Clinical trial NCT05249569
Conditions: Hepatocellular Carcinoma
Sponsor: University of Texas Southwestern Medical Center
Start date: 2022-11-04; Completion date: 2022-12-30
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Across cancer types, immune checkpoint inhibitors have been shown to induce complete response, partial response, and stable disease after initial evidence of radiographic increase in tumor burden. Treatment beyond progression should be considered when the patient is stable (or improving) symptomatically and if tumor reassessment can be performed within a short period.

Detailed description:
Preclinical evidence indicates that VEGF and VEGF-dependent angiogenesis may induce immune suppression in tumors by impairing antigen presenting cells and effector T-cells, and enhancing T-regulatory cells and monocytes. Thus, targeting VEGF may reprogram the tumor immune microenvironment to render cancers more vulnerable to immunotherapies. Indeed, the use of anti-VEGF strategies as an immunotherapy adjuvant has been associated with clinical benefit in multiple cancer types including HCC, and no new safety signals. While the clinical benefit of monotherapy axitinib in HCC is modest, use of axitinib as an immunotherapy adjuvant may circumvent primary resistance mechanisms to immune checkpoint inhibitors in HCC leading to more frequent or robust anti-tumor immunity.

Given the complimentary immune augmenting mechanisms of targeting VEGF and phosphatidylserine, combination axitinib, bavituximab, and avelumab, a PD-L1 antibody, represents a novel and rational immunotherapy regimen in HCC.

Arms: arm 1: Axitinib 5 mg PO BID Avelumab 10 mg/kg IV every 2 weeks (2 doses in a 4-week cycle) Bavituximab 3 mg/kg IV every 1 week (4 doses in a 4-week cycle) Study treatment will continue until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.
Interventions: intervention 1: Axitinib intervention 2: Avelumab intervention 3: Bavituximab
Intervention descriptions: intervention 1: Axitinib to be administered orally BID intervention 2: Avelumab to be administered as a 1-hour IV infusion on Day 1 and Day 15 of each 28-day cycle. intervention 3: Bavituximab to be administered weekly on Days 1, 8, 15 and 22 of the 28-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
STU2022-0116, Hsieh, FormA-ResearchProtocol, NS, 05-18-22 (1) 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 07/2020 
 
 
Official title: Single-Arm Phase II Study of Axitinib, Avelumab, and 
Bavituximab in Advanced HCC  
 
NCT number: NCT05249569 
IRB approved date: 05/18/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
STU2022-0116, Hsieh, FormA-ResearchProtocol, NS, 05-18-22 (1) 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 07/2020 
 
 
PROTOCOL NUMBER - PENDING 
Single-Arm Phase II Study of Axitinib, Avelumab, and Bavituximab in Advanced HCC  
 
Principal Investigator:  
David Hsieh 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
Harold C. Simmons Comprehensive Cancer Center  
 
 
 
 
5323 Harry Hines Boulevard  
 
 
 
 
Dallas, TX 75390-9179   
 
 
 
 
 
 
 
214-648-4180 
 
 
 
 
214-648-8146 (Fax) 
 
 
 
 
david.hsieh@utsouthwestern.edu 
 
Lead Sub-Investigator(s): 
 
 
 
 
Biostatistician: 
 
Chul Ahn 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Boulevard  
 
 
 
 
Dallas, TX 75390-9179  
 
 
 
 
214-648-9418 
 
 
 
 
chul.Ahn@UTSouthwestern.edu 
 
Study Drug/Treatment: 
Axitinib (Inlyta) 
 
 
 
 
Avelumab (Bavencio) 
 
 
 
 
Bavituximab 
 
IND/IDE Number: 
 
159270 
 
IND/IDE Holder Name:  
David Hsieh, MD 
 
Funding Source:  
Pfizer 
 
NCT Number: 
NCT05249569 
 
Version: 
Version 1.0, August 4, 2021 
Amended: 
 
 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Comprehensive Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


 
STU2022-0116, Hsieh, FormA-ResearchProtocol, NS, 05-18-22 (1) 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 07/2020 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
Amendment/Version #         Version 1.0, August 4, 2021 
           
PROTOCOL NUMBER - PENDING 
Single-Arm Phase II Study of Axitinib, Avelumab, and Bavituximab in Advanced HCC  
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................1 
STUDY SCHEMA .................................................................................3 
 
STUDY SUMMARY ..............................................................................3 
1.0 
BACKGROUND AND RATIONALE .....................................5 
1.1 Disease Background ....................................................................................... 5 
1.2 Study Agents/Therapies Background and Associated Known Toxicities ........ 6 
1.3 Rationale........................................................................................................ 13 
1.4 Rationale for Treatment Beyond Progression ............................................... 14 
1.5 Correlative Studies ........................................................................................ 14 
2.0 
STUDY OBJECTIVES ........................................................ 14 
2.1 Primary Objectives ........................................................................................ 14 
2.2 Secondary Objectives .................................................................................... 14 
2.3 Exploratory Objectives ................................................................................... 14 
2.4 Endpoints ....................................................................................................... 15 
3.0 
SUBJECT ELIGIBILITY ...................................................... 15 
3.1 Inclusion Criteria ............................................................................................ 15 


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3.2 Exclusion Criteria ........................................................................................... 17 
4.0 
TREATMENT PLAN ........................................................... 19 
4.1 Treatment Dosage and Administration .......................................................... 19 
4.2 Safety Lead-in, Toxicities, and Dosing Delays/Dose Modifications .............. 21 
4.3 Concomitant Medications/Treatments ........................................................... 27 
4.4 Registration Procedures ................................................................................ 28 
4.5 Duration of Therapy ....................................................................................... 29 
4.5 Treatment Beyond Progression ..................................................................... 29 
4.6 Duration of Follow Up .................................................................................... 29 
4.7 Removal of Subjects from Protocol Therapy ................................................. 30 
5.0 
STUDY PROCEDURES ...................................................... 30 
5.1 Screening/Baseline Procedures .................................................................... 30 
5.2 Procedures During Treatment ....................................................................... 31 
5.3 Time and Events Table .................................................................................. 33 
5.4 Removal of Subjects from Study ................................................................... 34 
5.5 Reporting of Pregnancy and Lactation to Sponsor (UT Southwestern) ........ 35 
6.0 
Measurement of Effect ...................................................... 35 
6.1 Antitumor Effect ............................................................................................. 35 
6.2 Safety/Tolerability .......................................................................................... 38 
7.0 
ADVERSE EVENTS ........................................................... 38 
7.1 Axitinib ........................................................................................................... 38 
7.2 Avelumab ....................................................................................................... 41 
7.3 Bavituximab ................................................................................................... 42 
7.4 Adverse Event Monitoring ............................................................................. 43 
7.5 Expedited Reporting to the SCCC DSMC ..................................................... 45 
7.6 Stopping Rules .............................................................................................. 47 


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8.0 
DRUG/TREATMENT INFORMATION ................................ 47 
8.1 Axitinib ........................................................................................................... 47 
8.2 Avelumab ....................................................................................................... 48 
8.3 Bavituximab ................................................................................................... 49 
9.0 
CORRELATIVES/SPECIAL STUDIES ............................... 50 
10.0 
STATISTICAL CONSIDERATIONS ................................... 50 
10.1 Study Design/Study Endpoints ...................................................................... 50 
10.2 Sample Size and Accrual .............................................................................. 50 
10.3 Data Analyses ............................................................................................... 51 
11.0 
STUDY MANAGEMENT ..................................................... 51 
11.1 Conflict of Interest .......................................................................................... 51 
11.2 Institutional Review Board (IRB) Approval and Consent ............................... 51 
11.3 Required Documentation (for multi-site studies) ........................................... 52 
11.4 Data Management and Monitoring/Auditing .................................................. 52 
11.5 Adherence to the Protocol ............................................................................. 53 
11.6 Amendments to the Protocol ......................................................................... 54 
11.7 Record Retention ........................................................................................... 54 
11.8 Obligations of Investigators ........................................................................... 54 
12.0 
REFERENCES.................................................................... 56 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AFP 
Alpha Fetoprotein 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
aPTT 
Activated thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BID 
bis in die/twice a day 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated Antigen 4 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DR 
Duration of Response 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HDPE 
High-Density Polyethylene 
HRPP 
Human Research Protections Program 
HR 
Hazard Ratio 
ICIs 
Immune Checkpoint Inhibitors 
IHC 
Immunohistochemistry 
IL-2 
Interleukin-2 
IND 
Investigational New Drug 
INR 
International normalized ratio 
irAEs 
Immune-Related Adverse Events 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
IV (or iv) 
Intravenously 


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LD 
Longest Diameter 
LOAEL 
Lowest-observed-adverse-effect level 
MI 
Molecular Intelligence 
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NOAEL 
No-observed-adverse-effect level 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PD-1 
Programmed cell Death protein 1 
PD-L1 
Programmed Death-Ligand 1 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PO 
peros/by mouth/orally 
PR 
Partial Response 
PS 
Phosphatidylserine 
PT 
Prothrombin time 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SLD 
Sum of the Longest Diameter 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SVR12 
Sustained Virologic Response after 12 weeks post-treatment 
TK 
Toxicokinetic 
USP 
United States Pharmacopeia 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptors 
WBC 
White Blood Cells 
 
 
 
 
 


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STUDY SCHEMA 
 
STUDY SUMMARY 
Title 
Multi-center phase II open-label study of bavituximab, axitinib, and 
avelumab in advanced hepatocellular carcinoma 
Short Title 
Phase II study of bavituximab, axitinib, and avelumab in advanced 
hepatocellular carcinoma 
Protocol Number 
TBD 
Phase 
Phase 2 with safety lead-in 
Methodology 
Open-label 
Study Duration 
24 months accrual/24 months follow-up 
Study Center(s) 
UT Southwestern Medical Center and Parkland Health and Hospital 
System 
Objectives 
To determine the objective response rate of combination axitinib, 
avelumab, and bavituximab in advanced HCC not previously treated with 
systemic therapy. 
Number of Subjects 
14-29 evaluable patients 
Diagnosis and Main 
Inclusion Criteria 
1. Patients must have a histologically confirmed diagnosis of 
hepatocellular carcinoma;   
2. No history of prior systemic therapy for HCC;  
3. Patients with advanced HCC not eligible for curative and/or 
locoregional therapies;  
4. Age ≥ 18 years;  
5. Child-Pugh Score A   
Study Product(s), Dose, 
Route, Regimen 
Axitinib 5 mg PO BID 
Avelumab 10 mg/kg IV every 2 weeks (maximal dose of 2000 mg; 2 
doses in a 4-week cycle) 
Bavituximab 3 mg/kg IV every 1 week (4 doses in a 4-week cycle) 
Duration of administration 
Study treatment will continue until disease progression, unacceptable 
toxicity, death, or discontinuation from the study treatment for any other 
reason. 


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Statistical Methodology 
Safety and tolerability assessment will be performed for the first 6 
evaluable patients in the safety lead-in. The primary endpoint of the trial 
will be objective response rate (ORR). A minimax two-stage method will 
be used to analyze ORR after the first 14 patients are accrued. 15 
additional patients will be enrolled if 2 or more of the first 14 patients 
have either a complete or partial response. 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
HCC is a devastating disease in the US and worldwide: Hepatocellular carcinoma (HCC) 
is the most common liver cancer and the fourth most frequent cause of cancer-related 
deaths worldwide.1 In contrast to the decreasing disease burden of other prevalent cancer 
types over time, HCC incidence and related mortality continues to increase in the US and 
globally.2 The increasing health burden attributed to HCC demonstrates an urgent need to 
develop better therapies, as many HCC patients are diagnosed beyond curative stages. In 
addition, because HCC often arises in the setting of cirrhosis, at-risk patients with 
irreversible liver injury remain at a perpetual risk of HCC. This highlights the importance of 
utilizing novel strategies in HCC treatment designs that may not be thwarted by known 
drug resistance mechanisms and are not associated with long-term sequelae.  
 
