the same day as study 
treatment administration must be performed prior to study treatment administration and 
Investigator must review results to ensure acceptability prior to initiating each new cycle of 
treatment.   


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Clinically significant treatment-related findings at the EOT/Safety Follow-Up Visit should be 
followed to resolution or stabilization. 
Clinical Laboratory Tests 
Hematology - local laboratory 
Leukocytes (WBC) 
Erythrocytes (RBC) 
Neutrophilsa 
Hemoglobin (HGB) 
Lymphocytes 
Hematocrit (HCT) 
Monocytes 
Mean corpuscular volume (MCV) 
Eosinophils 
Mean corpuscular hemoglobin concentration (MCHC) 
Basophils 
Platelets (PLT) 
 
 
Coagulation - local laboratory 
Activated partial thromboplastin time (aPTT) or Partial thromboplastin time (PTT) 
International normalized ratio (INR) or Prothrombin time (PT) 
 
 
Clinical Chemistry - local laboratory 
Serum Concentrations of: 
 
Alanine aminotransferase (ALT) 
Creatine kinase (CK) 
Albumin 
Creatinine 
Alkaline phosphatase 
Glucose, nonfasting 
Aspartate aminotransferase (AST) 
Magnesium 
Bilirubin, direct 
Potassium 
Bilirubin, total 
Sodium 
Blood urea nitrogen (BUN) or blood urea 
Uric acid 
Calcium 
T3 (free or total) 
Chloride 
T4 (free or total) 
 
TSH 
Urinalysis - local laboratory 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Urine leukocyte esterase 
pH 
 
 
 
Pregnancy Test (for female patients of childbearing potential) - local laboratory 
Serum pregnancy test 
Urine pregnancy test 
Abbreviations:  RBC = red blood cells; TSH = thyroid-stimulating hormone; WBC = white blood cells. 
a Neutrophils reported by automated differential hematology instruments include both segmented and band forms. 
7.1.17. 
Pregnancy Test 
A woman of child bearing potential must have a negative urine pregnancy test (e.g. within 72 
hours) prior to treatment.  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
A pregnancy test must be repeated prior to dosing on Day 1 of every cycle and at the end of 
treatment visit. Pregnancy tests (serum and/or urine tests) should be repeated prior to dosing on 
Day 1 of every cycle in the UK.  In all other countries pregnancy tests should be repeated as 
required by local guidelines.  


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If a subject inadvertently becomes pregnant while on treatment with study treatment, 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 without delay and within 24 hours if 
the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). The study Investigator will 
make every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to the Sponsor. If a male patient impregnates his female 
partner the study personnel at the site must be informed immediately and the pregnancy reported 
to the Sponsor and followed as described above and in Section 8.5. 
7.2. 
Efficacy Assessments 
7.2.1. 
Tumor Assessments 
Tumor response and progression will be assessed by the Investigator according to RECIST, 
Version 1.1 (Appendix A). Tumor assessments, including tumor markers, will be performed at 
the time points specified in Table 8. 
Tumor assessments should consist of clinical examination and appropriate imaging techniques 
(preferably CT scans of the chest, abdomen, and pelvis with appropriate slice thickness per 
RECIST); other studies (MRI, X-ray, positron emission tomography [PET] scan, and ultrasound) 
may be performed if required. The same methods used to detect lesions at baseline are to be used 
to follow the same lesions throughout the clinical study. Investigators should perform scans of 
the anatomical sites that, in their judgment, are appropriate to assess based on each patient’s 
tumor status. 
7.2.1.1. 
Baseline Tumor Imaging 
To meet screening criteria, baseline tumor imaging must be performed within 28 days prior to 
the first dose of study treatment. 
Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality and performed within 28 days prior to the first dose of study 
treatment. 
7.2.1.2. 
Tumor Imaging During Trial 
Tumor imaging will be conducted every 6 weeks (± 7 days) after initiation of treatment. until one 
of the following occurs: 
• disease progression  
• start of new anti-cancer treatment 
• withdrawal of consent 
• death 
• end of study 


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Imaging should follow calendar days and not be delayed for any dose interruptions that may 
occur. 
7.2.1.3. 
Timing of Repeat Imaging 
In patients with PD, a confirmatory scan should be performed at least 4 weeks later to confirm 
PD prior to removing the patient from study treatment. The confirmatory scan is recommended 
but not required, it is at the discretion of the treating physician. 
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not less than 
4 weeks from the date the response was first documented. The scan for confirmation of response 
must be performed at the earliest 4 weeks after the first indication of response, or at the next 
scheduled scan (6 weeks later), whichever is clinically indicated. 
7.3. 
Immunogenicity Assessments 
7.3.1. 
Antidrug Antibody Assessments 
Venous blood samples for the assessment of ADA levels will be drawn at the time points 
presented in Table 9 for bavituximab.  
Blood samples should be collected from the arm opposite from the investigational drug 
infusion, or from another site if collected within 24 hours of dosing.  
Residual ADA serum samples used for ADA analysis may also be used for exploratory PK 
and/or pharmacodynamic analyses related to bavituximab treatment. This could include using 
leftover serum for exploratory, alternative PK assay development and analysis. 
ADA samples will also be collected in the event of a clinically significant AE (such as infusion 
reaction/anaphylaxis) or if ADA is suspected, at which time those samples could be used to 
measure any relevant biomarkers, to understand the infusion reaction/adverse event better. After 
the primary clinical study report data cut-off date is reached, no additional ADA samples will be 
collected for the patients still on-going on the study. 
In the event of an IRR, blood samples will be collected for both PK and ADA at the following 
time points: (i) as soon as possible after the onset of the IRR, (ii) at the resolution of the IRR, and 
(iii) 30 days (±3 days) following the IRR. 
Please refer to the Laboratory Manual for details on collection and processing of blood ADA 
samples. 
7.4. 
Pharmacokinetic Assessments 
7.4.1. 
Blood Sample Collection 
Venous blood samples for the PK analysis of bavituximab will be drawn at the time points 
presented in Table 9. 
Blood samples should be collected from the arm opposite from the investigational drug 
infusion, or from another site if collected within 24 hours of dosing.  


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Residual PK serum samples used for PK analysis may also be used for exploratory PK and/or PD 
analyses related to bavituximab treatment. This could include using leftover serum for 
exploratory, alternative PK assay development and analysis. 
In the event of an IRR, blood samples will be collected for both PK and ADA at the following 
time points: (i) as soon as possible after the onset of the IRR, (ii) at the resolution of the IRR, and 
(iii) 30 days (±3 days) following the IRR. 
7.4.2. 
Sample Analysis 
PK parameters will be determined for bavituximab and pembrolizumab using non-
compartmental methods. Possible compartmental analysis and possible relationships between PK 
and pharmacodynamic variables, efficacy and/or selected toxicities will be explored, as 
appropriate. 
PK profiles to assess PK properties of single-agent bavituximab will be collected from all 
enrolled patients.  
PK and ADA samples will also be collected in the event of a clinically significant AE (such as 
infusion reaction/anaphylaxis) or if ADA is suspected, at which time those samples could be 
used to measure any relevant biomarkers, to understand the infusion reaction/adverse event 
better. After the primary clinical study report data cut-off date is reached, no additional PK and 
ADA samples will be collected for the patients still on-going on the study. 
Central laboratories will be used for bioanalysis of study drug in human serum. Please refer to 
the Laboratory Manual for details on collection and processing of blood PK samples. 
7.5. 
Biomarker Assessments 
7.5.1. 
Tumor Biopsies 
Patients must be consented for a mandatory fresh tissue biopsy to be performed in order to enroll 
in this trial. The fresh tumor biopsy must be prior to initial treatment (C1D1). If available, 
archival samples will also be collected. An optional fresh tumor biopsy is requested at the EOT 
for patients who discontinue due to PD 
The baseline fresh tumor tissue will be used to investigate potential response-predictive 
biomarkers. Those biomarkers include immunohistochemistry (IHC) as well as RNA 
signatures.The signatures generated will have the potential to inform patient stratification 
strategies for future trials. See the Laboratory Manual for sample processing details.  
Patient tissue samples will be assessed to determine 4 unique RNA signatures as well as whole 
exome sequencing for exploratory  analysis. The putative RNA signatures will be analyzed  to 
determine whether any  correlate to response to the combination treatment. Classifying patients 
to these four putative signatures will be derived from an expanded gene set  from that described 
in Uhlik et at 2016 and a unique classifier algorithm. These four classification signatures 
encompass  immunological and angiogenic characteristics in the tumor stroma. If patients with a  
particular signature/s  are more responsive to this combination treatment, future studies may be 
planned to select patients.   .  


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Residual sample material available after completion of the designated analyses may be used in 
the future for identification of predictive markers or to enhance understanding of disease biology 
unless prohibited by local laws or regulations. 
7.5.2. 
Biomarker Blood Samples 
All patients will have venous blood samples drawn at the time points specified in Table 9 for 
blood biomarkers including, but not limited to, immunomodulating cytokines and related factors.  
Complete instructions for processing, handling and shipment of blood samples will be provided 
in the Laboratory Manual.  
8. 
ADVERSE EVENT MANAGEMENT 
8.1. 
Definition of Adverse Events 
8.1.1. 
Adverse Event (AE) 
Patients will be monitored for all AEs from the time the first dose of study treatment is 
administered through 30 days after the last dose of study treatment. All AEs that occur from the 
signing of the ICF until the first dose of study treatment should be recorded on the AE eCRF 
page only if the event was related to a study procedure. Study procedure-related AEs that occur 
after signing of the ICF and before administration of study treatment will also be collected. 
An AE is the development of an undesirable medical condition or the worsening of a pre-existing 
medical condition following or during exposure to a pharmaceutical product, whether or not 
considered causally related to the study treatment.  
8.1.2. 
Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any study phase (i.e., baseline, treatment, 
washout, or follow-up), and at any dose of the investigational product, comparator or placebo, 
that fulfils one or more of the following: 
Results in death 
It is immediately life-threatening 
It requires in-patient hospitalization or prolongation of existing hospitalization 
It results in persistent or significant disability or incapacity 
Results in a congenital abnormality or birth defect 
It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
8.2. 
Clarifications to Serious Adverse Event Reporting 
Death is an outcome of an SAE and not an SAE in itself. When death is an outcome, report the 
event(s) resulting in death as the SAE term (e.g., “pulmonary embolism”). If the cause of death is 
unknown, report “Death, unknown cause” as the SAE term. 


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Pre-planned or elective hospitalizations including social and/or convenience situations (e.g. 
respite care) are excluded from SAE reporting. In addition, emergency room visits and admission 
under 23-hour observation are excluded from SAE reporting; however, such events should still 
be reported on the appropriate AE eCRF page. 
Events of progression of the patient’s underlying cancer as well as events clearly related to 
progression of the patient’s cancer (signs and symptoms of progression) should not be reported 
as a SAE unless the outcome is fatal during the study or within the safety reporting period. If the 
event has a fatal outcome during the study or within the safety reporting period, then the event 
causing the death must be recorded as an AE and as a SAE with CTC Grade 5 (fatal outcome) 
indicated. The AE/SAE term of Disease Progression should only be used when the Investigator 
is not able to distinguish the actual event that caused the death. 
Serious adverse events specifically related to subsequent anticancer therapies administered 
during the 30-day Safety Follow-up period are excluded from SAE reporting, as are 
hospitalizations for the administration of such therapy. If it is not known whether the SAE is 
related to the subsequent anticancer therapy, the SAE should be reported. 
8.3. 
Assessment of Causality 
The relationship of each AE to the study treatment (bavituximab and pembrolizumab) 
administration will be assessed by the Investigator after careful consideration of all relevant 
factors such as (but not limited to) the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to receipt of 
the study medication and de-challenge or re-challenge according to the following guidelines: 
YES (possible, probably or definitely related): there is a reasonable possibility that the study 
drug caused the event; one or more of the following criteria apply:  
The event follows a reasonable temporal sequence from administration of study drug.  
The event could not be reasonably attributed to the known characteristics of the patient’s clinical 
state, environment or toxic factors or other modes of therapy administered to the patient.  
The event follows a known pattern of response to study drug.  
The event disappears or decreases on cessation or reduction in dose of the study drug. In some 
situations, an AE will not disappear or decrease in intensity upon discontinuation of the study 
drug despite other clear indications of relatedness.  
NO (not related or definitely not related): There is no reasonable possibility that the study drug 
caused the event; one or more of the following criteria apply:  
The event does not follow a reasonable temporal sequence from administration of study drug.  
The event could be reasonably attributed to the known characteristics of the patient’s clinical 
state, concurrent illness, environment or toxic factor or other modes of therapy administered to 
the patient.  
The event does not follow a known pattern of response to study drug.  
The event does not disappear or decrease on cessation or reduction in dose of the study drug, and 
it does not reappear or worsen when the study drug is re-administered. 


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8.4. 
Assessment of Severity 
The severity rating of an AE refers to its intensity. The severity of each AE will be categorized 
using the NCI CTCAE v5.0. For any term that is not specifically listed in the CTCAE scale, 
intensity should be assigned a grade of 1 through 5 using the following CTCAE guidelines: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 8.1.2. An AE of severe intensity may 
not be considered serious. 
8.5. 
Pregnancy or Drug Exposure during Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with bavituximab and /or 
pembrolizumab, the participant will be immediately discontinued from study treatment. The site 
will contact the participant at least monthly and document the participant’s status until the 
pregnancy has been completed or terminated. The outcome of the pregnancy will be reported to 
the Sponsor without delay and within 24 hours if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to 
the mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. All pregnancies and exposure during breastfeeding, must be collected and reported 
from the time of treatment through 120 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anticancer therapy 
Pregnancies must be reported within 24 hours of the Investigator’s knowledge using the 
pregnancy form.  
Pregnancy in itself is not regarded as an AE or SAE unless there is a suspicion that an 
investigational product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the patient was 
discontinued from the study. 


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All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
8.6. 
Laboratory Abnormalities 
To the extent possible, all laboratory abnormalities observed during the course of the study will 
be included under a reported AE term describing a clinical syndrome (e.g., elevated BUN and 
creatinine in the setting of an AE of “renal failure”). In these cases (e.g., an AE of renal failure), 
the laboratory abnormality itself (e.g., elevated creatinine) does not need to be recorded as an 
AE.  
If a laboratory abnormality cannot be reported as a clinical syndrome, AND if the laboratory 
abnormality results in a therapeutic intervention (i.e., concomitant medication or therapy), is a 
DLT, or is judged by the Investigator to be of other particular clinical relevance, then the 
laboratory abnormality should be reported as an AE.  
Patients experiencing AEs or clinically significant laboratory abnormalities will be assessed and 
appropriate evaluations performed until all parameters have returned to baseline levels, or are 
consistent with the patient’s then-current physical condition.  
8.7. 
Reporting Adverse Events 
All AEs, serious and nonserious, will be fully documented on the appropriate eCRF. For each 
AE, the Investigator must provide its duration (start and end dates or ongoing), intensity, 
assessment of causality and whether specific action or therapy was required. 
All AEs that occur from the signing of the ICF until the first dose of study treatment should be 
recorded on the AE eCRF page only if the event was related to a study procedure. All other 
AEs/findings prior to first dose of study treatment should be recorded as medical history on the 
applicable eCRF page. All AEs occurring from the first dose of study treatment until 30 days 
after the last dose of study treatment must be recorded on the AE eCRF. 
All AEs meeting serious criteria, from the time of treatment/ allocation through 90 days following 
cessation of study treatment, or 30 days following cessation of study treatment if the participant 
initiates new anticancer therapy, whichever is earlier must be reported by the investigator.  
All SAEs and AESIs must be reported to the Sponsor’s designee within 24 hours of the 
Investigator’s knowledge. This should be done by completing the eCRF SAE Report Form. 
Detailed instructions for reporting SAEs are provided in a study manual. 
Investigators must follow patients with AEs/SAEs until the event has resolved, the condition has 
stabilized, withdrawal of consent, initiation of subsequent anticancer therapy, the patient is lost 
to follow up or death OR until the 30-day Safety Follow-up Visit, whichever occurs first. New 
and ongoing treatment-related SAEs should be followed beyond the 30-day Safety Follow-up 
Visit. If the patient dies, this should be captured as the outcome of the AE unless no link between 
the AE and the patient death can be established, in which case the AE will be marked as ongoing 
and the death will be reported as a separate event. 
If a patient is lost to follow up, this should be captured accordingly within the AE eCRF and on 
the follow up SAE report.  