Until recently, first-line systemic therapy for advanced HCC was limited to oral tyrosine 
kinase inhibitors chiefly targeting VEGF signaling. In the phase III randomized controlled 
SHARP trial, patients with advanced hepatocellular carcinoma (not eligible for surgical 
resection or transplantation) and preserved liver function (Child-Pugh A score) were 
randomly assigned to either systemic sorafenib or placebo.3 Seven patients in the 
sorafenib group (2%) and two patients in the placebo group (1%) had a partial response, 
and there were no complete responses. While median overall survival was significantly 
prolonged with sorafenib (10.7 months in the sorafenib group and 7.9 months in the 
placebo group), the clinical benefit was incremental and sorafenib was associated with a 
greater incidence of toxicities including diarrhea and skin reactions. Nearly a decade after 
the FDA approval of sorafenib followed by a series of failed superiority and non-inferiority 
phase III trials in advanced HCC, lenvatinib gained approval for first-line treatment of 
advanced HCC based on the results of the phase III randomized non-inferiority REFLECT 
trial.4 Patients with advanced HCC were randomized to either lenvatinib or sorafenib, and 
the median survival time for lenvatinib (13.6 months) was demonstrated to be non-inferior 
to sorafenib (12.3 months). Response rates with lenvatinib was 24.1% versus 9.2% with 
sorafenib, and toxicities were comparable between the two agents. Nonetheless, 57% of 
patients treated with lenvatinib had treatment-related treatment-emergent adverse events 
(AEs) of at least grade 3 and 18% had serious treatment-related treatment-emergent AEs. 
While both sorafenib and lenvatinib remain viable first-line options for patients with 
advanced HCC, the lack of progress in clinical benefit and considerable toxicities 
associated with oral tyrosine kinase inhibitors demonstrates an unmet need for more 
effective and safe HCC treatments. 
 
Efficacy of immunotherapy in HCC:  
Targeted manipulation of immune checkpoints including PD-1 and CTLA-4 using antibody-
based immune checkpoint inhibitors (ICIs) can induce striking and durable clinical 
responses in advanced cancers. Early phase studies demonstrated that the immune 
checkpoint inhibitors nivolumab and pembrolizumab were associated with encouraging 
objective responses in HCC including cancers refractory to sorafenib.5,6 In the phase I/II 
open-label, non-comparative CheckMate 040 study, patients received intravenous 
nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase and 3 mg/kg every 2 
weeks in the dose-expansion phase.5 The objective response rate was 20% (95% CI 15-
26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% 
CI 6-28) in the dose-escalation phase. Only three (6%) patients had treatment-related 
serious AEs (pemphigoid, adrenal insufficiency, liver disorder). In the phase II open-label 
KEYNOTE-224 study, patients who had been previously treated with sorafenib received 
200 mg pembrolizumab intravenously every 3 weeks.6 The overall response rate was 17% 
and 44% patients had stable disease. At the time of data cut-off, the 12-month overall 


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survival rate was 54%. Greater than grade 2 treatment-related AEs occurred in 26% of 
patients (grade 3 in 24%, grade 4 in 1%, and grade 5 in 1%).  
 
Results from the CheckMate 040 and KEYNOTE-224 studies collectively demonstrate that 
immunotherapies can induce meaningful response rates in patients with HCC which are 
safe and durable in a subset of patients. Their distinct mechanisms of action also suggest 
that immunotherapies may be effective among patients previously treated with oral tyrosine 
kinase inhibitors. However, the phase III KEYNOTE-240 trial testing pembrolizumab versus 
placebo in the second line setting did not meet its primary endpoint in prolonging overall 
survival and progression-free survival.7 Nonetheless, pembrolizumab was associated with 
a significant improvement in objective response rates (18.3% versus 4.4%) and a non-
statistically significant trend towards improved survival (HR, 0.781; 95% CI, 0.611 to 0.998; 
P = 0.02).8 The clinical benefit of combination immunotherapy regimens in HCC was 
recently demonstrated by the phase III IMbrave150 study testing atezolizumab and 
bevacizumab versus sorafenib in the first line setting.8 Patients received either 1200 mg of 
atezolizumab plus 15 mg/kg of bevacizumab intravenously every 3 weeks or 400 mg of 
sorafenib orally twice daily. Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) 
with atezolizumab plus bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. 
These results demonstrate that while use of immunotherapy as monotherapy may be 
associated with modest clinical benefit, a rationally designed combination immunotherapy 
regimen may provide meaningful clinical activity in HCC.  
1.2 
Study Agents/Therapies Background and Associated Known Toxicities 
 
 
 
1.2.1 
Axitinib: Overview 
Axitinib is an oral and selective inhibitor of vascular endothelial growth factor 
receptors (VEGFR)-1, 2, and 3. Since 2012, axitinib has been approved by the 
FDA for use in patients with advanced renal cell carcinoma (RCC). In 2019, the 
FDA approved axitinib plus pembrolizumab or avelumab as first-line treatment for 
patients with advanced RCC. Given the known efficacy of targeting VEGFR activity 
in HCC and the established safety of combining axitinib with immunotherapies in 
RCC, the use of axitinib in a combination immunotherapy regimen is anticipated to 
be safe and active in patients with advanced HCC. 
 
 
1.2.2 
Axitinib: Non-clinical experience 
Axitinib is a small molecule adenosine triphosphate-competitive inhibitor that binds 
to the unphosphorylated conformation of the catalytic domain of receptor tyrosine 
kinases.9 In contrast to other VEGFR targeting agents in clinical use such as 
sunitinib and sorafenib which inhibit multiple receptor tyrosine kinases, axitinib is 
a highly specific and potent inhibitor of VEGFR1-3.10 For instance, the 
concentration of axitinib that inhibits phosphorylation of VEGFR-1, -2 and -3 by 50 
% (IC50) is ≈0.1, 0.2 and 0.1–0.3 nmol/L, respectively, but is notably greater at 5, 
1.6 and 1.7 nmol/L for platelet-derived growth factor receptor-α and -β and stem-
cell factor receptor.11 In multiple studies, axitinib has been demonstrated to impair 
VEGFR effector signaling including activation of mitogen-activated protein kinases 
and have anti-angiogenic activity in a number of tumor models.10,12-14 
 
Axitinib pharmacokinetic (PK) parameters were determined from non-Good 
Laboratory Practice (GLP) studies conducted in Cesarean-derived (CD)-1 mice, 
Sprague-Dawley rats, Beagle dogs, and cynomolgus monkeys. Axitinib 
demonstrated low to moderate intravenous clearance with good oral solution 
bioavailability, consistent with moderate absorption from the gastrointestinal tract. 
The unbound fraction of axitinib in plasma determined by equilibrium dialysis was 
3.0%, 1.9%, 2.0%, and 0.5% in the mouse, rat, dog, and human, respectively. To 
assess the tissue distribution of axitinib, [14C] axitinib was orally administered to 
pigmented male B6C3F1/Crl BR mice and assessed using quantitative whole-body 


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autoradiography. Radiolabeled axitinib was rapidly absorbed and well distributed 
into most tissues and was not associated with persistence in any organ except for 
the pigmented uveal tract, liver, and gall bladder. In vitro studies indicated that 
axitinib is metabolized in the liver by CYP3A4/5, and to a lesser extent by CYP1A2, 
CYP2C19, and UGT1A1. 
 
 
1.2.3 
Axitinib: Clinical experience 
In a phase I, multicenter clinical trial of axitinib in patients (n = 36) with refractory 
tumors, the maximum tolerated dose for further phase II clinical trials was 
established as 5 mg bid daily.15 Axitinib was absorbed rapidly, with peak plasma 
concentrations occurring within 2 to 6 hours after dosing and plasma 
concentrations declined with a terminal plasma half-life between 2 and 5 hours. 
Steady state levels were reached within 15 days, with no unexpected accumulation 
of drug. Principal toxicities included hypertension, fatigue, diarrhea, stomatitis, 
nausea, and vomiting. Hypertension was the most frequent toxicity occurring in 22 
patients (61%) and in most cases (18 patients) this was controlled with 
antihypertensive medications. Objective responses were observed in a patient with 
adenoid cystic carcinoma and in 2 of 6 patients with RCC. 
 
The safety and activity of axitinib has been evaluated in patients with HCC in 3 
phase II studies. Kang et al. conducted a global, randomized, placebo-controlled 
phase II trial in patients with locally advanced or metastatic HCC, had Child–Pugh 
Class A liver disease, and progressed on or were intolerant to one prior 
antiangiogenic therapy. Patients were randomized (2:1) to axitinib 5 mg twice daily 
(n = 134) or placebo (n = 68) and the primary end point was overall survival. While 
axitinib was not associated with an overall survival benefit (HR, 0.907; 95% CI, 
0.646; P = 0.29), progression-free survival was significantly longer with axitinib 
than placebo (HR, 0.618; P = 0.004) and there was a non-statistically significant 
trends towards greater objective responses with axitinib versus placebo (9.7% 
versus 2.9%; P = 0.091). The most frequent AEs reported with axitinib was 
diarrhea (all grades, 54%; greater than grade 3, 20%), hypertension (all grades, 
54%; greater than grade 3, 26%), and hand–foot skin reaction (all grades, 34%; 
greater than grade 3, 15%). Laboratory abnormalities related to hepatic function 
were minimally or moderately increased with axitinib, demonstrating that the risk 
of hepatotoxicity is noticeably less in axitinib than other VEGF receptor inhibitors 
such as sunitinib and sorafenib.  
 
McNamara et al. conducted a single‐arm phase II trial of axitinib in patients with 
advanced HCC refractory to prior antiangiogenic treatments and had Child‐Pugh 
Class A/B7 liver disease.16 Axitinib was started at 5 mg twice daily orally, and 
titrated from 2 to 10 mg twice daily as tolerated. Of 26 patients evaluable for 
response, there were 3 partial responses per RECIST 1.1, and  6 partial responses 
and 1 complete response by modified RECIST. However, the median progression-
free survival and overall survival of 3.6 and 7.1 months was disappointing. The 
most 
frequent 
axitinib‐related 
grade 
3/4 
AEs 
were 
hypertension, 
thrombocytopenia, and diarrhea. 
 
Chan et al. conducted a single-arm phase II trial in patients with inoperable HCC 
who underwent transarterial chemoembolization followed by maintenance axitinib 
5 mg twice daily. The primary endpoint was the 2‐year overall survival rate. In the 
intention‐to‐treat population (50 patients), the 2‐year survival rate was 43.7%, 
which failed to meet the prespecified hypothesis of a 2-year survival rate of 50%. 
Grade 3 or greater axitinib-related complications included hand-foot skin reaction 
(14%) and hypertension (24%). 
 


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Clinical experience of axitinib combined with immunotherapies in advanced HCC 
is limited to a single phase 1B trial (VEGF Liver 100) in which interim results were 
reported on 22 patients treated with avelumab 10 mg/kg every two weeks plus 
axitinib 5 mg orally twice daily.17 The most common grade 3 treatment-related AEs 
were hypertension (50.0%) and hand-foot syndrome (22.7%) and no grade 4/5 
toxicities were observed. Objective response rates were 13.6% (95% CI, 2.9%-
34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, 
respectively. OS data were immature at data cutoff. These preliminary findings 
demonstrate that axitinib combined with avelumab was safe, consistent with the 
known safety profiles of avelumab and axitinib when administered as 
monotherapies. 
 
Complete information for axitinib may be found in the axitinib Investigator’s 
Brochure. 
 
 
1.2.4 
Avelumab: Overview 
Avelumab is a human IgG1 antibody directed against PD-L1 which competitively 
blocks the interaction between PD-L1 and its receptors PD-1 and B7-1. This results 
in the loss of inhibitory signals within immune cells including T cells which in turn 
induces anti-tumor immunity. T-cell exhaustion is frequently observed in HCC and 
PD-L1 expression is associated with worse prognosis, providing a rationale for 
targeting PD-1/PD-L1 in liver cancers which has now been confirmed in several 
clinical studies.18,19 
 
 
1.2.5 
Avelumab: Non-clinical experience 
Binding of PD-L1 to PD-1 and B7-1 receptors found on T cells and antigen 
presenting cells suppresses T cell cytotoxic activity, proliferation, and cytokine 
production. In syngeneic mouse tumor models, avelumab mediated blockade of 
PD-L1 activity resulted in decreased tumor growth.20 Given that PD-1 is expressed 
by many immune cell types and PD-L1 expression is chiefly confined to tumor cells 
in the tumor microenvironment, it is anticipated that anti-PD-L1 therapies such as 
avelumab may also have fewer immune related toxicities. Unique to the 
mechanism of action of avelumab compared to other existing anti-PD-1/PD-L1 
antibodies is its ability to induce antibody-dependent cellular cytotoxicity activity.21 
Toxicology studies in cynomolgus monkeys determined a starting dose of 1 mg/kg 
for avelumab dose-escalation in humans and this starting dose level was 
subsequently supported by preliminary pharmacokinetic data showing that this 
dose level produced serum concentrations associated with pharmacological 
activity.22 
 
 
1.2.6 
Avelumab: Clinical experience 
The phase 1, open-label, dose-escalation trial of avelumab (JAVELIN Solid Tumor) 
investigated the safety, pharmacokinetics, biological activity, and clinical activity of 
avelumab in patients with metastatic or locally advanced solid tumors. The phase 
1a dose escalation portion was conducted at the Center for Cancer Research of 
the National Cancer Institute which examined 53 patients with histologically or 
cytologically confirmed metastatic or locally advanced solid tumors for which no 
standard therapy existed or standard therapy had failed.22 A 3 + 3 multicohort 
escalation design was used to asses 4 dose levels with 4 patients at 1 mg/kg, 13 
at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg. Pharmacokinetic analysis (n=86) 
showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg 
and a half-life of 95–99 hours at the 10 mg/kg and 20 mg/kg doses. Target 
occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Of 18 patients 
treated in the dose-limiting toxicity analysis set, no dose-limiting toxicities were 
noted at dose levels 1, 2, or 3, and one dose-limiting toxicity was reported at dose 
level 4 in a patient with metastatic thymoma. Grade 3–4 treatment-related AEs 


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occurred in nine (17%) patients. Potential immune-related AEs occurred in 5 (7%) 
patients which was not associated with increasing dose levels of avelumab. Four 
(8%) of 53 patients had a partial response and 30 (57%) of 53 additional patients 
had stable disease, which was durable in three patients with a duration of 40 weeks 
or more. Based on these results, avelumab 10 mg/kg every 2 weeks was chosen 
as the dose for subsequent development. 
 
In the expansion phase of the JAVELIN Solid Tumor study and in phase 2 studies, 
avelumab was tested in multiple cancer types including bladder cancer, stomach 
cancer, head and neck cancer, mesothelioma, non-small cell lung cancer, ovarian 
cancer, and renal cancer, which have not demonstrated new safety signals. As of 
2020, avelumab is currently approved for metastatic Merkel cell carcinoma, locally 
advanced or metastatic urothelial carcinoma whose disease progressed during or 
following platinum-containing chemotherapy, and in combination with axitinib for 
the first-line treatment of patients with advanced renal cell carcinoma.  
 
The approval of avelumab for Merkel cell carcinoma was based on results from the 
phase II JAVELIN Merkel 200 study which enrolled 88 patients with refractory and 
metastatic Merkel cell carcinoma.23 Avelumab was given intravenously at a dose 
of 10 mg/kg every 2 weeks and the primary endpoint was confirmed objective 
response according to RECIST 1.1. The proportion of patients who achieved an 
objective response was 28 (31.8%), including 8 complete responses and 20 partial 
responses. Five grade 3 treatment-related AEs occurred in four (5%) patients: 
lymphopenia in two patients, blood creatine phosphokinase increase in one 
patient, aminotransferase increase in one patient, and blood cholesterol increase 
in one patient. No treatment-related grade 4 AEs or treatment-related deaths were 
reported. 
 
In a pooled analysis of two cohorts in the expansion phase of the JAVELIN Solid 
Tumor study, 329 patients with advanced or metastatic urothelial carcinoma that 
had progressed after at least one previous platinum-based chemotherapy received 
avelumab 10 mg/kg every 2 weeks.24 The primary endpoint was confirmed best 
overall response and the overall response of complete or partial response was 
recorded in 27 patients (17%), including nine (6%) complete responses and 18 
(11%) partial responses. The most frequent treatment-related AEs were infusion-
related reaction (29%) and fatigue (16%). Grade 3 or worse treatment-related AEs 
occurred in 8% patients, the most common of which were fatigue (2%), and 
asthenia, elevated lipase, hypophosphataemia, and pneumonitis (1% each). 8% 
of 249 patients had a serious adverse event related to treatment with avelumab, 
and one treatment-related death occurred (pneumonitis). 
 
In the open-label, dose-finding and dose-expansion, phase 1b JAVELIN Renal 100 
trial, patients with advanced renal-cell carcinoma enrolled in the dose-finding 
phase received 5 mg axitinib orally twice daily for 7 days, followed by combination 
therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib 
orally twice daily.24  Based on the pharmacokinetic data from the dose-finding 
phase, patients in the expansion phase directly received 10 mg/kg avelumab 
intravenously every 2 weeks and 5 mg axitinib orally twice daily. Six of six patients 
in the dose-finding phase and 26 of 49 patients in the dose-expansion phase had 
confirmed objective responses. 32 (58%) of 55 patients had grade 3 or worse 
treatment-related AEs, the most frequent being hypertension in 16 (29%) patients 
and increased concentrations of alanine aminotransferase, amylase, and lipase, 
and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. 
These encouraging results led to the phase 3 JAVELIN Renal 101 study which 
randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg/kg) 
intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 


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mg) orally once daily for 4 weeks (6-week cycle).25 The primary end points were 
progression-free survival and overall survival among patients with programmed 
death ligand 1 (PD-L1)-positive tumors. Among the 560 patients with PD-L1-
positive tumors (63.2%), the median progression-free survival was 13.8 months 
with avelumab plus axitinib, as compared with 7.2 months with sunitinib. In the 
overall population, the median progression-free survival was 13.8 months, as 
compared with 8.4 months. Among the patients with PD-L1-positive tumors, the 
objective response rate was 55.2% with avelumab plus axitinib and 25.5% with 
sunitinib. AEs of any grade during treatment occurred in 432 of 434 patients 
(99.5%) who received avelumab plus axitinib and in 436 of 439 patients (99.3%) 
who received sunitinib. AEs of grade 3 or higher during treatment occurred in 309 
patients (71.2%) and 314 patients (71.5%) in the respective groups. The most 
frequent grade 3 or higher toxicities with avelumab plus axitinib was hypertension 
(25.6%), diarrhea (6.7%), and palmar-plantar erythrodysaesthesia syndrome 
(5.8%). AEs that occurred during treatment led to discontinuation of both avelumab 
and axitinib in 33 patients (7.6%) who received the combination and led to 
discontinuation of sunitinib in 59 patients (13.4%) who received sunitinib.  
 
Complete information for avelumab may be found in the avelumab Investigator’s 
Brochure. 
 
 
1.2.7 
Bavituximab: Overview 
Bavituximab is a chimeric monoclonal antibody directed against the membrane 
phospholipid phosphatidylserine (PS). While phosphatidylserine is normally 
confined to the inner leaflet of the plasma membrane, phosphatidylserine is 
externalized during apoptosis, cell injury, cell activation and malignant 
transformation. Bavituximab exerts anti-tumor effects by targeting exposed 
phosphatidylserine in the tumor vascular endothelium which induces tumor vessel 
destruction and immune cell recruitment. Clinical studies have demonstrated that 
bavituximab is well-tolerated, and preliminary evidence suggests that bavituximab 
combined with immune checkpoint inhibitors has anti-tumor activity in HCC. 
 
 
1.2.8 
Bavituximab: Non-clinical experience 
Phosphatidylserine is a highly immunosuppressive molecule typically expressed 
on the inner leaflet of the plasma membrane of normal cells but “flips” and becomes 
externalized to the outer leaflet of the plasma membrane on cells that line tumor 
blood vessels and tumor cells creating a specific target for anticancer treatments. 
Bavituximab is an engineered immunoglobulin gamma 1 (IgG1) chimeric 
(human/mouse) mAb containing the variable region sequences of the murine 
phosphatidylserine targeting mouse antibody 3G4(2aG4) and human IgG1 k 
constant region sequences that targets phosphatidylserine (PS) after binding to 2-
glycoprotein 1 (2GP1). By targeting phosphatidylserine, bavituximab induces 
tumor-infiltrating lymphocytes and pro-inflammatory cytokines which is enhanced 
with anti-PD-1/PD-L1 therapy. In addition, bavituximab repolarizes myeloid derived 
suppressor cells and M2 macrophages to M1, resulting in dendritic cell maturation 
and induction of tumor-specific cytotoxic T-lymphocyte immunity. 
 
Nonclinical experiments have shown that antibody-mediated phosphatidylserine 
targeting 
can 
override 
phosphatidylserine-mediated 
immunosuppression, 
reactivate innate tumor immunity, and evoke adaptive antitumor immunity. In 
genetically modified nonclinical murine tumor models, phosphatidylserine targeting 
induces potent tumor-specific T-cell immunity in the transgenic adenocarcinoma 
mouse prostate tumor model such that the combination of anti-PS with castration 
cured 35% of the animals, compared to none in control groups. In separate pre-
clinical studies, the use of antibodies against PD-1 or PD-L1 have demonstrated 


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similar activity as single agents and when combined with other immune oncology 
agents.  
 
To support clinical development, bavituximab was evaluated in a series of dose 
range finding, repeated dose and specialized IV toxicology studies in appropriate 
species and in vitro systems. In vivo toxicology studies consisted of non-GLP dose 
range finding studies in the Sprague-Dawley® (SD) rat, rabbit and cynomolgus 
monkey as single IV dose administration, followed by GLP 8-week once-weekly 
dosing toxicology studies in the rat and monkey. The reversibility of any observed 
toxicity was determined in recovery studies included as part of the protocol for 
selected studies. The in vivo studies employed intravenous bolus dosing of 
bavituximab according to the current clinical dosing regimen and route of 
administration. Toxicokinetic (TK) analyses were conducted in rats and monkeys 
to facilitate correlating observed toxicity to systemic exposure to bavituximab.  
 
The nonclinical safety assessment program that has been undertaken fully 
supports the continual use of bavituximab in clinical trials in oncology patients. The 
nonclinical effects of bavituximab have been assessed in a comprehensive panel 
of studies, addressing the relationships of pharmacology, pharmacokinetics/ 
toxicokinetics, immunogenicity and toxicology; the target tissues for toxicity; the 
NOAELs and LOAELs; the noninvasive monitors for the key toxicologic responses; 
and the reversibility of adverse effects. Among the recovery animals at the high 
dose (100 mg/kg) in the rat toxicology study, there remained evidence of 
microscopic sub endocardial inflammation and/or fibrosis, however, there were no 
coagulation abnormalities. Similarly, bavituximab-related microscopic changes in 
monkeys were confined to a mild thrombus within the right ventricle of one male at 
100 mg/kg and no coagulation abnormalities in the recovery phase. Results from 
the bavituximab nonclinical program to date indicate a therapeutic benefit of 
combining bavituximab with conventional (chemotherapy) or immunotherapy 
(checkpoint blockade) for continued clinical evaluations and support the safety of 
the proposed dose of 3 mg/kg bavituximab administered intravenously once 
weekly in patients. 
 