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The Sponsor or designee is responsible for notifying the relevant regulatory authorities of 
applicable suspected unexpected serious adverse reactions (SUSARs) as individual notifications 
or through periodic line listings. It is the Principal Investigator’s responsibility to notify the IRB 
or IEC of all SAEs that occur at his or her site. Investigators will also be notified of all 
unexpected, serious, drug-related events (7/15 Day Safety Reports) that occur during the clinical 
trial. Each site is responsible for notifying its IRB or IEC of these additional SAEs as required by 
their IEC/IRB. 
8.8. 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
Adverse events of special interest (AESIs) are required to be reported by the Investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section 8.7 for 
reporting instructions). Adverse events of special interest for this study are as follows: 
An overdose of pembrolizumab as defined as any dose of 1000 mg or  ≥5 times the indicated 
dose, that is not associated with clinical symptoms or abnormal laboratory results. 
No specific information is available on the treatment of overdose of pembrolizumab. In the event 
of overdose, the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
An overdose of bavituximab is define as any dose of 15mg/kg or ≥5 times the indicated dose.   
 No specific information is available on the treatment of overdose of bavituximab. In the event of 
overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated. 
In the event of a known or suspected overdose, the patient should be monitored with appropriate 
hematology and clinical chemistry and should receive supportive therapy, as necessary. Please 
also refer to Section 6.3 for guidelines on the management of potential study treatment-related 
toxicities. 
 
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. The trial site guidance for 
assessment and follow up of these criteria can be made available. It may also be 
appropriate to conduct additional evaluation for an underlying etiology in the setting of 
abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to 
proceed with additional evaluation will be made through consultation between the study 
investigators and the Sponsor Clinical Director. However, abnormalities of liver blood 
tests that do not meet the criteria noted above are not AESIs for this trial. 


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9. 
STATISTICS 
This trial will evaluate safety and efficacy of the bavituximab-pembrolizumab combination in a 
disease setting in which pembrolizumab has shown promising but modest activity. The 
hypothesis to be evaluated is whether the bavituximab-pembrolizumab combination will yield an 
ORR superior to historical ORR of pembrolizumab in the 2nd-line or 3rd-line settings in patients 
who have not previously been exposed to an anti-PD-1 or anti-PD-L1 agent. Detail on all 
planned statistical analyses will be presented in a separate Statistical Analysis Plan (SAP).  
The minimum efficacy analysis will be conducted 3 months after 40 patients have received at 
least one dose of study treatment.  There will be no more than 4 additional patients enrolled 
during the time the minimum efficacy analysis is taking place.  Conducting an analysis at 
approximately 40 patients  will limit patients risks if the combination is not trending towards an 
added benefit, as defined by a response rate of 15% or greater (6/40) further exploration will be 
warranted before further enrollment to 80 patients (details provided in interim analysis section).  
9.1. 
Sample Size 
 
The primary efficacy objective of this Phase 2 study is the evaluation of ORR of bavituximab in 
combination with pembrolizumab in patients with advanced gastric or GEJ cancer. The sample 
size of 80 patients across both Group 1 and Group 2 was chosen to allow minimal enrollment 
within each  of our four putative biomarker signatures to allow for exploration of differential 
responses, more information about the biomarkers can be found in section 7.5.1. As noted above, 
an ORR of <15% will be regarded as futile as it will be unlikely to exceed the activity of 
pembrolizumab as a single agent in this study population.  
The following sample sizes apply:  
DLT Observation: up to 10 DLT-evaluable patients in total  
Phase 2: Minimum efficacy analysis: 40 total patients across both Group 1 and Group 2; Full 
enrollment: 80 patients  
For the CPI-naïve patient population assumptions, the historical ORR of pembrolizumab in the 
2nd-line setting was approximately 15% and an ORR of the bavituximab-pembrolizumab 
combination was set to 30%. Approximately 40 patients are needed to show a statistical 
superiority of bavituximab-pembrolizumab with 80% statistical power at one-sided type I error 
rate of α=0.10. In the 3rd-line setting if the historical ORR is assumed as 6%, if the true ORR 
of Bavituximab-Pembrolizumab combination is 15%, then approximately 40 patients are needed 
to show a statistical superiority of Bavituximab-Pembrolizumab with 74% statistical power at 
one-sided type I error rate of α=0.10. In addition, PDL1 status was able to impact outcomes in all 
lines of treatment with PDL1+ patients having better outcomes than negative.  By combining 
patients from DLT and the expansion phase, safety and efficacy information will be available for 
a total of 80 patients, assuming >6 responders are observed by 40.  Enrollment will not be 
controlled for the number of patients in each line nor PD-L1 status (2nd vs. 3rd line, positive vs. 
negative), these numbers could vary for each patient type (e.g. 2nd line PDL1+ vs. Third line 
PDL1 negative). Tables 9.1.1 and 9.1.2 show  how the power varies for with the 2nd and 3rd line 
cohorts with their respective sample sizes. 


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Table 9.1.1. Power in 2nd line Gastric Cancer 
2nd Line Subjects 
Responses (CR/PR) 
for p < 0.1 
Power for p1=0.25 
(%) 
Power for p1=0.3 
(%) 
20 
6 
38.3 
58.3 
30 
8 
48.5 
71.8 
40 
10 
56.0 
80.4 
50 
12 
61.8 
86.1 
60 
14 
66.5 
90.0 
Assume historical ORR with p0=0.15. 
Table 9.1.2. Power in 3rd line Gastric Cancer 
3rd Line Subjects 
Responses (CR/PR) 
for p < 0.1 
Power for p1=0.15 
(%) 
Power for p1=0.2 
(%) 
20 
4 
59.5 
79.3 
30 
4 
67.8 
87.7 
40 
5 
73.6 
92.4 
50 
6 
78.0 
95.2 
60 
6 
90.3 
98.7 
Assume historical ORR with p0=0.05. 
For the CPI-relpase patient population, the n was set to 20 patients for the initial assessment of 
safety, tolerability and initial antitumor activity.   
9.2. 
Analysis Populations 
The following analysis populations are defined for the study: 
Safety population: all patients who received at least 1 dose of bavituximab or pembrolizumab, 
regardless of their eligibility for the study. The safety evaluation will be performed based on the 
first dose a patient actually received. The safety population will be used for all analyses of 
dosing, exposure, and safety. 


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DLT-evaluable population: will include the first 3 patients up to a maximum of 10 patients who 
(1) receive at least 70% of the dose of bavituximab (2) complete the DLT observation period  or 
discontinue (from study treatment or from the study) during the DLT observation period (Cycle 
1) because of a DLT. 
PK population: will include all treated patients who received at least 1 full dose of bavituximab 
and pembrolizumab and have baseline and at least one postbaseline evaluable PK sample. 
Efficacy population: will include all patients (including DLT patients) who receive any quantity 
of study treatment at the dose recommended for the Phase 2 population.  
9.3. 
Statistical Analyses 
Statistical analysis of this study will be the responsibility of Oncologie, Inc. or its designee.  
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report. Additional exploratory 
analyses of the data will be conducted as deemed appropriate.  
9.3.1. 
Safety Analyses  
All patients who receive at least 1 dose of bavituximab or pembrolizumab will be evaluated for 
safety and toxicity. Data will be reviewed by group and dose level.  
Safety analyses will include summaries of the following:  
• DLTs: the number of patients who experienced any DLTs during the DLT observation 
period will be summarized by dose level 
• AEs, including severity and possible relationship to study treatment  
• AEs by Medical Dictionary for Regulatory Activities System Organ Class (SOC) by 
decreasing frequency of Preferred Term within SOC  
• Laboratory and nonlaboratory AEs by CTCAE v5.0 term, maximum CTCAE grade, and 
CTCAE Grade 3 and above (regardless of causality and at least possibly related to study 
treatment 
The final analysis will occur approximately 6 months after the last patient received his or her 
first dose of study treatment. Descriptive statistics will be derived where appropriate. Adverse 
events will be summarized by study arm; dose exposure and density for each study drug will be 
calculated for each group and dose level.  
Incidence tables of patients with AEs will be presented for all AEs by maximum severity, SAEs, 
AEs assessed as related to study treatment, and AEs resulting in discontinuation of study 
treatment.  
Listings of all safety data sorted by dose, group, patient and assessment date will be provided. 


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9.3.2. 
Pharmacokinetic/Pharmacodynamic Analyses  
Serum concentrations for bavituximab will be listed and summarized using descriptive statistics 
by cohort and group at each time point.  
Pharmacodynamic biomarkers will be listed and summarized using descriptive statistics by 
cohort and group  at each time point.  
The PK/PD relationship and relationship to tumor response may be explored.  
9.3.3. 
Efficacy Analyses  
In order to characterize the preliminary efficacy signal, the primary efficacy endpoint will be the 
best overall response rate (CR and PR) according to RECIST Version 1.1 (Appendix A) as 
determined by the Investigator. Corresponding confidence intervals (CIs) will also be provided.  
For planning purposes, ORR of <15% will be regarded as futile as the combination will be 
unlikely to exceed the activity of pembrolizumab as a single agent. 
Efficacy analysis will be performed on the full analysis set, and per protocol analysis set, 
including predefined biomarker subgroups (Section 9.3.2). 
Duration of Response (DoR), defined as the interval from the date measurement criteria are met 
for CR or PR (whichever is first recorded) until the earliest date of disease progression, as 
determined by Investigator assessment of objective radiographic disease assessments per 
RECIST 1.1 or death due to any cause if occurring sooner than progression. Only subjects who 
achieve an initial response will be evaluated for DOR. 
Stable disease (SD) at 6 weeks will also be used to derive the clinical benefit rate (CBR), 
consisting of ORR and SD.  
Progression-Free Survival (PFS) will be defined as the interval from the date of first dose of 
investigational agent until the earliest date of disease progression, as determined by Investigator 
assessment of objective radiographic disease assessments per RECIST version1.1 or death due to 
any cause if occurring sooner than progression.  
Overall survival (OS) defined as the interval from the date of first dose of investigational agent 
until the date of death. 
Presentations of efficacy will include patients enrolled in Part 1 as well as patients treated at the 
recommended dose. Individual changes in tumor burden over time will be presented graphically 
(for example, Waterfall plots). Details regarding statistical methodologies associated with 
analyses of the initial efficacy signal will be further defined in the SAP.  
9.3.4. 
Primary Analysis  
The primary analysis will be conducted approximately 6 months after the last patient receives his 
or her first dose of study treatment  


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9.3.5. 
Other Analyses  
9.3.5.1. 
Patient Characteristics  
Patient characteristics will be summarized:  
Patient demographics will be reported using descriptive statistics. Demographic data are 
collected and reported to demonstrate that a trial population represents the target patient 
population considered for regulatory approval.  
Baseline disease characteristics will be summarized by presenting frequency counts and 
percentages (for example, for pathological diagnosis [histological or cytological] and disease 
stage).  
A detailed description of patient disposition will be provided. It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated, as 
well as the number and percentage of patients discontinuing (overall and by reason for 
discontinuation).  
Disease-related therapies, including prior anticancer treatments and prior radiotherapies (such as 
type of therapy, regimen, and prior surgery)  
A summary of prior and concomitant medications by study arm will be reported. Other patient 
characteristics will be summarized as deemed appropriate. 
9.3.5.2. 
Poststudy-Treatment-Discontinuation Therapy  
The numbers and percentages of patients reporting poststudy-treatment-discontinuation 
anticancer therapies will be provided by type of therapy (surgery, radiotherapy, or systemic 
therapy) and by drug class and/or name, overall and by line of therapy.  
9.3.5.3. 
Treatment Compliance  
The number of dose omissions, reductions, and delays, number of cycles received, and dose 
intensity will be summarized for all treated patients.  
9.3.5.4. 
Interim Analysis  
Safety data will be reviewed during the study. The purpose of these data reviews is to evaluate 
the safety and tolerability for the initial dose schedule and determine if a DLT has been 
observed. Additional safety analyses will be performed when a total of 10 subject patients have 
received at least one dose of study therapy and followed for 3 months after the 10th patients 
receives the first dose of study therapy. At that point the available clinical safety data as well as 
laboratory data will be evaluated particularly for late-onset DLT-like toxicities.  
Interim analyses of the safety and efficacy data will be performed approximately 3 months after 
a total 40 patients across both Group 1 and Group 2 have received at least one dose of study 
treatment. The data from the interim analyses will be considered directional and used primarily 
for minimal efficacy analysis considerations.  After the analysis of 40 patients for ORR, the 
activity of study therapy across the entire population as well as in the combined pool of 
biomarker groups will be analyzed, and, if the data appear to be promising, the study population 
or the overall sample size may be adjusted via an amendment.  


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The study will be assessed for futility if the interim analysis finds no evidence for the activity of 
the study therapy beyond that expected for pembrolizumab monotherapy.  No formal statistical 
testing will be done at the interim analysis. Details on the procedures for the interim analysis will 
be provided in the SAP. 
9.4. 
Statistical Methods 
Tabular summaries of data will be descriptive in nature (i.e., number of patients [n], mean, 
standard deviation, median, minimum and maximum for continuous variables and n and percent 
for categorical variables). A more detailed description of analysis methods will be provided in 
the SAP to be completed prior to the clinical database lock. 


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10. 
STUDY ADMINISTRATION 
10.1. 
Regulatory and Ethical Considerations 
This study will be conducted in compliance with the protocol; GCPs, including ICH Technical 
Requirements for Registration of Pharmaceuticals for Human Use Guidelines; Food and Drug 
Administration (FDA) regulatory requirements; other regulatory authorities, and in accordance 
with the ethical principles of the Declaration of Helsinki. 
10.1.1. 
Regulatory Authority Approvals 
The Sponsor or designee will submit the study protocol plus all relevant study documents to 
applicable regulatory agencies for approval before the study start. No patient will be admitted to 
the study until appropriate regulatory approval of the study protocol has been received. 
Each Investigator must complete a Form FDA 1572 or equivalent and provide the completed 
form according to written instructions to the Sponsor (or designee). Each Investigator must 
submit to the Sponsor (or designee) financial disclosure information according to national law 
and/or local regulations. 
Data generated in the US will be handled in accordance with the Health Information Portability 
and Accountability Act (HIPAA). The study will be registered at www.clinicaltrials.gov using 
the Protocol Registration System. 
10.1.2. 
Institutional Review Board/Ethics Committees  
This protocol and any material to be provided to the patient (such as advertisements, patient 
information sheets, or descriptions of the study used to obtain informed consent) will be 
submitted by the Investigator to an IEC/IRB. This also applies to protocol amendments. 
The Sponsor will supply relevant data for the Investigator to submit the study protocol and 
additional study documents to the IEC/IRB. The Principal Investigator will submit the study 
protocol for review and approval by an IEC/IRB, according to national law and/or local 
regulations, and will provide the IRB with all appropriate materials. 
Verification of the IEC/IRB’s unconditional approval of the study protocol and the written ICF 
will be transmitted to the Sponsor. This approval must refer to the study by exact study protocol 
title and number, identify the documents reviewed, and state the date of the review. 
No patient will be admitted to the study until appropriate IEC/IRB approval of the study protocol 
has been received, the Investigator has obtained the signed and dated ICF, and the Sponsor is 
notified. 
The Principal Investigator will submit appropriate reports on the progress of the study to the 
IEC/IRB in accordance with applicable national law and/or local regulations and in agreement 
with the policy established by the IEC/IRB. 
The IEC/IRB must be informed by the Principal Investigator of all subsequent study protocol 
amendments and of SAEs or SUSARs occurring during the study that are likely to affect the 
safety of the patients or the conduct of the study. 


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10.2. 
Confidentiality of Information 
The Investigator must ensure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties. The Investigator must keep logs on screened 
and enrolled patients. In addition, the Investigator must have a list where the identity of all 
treated patients can be found. 
The Investigator agrees that all information received from the Sponsor, including, but not limited 
to, the IB, this protocol, eCRFs, the protocol-specified treatment, and any other study 
information, remain the sole and exclusive property of the Sponsor during the conduct of the 
study and thereafter. This information is not to be disclosed to any third party (except employees 
or agents directly involved in the conduct of the study or as required by law) without prior 
written consent from the Sponsor. The Investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study center to any third 
party or otherwise into the public domain. The Investigator shall be under additional obligations 
related to non-disclosure confidential information and the handling of intellectual property as set 
forth in the Clinical Trial Agreement. 
10.3. 
Patient Informed Consent 
All information about the clinical study, including the patient information and the ICF, is 
prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines, the Declaration of Helsinki and local regulations. 
It is the responsibility of the Investigator to obtain signed ICFs from each patient participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study and before undertaking any study-related procedures. 
The ICF, prepared by the Investigator with the assistance of the Sponsor, must be approved 
along with the study protocol by the IEC/IRB and be acceptable to the Sponsor. 
The patient must be provided with the patient information and ICF consistent with the study 
protocol version used and approved by the relevant IRB. The ICF must be in a language fully 
comprehensible to the prospective patient. Patients (and/or relatives, guardians, or legal 
representatives, if necessary) must be given sufficient time and opportunity to inquire about the 
details of the study and to discuss and decide on their participation in the study with the 
Investigator concerned. The patient and the person explaining about the study and with whom 
they discuss the informed consent will sign and date the ICF. A copy of the signed ICF will be 
retained by the patient and the original will be filed in the Investigator file unless otherwise 
agreed. 
10.4. 
Study Monitoring 
On behalf of the Sponsor, a clinical research organization monitor will contact and visit the 
Investigator at the study center before the entry of the first patient and at predetermined 
appropriate intervals during the study until after the last patient has completed. The monitor will 
also perform a study closure visit.  
In accordance with ICH GCP guidelines, the Investigator must ensure provision of sufficient 
time, reasonable space, and adequate qualified personnel for the monitoring visits. The visits are 


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for the purpose of verifying adherence to the study protocol and the completeness, consistency, 
and accuracy of data entered on the eCRF and other documents. 
The Investigator will make all source data (i.e., the various study records, the eCRFs, laboratory 
test reports, other  records, drug accountability forms, and other pertinent data) available for the 
monitor and allow access to them throughout the entire study period. Monitoring is done by 
comparing the relevant site records of the patients with the entries on the eCRF (i.e., source data 
verification). It is the monitor’s responsibility to verify the adherence to the study protocol and 
the completeness, consistency, and accuracy of the data recorded on the eCRFs. 
By agreeing to participate in the study, the Investigator agrees to cooperate with the monitor to 
ensure that any problems detected in the course of the monitoring visits are resolved. Contact 
information for the study monitor is located in the Investigator file. Representatives from the 
Sponsor may also contact and visit the Investigators and monitor data during the study. 
10.5. 
Electronic Case Report Form (eCRF) 
The data will be collected using an electronic data capture (EDC) system. Sites will receive 
training on the EDC system. All users will be supplied with unique login credentials. 
Before study start, the Investigator will prepare a list showing the signature and handwritten 
initials of all individuals authorized to make or change entries on eCRFs. This “study center 
personnel and delegation list” must be kept current throughout the study. 
For each patient enrolled, an eCRF must be completed, reviewed, signed, and dated by the 
Principal Investigator or Co-Investigator within a reasonable time period (< 2 weeks) after data 
collection. This also applies to records for those patients who fail to complete the study. If a 
patient withdraws from the study, the reason must be noted on the eCRF. If a patient is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be made 
to clearly document the outcome. 
Full information regarding EDC and completing eCRFs is included in a study manual. All 
questions or comments related to electronic capture should be directed to the assigned monitor. 
10.6. 
Study Termination and Site Closure 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures. In terminating the study, 
the Sponsor and the Investigator will ensure that adequate consideration is given to the protection 
of the patients’ interests. 
The Sponsor reserves the right to discontinue the study at any time for medical or administrative 
reasons. When feasible, a 30-day written notification will be given. 
The entire study will be stopped if: 
The protocol-specified treatment is considered too toxic to continue the study; 
Evidence has emerged that, in the opinion of the Sponsor or the Investigator(s), makes the 
continuation of the study unnecessary or unethical; 
The stated objectives of the study are achieved; 


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The Sponsor discontinues the development of study treatment. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow up must be recorded on the eCRF. All reasons for discontinuation of 
treatment must be documented. In terminating the study, the Investigator will ensure that 
adequate consideration is given to the protection of the patients’ interests. 
10.7. 
Modification of the Study Protocol 
Protocol amendments, except when necessary to eliminate an immediate hazard to patients, must 
be made only with the prior approval of the Sponsor. Agreement from the Investigator must be 
obtained for all protocol amendments and amendments to the informed consent document. The 
IEC/IRB must be informed of all amendments and give approval before their implementation. 
The Sponsor will submit any study protocol amendments to the concerned regulatory authorities 
for approval and keep the Investigator(s) updated as detailed in the ICH GCP guidelines. 
10.8. 
Retention of Study Documents 
The study site will maintain a study file, which should contain, at minimum, the IB, the protocol 
and any amendments, drug accountability records, correspondence with the IRB and the 
Sponsor, and other study-related documents. 
The Investigator agrees to keep records and those documents that include (but are not limited to) 
the identification of all participating patients, medical records, study-specific source documents, 
source worksheets, all original signed and dated ICFs, copies of all eCRFs, query responses, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities 
and the Sponsor or its designees. 
The Investigator shall retain records required to be maintained for a period of 5 years after the 
date a marketing application in an ICH region is approved for the drug for the indication for 
which it is being investigated or, if no application is to be filed or if the application is not 
approved for such indication, until at least 5 years after the investigation is discontinued. 
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor. In addition, the Investigator must make 
provision for the patients’ medical records to be kept for the same period of time. 
No data should be destroyed without the agreement of the Sponsor. Should the Investigator wish 
to assign the study records to another party or move them to another location, the Sponsor must 
be notified in writing of the new responsible person and/or the new location. The Sponsor will 
inform the Investigator, in writing, when the study-related records are no longer needed. 
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site. 
10.9. 
Clinical Study Report 
A clinical study report will be prepared under the responsibility and supervision of the Sponsor 
and signed by a Sponsor representative, thereby indicating their agreement with the analyses, 
results, and conclusions of the clinical study report. 


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10.10. 
Study Publication 
The conditions regulating dissemination of the information derived from this study are described 
in the Clinical Trial Agreement. 
10.11. 
Quality Assurance Audits 
Clinical centers may be audited by the Sponsor’s Quality Unit (QU) qualified auditor or designee 
as required per approved schedule. The purpose of an audit, which is independent of and separate 
from routine monitoring or Quality Unit (QU) functions, is to evaluate study conduct and 
compliance with the protocol, standard operating procedures, ICH GCPs, and the applicable 
regulatory requirements. The Investigator and the Sponsor may also be subject to an inspection 
by FDA, European regulatory authorities, or other applicable regulatory authorities at any time. 
The auditor and regulatory authorities will require authority from the Investigator to have direct 
access to the patients’ medical records. It is important that the Investigator(s) and their staff 
cooperate with the auditor or regulatory authorities during this audit or inspection. 


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11. 
REFERENCES 
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Chemnitz, Jens M., Parry, Richard V., Nichols, Kim E., June, Carl H., Riley, James L., SHP-1 and 
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Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and 
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Disis, Mary L. Immune Regulation of Cancer. Journal of Clinical Oncology.2010; 28 (29):4531-
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A., et al. Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting 
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Francisco, Loise M., Sage, Peter T., and Sharpe, Arlene H. The PD-1 pathway in tolerance and 
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Giese R, Budhu S, Barker C, et al. Phosphatidylserine targeting and radiation improves survival 
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cancers. Breast Cancer Res. 2016;18:50. 
Greenwald, Rebecca J., Freeman, Gordon J., and Sharpe, Arlene H. The B7 Family Revisited. 
Annual Reviews.2005; 23:515–48 
Hirano, F., et al., Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer  
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Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic 
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Ji, Yuan., Wang, Sue-Jane. Modified Toxicity Probability Interval Design: A safer and more 
reliable method than the 3+3 design for practical phase 1 trials. Journal of Clinical Onc, 2013; 1-
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Nomi, T., et al., Clinical significance and therapeutic potential of the programmed death-1 
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Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell 
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Braunstein, Inbal., Kobayashi, Sumire V., Linsley, Peter S., Thompson, 4 Craig B. 
and Riley, James L. CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by 
Distinct Mechanisms. MOLECULAR AND CELLULAR BIOLOGY, 2005; 0270-7306Pilon-
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Riley, James L., PD-1 signaling in primary T cells. Immunological Reviews. 2009; 0105-2896 
 
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blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the 
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12 APPENDICES 
Appendix A: Response Evaluation Criteria in Solid Tumor (RECIST) Version 1.1 
The RECIST guidelines (version 1.1) are described in Eisenhauer (2009) and at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with the following: 
• A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm); 
• A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable); 
• A minimum size of 20 mm by chest X-ray. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
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 not greater than 5 mm). At baseline and in follow up, only the short axis will be measured 
and followed. 
Nonmeasurable 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), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of skin and lung, and abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require particular 
comment. Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these techniques can 
be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
Blastic bone lesions are nonmeasurable. 


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Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor nonmeasurable) because they are, by definition, 
simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred as target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previous irradiated area or in an area subjected to other locoregional 
therapy are usually not considered measurable unless there has been demonstrated progression in 
the lesion. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the overall tumor response. 
Non-target Lesions 
RECIST criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary are 
difficult to delineate, this tumor should not be considered a target lesion. 
Guidelines for Evaluation of Measurable Disease 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 


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Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 
mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD 
since the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the LD 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. 
The appearance of one or more new lesions is also considered 
progression. 
 
 
Evaluation of Non-Target Lesions 
Complete Response 
Disappearance of all non-target lesions and normalization of tumor 
marker level. 
Stable Disease/Incomplete 
Response 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. 
 
 
If tumor markers are initially above the institutional ULN, they must normalize for a patient to 
be considered a complete responder. 
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 PD the smallest measurements recorded 
since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
Time Point Response 
A response assessment will occur at the protocol-specified time points. The tables below provide 
a summary of the overall response status calculation at each time point for patients who have 
measurable and non-measurable disease (non-target disease only). 


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Study ONCG100 
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Time point Response: Patients with Target (± non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; NE, Not evaluable. 
 
Evaluation of Best Overall Response When Confirmation of CR and PR Required 
Overall Response: 
First Time Point 
Overall Response: 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; NE, Not evaluable. 
 
a 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes this disease PD at that point (since disease must have reappeared after CR). Best response 
would depend on whether minimum duration for SD was met. However sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time 
point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
 


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Clinical Study Protocol 
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Study ONCG100 
Amendment 4 
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Time point Response: Patients with Nontarget Lesion Assessments 
Nontarget Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
CR 
No 
CR 
Normalization of tumor markers, tumor 
nodes < 10 mm 
Non-CR/non-PD 
No 
Non-
CR/non-PD 
 
Not all evaluated 
No 
NE 
 
Unequivocal PD 
Any 
PD 
 
Any 
Yes 
PD 
 
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”. This is a 
reason for stopping therapy, but is NOT objective PD. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response, which is most likely to occur in the case of PD; e.g., if only 2 
of 3 baseline target lesions are assessed and result in a > 20% increase in the sum, then the 
patient would be assessed as a PD regardless of the missing lesion. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective progression, 
even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspiration/biopsy) before confirming the CR status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
Radiographic tumor assessments are required. If an initial CR or PR is noted, confirmatory scans 
must be performed at least 4 weeks later. In the case of SD, follow-up measurements must have 
met the SD criteria at least once after study entry at a minimum interval of no less than 4 weeks. 


Oncologie, Inc. 
Clinical Study Protocol 
Bavituximab and Pembrolizumab 
Study ONCG100 
Amendment 4 
Page 100 of 102 
Confidential 
 
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 PD is objectively 
documented (taking as reference for PD 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 recurrent disease is objectively documented. 
Duration of Stable Disease 
SD 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. 
Reference: 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247. 
 


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Clinical Study Protocol 
Bavituximab and Pembrolizumab 
Study ONCG100 
Amendment 4 
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Appendix B: Creatinine Clearance Formula 
 
 
 


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Clinical Study Protocol 
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Study ONCG100 
Amendment 4 
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Appendix C: New York Heart Association Classification of Functional Cardiac Capacity 
Class 
Description 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, dyspnea, 
or palpitation. 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at rest, 
less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of congestive 
heart failure are present even at rest. With any physical activity, increased 
discomfort is experienced. 
From: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood vessels. 
Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964:114. 
 
 

SAP_001.pdf: 
Sponsor Name: Oncologie, Inc. 
Sponsor Protocol ID: ONCG100 
Labcorp Study ID: 000000176725 
 
 
Confidential 
 
Statistical Analysis Plan  
 
Oncologie, Inc. 
 
ONCG100 
 
 
Covance Study ID: 000000176725 
Document Version: 3.0 
Document Date: 27 September 2021 
 
 
 
 
Author: 
Margaret Connolly 
Labcorp Drug Development Lead Statistician 
 
 
Information described herein is confidential and may be disclosed only with the express written 
permission of the sponsor. 
 