 
1.2.9 
Bavituximab: Clinical experience 
To date, the clinical development program of bavituximab has enrolled 
approximately 900 patients, of whom over 600 patients have been treated with 
bavituximab. Most patients were treated with combination therapy in oncology 
studies. Common AEs (20%) were reported in patients receiving bavituximab, 
including the following: nausea, alopecia, fatigue, diarrhea, neutropenia, anemia, 
pyrexia, and asthenia. Many of the reported common AEs were considered to be 
related to the concomitant administration of chemotherapy or the patient’s 
underlying malignancy.  
 
Phase I and Ib single-agent studies of bavituximab in combination with 
chemotherapy have been completed in patients with advanced cancer. Based on 
efficacy results from these studies and on PK data (which determined the 
maximum binding of β2-GP1), a dose of 3 mg/kg bavituximab was determined and 
selected for further clinical study. The studies also showed the tolerability profile 
to be consistent with expectations based on animal studies and demonstrated 
adequate efficacy to warrant further study. Several Phase II studies of bavituximab 
in combination with chemotherapy have been completed.  
 
The double-blind, placebo-controlled, multicenter, phase 3 SUNRISE study tested 
the efficacy and safety of bavituximab combined with docetaxel in patients with 
previously treated advanced non-squamous lung adenocarcinoma.26 Patients 
were randomized 1:1 to receive docetaxel 75 mg/m2 intravenously on day 1 of a 


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21-day cycle plus blinded study treatment (either placebo or bavituximab 3 mg/kg 
intravenously weekly). The primary end point was overall survival and secondary 
end points included progression-free survival, objective response rate, and safety. 
597 patients were enrolled and the median overall survival was 10.5 months in the 
docetaxel plus bavituximab arm and 10.9 months in the docetaxel plus placebo 
arm. There was also no difference in progression-free survival (HR 1.00; 95% CI 
0.82–1.22; P = 0.990) or objective response rates (14% in the docetaxel plus 
bavituximab arm and 11% in the docetaxel plus placebo arm; P = 0.18). In a post 
hoc analysis, overall survival favored the bavituximab arm among patients who 
received immune checkpoint inhibitor therapy after study therapy (n = 93, 16%) 
with a median survival time not reached versus 12.6 months (HR 0.46; 95% CI 
0.26–0.81; P = 0.006). There was no apparent difference in rates of characteristic 
immune-related adverse events, and AEs in both arms were largely consistent with 
AEs expected with docetaxel monotherapy. While this study did not support the 
addition of bavituximab to chemotherapy in refractory lung adenocarcinoma, the 
improved overall survival of patients who received bavituximab and subsequent 
immunotherapy rather than targeted therapies or chemotherapy suggests that 
bavituximab may sensitize cancers to immune checkpoint inhibitors.  
 
Bavituximab plus sorafenib was examined in a single-arm phase 2 trial of patients 
with unresectable HCC, Eastern Cooperative Oncology Group (ECOG) score ≤ 2, 
and Child-Pugh score A/B7.27 Time to progression was the primary endpoint and 
38 patients received intravenous bavituximab 3 mg/kg weekly and oral sorafenib 
400 mg twice daily. The median time to progression of patients receiving 
bavituximab and sorafenib was 6.7 months, which did not reach pre-specified 
significance. Treatment-related AEs were observed in 63% of patients, with the 
most commonly reported therapy-related symptoms being diarrhea (32%), fatigue 
(26%), and anorexia (24%). There were no grade 4-5 AEs and grade 3 AEs 
included diarrhea (5%), vomiting (3%), upper gastrointestinal bleeding (3%), 
fatigue (3%), hypertension (3%), and palmar-plantar erythrodysaesthesia 
syndrome (3%). These AEs were consistent with toxicities expected with 
monotherapy sorafenib. While this study did not provide evidence for improved 
efficacy of bavituximab plus sorafenib over sorafenib alone, the combination 
regimen was well-tolerated and safe in patients with advanced HCC and 
underlying liver disease.27  
  
Bavituximab in combination with the anti-PD-1 antibody pembrolizumab is now 
under investigation across 3 disease types including gastroesophageal cancers 
(NCT04099641), 
head 
and 
neck 
cancers 
(NCT04150900), 
and 
HCC 
(NCT03519997). A single-arm phase 2 study with a two-stage design for patients 
with unresectable HCC is currently being conducted at the Harold C. Simmons 
Comprehensive Cancer Center and Parkland Hospital and Health System. 
Patients receive pembrolizumab 200 mg intravenously every 3 weeks and 
bavituximab 3 mg/kg intravenously weekly. The primary endpoint is the best 
objective response rate. This study is currently enrolling in its second stage after 
meeting its predefined response rate to continue enrollment. Preliminary analysis 
of 36 patients who received at least one infusion of pembrolizumab and 
bavituximab and evaluable for safety shows that this combination is safe and well 
tolerated in patients with advanced HCC with no unexpected safety events. 
Treatment-related AEs are shown below: 
 
Treatment-related adverse event 
All grade (%) 
Grade 3 or 4 (%) 
Colitis/diarrhea 
7 (19.4) 
2 (5.6) 
Aspartate aminotransferase increased 
5 (13.9) 
0 
Alanine aminotransferase increased 
4 (11.1) 
0 


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Maculopapular rash 
4 (11.1) 
1 (2.8) 
Chills 
3 (8.3) 
0 
Pruritus 
3 (8.3) 
0 
Arthralgia 
2 (5.6) 
0 
Fatigue 
2 (5.6) 
0 
Thrombocytopenia 
2 (5.6) 
0 
Abdominal pain 
1 (2.8) 
0 
Creatinine increased 
1 (2.8) 
0 
Dyspnea  
1 (2.8) 
0 
Fever 
1 (2.8) 
0 
Mucositis 
1 (2.8) 
0 
Albumin decreased 
1 (2.8) 
0 
 
1.3 
Rationale 
Sensitizing HCC to immunotherapy using axitinib. Preclinical evidence indicates that VEGF 
and VEGF-dependent angiogenesis may induce immune suppression in tumors by 
impairing antigen presenting cells and effector T-cells, and enhancing T-regulatory cells 
and monocytes.28 Disruption of the endothelium may also enhance lymphocyte recruitment 
within tumors.29,30 Thus, targeting VEGF may reprogram the tumor immune 
microenvironment to render cancers more vulnerable to immunotherapies. Indeed, the use 
of anti-VEGF strategies as an immunotherapy adjuvant has been associated with clinical 
benefit in multiple cancer types including HCC, and no new safety signals.8,31-33 While the 
clinical benefit of monotherapy axitinib in HCC is modest, use of axitinib as an 
immunotherapy adjuvant may circumvent primary resistance mechanisms to immune 
checkpoint inhibitors in HCC leading to more frequent or robust anti-tumor immunity. This 
is consistent with results from the phase 3 IMbrave150 study which demonstrated the 
superiority of atezolizumab plus bevacizumab versus sorafenib alone.8 
 
Rationale for combining axitinib and immune checkpoint inhibitor with the anti-
phosphatidylserine antibody bavituximab. Phosphatidylserine is a cytoplasmic-facing 
anionic phospholipid which has multiple essential functions in cellular membranes.34,35 
Externalization of phosphatidylserine occurs as a result of apoptosis or cellular stress, but 
is also frequently observed in cancer cells and within stromal cells.34 Of therapeutic 
relevance, exposed phosphatidylserine and phosphatidylserine-dependent receptors 
including the Tyro3, Axl, and Mer (TAM) family of negative immune regulators facilitate 
cancer immune escape.34 Indeed, preclinical evidence indicates that antibody-based 
targeting of phosphatidylserine promotes pro-inflammatory pathways, recruitment of 
tumoricidal macrophages, dendritic cell maturation, and potent T-cell immunity in multiple 
cancer models.36 While bavituximab has been demonstrated to be well tolerated as a single 
agent and in combination with chemotherapy, its use as a single agent in a phase I study 
of refractory advanced solid cancers and in combination with docetaxel in advanced non-
small-cell lung cancer did not show significant clinical benefit.26,37,38 Notably, prior use of 
bavituximab was not guided by its immunogenic mechanism of action. The pleiotropic pro-
inflammatory and -immunogenic effects of bavituximab on tumor cells, immune cells, and 
stroma suggests that it may enhance the activity of immune checkpoint inhibitors. This is 
supported by preclinical evidence that targeting phosphatidylserine enhances either PD-1 
or CTLA-4 blockade in melanoma, breast, and colon cancer models, and preliminary 
results from a phase II study underway at UT Southwestern testing the combination of 
bavituximab and pembrolizumab in HCC.39-41 Initial results from a two-stage phase II study 
testing bavituximab plus pembrolizumab in advanced HCC has demonstrated good 
tolerability and promising activity based on objective response rates meeting pre-specified 
goals in order to transition to the second stage of the study. Given the complimentary 


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immune augmenting mechanisms of targeting VEGF and phosphatidylserine, we 
hypothesize that combination axitinib, bavituximab, and avelumab, a PD-L1 antibody, 
represents a novel and rational immunotherapy regimen in HCC. We propose to test this 
by studying the clinical efficacy and safety of combination axitinib, bavituximab, and 
avelumab treatment in a single arm phase II trial using a two-stage design.  
1.4 
Rationale for Treatment Beyond Progression 
Across cancer types, immune checkpoint inhibitors have been shown to induce complete 
response, partial response, and stable disease after initial evidence of radiographic 
increase in tumor burden.  This initial increase in tumor burden may be attributed to 
immune-cell infiltration in the setting of a T-cell response. Therefore, this study will allow 
all patients to continue their assigned treatment after apparent radiographic progression 
per RECIST v1.1, provided the benefit-risk ratio is judged to be favorable by the 
investigator. Treatment beyond progression should be considered when the patient is 
stable (or improving) symptomatically and if tumor reassessment can be performed within 
a short period. 
1.5 
Correlative Studies 
Molecular profiling including exome and transcriptome sequencing of baseline or multiplex 
immunohistochemistry of archived tissue specimens will allow us to identify predictive 
markers of treatment response. As this testing will be performed on tissue obtained as a 
component of routine care, there is no additional risk to the patient. Tissue sampling at the 
time of progression is encouraged but not required. Tissue at progression may undergo 
similar testing to identify markers or mechanisms of resistance.  
 
Archival tissue will also be examined using the XernaTM TME Panel which is a RNA-based 
gene expression assay to classify patients based on the biology of the tumor 
microenvironment (TME). 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To determine the best objective response rate assessed by RECIST guidelines 
(version 1.1) of combination axitinib, bavituximab, and avelumab in patients with 
advanced HCC not previously treated with systemic therapies. 
2.2 
Secondary Objectives 
 
2.2.1 
To determine the disease control rate, overall survival, 6-month progression-free 
survival, and duration of response of combination axitinib, bavituximab, and 
avelumab compared to historical controls. 
 
2.2.2 
To evaluate the overall safety profile of combination axitinib, bavituximab, and 
avelumab. 
 
2.3 
Exploratory Objectives 
 
2.3.1 
To explore the objective response rate as assessed by iRECIST of combination 
axitinib, bavituximab, and avelumab in patients with advanced HCC. 
 


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2.3.2 
To explore the utility of tissue and/or serum-based markers as predictors of therapy 
response. 
2.4 
Endpoints 
 
Primary endpoint: 
Objective response rate (ORR) based on Investigator assessment per RECIST v.1.1. 
 
Secondary endpoint:  
Progression-free survival (PFS), overall survival (OS), and duration of response (DR) 
based on Investigator assessment, per RECIST v.1.1. 
 