 


Sponsor Name: Oncologie, Inc. 
Sponsor Protocol ID: ONCG100 
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Table of Contents 
Statistical Analysis Plan .................................................................................. 1 
Table of Contents ........................................................................................... 2 
List of Tables ................................................................................................. 4 
Reviewers ..................................................................................................... 5 
Version History .............................................................................................. 5 
Glossary of Abbreviations ................................................................................ 6 
1. 
Source Documents ................................................................................. 8 
2. 
Protocol Details ..................................................................................... 9 
2.1 
Study Objectives................................................................................. 9 
2.2 
Overall Study Design ........................................................................... 9 
2.3 
Sample Size and Power ..................................................................... 14 
3. 
Efficacy and Safety Variables................................................................. 16 
3.1 
Primary Endpoints ............................................................................. 16 
3.2 
Secondary Endpoints ......................................................................... 16 
3.3 
Tertiary Endpoints ............................................................................. 16 
4. 
Analysis Populations ............................................................................. 18 
4.1 
Safety Population .............................................................................. 18 
4.2 
DLT-evaluable population ................................................................... 18 
4.3 
PK Population ................................................................................... 18 
4.4 
Efficacy Population ............................................................................ 18 
5. 
Data Handling ..................................................................................... 19 
5.1 
Time points and Visit Windows ........................................................... 19 
5.1.1 
General Definitions ...................................................................... 19 
5.1.2 
Screening Period and Baseline ...................................................... 19 
5.1.3 
Treatment Period ........................................................................ 19 
5.1.4 
Visit Windows ............................................................................. 19 
5.2 
Handling of Dropouts, Missing Data, and Outliers .................................. 21 
6. 
Statistical Methods ............................................................................... 24 
6.1 
General Principles ............................................................................. 24 
6.2 
Subject Disposition and Data Sets Analyzed ......................................... 24 


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6.3 
Protocol Deviations ........................................................................... 25 
6.4 
Demographics and Other Baseline Characteristics ................................. 25 
6.4.1 
Screening and Baseline Details ...................................................... 26 
6.4.2 
Medical History ........................................................................... 26 
6.4.3 
Prior and Concomitant Medications ................................................ 27 
6.5 
Measurements of Treatment Compliance – not applicable ...................... 27 
6.6 
Efficacy ............................................................................................ 27 
6.6.1 
Primary Efficacy Analysis .............................................................. 27 
6.6.2 
Secondary Efficacy Analysis .......................................................... 28 
6.6.3 
Sensitivity Analyses for Primary and Secondary Efficacy Analysis ...... 31 
6.6.4 
Pharmacokinetic (PK) Analysis ...................................................... 31 
6.6.5 
Pharmacodynamic Variables ......................................................... 31 
6.6.6 
Immunogenicity Analysis .............................................................. 31 
6.6.7 
Subgroup Correlation Analysis ...................................................... 32 
6.7 
Safety ............................................................................................. 34 
6.7.1 
Extent of Exposure ...................................................................... 34 
6.7.2 
Adverse Events ........................................................................... 35 
6.7.3 
Laboratory Evaluations ................................................................. 39 
6.7.4 
Vital Signs .................................................................................. 41 
6.7.5 
Electrocardiograms ...................................................................... 41 
6.7.6 
Physical Examination ................................................................... 41 
6.7.7 
ECOG Performance Status ............................................................ 41 
6.8 
Interim Analysis................................................................................ 42 
7. 
Changes in Planned Analysis ................................................................. 43 
8. 
Laboratory Tests, Standard International (SI) Units and Decimal Precision .. 44 
9. 
Severity Grades in Clinical Laboratory Listings and Tables ......................... 47 
 
 
 


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List of Tables 
Table 1: 
Schedule of Assessments .............................................................. 11 
Table 2: 
Power in 2nd line Gastric Cancer or Gastroesophageal Junction ......... 15 
Table 3: 
Power in 3rd line Gastric Cancer or Gastroesophageal Junction .......... 15 
Table 4: 
Definition of Visit Windows for Tumor Response............................... 21 
Table 5: 
Rules for Determining Date of Progression or Censor for Progression-
Free Survival ............................................................................... 29 
Table 6: 
Pharmacokinetic/Pharmacodynamic/Biomarker Blood Sample Specific 
Collections – Collection Times ....................................................... 32 
Table 7: 
Clinical Laboratory Tests ............................................................... 44 
Table 8: 
Hematology Severity Grades of Laboratory Abnormal Results ............ 48 
Table 9: 
Coagulation Severity Grades of Laboratory Abnormal Results ............ 49 
Table 10: 
Clinical Chemistry Severity Grades of Laboratory Abnormal Results ... 50 
 
 


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Reviewers 
The following reviews of the Draft SAP prior to Version 3 were conducted: 
 
Version History  
Version # 
Description of Changes 
Version Date 
1.0 
Not applicable 
24 October 2019 
2.0 
Update per Protocol Amendment 3, 06 February 2020 
09 September 2020 
3.0 
Update per Protocol Amendment 4, 14 September 2020 
27 September 2021 
 
 
Name and Title  
 Role 
Version Last 
Reviewed 
Company/ 
Organization 
Susan MacIntyre 
Clinical Development 
Draft Version 2.1 
Oncologie, Inc.   
Kerry Culm-Merdek 
Clinical Development 
Draft Version 2.1 
Oncologie, Inc.   
Lukas Makris 
Statistics 
Draft Version 2.1 
Oncologie, Inc.   


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Glossary of Abbreviations 
Abbreviation 
Term 
ADA 
Antidrug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the curve  
B 
Biomarker 
β2-GP1 
Beta2 glycoprotein 1 
BILI 
Bilirubin, total 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
CK 
Creatine kinase 
Cmax 
Maximum concentration 
CPS 
Combined Positive Score 
CR 
Complete response 
CRF 
Case report form 
CTCAE 
Common terminology criteria for adverse events 
Ctrough 
Lowest dose concentration prior to the next dose 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
FU 
Follow-up 
GEJ 
Gastroesophageal junction 
HER2 
Human epidermal growth factor receptor 2 
irAE 
Immune-related adverse event 
Meds 
Medications 
MedDRA 
Medical dictionary for regulatory activities 
MSI 
Micro satellite instability 
NLR 
Neutrophil to lymphocyte ratio 
PD-1 
Programmed cell death protein 1 
PDL1 
Programmed death-ligand 1 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PR 
Partial response 
PS 
Performance status EOT 
PT 
Preferred Term 
Q3W 
Every 3 weeks 


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RBC 
Red blood cells 
RECIST 
Response evaluation criteria in solid tumors 
RDE 
Recommended dose for expansion 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SD 
Standard deviation 
SE 
Standard error 
SI 
Standard international (International System of Units) 
SOC 
System organ class 
SoD 
Sum of Diameters 
SRC 
Safety review committee 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, figures and listings 
TNM 
Tumor, Node, Metastasis 


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1. Source Documents 
The Statistical Analysis Plan was written based on the following documentation: 
Document 
Date 
Version 
Protocol Amendment 1 
20Mar2019 
Amendment 1 
Protocol Amendment 1A (United Kingdom 
only) 
05Sep2019 
 
Production 1.0 Casebook 
19Jul2019 
 
 
The Amended Statistical Analysis Plan was written based on the following 
documentation: 
Document 
Date 
Version 
Protocol Amendment 3 
06Feb2020 
Amendment 3 
Production 2.0 Casebook 
29APR2020 
 
 
The Version 3 Statistical Analysis Plan was written based on the following 
documentation: 
Document 
Date 
Version 
Protocol Amendment 4 
14Sep2020 
Amendment 4 
Production 3.0 Casebook 
24Sep2020 
 
 


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2. Protocol Details 
2.1 Study Objectives 
Study objectives are the same for both Group 1 (CPI naïve) and Group 2 (CPI 
relapse). 
The objectives of the study are: 
Primary:  
• 
To assess the safety and tolerability of bavituximab in combination with 
pembrolizumab in patients with advanced gastric/gastroesophageal junction 
(GEJ) cancer  
• 
To assess the antitumor activity of the treatment combination based on 
Response Evaluation Criteria in Solid Tumors (RECIST) Guideline Version 1.1 
(Protocol Appendix A) 
Secondary:  
• 
To further characterize the antitumor activity of the treatment combination 
based on additional assessments of clinical benefit 
• 
To evaluate bavituximab concentrations when administered in combination 
with pembrolizumab 
• 
To assess the potential immunogenicity of bavituximab  
Tertiary: 
• 
To evaluate a novel biomarker signature panel and correlate with efficacy 
outcomes in patients treated with bavituximab-pembrolizumab combination 
 
2.2 Overall Study Design 
This is a Phase 2, multicenter, open-label, non-randomized study with an initial safety 
analysis to assess the safety and tolerability of bavituximab administered in 
combination with pembrolizumab, a PD-1 inhibitor, in patients with advanced gastric 
or GEJ adenocarcinoma who have either progressed on standard chemotherapy and 
are naïve to CPI therapy (Group 1), or have progressed following treatment with CPI 
either alone or in combination with chemotherapy (Group 2).   
Following a minimum of 3 and a maximum of 10 patient safety run-in with 
bavituximab (3 mg/kg IV weekly) and pembrolizumab (200 mg IV every 3 weeks 
[Q3W]), additional patients will be recruited if the initial doses of the regimen are 
tolerable.  Lower doses of bavituximab may be explored if the initial doses are not 
tolerable.  Primary anti-tumor activity will be documented by Investigator-assessed 
objective response per RECIST 1.1.  Approximately 80 patients will be enrolled in the 


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study, a minimum of 40 patients will be enrolled in Group 1 and a minimum of 
20 patients will be enrolled in Group 2. 
The first 3 patients will be evaluated for dose-limiting toxicities (DLTs) for the purpose 
of declaring the tentative RDE.  The SRC will review data from these patients for DLTs 
at the end of the first 3-week cycle. 
After a minimum of 3 and maximum of 10 eligible patients are enrolled and treated 
for at least 1 cycle (3 weeks), the SRC will review data from these patients to 
determine the recommended dose for expansion (RDE).  In case of DLTs, de-
escalating doses of bavituximab in combination with pembrolizumab will be assessed.  
After the DLT observation period, expansion may proceed.  The cumulative safety 
data from the initial 3 to 10 patients will be evaluated by the SRC, as well as 
subsequent safety data from the expansion population, as deemed appropriate by 
the SRC.   
Once the RDE of the combination of bavituximab and pembrolizumab has been 
confirmed, additional patients will be recruited if the initial doses of the regimen are 
tolerable.  Patients will be assessed for preliminary efficacy and pharmacodynamic 
effects, as well as safety and tolerability.  Patients will be evaluated regularly for 
safety and efficacy according to the Schedule of Assessments (Table 1).   
Safety data monitored throughout the course of the study is including but not limited 
to; reviewing trends in safety data, laboratory analytes, and adverse events (AEs) 
including monitoring of adverse events of special interest (AESIs).   
The SRC, comprised of a medical monitor, statistician, the primary Investigator, and 
ad hoc SRC members, as needed, will be responsible for review of safety data.  The 
SRC will convene regularly to review data to assess DLTs and will convene at least 
yearly to review all safety data.   
Additional formal meetings for the SRC will occur  
(a) 
when a total of 10 patients have received at least one dose of study 
therapy and followed for 3 months after the 10th subject patient receives 
the first dose of study therapy and  
(b) 
when a total of 40 patients have received at least one dose of study 
therapy and followed for 3 months after the 40th patient receives the first 
dose of study therapy   
Special attention will be paid for later-onset DLT-like toxicities.   
 


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Table 1: 
Schedule of Assessments 
Procedure or 
Assessment 
Screening  
Cycle 1 (21 
days)a 
Day in Cycle 
Cycle 2 (21 
days)a 
Day in Cycle 
± 1 day 
Cycle 3 (21 
days)a 
Day in Cycle 
± 1 day 
Cycle 4 
and 
Subse- 
quent 
Cyclesa 
±3 days 
EOT 
Visitb 
Safety 
FU Visit 
30 
±3 days 
Survival 
FU 
Every  
12 wks 
Days 
 -28 to -1 
1 ±3 
days 
8 ±3 
days 
15±3 
days 
1 ±3 
days 
8 ±3 
days 
15±3 
days 
1 ±3 
days 
8 ±3 
days 
15±3 
days 
Optional Future Tissue 
Study Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Tissue Biopsy 
Xc 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ Signs and 
Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Cancer Treatment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Meds 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Directed Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Review of AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital SignsP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Body Weight/Height  
(Height at screening only) X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG PSe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedure or 
Assessment 
Screening  
Cycle 1 (21 
days)a 
Day in Cycle 
Cycle 2 (21 
days)a 
Day in Cycle 
± 1 day 
Cycle 3 (21 
days)a 
Day in Cycle 
± 1 day 
Cycle 4 
and 
Subse- 
quent 
Cyclesa 
±3 days 
EOT 
Visitb 
Safety 
FU Visit 
30 
±3 days 
Survival 
FU 
Every  
12 wks 
Days 
 -28 to -1 
1 ±3 
days 
8 ±3 
days 
15±3 
days 
1 ±3 
days 
8 ±3 
days 
15±3 
days 
1 ±3 
days 
8 ±3 
days 
15±3 
days 
Administer Bavituximab 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
(Day 
1,8,15) 
 
 
 
Administer Pembrolizumab  
X 
 
 
X 
 
 
X 
 
 
X (Day 1) 
 
 
 
PK/PDf 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
ADAf 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Biomarker Blood Samplef 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
Hematologyg,h 
X 
X 
 
 
X 
 
 
X 
 
 
X (Day 1) 
X 
X 
 
Coagulationg,i 
X 
X 
 
 
X 
 
 
X 
 
 
X (Day 1)  
 
 
Clinical Chemistryg,j 
X 
X 
 
 
X 
 
 
X 
 
 
X (Day 1) 
X 
X 
 
Thyroid Panel]i 
X 
 
 
 
 
 
 
X 
 
 
X (Day 1 
every 
other 
cycle) 
 
X 
 
Urinalysisg,k 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testl 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Tumor Imagingm,n 
X 
 
 
 
 
 
 
X 
 
 
 
Xo 
 
 
Post-study Anti-cancer 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: ADA=antidrug antibody, AE=adverse event, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, FU=follow-up; 
Meds=medications, PK=pharmacokinetic, PS=performance status, Q3W=every 3 weeks, SAE=serious adverse event, TSH=thyroid-stimulating hormone, 
W=weeks. 
a 
Unless otherwise specified, assessments/procedures are to be performed prior to dose administration on Day 1 of each cycle. 
b 
Patients who discontinue both study treatments should be scheduled for an EOT visit within 15 days following the last dose date of study 
treatment.   


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c 
Baseline tumor tissue will be collected prior to enrollment on study for exploratory biomarker and PDL1 status (see study manual for 
details). 
d 
An optional biopsy is also requested at the time of discontinuation for PD. 
e 
Screening ECOG should be performed within 72 hours prior to first dose of treatment.   
f 
Refer to Table 6 for details on PK, ADA and biomarker blood sample scheduling.   
g 
Laboratory Screening Tests should be performed within 72 hours prior to first dose of treatment.  For all subjects, unresolved abnormal 
labs resulting in drug-related AEs should be followed until resolution.   
h 
CBC w/differentials will be collected and assessed within 72 hours of Day 1 of each cycle prior to dosing.   
i 
T3 (free or total) or T4 (free or total), and TSH will be collected and assayed prior to C1D1, C3D1, and every other cycle thereafter (e.g., 
C5D1, C7D1, etc.).   
j 
Chemistry will be collected within 72 hours of Day 1 of each cycle prior to dosing.   
k 
Urinalysis is conducted post screening every other cycle as clinically indicated. 
l 
For women of reproductive potential, a negative pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  
Pregnancy tests (serum and/or urine tests) should be repeated prior to dosing on Day 1 of every cycle in the UK.  In all other countries 
pregnancy tests should be repeated as required by local guidelines. 
m 
Tumor imaging at screening: Imaging will be performed within 28 days prior to the first dose of trial treatment.  For all subjects, already 
available imaging scans performed as part of routine clinical management are acceptable if they are of diagnostic quality and performed 
within the acceptable timeframe. 
n 
The first on-study tumor imaging will be performed 6 weeks (±7 days) after initiation of treatment and then every 6 weeks (±7 days) 
thereafter (or more frequently if clinically indicated).  Timing of imaging follows calendar days and should not be adjusted due to dose 
interruptions.  The same imaging technique, acquisition, and processing parameters for a subject should be used throughout the trial. 
o 
Subjects without confirmed PD who discontinue treatment will have imaging performed at the time study treatment is discontinued (i.e.  
date of discontinuation ± 4-week window).  If a scan was obtained within 4 weeks prior to discontinuation of treatment, then imaging at 
treatment discontinuation is not required.  Continue to monitor disease status as indicated in Protocol Section 7.2.1.3.   
P 
Vital signs will be captured approximately 30 minutes prior to pembrolizumab; 30 minutes prior to bavituximab administration and within 
60 minutes post bavituximab 
 


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Patients will be assessed for tumor response/progression per RECIST Version 1.1.  
The initial tumor assessment on study therapy will be conducted 6 weeks after 
initiation of treatment, then every 6 weeks until disease progression or another 
withdrawal criterion is met.   
An End-of-Treatment Visit will be performed at the time of treatment 
discontinuation followed by a Safety Follow-Up Visit 30 days after the end of 
treatment. 
2.3 Sample Size and Power 
The primary efficacy objective of this Phase 2 study is the evaluation of ORR of 
bavituximab in combination with pembrolizumab in patients with advanced gastric or 
GEJ cancer.  The sample size of approximately 80 patients across both Group 1 and 
Group 2 was chosen to allow minimal enrollment within each of our four putative 
biomarker signatures to allow for exploration of differential responses.  As noted 
above, an ORR of <15% for Group 1 will be regarded as futile as it will be unlikely to 
exceed the activity of pembrolizumab as a single agent in this study population.   
The following sample sizes apply:  
DLT Observation: up to 10 DLT-evaluable patients in total  
Phase 2: Minimum efficacy analysis: 40 total patients across both Group 1 and 
Group 2; Full enrollment: approximately 80 patients  
For the CPI-naïve patient population assumptions, the historical ORR of 
pembrolizumab in the 2nd-line setting was approximately 15% and an ORR of the 
bavituximab-pembrolizumab combination was set to 30%.  Approximately 40 
patients are needed to show a statistical superiority of bavituximab-pembrolizumab 
with 80% statistical power at one-sided type I error rate of α=0.10.  In the 3rd-line 
setting if the historical ORR is assumed as 6%, if the true ORR of Bavituximab-
Pembrolizumab combination is 15%, then approximately 40 patients are needed to 
show a statistical superiority of Bavituximab-Pembrolizumab with 74% statistical 
power at one-sided type I error rate of α=0.10.  In addition, PDL1 status was able to 
impact outcomes in all lines of treatment with PDL1+ patients having better outcomes 
than negative.  By combining patients from DLT and the expansion phase, safety and 
efficacy information will be available for a total of 80 patients, assuming >6 
responders are observed by 40.  Enrollment will not be controlled for the number of 
patients in each line nor PD-L1 status (2nd vs.  3rd line, positive vs.  negative), these 
numbers could vary for each patient type (e.g.  2nd line PDL1+ vs.  Third line PDL1 
negative).  Table 2 and Table 3 show how the power varies for with the 2nd and 3rd 
line cohorts with their respective sample sizes. 