Adverse events (AEs) and laboratory abnormalities as graded by National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 
 
3.0 
SUBJECT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered.  
3.1 
Inclusion Criteria 
3.1.1 
Patient must have a histologically confirmed diagnosis consistent with HCC; known 
fibrolamellar HCC, or combined HCC-cholangiocarcinoma will be excluded. 
 
3.1.2 
Locally advanced or metastatic disease 
 
3.1.2.1 Patients with locally advanced or metastatic disease must have disease 
 
deemed not amenable to surgical and/or locoregional therapies or 
 
patients who have progressed following surgical and/or locoregional 
 
therapies. 
 
3.1.2.2 Measurable disease, as defined as lesions that can accurately be 
 
measured in at least one dimension according to RECIST version 1.1 at 
 
least 1 cm with contrast enhanced dynamic imaging (magnetic 
 
resonance imaging or computed tomography). 
 
3.1.3 
Availability of recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block 
or slides (biopsied tumor lesion should not be a RECIST target lesion): 1) the 
biopsy or resection was performed within 2 years of AND 2) the patient has not 
received any intervening systemic anti-cancer treatment from the time the tissue 
was obtained.  
 
3.1.4 
Prior therapy is allowed provided the following are met: at least 4 weeks since prior 
locoregional therapy including surgical resection, chemoembolization, definitive 
radiotherapy with intent of disease control, or ablation. Provided target lesion has 
increased in size by 25% or more or the target lesion was not treated with 
locoregional therapy. Patients treated with palliative radiotherapy for symptoms will 
be eligible as long as the target lesion is not the treated lesion and radiotherapy 
will be completed at least 2 weeks prior to study drug administration. 
 
3.1.5 
Age ≥ 18 years 
 
3.1.6 
Child-Pugh Score A 
 
3.1.7 
ECOG Performance score of 0-1 


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3.1.8 
Adequate organ and marrow function as defined below: 
 
3.1.8.1 Platelet count ≥ 50,000/mm3 
 
3.1.8.2 Hgb ≥ 8.5 g/dl 
 
3.1.8.3 Absolute neutrophil ≥ 1,500 cells/mm3 
 
3.1.8.4 Total bilirubin ≤ 2.0 mg/ml 
 
3.1.8.5 INR ≤ 1.7 
 
3.1.8.6 AST, ALT ≤5 times ULN 
 
3.1.8.7 Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min 
 
3.1.8.8 Albumin ≥ 2.5 g/dl 
 
 
3.1.9 
All men, as well as women of child-bearing potential must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) 4 weeks 
prior to study entry, for the duration of study participation, and for 90 days following 
completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
3.1.9.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, marital status, having undergone a tubal ligation, or remaining 
celibate by choice) who meets the following criteria: 
 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
3.1.10 Women of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication. 
 
3.1.11 Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, 
or HCV-HCC defined as follows:  
 
1) HBV-HCC: Controlled (treated) hepatitis B subjects will be allowed if they meet 
the following criteria: Antiviral therapy for HBV must be given for at least 12 
weeks and HBV viral load must be less than 100 IU/mL prior to first dose of 
study drug.  Subjects on active HBV therapy with viral loads under 100 IU/ml 
should stay on the same therapy throughout study treatment. Subjects who 
are anti-HBc (+), negative for HBsAg, negative for anti-HBs, and have an HBV 
viral load under 100 IU/mL do not require HBV anti-viral prophylaxis.  
 
2) HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV 
RNA or antibody. Patients who have failed HCV therapy as evidenced by 
detectable HCV RNA will be eligible. Subjects with chronic infection by HCV 
who are treated (successfully or treatment failure) or untreated are allowed on 
study. In addition, subjects with successful HCV treatment are allowed as long 
as there are ≥4 weeks between completion of HCV therapy and start of study 
drug. Successful HCV treatment definition: SVR12. 


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3.1.12 Ability to understand and the willingness to sign a written informed consent. 
 
3.1.13 Patients who have received the vector, protein subunit, or nucleic acid COVID-19 
vaccines are eligible to enroll. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Prior liver transplant.  
 
3.2.2 
Prior systemic therapy directed at advanced or metastatic HCC. 
 
3.2.3 
Prior immunotherapy with IL-2, or anti-PD-1, anti-PD-L1, or anti-cytotoxic T-
lymphocyte-associated antigen-4 (CTLA-4) antibody, or any other antibody or drug 
specifically targeting T-cell co-stimulation or immune checkpoint pathways. 
 
3.2.4 
Prior therapy with axitinib or any prior therapies with other VEGF pathway 
inhibitors. 
 
3.2.5 
Clinically significant, uncontrolled heart disease and/or recent events including any 
of the following:  
 
3.2.5.1 History of acute coronary syndromes (including myocardial infarction, 
unstable angina, coronary artery bypass grafting, coronary angioplasty, or 
stenting) or symptomatic pericarditis within 12 months prior to screening). 
 
3.2.5.2 History of documented congestive heart failure (New York Heart 
Association functional classification III-IV). 
 
3.2.5.3 History of cerebrovascular accident, transient ischemic attack, deep vein 
thrombosis, or pulmonary embolism within 6 months of screening. 
 
3.2.5.4 Patient has a left ventricular ejection fraction <40% as determined by 
MUGA scan or ECHO (MUGA and ECHO are not required prior to 
enrollment). 
 
3.2.6 
Known human immunodeficiency virus (HIV) positive (testing not required). 
 
3.2.7 
History of cerebrovascular accident, transient ischemic attack, or thromboembolic 
events (including both pulmonary embolism and deep venous thrombus but not 
including tumor thrombus) within the last 6 months. 
 
3.2.8 
Hypersensitivity to IV contrast; not suitable for pre-medication. 
 
3.2.9 
Active or fungal infections requiring systemic treatment within 7 days prior to 
screening. 
 
3.2.10 Known history of, or any evidence of, interstitial lung disease or active 
noninfectious pneumonitis. 
 
3.2.11 Evidence of poorly controlled hypertension which is defined as systolic blood 
pressure >159 mmHg or diastolic pressure >99 mmHg despite optimal medical 
management. 
 


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3.2.12 Pre-existing thyroid abnormality with thyroid function that cannot be maintained in 
the normal range with medication. 
 
3.2.13 Active, known, or suspected autoimmune disease with the exception of subjects 
with vitiligo, type I diabetes mellitus, resolved childhood asthma or atopy. Subjects 
with suspected autoimmune thyroid disorders may be enrolled if they are currently 
euthyroid or with residual hypothyroidism requiring only hormone replacement. 
Subjects with psoriasis requiring systemic therapy must be excluded from 
enrollment. 
 
3.2.14 Patient has any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, cause unacceptable safety risks, 
contraindicate patient participation in the study or compromise compliance with the 
protocol (e.g. chronic pancreatitis, active untreated or uncontrolled fungal, 
bacterial, or viral infections, etc.). 
 
3.2.15 Known history of active bacillus tuberculosis. 
 
3.2.16 Subjects with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg/day prednisone equivalent) or other immunosuppressive medications 
within 14 days of study administration. Inhaled or topical steroids and adrenal 
replacement doses >10 mg/day prednisone equivalents are permitted in the 
absence of autoimmune disease. 
 
3.2.17 Patient who has received definitive radiotherapy with the sole intent of disease 
control ≤ 4 weeks prior to study entry. Palliative radiotherapy for symptomatic 
control (such as to bone metastases) is acceptable (if completed at least 2 weeks 
prior to study drug administration and no additional radiotherapy for the same 
lesion is planned). 
 
3.2.18 Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects (tumor biopsy is not considered as major 
surgery). 
 
3.2.19 Clinically apparent ascites on physical examination, ascites present on imaging 
studies is allowed. 
 
3.2.20 Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3). 
 
3.2.21 Active gastrointestinal bleeding within previous 2 months. 
 
3.2.22 History of any condition requiring anti-platelet therapy (aspirin >300 mg/day, 
clopidogrel >75 mg/day). 
 
3.2.23 Diagnosis of any other malignancy within 5 years prior to screening visit, except 
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ 
of the breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer 
on surveillance with no plans for treatment intervention (eg, surgery, radiation, or 
castration). 
 
3.2.24 Prisoners or subjects who are involuntarily incarcerated. 
 
3.2.25 History of leptomeningeal disease. 
 
3.2.26 Symptomatic or clinically active brain metastases. 
 


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3.2.27 Pregnant or nursing (lactating) women, where pregnancy is defined as the state of 
a female after contraception and until the termination of gestation, confirmed by a 
positive hCG laboratory test. 
 
3.2.28 Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV 
infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.  
 
3.2.29 Known prior or suspected hypersensitivity to study drugs or any component in their 
formulations. 
 
3.2.30 Current use or anticipated need for drugs that are known strong CYP3A4/5 
inducers, including their administration within 10 days prior to patient receiving 
the first study treatment, eg, phenobarbital, rifampin, phenytoin, carbamazepine, 
rifabutin, rifapentin, clevidipine, St John’s wort. 
 
3.2.31 Patients with 2+ proteinuria on urine dipstick analysis and confirmed to have ≥2 
grams of protein in a 24-hour urine collection. 
 
3.2.32 Current use or anticipated need for treatment with drugs or foods that are known 
strong CYP3A4/5 inhibitors, including their administration within 10 days prior to 
patient 
receiving 
the 
first 
study 
treatment, 
(eg, 
grapefruit 
juice 
or 
grapefruit/grapefruit-related citrus fruits, ketoconazole, miconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, 
ritonavir, 
nelfinavir, 
amprenavir, 
fosamprenavir 
nefazodone, 
lopinavir, 
troleandomycin, mibefradil, and conivaptan). The topical use of these medications 
(if applicable), such as 2% ketoconazole cream, is allowed. 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.1 
For the purpose of this study, the investigational products are avelumab, axitinib, 
and bavituximab. All investigational drugs will be administered on an outpatient 
basis. 
 
4.1.2 
Avelumab dosage form and packaging: Avelumab is a sterile, clear, and colorless 
solution intended for IV administration. Avelumab is formulated as a 20.0 mg/mL 
solution and will be supplied by Pfizer in single-use glass vials, stoppered with a 
rubber septum and sealed with an aluminum polypropylene flip-off seal. Avelumab 
will be dosed at the investigational site. For application in this trial, avelumab drug 
product must be diluted with 0.9% saline solution (sodium chloride injection). 
 
4.1.3 
Avelumab administration: Avelumab will be administered as a 1-hour IV infusion 
on Day 1 and Day 15 of each 28-day cycle. Avelumab may be administered up to 
3 days before or after the scheduled Day 1 of each dose due to administrative 
reasons. Avelumab should be administered at least 30 minutes after the 
bavituximab infusion (on days when both are administered). In order to mitigate 
infusion-related reactions, a required premedication regimen of 25 to 50 mg IV or 
oral equivalent diphenhydramine and 650 mg IV or oral equivalent acetaminophen 
will be administered immediately prior to administration of avelumab for the first 4 
infusions of avelumab. Premedication should be administered for subsequent 
avelumab doses based upon clinical judgment and presence/severity of prior 
infusion reactions. Sites should make every effort to target infusion timing to be as 
close to 1 hour as possible (no longer than 2 hours).  
 


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The dose amount required to prepare the avelumab infusion solution will be based 
on the patient’s weight in kilograms (kg). All patients should be weighed within 7 
days prior to dosing for every cycle. If the patient experienced either a weight loss 
or gain >10% compared to the weight used to calculate the prior dose, the amount 
of study drug required for preparation and administration for the current cycle must 
be recalculated using this most recent weight obtained. The maximum dose is 
2000 mg for all adult patients. Avelumab dose reduction for toxicity management 
is not permitted, however next cycle administration may be omitted due to 
persisting toxicity. 
 
4.1.4 
Axitinib dosage form and packaging: Axitinib will be supplied by Pfizer as 1 mg 
and 5 mg film-coated tablets for oral administration in light-resistant high-density 
polyethylene (HDPE) bottles with desiccant. 
 
4.1.5  
Axitinib administration: Axitinib will be provided in quantities appropriate for the 
study visit schedule. A qualified staff member will provide the study treatment via 
a unique container number. Axitinib will be dispensed every 4 weeks or as 
otherwise indicated. 
 
 
Axitinib will be administered orally BID at approximately the same time in the 
morning and evening on a continuous dosing schedule. Axitinib tablets are to be 
taken approximately 12 hours apart and may be administered without regard to 
meals or avelumab and bavituximab administration. Tablets must not be crushed, 
split, or dissolved, and patients should be instructed to swallow the study 
medication whole without manipulation or chewing of the medication prior to 
swallowing. 
 
 
Patients must be instructed that if they miss a dose or vomit any time after taking 
a dose, they must not “make it up” with an extra dose, but instead resume 
subsequent doses as prescribed. Any missed dose may be taken late, up to 3 
hours, before the next scheduled dose of that day, otherwise, it should be skipped 
and dosing resumed with subsequent doses as prescribed. Patient must be 
instructed to record all doses (missed or vomited doses or extra doses) in a dosing 
diary supplied by the site.  
 
4.1.6  
Bavituximab dosage form and packaging: Bavituximab is supplied OncXerna as 
a sterile, preservative-free solution with 10 mM acetate at pH 5.0 and diluted with 
0.9% saline (normal saline) to a final volume of 100 mL. 
 
4.1.7 
Bavituximab administration: Bavituximab will be administered weekly on Days 1, 
8, 15 and 22 of the 28-day cycle.   
 
Infusion preparation and administration are to be performed as follows: 
 
1. 
Draw up the volume of a vial using a sterile syringe attached to an 
 
appropriate needle (a vented spike or other appropriate transfer device 
 
may be used). Fill treatment into a sterile glass bottle or plastic IV bag.  
 
2. 
Using aseptic techniques, repeat procedure until the calculated volume 
 
has been put into the container. Bring the final volume to 100 mL using 
 
0.9% Sodium Chloride Injection, USP.  
 
3. 
Administer through a low protein binding 0.2-micrometer in-line filter 
 
(placed as proximal to the patient as practical). 
 
4. 
Affix the infusion line and prime it with infusate before starting the 
 
infusion. Infuse the solution intravenously over 90 (± 10) minutes. No 
 
reduction in infusion time will be permitted. Flush the line with normal 
 
saline after infusion. 
 
REGIMEN DESCRIPTION 


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Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Bavituximab 
 
3 mg/kg in NS 
IV over 90 min 
Days 1, 8, 
15, 22 
4 weeks 
(28 
days) 
 
Avelumab 
Premedicate with 
diphenhydramine 
and acetaminophen 
prior to avelumab. 
10 mg/kg in NS 
(maximum 
dose is 2000 
mg) 
IV over 60 min 
at least 30 min 
after 
bavituximab 
Days 1, 
15 
Axitinib 
 
5 mg tablet 
PO BID  
Daily 
 
4.2 
Safety Lead-in, Toxicities, and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table (Section 5.3). Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 5.0.  
 
4.2.1 
Safety Lead-in and Dose-limiting Toxicities 
A safety and tolerability assessment will be performed for patients treated with 
axitinib, bavituximab, and avelumab after the first 6 patients evaluable for dose-
limiting toxicities have completed 1 cycle (ie, Cycle 1 Day 28). Patients will be 
considered evaluable for dose-limiting toxicities assessment if they have 
completed all scheduled study visits during the first cycle and have received 2 
(100%) of the 2 planned doses of avelumab and at least 3 (75%) of the 4 planned 
doses of bavituximab in Cycle 1.  
 
Dose-limiting toxicities are defined as any Grade 3 or greater AE that occurs during 
the first cycle (28 days) and are considered to be related (possible, probable, or 
definite) to study drug, specifying attribution to axitinib, avelumab, bavituximab, or 
all drugs. Intolerable Grade 2 gastrointestinal toxicities (such as persistent 
nausea/vomiting or diarrhea) will also be considered dose-limiting toxicities if they 
are considered to be related to any study drug. See Tables 2 and 3 below and 
Section 7.0 for AEs associated with axitinib, avelumab, or bavituximab. 
 
Enrollment of additional patients after the first 6 potentially evaluable patients for 
dose limiting toxicities will be suspended until after assessment of the safety lead-
in phase by the UTSW Simmons Cancer Center Gastrointestinal Disease-Oriented 
Teams (GI DOT) is complete.  
• 
If ≤1 dose-limiting toxicity occurs, trial enrollment will proceed without any 
modifications. 
• 
If ≥2 dose-limiting toxicities occurs, all treatment-related AEs will be 
reviewed by the GI DOT for consideration of modification or termination of 
the study. Modifications may include reducing the starting dose of axitinib 
by one dose level to 3 mg BID for all subsequent patients enrolled and not 
permitting dose re-escalation above dose level 0. 
 
4.2.2 
Axitinib dose reduction and re-escalation 
Dosing interruption and/or dose  reduction by 1, and if needed, 2 dose levels (one 
dose level decrease at a time) as indicated in Table 1 will be allowed depending 
on the type and  severity of toxicity encountered. Patients who have undergone 
dose reduction may undergo dose re-escalation to prior dose levels in the absence 
of grade 2 or greater AEs for at least 28 days. 
 


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If patient develops decompensated cirrhosis (Child Pugh B), axitinib dosing should 
be reduced to the -1 dose level. Subsequent dosing can be increased or decreased 
according to the patient’s tolerance. Patients must not have irreversible toxicities 
related to the axitinib to be eligible for dose re-escalation of axitinib after dose 
reduction. 
 
 
 
 
Table 1. 
Axitinib dose levels. 
Dose level 
Dose 
0 
5 mg BID 
-1 
3 mg BID 
-2 
2 mg BID 
 
 
Further dose reductions less than dose level -2 are not permitted. 
4.2.3 
Axitinib dose modifications, and avelumab and bavituximab infusion omissions 
 
for treatment-related toxicities. 
Toxicities related to axitinib may primarily stem from the known on-target effects 
of inhibiting VEGFR including hypertension and proteinuria. In contrast, toxicities 
related to avelumab and bavituximab may be due to immune related AEs (irAEs). 
Management of specific irAEs should be consistent with American Society of 
Clinical Oncology (ASCO) Clinical Practice Guidelines (2018). For Grade 2 irAEs, 
avelumab and bavituximab should be permanently discontinued if AE does not 
resolve to at least Grade 1 within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. Specific 
dose modifications and infusion omissions depend on the severity of toxicities as 
detailed in Table 2 and Table 3. 
 
If any study drug is withheld or discontinued, the remaining study drugs can be 
continued as long as the patient is experiencing clinical benefit, as determined by 
the investigator per medical judgment. 
 
Table 2. Dose modifications and infusion omissions for toxicities. 
Toxicity 
NCI 
CTCAE 
Grade 
Axitinib 
Avelumab 
Bavituximab 
Hypertension 
1 
Continue at same dose 
level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
2 
If not on maximal anti-
hypertensive treatment, 
institute new or additional 
antihypertensive 
medication and continue at 
the same dose level. 
If on maximal anti-
hypertensive treatment, 
reduce by 1 dose level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
3 
For first and subsequent 
occurrence, withhold until 
BP is less than 150/100 
mm Hg and adjust 
antihypertensive 
medication. Then, reduce 
by 1 dose level and 
resume treatment. 
Continue as per 
schedule. 
Continue as per 
schedule. 


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If on maximal anti-
hypertensive treatment, 
reduce by 1 dose level. 
If axitinib dosing is 
interrupted, patients 
receiving 
antihypertensive 
medications should be 
monitored 
closely for hypotension as 
BP usually 
decreases within 1-2 days 
after the last dose. 
4 
Repeat dose reduction by 
one lower dose level.  
Permanent discontinuation 
if already on maximal anti-
hypertensive treatment. 
Continue as per 
schedule. 
Continue as per 
schedule. 
Proteinuria 
1 
Continue at same dose 
level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
2-3 
Continue at same dose 
level if proteinuria is 
<2gm/24 hours.  
If proteinuria is >2gm/24 
hours, withhold until 
proteinuria is <2 g/24 
hours. 
Time of repeat urine 
collection is at investigator 
discretion. 
Then, resume at the same 
dose level or reduce by 1 
dose level as per 
investigator judgment. 
Continue as per 
schedule. 
Continue as per 
schedule. 
irAEs (except for 
endocrinopathies) 
1 
Continue at same dose 
level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
2 
Continue at same dose 
level. 
Withhold until Grade ≤1. 
If Grade 2 event does 
not resolve to Grade 1 
after holding for at least 
2 cycles (8 weeks), 
permanently discontinue. 
Withhold until Grade ≤1. 
If Grade 2 event does 
not resolve to Grade 1 
after holding for at least 
2 cycles (8 weeks), 
permanently discontinue. 
3-4 
Hold treatment until Grade 
≤1 and restart at same 
dose level.  
Permanently 
discontinue. 
Permanently 
discontinue. 
Immune related 
hypothyroidism 
1 
Continue at same dose 
level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
2 
Continue at same dose 
level. 
May hold until patient is 
on thyroid hormone 
supplementation or 
symptoms resolve to 
baseline.  
May hold until patient is 
on thyroid hormone 
supplementation or 
symptoms resolve to 
baseline. 


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3-4 
Hold treatment until Grade 
≤1 and restart at same 
dose level. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1 while on 
thyroid supplementation. 
Patient should be 
referred to Endocrine. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1 while on 
thyroid supplementation. 
Patient should be 
referred to Endocrine. 
Immune related 
hyperthyroidism 
1 
Continue at same dose 
level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
2 
Continue at same dose 
level. 
May hold until patient 
symptoms resolve to 
baseline. Consider β -
blockers for symptomatic 
control rather than 
steroids initially. For 
persistent symptoms >6 
weeks, patient will need 
to be evaluated for 
Grave’s disease. 
May hold until patient 
symptoms resolve to 
baseline. Consider β -
blockers for symptomatic 
control rather than 
steroids initially. For 
persistent symptoms >6 
weeks, patient will need 
to be evaluated for 
Grave’s disease. 
3-4 
Hold treatment until Grade 
≤1 and restart at same 
dose level. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1 with 
appropriate therapy. 
Patient should be 
referred to Endocrine. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1 with 
appropriate therapy. 
Patient should be 
referred to Endocrine. 
Immune related 
adrenal 
insufficiency 
1 
Continue at same dose 
level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
2 
Continue at same dose 
level. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1 with 
replacement hormones. 
Maintenance 
replacement therapy with 
prednisone 5-10 mg 
daily (or equivalent). May 
require fludrocortisone 
(0.1 mg/d) for 
mineralcorticoid 
replacement. May need 
to use doses 2-3 times 
maintenance dose for 
management of acute 
symptoms.  
Hold until symptoms 
resolve to baseline or 
until Grade ≤1 with 
replacement hormones. 
Maintenance 
replacement therapy with 
prednisone 5-10 mg 
daily (or equivalent). May 
require fludrocortisone 
(0.1 mg/d) for 
mineralcorticoid 
replacement. May need 
to use doses 2-3 times 
maintenance dose for 
management of acute 
symptoms. 
3-4 
Permanently discontinue. Permanently 
discontinue. 
Permanently 
discontinue. 
Immune related 
hypophysitis 
1 
Continue at same dose 
level. 
Consider holding until 
patient is stabilized on 
replacement therapy. 
Patient should be 
referred to Endocrine. 
Consider holding until 
patient is stabilized on 
replacement therapy. 
Patient should be 
referred to Endocrine. 
2 
Continue at same dose 
level. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1 with 
replacement hormones. 
Patient should be 
referred to Endocrine. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1 with 
replacement hormones. 
Patient should be 
referred to Endocrine. 