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Table 2: 
Power in 2nd line Gastric Cancer or Gastroesophageal Junction 
2nd Line Subjects 
Responses (CR/PR) 
for p < 0.1 
Power for p1=0.25 
(%) 
Power for p1=0.3 
(%) 
20 
6 
38.3 
58.3 
30 
8 
48.5 
71.8 
40 
10 
56.0 
80.4 
50 
12 
61.8 
86.1 
60 
14 
66.5 
90.0 
Assume historical ORR with p0=0.15. 
Table 3: 
Power in 3rd line Gastric Cancer or Gastroesophageal Junction 
3rd Line Subjects 
Responses (CR/PR) 
for p < 0.1 
Power for p1=0.15 
(%) 
Power for p1=0.2 
(%) 
20 
4 
59.5 
79.3 
30 
4 
67.8 
87.7 
40 
5 
73.6 
92.4 
50 
6 
78.0 
95.2 
60 
6 
90.3 
98.7 
Assume historical ORR with p0=0.05. 
For the CPI-relapse patient population, the n was set to 20 patients for the initial 
assessment of safety, tolerability and initial antitumor activity.   


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3. Efficacy and Safety Variables 
3.1 Primary Endpoints 
• Incidence and severity of AEs and SAEs graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0, including changes in clinical laboratory parameters 
• Objective response rate (ORR) as assessed by the Investigator per RECIST 
Version 1.1 
3.2 Secondary Endpoints 
• Duration of response (DoR), disease control rate (DCR) (as defined by ORR and 
stable disease rate at 6 weeks), progression-free survival (PFS), and overall 
survival (OS) 
• Bavituximab serum concentrations before and after bavituximab infusions 
- Beta2-glycoprotein 1 (β2-GP1) serum concentrations and change from 
baseline before and after bavituximab infusions 
• Presence of anti-bavituximab antibodies (anti-drug antibodies [ADAs]) 
3.3 Tertiary Endpoints 
• Analysis of tissue to determine percentage of patients with defined genetic 
signature 
- Tumor micro environment (TME) RNA profile genetic signatures will be 
evaluated in baseline tumor tissue sample and categorized to Biomarker (B)+/- 
- TME panel-1 scores will also be reported in 4 categories IA = Immune Active; 
ID = Immune Desert; A = Angiogenic; IS = Immune Suppressed. 
• Preliminary correlation of ORR to genetic signature 
- Correlation of DCR and PFS to genetic signature 
• Status of genomic and immune biomarkers in blood and tissue samples at 
baseline and change from baseline upon treatment 
- Biomarker and pharmacodynamic (PD) data for this analysis include: 
o Tumor PDL1 Combined Positive Score (CPS), central laboratory 
assessment of screening biopsy sample 
o Tumor micro satellite instability (MSI) status at screening  
o Pharmacodynamic (PD) Beta2-glycoprotein 1 (β2-GP1) evaluated prior 
to dosing 
o Baseline leukocytes, neutrophils (absolute count), and 
neutrophils/leukocytes (NLR) 


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o Patient medical history of Human epidermal growth factor receptor 2 
(HER2) positivity and Epstein-Barr virus (EBV) status 


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4. Analysis Populations 
4.1 Safety Population 
All patients who received at least 1 dose of bavituximab or pembrolizumab, 
regardless of their eligibility for the study.  The safety evaluation will be performed 
based on the first dose a patient actually received.   
The safety population will be used for all analyses of dosing, exposure, and safety. 
4.2  DLT-evaluable population  
The DLT-evaluable population will include the first 3 patients up to a maximum of 10 
patients who (1) receive at least 70% of the dose of bavituximab (2) complete the 
DLT observation period or discontinue (from study treatment or from the study) 
during the DLT observation period (Cycle 1) because of a DLT. 
In addition, a patient among the first 10 patients who experienced a DLT event during 
the DLT observation period after receiving a dose of bavituximab less than 70% of 
the planned dose will be included in the DLT-evaluable population. 
The DLT-evaluable population will be used to assess incidence of DLT. 
4.3 PK Population 
The PK population will include all treated patients who received at least 1 full dose of 
bavituximab and pembrolizumab and have baseline and at least one postbaseline 
evaluable PK sample.   
This population will be used for PK analyses. 
4.4 Efficacy Population 
All patients who received at least 1 dose of bavituximab or pembrolizumab, 
regardless of their eligibility for the study.   
The efficacy population will be used for all analyses of tumor response. 


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5. Data Handling 
5.1 Time points and Visit Windows 
5.1.1 General Definitions 
All assessment days will be related to the first day of first dose of study treatment 
(C1D1). 
Day 1 is defined as the day of first dose of study treatment.  Relative days after Day 
1 are calculated as (assessment date – Day 1 date) + 1.  Relative days prior to Day 
1 are calculated as (assessment date – Day 1 date).  The day prior to Day 1 is Day -1. 
5.1.2 Screening Period and Baseline 
For all subjects, the screening period is defined as the period from informed consent 
to Day -1.  Tumor imaging will be performed within 28 days prior to the first dose of 
trial treatment.  In case available imaging scans performed as part of routine clinical 
management are used then the baseline tumor assessment may have been collected 
prior to informed consent. 
The baseline value for a variable is defined as the last non-missing value collected 
before the first dose of treatment.  The baseline may then be collected within 28 days 
prior to first dose, in the screening period, or prior to dose administration on Day 1. 
5.1.3 Treatment Period 
Unless otherwise specified, assessments/procedures are to be performed prior to 
dose administration on Day 1 of each cycle.  Scheduled assessments on Day 1 will 
be assigned to baseline unless the time (HH:MM) of data collection and start of 
infusion time (HH:MM) are both recorded and the data collection time is after start 
of infusion.  In this case, the assessment will be assigned to the treatment period.  
Adverse events and medications starting on Day 1, will be assigned to the Treatment 
Period. 
The Treatment Period is defined as the period from the date of the first dose of 
treatment up to and including the date of treatment discontinuation, or, if that is 
missing then the date of death or withdrawal of consent (where recorded) or the 
last dose date. 
5.1.4 Visit Windows 
Safety data will be analyzed using nominal study visits as defined in the Study 
Schedule (Table 1) and eCRF.  No visit windows will be applied for summary and 
analysis of safety assessments (clinical laboratory tests, vital signs, and ECOG 
performance status).  No visit windows will be applied for summary and analysis of 


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these endpoints.  In case of multiple assessments at a scheduled visit, the first will 
be considered as the scheduled assessment and later assessments will be repeat or 
unscheduled.   
Study drug dose date relative days after C1D1 will be compared to expected visit 
relative days.  Number of days delayed will be calculated for dose delays > 3 days. 
Tumor imaging will be performed 6 weeks (±7 days) after initiation of treatment and 
then every 6 weeks (±7 days).  Patients without confirmed PD who discontinue 
treatment will have imaging performed at the time study treatment is discontinued 
(i.e.  date of discontinuation ± 4-week window).  If a scan was obtained within 4 
weeks prior to discontinuation of treatment, then imaging at treatment 
discontinuation is not required. 
Table 4 provides the relative study day ranges to be applied to the imaging date to 
derive the analysis visit for by visit analyses of tumor response assessments.   
The following considerations are to be followed when deriving the analysis visits:  
• The relative day number of the assessment lies between the lower and upper 
boundary of the visit window (the boundary values are included) 
• Both scheduled and unscheduled assessments are included for visit windowing 
• A scan that meets EOT criteria (that is, within 4 weeks of treatment 
discontinued and patient discontinued treatment without confirmed PD) will not 
be classified as scheduled 
• If there are two or more valid assessments for a defined window the following 
rules will be applied: 
o If both scheduled and unscheduled assessments fall within the same 
visit window, the scheduled assessment with non-missing assessment 
results will be used for analysis 
o If there are multiple scheduled assessments with non-missing 
assessment results for any specified visit window and the assessment 
that is closest to the planned study day will be used for analysis 
o If there are multiple assessments for any specified visit and none of 
them are from scheduled assessment, the assessment with 
non-missing results and closest to the planned study day will be used 
for analysis 
o If there are two or more unscheduled assessments with non-missing 
results and the same distance to the planned study day, the 
assessment prior to the planned study day will be used for analysis. 


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Table 4: 
Definition of Visit Windows for Tumor Response 
Visit 
Target Day of Visita 
Protocol Visit 
Windows 
Analysis Visit 
Window 
Screening 
>= -28 
-28 to -1 
-28 to -1b 
Week 6 
43 
36 to 50 
Day 36 to Day 57 
Week 12 
85 
78 to 92 
Day 58 to Day 99 
Week 18 
127 
120 to 134 
Day 100 to Day 141 
Week 24 
169 
162 to 176 
Day 142 to Day 183 
.  .  . 
.  .  . 
.  .  . 
.  .  . 
EOT 
EOTc 
EOT – 28, EOT + 28 
EOT – 28, EOT + 28d 
a Relative to first dose of treatment. 
b use latest scan prior to Day C1D1 
c End of treatment (EOT), date of the discontinuation event 
d A scan meeting EOT criteria (patient discontinued treatment without confirmed PD) 
will not be classified as scheduled. 
NA= Not Applicable 
5.2 Handling of Dropouts, Missing Data, and Outliers 
During the Safety run-in phase, patients who are lost to follow up, withdraw consent 
for study participation prior to receiving study treatment, or who withdraw prior to 
completing Cycle 1 for reasons other than DLT may be replaced.   
Treatment may be continued until one of the following criteria applies: 
• 
Progressive disease (PD): In patients with PD, a confirmatory scan should be 
performed at least 4 weeks later to confirm PD prior to removing the patient 
from study treatment.  The confirmatory scan is recommended but not 
required, it is at the discretion of the treating physician 
• 
Intervening illness that prevents further administration of treatment. 
• 
Recurrent Grade 2 pneumonitis 
• 
Unacceptable AE(s). 
• 
The patient, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of the study 


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indication.  Discontinuation from study treatment will occur prior to 
introduction of the new agent. 
• 
Significant patient non-compliance with the protocol. 
• 
Completion of 35 cycles (approximately 2 years) with pembrolizumab.   
o Note: The number of treatments is calculated starting with the first 
dose of pembrolizumab. 
• 
Discontinuation of treatment may be considered for participants who have 
attained a confirmed complete response (CR) and have been treated for at 
least 8 cycles (at least 24 weeks), beyond the date when the initial CR was 
declared.   
• 
Pregnancy. 
• 
Patient decision to withdraw from the study. 
• 
Investigator decision to withdraw the patient from the study. 
• 
Patient is lost to follow up. 
• 
Sponsor decision to end the study. 
Missing or Partial Adverse Event and Prior/Concomitant Medication Start 
Dates 
• 
If the day is missing but both the month and year are non-missing, then the 
missing day will be imputed as 01.  For an AE, however, if the month and year 
are the same as the month and year of the date of the first dose of study 
medication, then the missing day will be imputed to be the day part of the first 
dose date. 
• 
If both the day and month are missing but the year is non-missing, then the 
missing day and month will be imputed as 01JAN.  For an AE, however, if the 
year is the same as the year of the date of the first dose of study medication, 
then the missing day and month will be imputed to be the day and month parts 
of the first dose date.   
• 
If the date is completely missing, then the start date will be imputed to be the 
earlier of the date of the first dose of study medication and the AE or medication 
end date.  If the end date is partial, then impute the end date first before 
imputing the start date.   
Missing or Partial Adverse Event and Prior/Concomitant Medication End 
Dates 
If the AE or medication is reported as ongoing (or for an AE, not resolved/not 
recovered or recovering/resolving), then the end dates should be blank; otherwise, 
the following rules for imputation should be followed: 


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• 
If the day is missing but both the month and year are non-missing, then the 
missing day will be imputed as the last day of the month. 
• 
If both the day and month are missing but the year is non-missing, then the 
missing day and month will be imputed as 31DEC.  For an AE, however, if the 
year is the same as the year of the date of the last dose of study medication, 
then the missing day and month will be imputed to be the day and month parts 
of the last dose date.   
• 
If the date is completely missing, then the end date will be imputed to be the 
date of the first visit that is after the AE start date or the subject’s last dose 
date, if there is no visit that is after the AE start date.  If the start date is 
partial, then impute the start date first before imputing the end date.   
If the imputation rules above result in an end date being earlier than the start date, 
where one or both dates are imputed, then end date will be set to start date + 1.  If 
an imputed start date is after the end date, then the start date will be set to the end 
date – 1.  Prior to database lock, all imputed adverse event dates will be reviewed by 
the study team and approved by the sponsor for clinical relevance.  Imputed dates 
may be adjusted based on this review. 
Missing or Partial Diagnosis Dates of Historical Conditions of Interest 
• 
If the day is missing but both the month and year are non-missing, then the 
missing day will be imputed as 01. 
• 
If both the day and month are missing but the year is non-missing, then the 
missing day and month will be imputed as 01JAN. 
• 
If the date is completely missing, then it will not be imputed. 
Outliers 
No rules for outlier detection are planned. 
 