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3-4 
Permanently discontinue. Permanently 
discontinue. 
Permanently 
discontinue. 
Immune related 
diabetes 
1 
Continue at same dose 
level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
2 
Continue at same dose 
level. 
Considering holding until 
patient is stabilized 
(Grade ≤1) on 
replacement therapy. 
Insulin should be 
initiated as default 
treatment rather than 
oral therapies. Patient 
should be referred to 
Endocrine. 
Considering holding until 
patient is stabilized 
(Grade ≤1) on 
replacement therapy. 
Insulin should be 
initiated as default 
treatment rather than 
oral therapies. Patient 
should be referred to 
Endocrine. 
3-4 
Hold treatment until Grade 
≤1 and restart at same 
dose level. 
Hold until patient is 
stabilized (Grade ≤1) on 
replacement therapy. 
Insulin should be 
initiated as default 
treatment rather than 
oral therapies. Patient 
should be referred to 
Endocrine. 
Hold until patient is 
stabilized (Grade ≤1) on 
replacement therapy. 
Insulin should be 
initiated as default 
treatment rather than 
oral therapies. Patient 
should be referred to 
Endocrine. 
Immune related 
colitis/diarrhea 
1 
Continue at same dose 
level. 
Consider holding until 
symptoms resolve to 
baseline or until Grade 
≤1. Consider 
antidiarrheals if other 
causes are excluded. 
Consider holding until 
symptoms resolve to 
baseline or until Grade 
≤1. Consider 
antidiarrheals if other 
causes are excluded. 
2 
Continue at same dose 
level. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1. Steroids 
may be considered if 
indicated on an 
individual basis. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1. Steroids 
may be considered if 
indicated on an 
individual basis. 
3 
Hold treatment until Grade 
≤1 and restart at same 
dose level. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1. 
Administer steroids at 1-
2 mg/kg/d prednisone or 
equivalent with taper 
over 4 weeks. Patient 
should be referred to 
Gastroenterology. 
Consider colonoscopy. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1. 
Administer steroids at 1-
2 mg/kg/d prednisone or 
equivalent with taper 
over 4 weeks. Patient 
should be referred to 
Gastroenterology. 
Consider colonoscopy. 
4 
Permanently discontinue. Permanently 
discontinue. 
Permanently 
discontinue. 
Immune related 
pneumonitis 
1 
Continue at same dose 
level. 
Hold if there is 
progression with repeat 
CT chest at 3-4 weeks 
and treat as Grade 2. 
Hold if there is 
progression with repeat 
CT chest at 3-4 weeks 
and treat as Grade 2. 
2 
Continue at same dose 
level. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1. 
Administer steroids at 1-
Hold until symptoms 
resolve to baseline or 
until Grade ≤1. 
Administer steroids at 1-


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2 mg/kg/d prednisone or 
equivalent with taper 
over 4 weeks. Consider 
Pulmonology consult. 
Monitor every 3-4 days, 
if no clinical 
improvement, treat as 
Grade 3. 
2 mg/kg/d prednisone or 
equivalent with taper 
over 4 weeks. Consider 
Pulmonology consult. 
Monitor every 3-4 days, 
if no clinical 
improvement, treat as 
Grade 3. 
3-4 
Permanently discontinue. Permanently 
discontinue. 
Permanently 
discontinue. 
Immune related 
hepatitis 
1 
Continue at same dose 
level. 
Continue as per 
schedule. 
Continue as per 
schedule. 
2 
Continue at same dose 
level. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1. Steroids 
may be considered if 
indicated on an 
individual basis. 
Hold until symptoms 
resolve to baseline or 
until Grade ≤1. Steroids 
may be considered if 
indicated on an 
individual basis. 
3-4 
Permanently discontinue. Permanently 
discontinue. 
Permanently 
discontinue. 
 
Table 3. Dose modifications for drug-related adverse events potentially associated with axitinib and not 
considered immune-related. 
 
Toxicity 
NCI 
CTCAE 
Grade 
Axitinib 
Diarrhea 
1-2 
Continue at same dose level. 
 
3 
Hold until symptoms resolve to baseline or until Grade 
≤1. Then, resume at the same dose level or reduce by 
1 dose level as per investigator judgment. 
 
4 
Permanently discontinue. 
Hemorrhage/bleeding 
1 
For CNS bleeding, permanently discontinue. For non-
CNS bleeding, continue at same dose level. 
 
2 
For pulmonary and GI bleed (other than hemorrhoidal 
bleeding or in setting of colitis), permanently 
discontinue. For other bleeding events, hold until 
symptoms resolve to baseline or until Grade ≤1. Then, 
resume at the same dose level or reduce by 1 dose 
level as per investigator judgment. 
 
3-4 
Permanently discontinue.  
Palmar-plantar erythrodysethesia  
syndrome 
1-2 
Continue at same dose level. Consider the use of 
topical pain relievers and/or moisturizing exfoliant 
creams. 
 
3 
Hold until symptoms resolve to baseline or until Grade 
≤1. Consider the use of topical or parenteral pain 
relievers and/or moisturizing exfoliant creams. Then, 
resume at the same dose level or reduce by 1 dose 
level as per investigator judgment. 
AST, ALT or bilirubin elevation 
1 
Continue at same dose level. 
 
2 
Hold until symptoms resolve to baseline or until Grade 
≤1. Then, resume at same dose level. 
 
3-4 
Hold until symptoms resolve to baseline or until Grade 
≤1. Then, reduce by 1 dose level. 
Hematologic abnormalities 
1-3 
Continue at same dose level. 


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4 
Hold until symptoms resolve to baseline or until Grade 
≤1. Restart axitinib dose reduced by 1 dose level. 
Note: Grade 4 lymphopenia not  associated  with  
clinical  events,  (e.g, opportunistic infection) may 
continue on with axitinib. 
Stevens-Johnson  
syndrome 
3-4 
Permanently discontinue. 
Other non-hematologic toxicities 
and laboratory abnormalities 
1-2 
Continue at same dose level. 
 
3 
Hold until symptoms resolve to baseline or until Grade 
≤2. 
For 
toxicities 
controlled 
with 
symptomatic 
medications or asymptomatic laboratory abnormalities, 
continue at the same dose level or reduce by 1 dose 
level as per investigator judgment. For all other 
toxicities, reduce by 1 dose level. 
 
4 
Hold until symptoms resolve to baseline or until Grade 
≤2. Then, reduce by 1 dose level as per investigator 
judgment. Permanently discontinue axitinib for Grade 4 
toxicities that meet any of the following conditions: 
1) recurrent 
2) life-threatening 
3) reversible 
posterior 
leukoencephalopathy 
syndrome 
4) arterial thrombosis/ischemia 
 
 
4.2.4 
Infusion related reactions.  
Because avelumab and bavituximab are administered as infusions, infusion reactions are 
possible and may include symptoms such as fever, chills, shortness of breath, headache, 
and rigors. Infusion modifications depend on the severity of reactions as detailed in Table 
4 below.  
 
Table 4. Infusion-related reactions caused by avelumab or bavituximab. 
NCI CTCAE 
Grade 
Infusion modifications 
1 
Decrease the avelumab and/or bavituximab 
infusion rate by 50%. 
2 
Temporarily discontinue avelumab and/or 
bavituximab infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any worsening. 
3-4 
Stop the infusion immediately and 
disconnect infusion tubing from the patient. 
Patients may not receive further treatment. 
 
4.3 
Concomitant Medications/Treatments 
Medications or vaccinations specifically prohibited in the Exclusion Criteria are also not 
allowed during the active treatment period, except for administration of the inactivated 
influenza vaccine and protein subunit, vector, or nucleic acid COVID-19 vaccines. 
 
4.3.1 Inhibitors and inducers of CYP enzymes 


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In vitro studies with human liver microsomes and recombinant CYP enzymes indicate that 
axitinib metabolism is primarily mediated by the CYP3A4/5, and to a lesser extent by 
CYP1A2, CYP2C19, and UGT1A1. 
 
The concomitant use of strong CYP3A4/5 inhibitors (eg, grapefruit juice or 
grapefruit/grapefruit-related 
citrus 
fruits, 
ketoconazole, 
miconazole, 
itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, 
nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil, 
and conivaptan) are not permitted. The topical use of these medications (if applicable), 
such as 2% ketoconazole cream, is allowed. Selection of an alternate concomitant 
medication with no or minimal CYP3A4/5 inhibition potential is recommended. Consider a 
dose reduction (by approximately 50%) if axitinib must be dosed with a CYP3A4/5 inhibitor. 
If axitinib dose is reduced due to concomitant CYP3A4/5 inhibitor use, axitinib dose may 
be increased based on tolerability. Reference Section 4.2.1-Axitinib dose reduction and re-
escalation, Table 1.  
 
4.3.2 Prohibited concomitant medications 
1) Antineoplastic systemic chemotherapy or biological therapy; 
2) Immunotherapy not specified in this protocol;  
3) Chemotherapy not specified in this protocol;  
4) Investigational agents other than axitinib, avelumab, and bavituximab; 
 
4.3.3 Concomitant surgery 
If a major surgery or an interventional procedure is required, treatment with axitinib must 
be interrupted at least 24 hours before the procedure, and the patient’s blood pressure 
should be monitored closely for hypotension. Patients may resume axitinib 7 days after 
minor surgery and 2-3 weeks after major surgery, assuming the wound has completely 
healed and there are no wound-healing complications. For surgical procedures, avelumab 
and bavituximab may be delayed as determined by the investigator. Reference Section 
11.5 for both planned and emergency deviation reporting/approval requirements. 
 
4.3.4 Concomitant radiation 
Local radiotherapy (limited field) of isolated lesions with palliative intent is acceptable and 
allowed throughout the study if considered medically necessary by the treating physician. 
All attempts should be made to rule out disease progression in the event of increased 
localized pain. If palliative radiotherapy is needed to control pain, the site(s) of disease 
causing pain should also be present at baseline; otherwise, painful lesion(s) requiring 
radiotherapy will be considered as a sign of disease progression. Lesions that have been 
radiated cannot be target lesions. 
 
4.3.5 Steroid use 
Given concerns that systemic steroids may impact the efficacy of immune checkpoint 
inhibitors, steroid use during treatment should be avoided. Steroid use is permitted as 
follows: 
1) Therapeutic use for the management of irAEs. 
2) Steroid replacement for adrenal insufficiency with maintenance doses ≤10 
mg of prednisone daily. 
3) Prophylactic use for contrast allergies prior to CT or MRI scans. 
4.4 
Registration Procedures 
All subjects must be registered with the GI DOT before enrollment to study. Prior to 
registration, eligibility criteria must be confirmed with the GI DOT clinical research 
manager. To register a subject, call 214-648-7031 Monday through Friday, 
9:00AM-5:00PM.  
 


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UTSW will be given site number 01, and the satellite site will be 02. New subjects at 
UTSW will receive a number beginning with 01-001 upon study consent such that the first 
subject consented is numbered 001, the second subject consented receives the number 
002, etc. The first subject consented at the satellite site will be 02-001. 
 