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6. Statistical Methods 
6.1 General Principles 
All data processing, summarization and analyses will be performed using SAS Version 
9.4 (or later) of the SAS statistical software package. 
The following principles will be applied to all TFLs unless otherwise stated: 
Principle 
Value 
Significance tests 
Two-sided and use a 5% significance level  
Group labels and order 
presented 
Tables: Group 1 CPI Naïve, Group 2 CPI Relapse, 
Overall  
Listings: Group 1, Group 2 
Tables 
Data in summary tables presented by Group and visit 
(where applicable).   
Listings 
All data collected presented by Group, site, subject, and 
visit (where applicable)a.   
Descriptive summary statistics 
for continuous variables 
Number of subjects/observations (N), mean, standard 
deviation (SD), median, and range.   
Descriptive summary statistics 
for categorical variables 
Frequency counts and percentages [n (%)] 
Denominator for percentages 
Number of subjects in the analysis population, unless 
stated otherwise in table shell(s) 
Include “Missing” as category 
Number missing is greater than zero. 
Display for 0 percentages 
Blank 
Display to the same number 
of decimal places as collected 
or standardized valueb 
Minimum 
Maximum 
Display to one more decimal 
place than collected or 
standardized valueb 
Mean 
Median 
Display to two more decimal 
places than collected or 
standardized valueb 
Standard Deviation 
Standard Error 
Limit of precision for displays 
3 decimal places 
Date Format 
DDMMMYYYY 
a Data of screen failure patients, where listed, follows data of enrolled patients. 
b Decimal precision rules for clinical laboratory data are presented in Section 8 
6.2 Subject Disposition and Data Sets Analyzed 
Subject disposition will be listed and summarized and will include the number and 
percentage of subjects:  
• 
screened; 


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• 
screen failures; 
• 
treated; 
• 
in treatment; 
• 
discontinued treatment and reason for discontinuation; 
• 
in long term follow-up; 
• 
discontinued study and reason; 
Patients in the in each study population (Safety, DLT-evaluable, Efficacy, PK and Per-
protocol) will also be listed and summarized.   
6.3 Protocol Deviations 
Protocol deviations are defined as any change, divergence, or departure from the 
study design or procedures defined in the study protocol.  Important protocol 
deviations are a subset of protocol deviations and may significantly impact the 
correctness, accuracy, and/or reliability of the study data or that may significantly 
affect a subject’s rights, safety, or well-being.   
Important protocol deviations will be listed and summarized for the Safety Population. 
Important protocol deviations will be reviewed to identify any deviation that may 
significantly affect the completeness, accuracy, and/or reliability of the study data.  
Sensitivity analyses that exclude these patients will be performed for the primary and 
selected secondary efficacy endpoints (refer to Section 6.6.3). 
6.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized for the Safety 
Population.  Standard descriptive statistics will be presented for the continuous 
variables of: 
The following demographic data will be summarized:  
• 
Sex 
• 
Age at screening (years) 
• 
Race and ethnicity  
The following baseline disease characteristics will be summarized: 
• 
Site of adenocarcinoma (Gastric or GE Junction) 
• 
TNM staging of diagnosis at study entry 
• 
Siewert classification 
• 
Tumor Biomarkers at Screening 
o HER2 status at diagnosis (positive, negative) 
o EBV status at diagnosis (positive, negative) 


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o MSI stability (high, low) 
o Central Lab PDL1 Combined Positive Score (CPS) 
o Xerna TME Panel phenotype (IA, A, IS, ID) 
o Xerna TME Panel subtype (B+/ B-)- 
• 
Blood biomarker, β2-GP1 concentration 
• 
Treatment of Gastric/GEJ cancer before enrollment  
o Radiotherapy (yes, no) 
 
Procedure  
 
Indication 
 
Dose 
o Surgery (yes, no) 
o Systemic Anti-cancer therapy 
 
Number of previous lines of therapy (1, 2, 3, 4 or more) 
 
Received neo-adjuvant, palliative, adjuvant or other indication  
 
Best overall response on any previous therapy  
 
Reason for treatment discontinuation 
• 
Baseline height (cm) and weight (kg) 
• 
Vital signs:  blood pressure (mm Hg), heart rate (bpm), respiratory rate 
(rpm), and temperature (°C)  
• 
ECOG PS 
• 
Baseline leukocytes, neutrophils (absolute count), and NLR  
6.4.1 Screening and Baseline Details 
The following baseline characteristics will be presented in cross-tabulated frequency 
tables by Group for the Efficacy Population. Patient counts in each category will be 
represented in grouped frequency charts. 
• 
Tumor stage frequency across TME Panel-1 
Screening and baseline neutrophils, lymphocyte, and NLR will be listed for all patients 
with Screening NLR assessed. The NLR values will be presented in a scatterplot by 
patient. 
6.4.2 Medical History 
Medical history will include all active conditions and any condition diagnosed within 
the last 10 years that are considered clinically significant by the Investigator.  Details 
regarding the patient’s gastric or GEJ adenocarcinoma will be recorded separately 
and NOT listed as medical history.   
Autoimmune disorders, regardless of onset date.   
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [Version 22.0].  All medical history will be listed, and the number and 


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percentage of subjects with any medical history will be summarized for Safety 
Population by system organ class (SOC) and preferred term (PT).   
6.4.3 Prior and Concomitant Medications 
Patients are allowed to continue the medications that they are taking at baseline.  
Patients may also receive concomitant medications that are medically indicated as 
standard care for the treatment of symptoms and intercurrent illnesses.   
All concomitant medications received within 28 days prior to the first dose of study 
treatment and up to 30 days after the last dose of study treatment will be recorded.  
Concomitant medications administered for treatment of SAEs and AESIs 30 days or 
more after the last dose of study treatment will be recorded. 
Medications received prior to or concomitantly with treatment will be coded by 
Covance using the WHODrug Dictionary Version 2019, Anatomical Therapeutic 
Chemical (ATC) Classification codes.   
Prior medications and concomitant medications are defined as follows: 
Prior medications are those with a stop date prior to the first dose date of study 
treatment.   
Concomitant medications are those with a start date on or after the first dose date 
of study treatment, or those with a start date before the first dose date of study 
treatment and a stop date on or after the first dose date of study treatment or 
ongoing end of study. 
Prior medications and concomitant medications will be listed and summarized 
separately for Safety Population. 
6.5 Measurements of Treatment Compliance – not applicable 
6.6 Efficacy 
The efficacy analyses will be based on the Efficacy Population, including predefined 
biomarker subgroups as needed.   
6.6.1 Primary Efficacy Analysis 
Based on RECIST Version 1.1 (Protocol Appendix A) criteria, a patient may achieve 
as best overall response either complete response (CR), partial response (PR), stable 
disease (SD), or progressive disease (PD).  The Objective Response Rate (ORR) is 
calculated as the number of patients achieving a CR or PR divided by the number of 
efficacy patients.   


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The ORR and 95% confidence interval (CI) will be presented for the Efficacy 
Population Group 1, Group 2, and Overall.  The 95% CI will be calculated using the 
Clopper-Pearson method.   
A supplementary summary will be presented of the confirmed and unconfirmed best 
overall response and the overall rate of CR or PR with 95% CI among these 
responses. 
6.6.2 Secondary Efficacy Analysis 
6.6.2.1 
Disease Control Rate (DCR)  
DCR is defined as the percent of patients in the Efficacy population with a CR or PR 
(patients with OR), or SD, PR or CR evaluated at 6 weeks or later after the date of 
first dose.  The same analysis approach used for the primary efficacy analysis will be 
applied on DCR.   
6.6.2.2 
Time to Response and Duration of Response (DoR) 
Time to response and DoR are calculated only for patients with a CR or PR response.  
A supplementary analysis of time to response and DoR will be performed for patients 
with confirmed or unconfirmed CR or PR. 
DoR, defined as the interval in months from the date measurement criteria are met 
for CR or PR (whichever is first recorded) until the earliest date of disease 
progression, as determined by Investigator assessment of objective radiographic 
disease assessments per RECIST 1.1 or death due to any cause if occurring sooner 
than progression (1 + date of progression – date of response / 30.4375).  Duration 
of response is expressed as months, and will add 1 day to account for the date 
measurement criteria was met. 
DoR will be analyzed using the Kaplan-Meier (K-M) method to compute the time-to-
event curve.  The K-M curves for Group 1 and Group 2 will be displayed in a graphic 
presentation.  The median event time as well as times to 25th and 75th percentile 
event times will be calculated.  A 95% confidence interval for each quartile will be 
calculated using the log-log transformed survival function confidence interval at each 
time. 
Time to response is the interval in months from first treatment until the first date of 
a confirmed CR or PR response.  Months will be reported to 2 decimals as (1+ date 
of first response – date of first treatment)/30.4375. 
6.6.2.3 
Progression-Free Survival (PFS) 
PFS is defined as the interval in months from the date of first dose of investigational 
agent until the earliest date of disease progression (date of disease progression – 


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date of first dose + 1)/30.4375.  Disease progression is determined by Investigator 
assessment of objective radiographic disease assessments per RECIST version1.1 or 
death due to any cause if occurring sooner than progression in Efficacy population. 
PFS will be analyzed Using the K-M method to compute the time-to-event curve.  The 
K-M curves for Group 1 and Group 2 will be displayed in a graphic presentation.  The 
25th, 50th, and 75th percentile event times will be calculated and 95% confidence 
intervals for each quartile based on intervals about the log-log transformed survival 
function. 
Time to Progression Censoring Rules  
Patients lacking evidence of disease progression, including those who initiate non-
study anti-cancer therapy prior to disease progression, will have their DoR and PFS 
event times censored on the last tumor assessment date at which disease status was 
determined.  
Table 5: 
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival 
Rule 
Situation 
Date of Progression or Censor 
Outcome 
1 
No Baseline tumor assessment 
Date of first dose 
Censored 
2 
No post-baseline assessments and no death 
Date of first dose 
Censored 
3 
No documented progression and no death 
(with a post-baseline tumor assessment) 
Date of last adequate tumor assessment 
Censored 
4 
Patient lost to follow-up (or withdrew 
consent from study participation) before 
documented progression or death 
Date of last adequate tumor assessment 
Censored 
5 
Documented progression 
Date of documented progression 
If the tumor assessment was done on 
multiple days, use the earliest date for that 
visit 
Progressed 
6 
Death without document progression 
Date of death 
Progressed 
7 
Documented progression or death after 
missing ≥2 consecutive post-baseline tumor 
assessments 
Date of last adequate tumor assessment 
before missed assessments or date of 
enrollment, whichever is later 
Censored 
Note: Progression-free survival and associated outcome is determined by the earliest of the dates above, if more than 
one situation applies 
 


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6.6.2.4 
Overall survival (OS)  
OS is defined as the interval in months from the date of first dose of investigational 
agent until the date of death (Date of death – date of first dose + 1 / 30.4375) in 
Safety population.  All deaths will be included in the analysis. 
OS will be analyzed using the K-M method to compute the time-to-event curve.  The 
K-M curves for Group 1 and Group 2 will be displayed in a graphic presentation.  The 
median event time as well as times to 25th and 75th percentile event times will be 
calculated and the and a 95% confidence interval for each quantile. 
Follow-up time for OS analysis will be assessed using reverse K-M method, reversing 
censor and event flags.  The reverse K-M curves for Group 1 and Group 2 will be 
displayed in a graphic presentation and median time on study for censored 
observations estimates will be reported for each group. 
Overall Survival Censoring Rules  
Patients with no known date of death will have their survival event time censored at 
the latest date of last completed visit or patient contact or last known date alive 
recorded on the eCRF.  Duration of survival is expressed as months from date of first 
treatment (Day 1). 
6.6.2.5 
Time on Study Treatment and Time to Best Overall Response 
Time on study treatment and time to confirmed best overall response will be 
presented in a listing and summary figure (swimmer’s plot) representing individual 
patients on the vertical axis, ordered by months on treatment, horizontal bars to 
end of treatment and symbols to represent first confirmed CR or PR.  For this 
analysis time on treatment will be calculated to 2 decimal places: months on 
treatment = ((date of last dose – date of first dose) + 1)/30.4375 and months to 
best response =((tumor assessment date – date of first dose) + 1)/30.4375.   
6.6.2.6 
Tumor Response  
Tumor response of individual target lesions will be listed and the sum of diameters 
(SoD) will be listed.  Maximum percentage reduction from baseline of the target lesion 
SoD will be summarized.   
Waterfall plots will depict individual patient measurements of maximum percentage 
reduction on the vertical axis and ordered on the horizontal axis the patients with 
least to greatest reduction.  The plot will use different colors to represent best overall 
response classification. 
Individual patient response, SoD percent change from baseline will also be 
represented in a spider plot, weeks on study as the horizontal axis, percent change 


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on the vertical axis, trend lines through the individual SoD percentage change, and 
line colors to represent best overall response classification. 
6.6.3 Sensitivity Analyses for Primary and Secondary Efficacy Analysis 
To assess the impact of including subjects with any deviation expected to have 
significant effect on accuracy or reliability of the study data, the efficacy analysis of 
OR, DoR, DCR, PFS, and OS will be repeated using the efficacy population with 
patients excluded.  Patients identified in the data classification document will be 
excluded. 
6.6.4 Pharmacokinetic (PK) Analysis 
Pharmacokinetic (PK) analysis will include listings by group for minimum serum 
concentration of bavituximab (Ctrough) across cycles 1 to 6 and the maximum dose 
concentration (Cmax) on Day 1 and Day 15 of Cycle 1. 
Bavituxmab serum concentrations will be summarized by group for the PK population 
using descriptive statistics at each cycle and study day (see Table 6).  Listings will 
represent actual elapsed time post dose. Further PK and PK/PD analysis may be 
described in separate plans. 
6.6.5 Pharmacodynamic Variables 
Beta2 glycoprotein 1 concentrations and change from baseline will l be listed and   
summarized using descriptive statistics by group, cycle and study day per the sample 
collection schedule described in Table 6. Change from baseline β2 GP1 by time on 
treatment will be presented in individual and summary graphs.   
6.6.6 Immunogenicity Analysis 
Anti-drug antibodies (ADA) will be collected as described in Table 6.  The number and 
percentage of patients with pre-existing ADA will be reported and incidence of 
seroconversion (patient’s ADA changed from negative to positive) will be summarized 
by time point.  Descriptive summaries (n, median, minimum and maximum) of 
antibody titers will be provided at each time point for the Safety population.  Negative 
ADA will be set =1 for numeric titer summaries.  Results of immunogenicity testing 
will be provided in listings. 


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Table 6: 
Pharmacokinetic/Pharmacodynamic/Biomarker Blood Sample 
Specific Collections – Collection Times 
 
 
Bavituximaba 
Biomarker 
Blood 
Sample 
 
Visit 
Time Point 
PK/PD ADA 
Window 
Cycle 1 Day 1 
Prior to dosingb 
X 
X 
X 
Within 24 hours prior to bavituximab 
administration 
Cycle 1 Day 1 
1 hour post 
EOIc 
X 
 
 
+/-30 minutes post bavituximab infusion  
Cycle 1 Day 15 
Prior to dosingb 
X 
 
X 
Within 24 hours prior to bavituximab 
administration  
Cycle 1 Day 15 
1 hour post 
EOIc 
X 
 
 
+/-30 minutes post bavituximab infusion  
Cycle 2 Day 1 
Prior to dosingb 
X 
X 
X 
Within 24 hours prior to bavituximab 
administration 
Cycle 2 Day 15 
Prior to dosingb 
X 
 
X 
Within 24 hours prior to bavituximab 
administration 
Cycle 3 Day 1 
Prior to dosingb 
X 
 
 
Within 24 hours prior to bavituximab 
administration 
Cycle 4 Day 1 
Prior to dosingb 
X 
X 
 
Within 24 hours prior to bavituximab 
administration 
Cycle 6 Day 1 
Prior to dosingb 
X 
 
 
Within 24 hours prior to bavituximab 
administration 
30-day Follow-up 
Follow-up 
 
X 
X 
Any time during the Safety Follow-up Visit 
Abbreviations: EOI = end of infusion; ADA=antidrug antibody; PK = pharmacokinetics. 
a In the event of an infusion-related reaction (IRR), blood samples will be collected for both PK and ADA at the 
following time points: (i) as soon as possible after the onset of the IRR, (ii) at the resolution of the IRR, and (iii) 
30 days (±3 days) following the IRR. 
b   Pre-dose PK samples are collected within 24 hours prior to infusion of bavituximab. 
c   Post-dose PK samples are collected 1 hour (+/-30 minutes) post bavituximab infusion  
 
6.6.7 Subgroup Correlation Analysis 
Efficacy correlation analyses will be based on the Efficacy Population, and will 
evaluate the relationship between key efficacy parameters including ORR, PFS, DCR, 
and OS and the following predefined key biomarker subgroups: 
• 
NLR evaluated at baseline 
• 
Xerna TME Panel subtype B+/B- 
• 
Tumor PDL1 CPS 
More specifically, correlation analyses will be evaluated for the following subgroups 
for all patients and by patient group (group 1, group 2): 
• 
Major Subgroup Analyses 


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o NLR<4/ NLR≥4 
o B+/B- (Frequencies and proportions are represented in Barchart for 
B+/B- and also for TME Panel-1 classes) 
o B+ and NLR<4 
o B- and NLR<4 
• 
Subgroup Analyses by CPS 
o CPS<1 and NLR<4 
o CPS<1 and NLR≥4 
o CPS<1 and B+ 
o CPS<1 and B- 
o CPS<1 and B+ and NLR<4 
o CPS<1 and B- and NLR<4 
o CPS≥1 and NLR<4 
o CPS≥1 and NLR≥4 
o CPS≥1 and B+ 
o CPS≥1 and B- 
o CPS≥1 and B+ and NLR<4 
o CPS≥1 and B- and NLR<4 
• 
Subgroup Analyses by MSS 
o MSS and NLR<4 
o MSS and NLR≥4 
o MSS and B+ 
o MSS and B- 
o MSS and B+ and NLR<4 
o MSS and B- and NLR<4 
• 
Subgroup Analyses by Line of Therapy  


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o 2nd line 
o 2nd line and NLR <4 
o 2nd line and NLR≥4 
o 2nd line and CPS<1 and B+ 
o 2nd line and CPS<1 and B- 
o 2nd line and CPS<1 and B+ and NLR<4 
o 2nd line and CPS<1 and B- and NLR<4 
o 3rd line and higher 
o 3rd line and NLR<4 
o 3rd line and NLR≥4 
o 3rd line and CPS<1 and B+ 
o 3rd line and CPS<1 and B- 
o 3rd line and CPS<1 and B+ and NLR<4 
o 3rd line and CPS<1 and B- and NLR<4 
• 
NLR time profiles will be presented in a listing, time profile plot and spider plot 
o Individual NLR by visit 
o NLR % change from baseline grouped by best response (CR, Confirmed 
PR, SD or PD) 
6.7 Safety 
All safety analysis will be based on the Safety population. 
6.7.1 Extent of Exposure 
Dose record: The number of dose omissions, reductions, and delays, number of cycles 
received, percentage compliance, and dose intensity will be summarized for all 
treated patients in safety population.  Percentage compliance will be defined as 100 
times the number of infusions received divided by the number of infusions expected 
during the interval from first to last dose.  For pembrolizumab, the number of 
infusions expected is the number of cycles of treatment completed by the patient.  
For bavituximab, the number of infusions expected is the number of cycles times 3.  
Dose intensity (mg/week) will be defined as the cumulative dose (mg) divided by the 
treatment duration (weeks). 


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Study drug exposure: Exposure will be summarized for pembrolizumab and 
bavituximab separately.  The exposure variables are defined as; 
• 
Duration of exposure (days) = (date of last dose – date of first dose) + 1; 
• 
Cumulative dose (mg) = the sum of doses during all treatment cycles; 
• 
Actual dose (mg/cycle) = cumulative dose (mg)/ (duration of treatment 
(cycle));  
• 
Relative dose (%) = (actual dose (mg/cycle)/scheduled dose (mg/cycle)) 
* 100 
Dose records and summary calculations of dose omissions, reductions, and delays, 
number of cycles received, percentage compliance, dose intensity, duration, 
cumulative dose, actual dose and relative dose will be listed and summarized using 
descriptive statistics for the Safety population. 
6.7.2 Adverse Events 
6.7.2.1 
Adverse Events Reporting 
All AEs that occur from the signing of the ICF until the first dose of study treatment 
will be recorded only if the event was related to a study procedure.  All other 
AEs/findings prior to first dose of study treatment will be recorded as medical history.  
All AEs occurring from the first dose of study treatment until 30 days after the last 
dose of study treatment will be recorded. 
AEs and laboratory abnormalities will be graded according to the CTCAE v5.0 grading 
system and recorded on the eCRF.  Verbatim terms for each AE will be coded using 
MedDRA Version 22.0.   
The relationship between an AE and study treatment is assessed as Yes (possible, 
probably or definitely related), No (not related or definitely not related).  Relationship 
between an AE and study treatment is recorded as related to bavituximab, related to 
pembrolizumab, or related to both. 
An SAE is an AE occurring during any study phase (i.e., baseline, treatment, washout, 
or follow-up), and at any dose of the investigational product, comparator or placebo, 
that fulfils one or more of the following: 
• 
Results in death 
• 
is immediately life-threatening 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability or incapacity 


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• 
results in a congenital abnormality or birth defect an important medical event 
that may jeopardize the patient or may require medical intervention to 
prevent one of the outcomes listed above. 
All AEs meeting serious criteria, from the time of treatment/ allocation through 90 
days following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy, whichever is earlier, will 
be reported.   
Investigators will follow patients with AEs/SAEs until the event has resolved, the 
condition has stabilized, withdrawal of consent, initiation of subsequent anticancer 
therapy, the patient is lost to follow up or death OR until the 30-day Safety Follow-
up Visit, whichever occurs first.  New and ongoing treatment-related SAEs will be 
followed beyond the 30-day Safety Follow-up Visit.  If the patient dies, this will be 
captured as the outcome of the AE.  Death will be reported as a separate event only 
if no link between the AE and patient death can be established. 
Adverse events of special interest (AESIs) are required to be reported to the Sponsor 
immediately.  Adverse events of special interest for this study are defined in protocol 
Section 8.8.   
All AEs are classified as either pre-treatment AEs or treatment–emergent AEs (TEAEs) 
as follows: 
• 
Pre-treatment AEs are events that start prior to the date of first dose of 
study treatment. 
• 
TEAEs are events with start date on or after the date of first dose of study 
treatment whose severity worsens on or after the date of first dose of study 
treatment.   
6.7.2.2 
Adverse Events Listings and Overall Summary 
All AE data will be listed.  Pre-treatment AEs will be presented and a separate listing.  
All other listings and AE summary tables will present only TEAEs.  Listings of serious 
TEAEs (SAEs), AEs leading to discontinuation of study treatment and TEAEs resulting 
in death will be produced.  The AEs related to study drug and AEs leading to study 
drug interrupted or withdrawn will be listed.  Any DLT will be listed with information 
of the DLT criteria. 
Summary tables of TEAEs will be produced for the Safety population.   
The categories of AE relationship to study drug will be combined for separate 
summaries of AEs related to bavituximab and AEs related to pembrolizumab.   


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An overview table will summarize the number and percentage of study subjects with 
at least one of the following TEAEs, where subjects with more than one TEAE in a 
particular category are counted only once in that category: 
• 
any AE;  
• 
Any DLT; 
• 
Any AE with severity grade ≥ 3; 
• 
any AE by maximum severity (Grade 1 to 5), a subject is counted only once at 
the highest severity grade of all AEs experienced by the subject; 
• 
any AE related to bavituximab 
and AE related to bavituximab with severity grade ≥ 3 
• 
any AE related to pembrolizumab 
and AE related to pembrolizumab with severity grade ≥ 3 
• 
any AE related to bavituximab and pembrolizumab 
and AE related to bavituximab and pembrolizumab with severity grade ≥ 3 
• 
AE leading to treatment discontinuation (bavituximab, pembrolizumab, or 
either);  
• 
AE leading to dose modification (bavituximab dose reduced, bavituximab 
interrupted, pembrolizumab drug interrupted) 
• 
AE related to bavituximab leading to treatment discontinuation (bavituximab, 
pembrolizumab, or either) 
• 
AE related to pembrolizumab leading to treatment discontinuation (bavituximab, 
pembrolizumab, or either) 
• 
AE related to bavituximab and pembrolizumab leading to treatment 
discontinuation (bavituximab, pembrolizumab, or either) 
• 
SAE;  
• 
treatment-related SAE (bavituximab, pembrolizumab, or both);  
• 
SAE leading to death; 
• 
treatment-related SAE leading to death;  
 


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6.7.2.3 
Adverse Events by System Organ Class (SOC) and Preferred 
Term (PT) 
The number and percentage of subjects reporting each TEAE will be summarized by 
System Organ Class (SOC) and Preferred Term (PT) for the Safety population.  Tables 
will be sorted alphabetically by SOC.  PTs will be sorted by descending overall total.  
The following summaries will be produced: 
• 
AEs, by SOC and PT; 
• 
AEs by PT; 
• 
AEs related to study treatment, by SOC and PT (grouped to bavituximab, 
pembrolizumab, or both); 
• 
AEs related to study treatment, by PT (grouped to bavituximab, pembrolizumab, 
or both); 
• 
AEs severity grade ≥ 3, by SOC and PT; 
• 
AEs severity grade ≥ 3, by PT; 
• 
AEs severity grade ≥ 3 related to study treatment, by SOC and PT (grouped to 
bavituximab, pembrolizumab, or both); 
• 
AEs severity grade ≥ 3 related to study treatment, by PT (grouped to 
bavituximab, pembrolizumab, or both); 
• 
AEs by relationship to study treatment, by SOC and PT; 
• 
AEs by maximum severity, by SOC and PT; 
• 
AEs related to study treatment by severity, by SOC and PT (grouped to 
bavituximab, pembrolizumab, or both); 
• 
AEs causing discontinuation from bavituximab study treatment, by SOC and PT; 
• 
AEs causing discontinuation from pembrolizumab study treatment, by SOC and 
PT; 
• 
AEs related to study treatment leading to discontinuation from study treatment, 
by SOC and PT (related to bavituximab and leading to bavituximab discontinued 
or related to pembrolizumab and leading to pembrolizumab discontinued); 
• 
AEs leading to bavituximab dose reduced, by SOC and PT;  
• 
AEs related to study treatment leading to bavituximab dose reduced, by SOC 
and PT (related to bavituximab); 


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• 
AE leading to study treatment interrupted (bavituximab interrupted, 
pembrolizumab drug interrupted) 
• 
AEs related to study treatment leading to study treatment interrupted, by SOC 
and PT (related to bavituximab and leading to bavituximab interrupted or 
related to pembrolizumab and leading to pembrolizumab interrupted); 
In the above summaries, subjects with more than one AE within a particular SOC are 
counted only once for that SOC.  Similarly, subjects with more than one AE within a 
particular PT are counted only once for that PT.  For summaries by severity, subjects 
with multiple AEs within a particular SOC or PT will be counted under the category of 
their most severe AE within that SOC or PT.  AEs with missing intensity/severity will 
be included (as severe) in the overall count of subjects with AEs, but will not be 
included in the counts of subjects with AEs within a SOC or PT.   
6.7.2.4 
Serious Adverse Events (SAE), Adverse Events of Special 
Interest (AESI) and Deaths 
The number and percentage of subjects reporting TE SAE and TE AESI will be 
summarized by System Organ Class (SOC) and Preferred Term (PT) for the Safety 
population.  Tables will be sorted alphabetically by SOC.  PTs will be sorted by 
descending overall total.  The following summaries will be produced: 
• 
SAEs, by SOC and PT; 
• 
SAEs related to study treatment, by SOC and PT; 
• 
TEAEs leading to death, by SOC and PT; 
• 
Treatment-emergent AESI by SOC and PT; 
• 
Treatment related, treatment-emergent AESI by maximum severity, by SOC and 
PT (related grouped to bavituximab, pembrolizumab, or both) 
All deaths will be listed including deaths resulting from AEs, from disease progression, 
and deaths reported during survival follow-up period.  The death listing will present 
study period, primary cause of death and the number of days between the date of 
the last dose of study drug and death.  The number and percentage of patients who 
died will be summarized by study period: pre-treatment, treatment period through 
30-day follow-up, and survival follow-up period. 
6.7.3 Laboratory Evaluations 
Blood and urine samples will be collected at the time points specified in Table 1.  
Screening results for study eligibility will be performed within 72 hours prior to first 
dose of treatment.  Additional clinical laboratory tests can be obtained at any time 


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during the study at the Investigator’s discretion.  Local laboratories will perform the 
assessments. 
All blood and urine collections for clinical laboratory tests occurring on the same day 
as study treatment administration will be performed prior to study treatment 
administration. 
Laboratory tests of Table 7 will be performed by local labs and converted to 
International System of Units (SI) units.  The SI units and decimal presentation 
format for laboratory data listings are presented in Section 8. 
Quantitative hematology, coagulation, clinical chemistry (including thyroid), and 
urinalysis results will be listed and summarized by visit using standard descriptive 
statistics for the Safety population.  Changes from baseline will also be summarized.  
For each laboratory test, the baseline value will be defined as last scheduled value 
collected prior to the first dose of study treatment.  Only data from scheduled visits 
will be included in the descriptive summary tables.  Qualitative urinalysis and 
pregnancy test results will be listed only.   
Out-of-reference-range values will be flagged as high (H) or low (L) in the listings.  A 
shift table will be presented to summarize shifts from baseline to the scheduled Day 1 
assessment of each treatment cycle. 
Clinically significant laboratory abnormalities will be recorded to the AE eCRF and will 
be graded according to the CTCAE v5.0 grading system.  In addition, criteria to assign 
laboratory toxicity grade based on CTCAE Version 5.0 will be used to assign severity 
grades to selected abnormal laboratory results.  Details of statistically derived CTCAE 
grades are presented below in Section 9.  These derived severity grades will be 
reported in the clinical laboratory listings and summarized in laboratory shift tables.  
A listing of laboratory tests for review of potential drug induced liver injury (patient 
cases) will include results of all scheduled and unscheduled alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), total bilirubin (BILI), and alkaline 
phosphatase tests evaluated from baseline through safety follow-up of any patient 
with (ALT > 3xULN or AST > 3xULN) and (BILI > 2xULN). The criterion will be 
assessed using the patient’s maximum ALT, AST, and BILI over the interval from 
baseline through safety follow-up. All test results will be reported as a ratio to the 
corresponding test upper limit of normal range. 
For hematology, coagulation, and serum chemistry, shift tables presenting changes 
CTCAE grading from baseline to worst post-baseline result will be provided.  Where 
defined, low and high shifts will be summarized separately.  This analysis will include 
scheduled and unscheduled post-baseline assessments. 


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6.7.4 Vital Signs 
The following vital signs will be listed and summarized by visit. 
• 
systolic and diastolic blood pressure (mmHg); 
• 
pulse rate (bpm); 
• 
respiration rate (breaths/min); 
• 
body temperature (°C). 
• 
weight (kg) 
Vital signs data and changes from baseline in vital signs will be summarized by visit 
using standard descriptive statistics for the Safety population.  The baseline value 
will be defined as last scheduled value collected prior to the first dose of study 
treatment.  For post-baseline, only data from scheduled visits will be included in the 
summary tables.   
Height (meter) will be measured at screening only.  Height will be summarized on 
baseline characteristics for the Safety population. 
6.7.5 Electrocardiograms 
A standard 12-lead ECG will be performed using local standard procedures once at 
screening.   
The quantitative ECG measurements will be listed for the Safety population. 
The Investigator assessment of ECG (categories “normal”, “abnormal, not clinically 
significant” and “abnormal, clinically significant”) will be listed.  Clinically significant 
abnormal findings will be listed as medical history. 
6.7.6 Physical Examination 
Clinically significant abnormal physical examination findings noted during screening 
will be listed as medical history.   
New clinically significant abnormal findings should be recorded as AEs. 
6.7.7 ECOG Performance Status 
ECOG performance status will be assessed at the time points specified in  
  For each assessment, the status scores and percentage of subjects will be 
summarized by visit for the Safety Population. 


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6.8 Interim Analysis 
Safety data will be reviewed during the study.  The purpose of these data reviews is 
to evaluate the safety and tolerability for the initial dose schedule and determine if a 
DLT has been observed.   
Safety analyses will be performed when a total of 10 subject patients have received 
at least one dose of study therapy and followed for 3 months after the 10th patients 
receives the first dose of study therapy.  At that point the available clinical safety 
data as well as laboratory data will be evaluated particularly for late-onset DLT-like 
toxicities.  Treatment exposure, AEs and laboratory results will be listed for 
DLT-evaluable and Safety populations.  Summary tables of demographics, 
disposition, AEs and SAEs by CTCAE grade and relationship to study treatment, and 
laboratory shift will be presented. 
Interim analyses of the safety and efficacy data will be performed approximately 3 
months after a total 40 patients across both Group 1 and Group 2 have received at 
least one dose of study treatment.  The data from the interim analyses will be 
considered directional and used primarily for minimal efficacy analysis considerations.  
ORR will be summarized and supporting listings will be presented.  Primary and 
secondary efficacy endpoints will be listed by study treatment for Efficacy population.  
Safety variables like treatment exposure, AEs, lab results will be summarized.  After 
the analysis of 40 patients for ORR, the activity of study therapy across the entire 
population as well as in the combined pool of biomarker groups will be analyzed, and, 
if the data appear to be promising, the study population or the overall sample size 
may be adjusted via an amendment. 


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7. Changes in Planned Analysis 
Protocol states ‘Efficacy analysis will be performed on the full analysis set, and per 
protocol analysis set, including predefined biomarker subgroups’.  Per protocol 
analysis set is not defied in this SAP, but a sensitivity analysis that excludes patients 
with specified important protocol deviations will be performed for the primary and 
secondary efficacy endpoints.  These important protocol deviations will be identified 
in a data classification document, which is finalized prior to database lock. 


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8. Laboratory Tests, Standard International (SI) Units and 
Decimal Precision 
Table 7: 
Clinical Laboratory Tests 
Hematology - local laboratory 
Leukocytes (WBC) 
Erythrocytes (RBC) 
Neutrophils a 
Hemoglobin (HGB) 
Lymphocytes 
Hematocrit (HCT) 
Monocytes 
Mean corpuscular volume (MCV) 
Eosinophils 
Mean corpuscular hemoglobin concentration (MCHC) 
Basophils 
Platelets (PLT) 
Coagulation - local laboratory 
Activated partial thromboplastin time (aPTT) or Partial thromboplastin time (PTT) 
International normalized ratio (INR) or Prothrombin time (PT) 
Clinical Chemistry - local laboratory 
Alanine aminotransferase (ALT) 
Creatine kinase (CK) 
Albumin 
Creatinine 
Alkaline phosphatase 
Glucose, nonfasting 
Aspartate aminotransferase (AST) 
Magnesium 
Bilirubin, direct 
Potassium 
Bilirubin, total 
Sodium 
Blood urea nitrogen (BUN) or blood urea 
Uric acid 
Calcium 
T3 (free or total) 
Chloride 
T4 (free or total) 
 
TSH 
Urinalysis - local laboratory 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Urine leukocyte esterase 
pH 
 
Pregnancy Test (for female patients of childbearing potential) - local laboratory 
Serum pregnancy test 
Urine pregnancy test 
Abbreviations:  RBC = red blood cells; TSH = thyroid-stimulating hormone; WBC = white blood cells. 
a Neutrophils reported by automated differential hematology instruments include both segmented and band forms. 
Listings and tables will report all quantitative laboratory tests using SI units and 
decimal precision indicated below: 
Hematology 
LBTESTCD 
LBTEST 
SI Units 
(LBSTRESU) 
Decimal 
Precision 
Leukocytes (WBC 
WBC 
Leukocytes 
10^9/L 
1 
Neutrophils  
NEUT 
Neutrophils 
10^9/L 
1 
Lymphocytes 
LYM 
Lymphocytes 
10^9/L 
1 
Monocytes  
MONO 
Monocytes 
10^9/L 
2 


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Hematology 
LBTESTCD 
LBTEST 
SI Units 
(LBSTRESU) 
Decimal 
Precision 
Eosinophils 
EOS 
Eosinophils 
10^9/L 
2 
Basophils 
BASO 
Basophils 
10^9/L 
2 
Erythrocytes (RBC) 
RBC 
Erythrocytes 
10^12/L 
1 
Hemoglobin (HGB) 
HGB 
Hemoglobin 
g/L 
0 
Hematocrit (HCT) 
HCT 
Hematocrit 
L/L 
2 
Mean corpuscular volume (MCV) 
 
 
fL 
0 
Mean corpuscular hemoglobin 
concentration (MCHC) 
 
 
g/L 
0 
Platelets (PLT) 
PLAT 
Platelets 
10^9/L 
0 
 
Coagulation 
LBTESTCD 
LBTEST 
SI Units 
(LBSTRESU) 
Decimal 
Precision 
activated partial thromboplastin 
time (aPTT) 
APTT 
Activated Partial 
Thromboplastin 
Time 
sec 
0 
partial thromboplastin time 
(PTT) 
PTT 
 
sec 
0 
International normalized ratio 
(INR) 
INR 
Thyroxine, Free 
No unit 
1 
Prothrombin time (PT) 
PT 
Prothrombin Time 
sec 
1 
% Prothrombin time (PT) 
PT 
Prothrombin Time 
% 
0 
 
Chemistry 
LBTESTCD 
LBTEST 
SI Units 
(LBSTRESU) 
Decimal 
Precision 
Alanine aminotranferase 
(ALT)  
ALT 
Alanine 
Aminotransferase 
microkat/L 
2 
Albumin 
ALB 
Albumin 
g/L 
0 
Alkaline phosphatase  
ALP 
Alkaline Phosphatase 
microkat/L 
2 
Aspartate aminotranferase 
(AST) 
AST 
Aspartate 
Aminotransferase 
microkat/L 
2 
Bilirubin, direct 
BILDIR 
Direct Bilirubin 
µmol/L * 
2 
Bilirubin, total 
BILI 
Bilirubin 
µmol/L * 
2 
Blood Urea Nitrogen (BUN)  
UREAN 
Urea Nitrogen 
mmol/L 
1 
Blood Urea 
UREA 
Blood Urea 
mmol/L 
1 
Calcium (Ca) 
CA 
Calcium 
mmol/L 
1 
Chloride (Cl) 
CL 
Chloride 
mmol/L 
0 
Creatine kinase (CK) 
CK 
Creatine kinase 
microkat/L 
2 


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Chemistry 
LBTESTCD 
LBTEST 
SI Units 
(LBSTRESU) 
Decimal 
Precision 
Creatinine  
CREAT 
Creatinine 
µmol/L * 
0 
Glucose, nonfasting 
GLUC 
Glucose 
mmol/L 
1 
Magnesium 
MG 
Magnesium 
mmol/L 
1 
Potassium (K) 
K 
Potassium 
mmol/L 
1 
Sodium (Na) 
SODIUM 
Sodium 
mmol/L 
0 
Uric acid  
URATE 
Urate 
µmol/L * 
0 
* µmol/L may print as umol/L 
 
 
Thyroid Function Testing 
LBTESTCD 
LBTEST 
SI Units 
(LBSTRESU) 
Decimal 
Precision 
T3 (free) 
T3 
 
nmol/L 
2 
T3 (total) 
T3FR 
 
pmol/L 
2 
T4 (free) 
T4 
 
nmol/L 
1 
T4 (total) 
T4FR 
 
pmol/L 
1 
TSH 
TSH 
 
microIU/L 
0 
 
Urinalysis (dipstick) 
LBTESTCD 
LBTEST 
SI Units 
(LBSTRESU) 
Decimal 
Precision 
pH 
PH 
pH 
(no unit) 
1 
Specific gravity 
SPGRAV 
Specific Gravity 
(no unit) 
3 
Blood, Glucose, Ketones, Protein, and Urine leukocyte esterase are qualitative assessments. 
 


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9. Severity Grades in Clinical Laboratory Listings and Tables 
Clinically significant laboratory abnormalities and CTCAE grades will be recorded to the AE eCRF and will be graded 
according to the CTCAE v5.0 grading system.  In addition, the following tables of criteria to assign laboratory toxicity 
grade are based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Published: November 27, 
2017.  These will be used to assign severity grades to selected abnormal laboratory results.  The derived severity 
grades will be reported in the clinical laboratory listings and summarized in laboratory shift tables. 
In the following tables, ‘Clinical’ indicates that the CTCAE definition includes clinical signs and symptoms.  Assignment 
of severity grade by statistical programming will not evaluate clinical signs or symptoms. 
 
 


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Table 8: 
Hematology Severity Grades of Laboratory Abnormal Results 
Hematology 
Hypo/ 
Hyper 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Leukocytes 
(WBC) 
Hyper 
Leukocytosis 
NA 
NA 
>100,000/mm3 
Clinical  
Leukocytes 
(WBC) 
Hypo 
White blood cell 
decreased 
<LLN -  
3.0 x 10e9 /L 
<3.0 -  
2.0 x 10e9 /L 
<2.0 –  
1.0 x 10e9 /L 
<1.0 x 10e9 /L 
Neutrophils  
Hypo 
Neutrophil count 
decreased 
<LLN -  
1.5 x 10e9 /L 
<1.5 -  
1.0 x 10e9 /L 
<1.0 -  
0.5 x 10e9 /L 
<0.5 x 10e9 /L 
Lymphocytes 
Hypo 
Lymphocyte count 
decreased 
<LLN -  
0.8 x 10e9/L 
<0.8 -  
0.5 x 10e9 /L 
<0.5 -  
0.2 x 10e9 /L 
<0.2 x 10e9 /L 
Lymphocytes 
Hyper 
Lymphocyte count 
increased 
NA 
> 4 -  
20 x10e9/L 
> 20 10e9/L 
NA 
Hemoglobin  
Hypo 
Anemia 
<LLN - 100 g/L 
<100 - 80g/L 
<80 g/L; Clinical 
Clinical  
Hemoglobin  
Hyper 
Hemoglobin 
increased 
>0 - 2 g/dL 
above  
max(ULN, BL) 
>2 - 4 g/dL 
above  
max(ULN, BL) 
>4 g/dL above 
max(ULN, BL) 
NA 
Platelets 
Hypo 
Platelet count 
decreased 
<LLN - 
75.0 x 10e9 /L 
<75.0 -  
50.0 x 10e9 /L 
<50.0 - 25.0 x 
10e9 /L 
<25.0 x 10e9/L 
BL = baseline; LLN = lower limit of normal range; NA = not applicable, no toxicology grade will be assigned;  
ULN = upper limit of normal range. 
 
 
 


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Table 9: 
Coagulation Severity Grades of Laboratory Abnormal Results 
Coagulation 
Hypo/ 
Hyper 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Activated partial 
thromboplastin time 
(aPTT) 
Hyper 
aPTT 
prolonged 
>ULN - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN; Clinical 
NA 
International normalized 
ratio (INR) [1] 
Hyper 
INR increased 
>1.2 - 1.5;  
>1 - 1.5 x baseline if 
on anticoagulation  
>1.5 - 2.5;  
>1.5 - 2.5 x baseline 
if on anticoagulation 
>2.5;  
>2.5 x baseline if on 
anticoagulation; 
Clinical 
NA 
BL = baseline; LLN = lower limit of normal range; NA = not applicable, no toxicology grade will be assigned;  
ULN = upper limit of normal range. 
[1] The calculation will not reference concomitant medication but will use the second rule if baseline INR > 1.1. 
 
 
 


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Table 10: 
Clinical Chemistry Severity Grades of Laboratory Abnormal Results 
Serum 
Chemistry 
Hypo/ 
Hyper 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alanine 
aminotransferase 
(ALT)  
Hyper 
Alanine 
aminotransferase 
increased 
>ULN - 3.0 x ULN 
if baseline was 
normal; 1.5 - 3.0 
x baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 
x baseline if 
baseline was 
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 
Albumin  
Hypo 
Hypoalbuminemia 
<LLN - 30 g/L 
<30 - 20 g/L 
<20 g/L 
Clinical 
Alkaline 
phosphatase 
Hyper 
Alkaline phosphatase 
increased 
>ULN - 2.5 x ULN 
if baseline was 
normal; 2.0 - 2.5 
x baseline if 
baseline was 
Abnormal 
>2.5 - 5.0 x ULN if 
baseline was 
normal; >2.5 - 5.0 
x baseline if 
baseline was 
Abnormal 
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 
Aspartate 
aminotransferase 
(AST) 
Hyper 
Aspartate 
aminotransferase 
increased 
>ULN - 3.0 x ULN 
if baseline was 
normal; 1.5 - 3.0 
x baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 
x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal 
Bilirubin, Direct 
Hyper 
Blood bilirubin 
increased 
 >ULN - 1.5 x ULN 
if baseline was 
normal; > 1.0 - 
1.5 x baseline if 
baseline was 
abnormal 
>1.5 - 3.0 x ULN if 
baseline was 
normal; >1.5 - 3.0 
x baseline if 
baseline was 
abnormal 
>3.0 - 10.0 x ULN 
if baseline was 
normal; >3.0 - 
10.0 x baseline if 
baseline was 
abnormal 
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if baseline 
was abnormal 
Bilirubin, Total 
Hyper 
Blood bilirubin 
increased 
 >ULN - 1.5 x ULN 
if baseline was 
normal; > 1.0 - 
1.5 x baseline if 
baseline was 
abnormal 
>1.5 - 3.0 x ULN if 
baseline was 
normal; >1.5 - 3.0 
x baseline if 
baseline was 
abnormal 
>3.0 - 10.0 x ULN 
if baseline was 
normal; >3.0 - 
10.0 x baseline if 
baseline was 
abnormal 
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if baseline 
was abnormal 
Calcium (Ca) 
[Corrected serum 
calcium] [1] 
Hyper 
Hypercalcemia 
[>ULN - 2.9 
mmol/L]  
[>2.9 - 3.1 
mmol/L]  
[>3.1 - 3.4 
mmol/L]; Clinical 
[>3.4 mmol/L]; 
Clinical 


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Serum 
Chemistry 
Hypo/ 
Hyper 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Calcium (Ca) 
[Corrected serum 
calcium] [1] 
Hypo 
Hypocalcemia 
[<LLN - 2.0 
mmol/L]  
[<2.0 - 1.75 
mmol/L]  
[<1.75 - 1.5 
mmol/L]; Clinical 
[<1.5 mmol/L]; 
Clinical 
Creatinine (Cr) 
Hyper 
Creatinine increased 
>ULN - 1.5 x ULN; 
>1 - 1.5 x baseline 
>1.5 - 3.0 x 
baseline; >1.5 - 
3.0 x ULN 
>3.0 x baseline; 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
Magnesium (Mg)  
Hyper 
Hypermagnesemia 
>ULN - 1.23 
mmol/L 
NA 
>1.23 - 3.30 
mmol/L 
>3.30 mmol/L; 
Clinical 
Magnesium (Mg)  
Hypo 
Hypomagnesemia 
<LLN - 0.5 mmol/L 
<0.5 - 0.4 
mmol/L; Clinical 
<0.4 - 0.3 
mmol/L; Clinical 
<0.3 mmol/L; 
Clinical 
Potassium (K) 
Hyper 
Hyperkalemia 
>ULN - 5.5 
mmol/L 
>5.5 - 6.0 
mmol/L; Clinical 
>6.0 - 7.0 
mmol/L; Clinical 
>7.0 mmol/L; 
Clinical 
Potassium (K) 
Hypo 
Hypokalemia 
<LLN - 3.0 
mmol/L; Clinical 
<LLN - 3.0 
mmol/L; Clinical 
<3.0 - 2.5 
mmol/L; Clinical 
<2.5 mmol/L; 
Clinical 
Sodium (Na) 
Hyper 
Hypernatremia 
>ULN - 150 
mmol/L 
>150 - 155 
mmol/L; Clinical 
>155 - 160 
mmol/L; Clinical 
>160 mmol/L; 
Clinical 
Sodium (Na) 
Hypo 
Hyponatremia 
<LLN - 130 
mmol/L 
125-129 mmol/L; 
Clinical 
120-124 mmol/L; 
Clinical  
<120 mmol/L; 
Clinical 
BL = baseline; LLN = lower limit of normal range; NA = not applicable, no toxicology grade will be assigned; ULN = upper limit of normal 
range. 
[1] Corrected serum calcium (mmol/L) = total calcium (mmol/L) + 0.02 [40 – albumin (g/L)].  Corrected calcium will be used for 
assignment of toxicology grade by statistical programming.