Upon confirmation of eligibility and enrollment as per the afore-mentioned instructions, 
the subject will be assigned a secondary number in the order of enrollment. For example, 
subject 001 at UTSW will become 01-001-01 upon enrollment. If subject 01-002 screen 
fails, and subject 02-001 is the next subject enrolled, subject 02-001 will become 02-001-
02 and so-on – the enrollment numbers are consecutive across both sites.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration/randomization code 
according to the numbering schema outlined above, which should then be entered as the 
patient study id in Velos upon updating the status to enrolled. 
4.5 
Duration of Therapy 
Study treatment with axitinib, avelumab, and bavituximab will continue until disease 
progression, unacceptable toxicity, death, or discontinuation from the study treatment for 
any other reason.  
4.5 
Treatment Beyond Progression 
If a patient has evidence of progression per RECISTv1.1 while receiving axitinib, 
avelumab, and bavituximab, they will be permitted to continue the study treatment if they 
meet all the following criteria: 
1) Evidence of clinical benefit or stability, as determined by the investigator following a 
review of all available data. 
2) No significant, unacceptable, or irreversible toxicities related to the trial treatment. 
3) No other treatment discontinuation criteria are met. 
4) Absence of clinical disease progression including worsening symptoms or laboratory 
tests (such as new or worsening hypercalcemia) indicating unequivocal progression 
of disease. 
5) Absence of decline in ECOG Performance Status that can be attributed to disease 
progression. 
6) Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites (e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention. 
 
Re-assessment of tumor burden must be no sooner than 4 weeks, but no longer than 9 
weeks per iRECIST. Progressive disease is confirmed per iRECIST criteria and is 
evidenced by the appearance of more new lesions, increase size of prior new lesions (≥5 
mm increase in sum of measures), or increase size of target and non-target lesions (≥5 
mm increase in sum of measures). Patients with confirmed progressive disease per 
iRECIST will be permanently discontinued from the trial. 
4.6 
Duration of Follow Up 
Ongoing adverse events will be followed until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, new anti-cancer treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or it is determined 
that the study treatment or participation is not the cause of the adverse event.  
 
Survival follow-up information will be collected via telephone calls, patient medical records, 
and/or clinic visits approximately every 3 months up to 2 years, until death, loss to follow-
up, or until study termination by the Sponsor. 


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4.7 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.4 apply. 
Notify the Principal Investigator and document the reason for treatment discontinuation and 
the date of discontinuation. The subject should be followed-up per protocol.  
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 28 days prior to registration unless 
otherwise stated. The screening procedures include: 
 
 
5.1.1 
Informed Consent  
Patients must provide a signed informed consent form prior to any study specific 
evaluations including screening.  
5.1.2 
Medical history 
Complete medical and surgical history, and history of infections. Any ongoing 
sign/symptoms at registration should be assessed and graded per CTCAE, and 
followed as per Section 7. 
5.1.3 
Demographics  
Documentation of demographic data will include age, sex, race, and self-reported 
race/ethnicity. 
5.1.4 
Review subject eligibility criteria  
Eligibility will be determined according to the inclusion/exclusion criteria as 
described in Section 3. 
5.1.5 
Review previous and concomitant medications 
5.1.6 
Physical exam including vital signs, height, and weight 
 
Vital signs (temperature, pulse, respirations, blood pressure), height, and weight. 
5.1.7 
Performance status 
Performance status evaluated prior to study entry according to the ECOG Scale of 
Performance Status. 
5.1.8 
Hematology 
Complete blood counts with differential. 
5.1.9 
Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate), glucose, and total bilirubin. Other labs include 
TSH, free T3 and T4, AFP, and lipase 
5.1.10 Coagulation tests 
 
aPTT, PT/INR. 
5.1.11 Hepatitis B and C testing 


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HBsAg, HBcAb, anti-HCV, HBV DNA, and HCV RNA 
5.1.12 Urinalysis 
5.1.13 Pregnancy test (for females of child-bearing potential) 
Urine or serum pregnancy test. 
5.1.14 Tumor assessment  
Baseline tumor burden will be assessed by CT chest/abdomen/pelvis with contrast 
or MRI abdomen/pelvis with contrast and CT chest with or without contrast 
according to RECIST version 1.1. 
 
5.1.15 Archival tumor tissue 
 
 
Request archival tumor tissue (FFPE Block or 10-15 slides). 
5.2 
Procedures During Treatment 
5.2.1 
Day 1 of each cycle 
• Physical exam, vital signs 
• Weight 
• Serum Pregnancy Test 
• ECOG performance status 
• CBC with differential 
• CMP 
• PT/INR 
• aPTT 
• TSH, free T3, free T4 
• HBV DNA (every four cycles beginning cycle 5) if HBsAg, HBcAb, or HBV 
DNA are positive at time of screening. 
• HCV RNA (every four cycles beginning with cycle 5) if anti-HCV and HCV 
RNA are positive at the time of screening. 
• AFP 
• Lipase 
• Urinalysis 
• Review AEs 
• Medication Review  
• Drug Accountability/ Pill Diary Review 
5.2.2 
Day 8, 15, 22 of each cycle 
• Vital signs 
• CMP (only on Day 15) 
• Weight 
• Medication Review 
• Review AEs 
5.2.3 
End of treatment 
• Physical exam, vital signs 
• ECOG performance status 
• Serum Pregnancy Test 
• CBC with differential 
• CMP  
• PT/INR 
• aPTT 


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• AFP 
• Lipase 
• Urinalysis 
• Medication Review 
• Review AEs 
• Drug Accountability/Pill Diary Review 
• Tumor Measurements 
5.2.4 
30 days after treatment termination 
• Physical exam, vital signs 
• CBC with differential 
• CMP 
• PT/INR 
• aPTT 
• TSH, free T3, free T4 
• AFP 
• Urinalysis 
• Review AEs 
• ECOG Performance Status 
• Pregnancy Test 
5.2.5 
90 days after treatment termination 
• Physical exam, vital signs 
• CBC with differential 
• CMP 
• PT/INR 
• aPTT 
• TSH, free T3, free T4 
• Urinalysis 
• Review AEs 
• ECOG Performance Status 
5.2.6 
Survival follow up 
• Survival 
 
 


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5.3 Time and Events Table 
a Date of treatment discontinuation or withdrawal. 
b Written informed consent can be obtained up to 30 days prior to study entry and is required before 
performing any study-specific tests or procedures. Results of standard-of-care tests or 
examinations performed prior to obtaining informed consent and within 28 days prior to study entry 
may be used for screening assessments rather than repeating such tests.  Screening local 
Trial Period: 
Screenin
g 
Treatment 
End of 
treatmenta 
Follow-up 
D1 
D8 
D15 
D22 
 
30-day post 
last dose 
90-day post 
last dose 
Survival 
follow 
upj 
Scheduling window 
-28 to -1 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Administrative procedures 
Informed consentb 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Medication review 
X 
Xc 
X 
X 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Request 
archival 
tissue 
(FFPE block or 10-15 slides) 
X 
 
 
 
 
 
 
 
 
Drug 
Accountability/Pill 
Diary  
 
X 
 
 
 
X 
 
 
 
Clinical Procedures 
Medical history including 
cancer, surgical and 
infections 
 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weightd 
X 
X 
X 
X 
X 
 
 
 
 
Complete physical exam 
X 
Xc 
 
 
 
X 
X 
X 
 
Review AEs 
 
Xc 
X 
X 
X 
X 
X 
X 
 
ECOG performance Status 
X 
Xc 
 
 
 
X 
X 
X 
 
Tumor measurementse 
X 
Every 8 weeks 
X 
 
 
 
CMPf 
X 
Xc 
 
X 
 
X 
X 
X 
 
CBC with differentialf 
X 
Xc 
 
 
 
X 
X 
X 
 
HBV and HCV serologies 
X 
 
 
 
 
 
 
 
 
HBV DNA and/or HCV RNAf 
 
X 
Every four 
cycles 
beginning 
C5 g 
 
 
 
 
 
 
 
Alpha-Fetoprotein (AFP) 
X 
Xc 
 
 
 
X 
 
 
 
Lipase 
X 
Xc 
 
 
 
X 
 
 
 
aPTT, PT/INRf 
X 
Xc 
 
 
 
X 
X 
X 
 
Urinalysisf 
X 
Xc,h 
 
 
 
X 
X 
X 
 
TSH, free T3, free T4 
X 
Xc 
 
 
 
 
X 
X 
 
Pregnancy testf,i 
X 
Xc 
 
 
 
X 
X 
 
 
Survival follow-up 
 
 
 
 
 
 
 
X 
X 
Drugs 
Avelumab 
 
X 
 
X 
 
 
 
 
 
Axitinib 
 
Taken continuously twice daily 
 
 
 
 
Bavituximab 
 
X 
X 
X 
X 
 
 
 
 


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laboratory assessments obtained ≤96 hours prior to the initiation of study treatment do not have to 
be repeated for Cycle 1 day 1. 
c Medication review, physical exam, review of AEs, ECOG performance status, and laboratories 
may be obtained ≤72 hours before Day 1 of each cycle. 
d The dose of avelumab and bavituximab will be based on the patient's weight measured ≤14 days 
prior to baseline (the initiation of study treatment) and will remain the same throughout the study 
unless there is a weight change of >10% from baseline. 
e Tumor assessments should be performed as close as possible to 8 weeks ± 1 week. Baseline 
tumor burden will be assessed by CT chest/abdomen/pelvis or MRI abdomen/pelvis and CT chest 
according to RECIST version 1.1. It is recommended that the same modality be used for all tumor 
assessments. 
f Laboratory assessments from each cycle must be reviewed prior to study treatment administration 
for each cycle. Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), glucose, total bilirubin, lipase, HBV DNA (if relevant), and HCV RNA (if relevant). 
g HBV DNA (every four cycles beginning with cycle 5) is only tested if HBsAg, HBcAb, or HBV DNA 
are positive at time of screening. HCV RNA (every four cycles beginning with cycle 5) is only tested 
if anti-HCV and HCV RNA are positive at the time of screening. 
h If urinalysis shows 2+ proteinuria, patient should undergo a 24-hour urine collection. 
i Applicable to female of child-bearing potential as defined in Section 3.1. Serum pregnancy test 
must be performed on Day 1 of each cycle. 
j Survival follow-up information will be collected via telephone calls, patient medical records, and/or 
clinic visits approximately every 3 months up to 2 years until death, loss to follow-up, or until study 
termination by the Sponsor. Survival follow-up to start 3 months after 90-Day post last dose visit. 
 
5.4 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own request, 
or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
1) 
Subject voluntarily withdraws from treatment (follow-up permitted). 
2) 
Subject withdraws consent (termination of treatment and follow-up). 
3) 
Subject is unable to comply with protocol requirements. 
4) 
Subject demonstrates clinical or radiographic evidence of disease progression 
based on Investigator assessment (note, continued treatment with study 
drug/treatment including treatment beyond RECIST 1.1 progression is deemed 
appropriate at the discretion of the investigator, but patients must discontinue trial 
treatment if progression is confirmed based on iRECIST). 
5) 
Subject experiences toxicity that makes continuation in the protocol unsafe. 
6) 
Treating physician judges that continuation on the study would not be in the 
subject’s best interest. 
7) 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event). 
8) 
Development of second malignancy (except for basal cell carcinoma or squamous 
cell carcinoma of the skin) that requires treatment, which would interfere with this 
study. 
9) 
Lost to follow-up. If a research subject cannot be located to document survival after 
a period of 6 months, the subject may be considered “lost to follow-up”. 


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5.5 
Reporting of Pregnancy and Lactation to Sponsor (UT Southwestern)    
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.  
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to 
be excluded from the trial or are the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  
Pregnancies and lactations that occur from the time of treatment allocation through 120 
days following cessation of Sponsor’s product, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier, must be reported by 
the investigator.  
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, the 
outcome (health of infant) must also be reported.  
 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) 
Committee [Eur J Cancer. 2009;45(2):228-247]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of their 
first treatment with study therapy. 
 
Evaluable for objective response.  Only those subjects who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response. These 
subjects will have their response classified according to the definitions stated 
below. (Note: Subjects who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
6.1.2 
Disease Parameters 
 
Measurable Disease: Tumor lesions: Must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) with 
a minimum size of: 
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
2. 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable) 
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). Lymph 


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nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. Pathological nodes which 
are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes 
will contribute to the baseline sum. The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor. Nodal 
size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is 
the short axis. For example, an abdominal node which is reported as being 20 mm 
x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. 
In this example, 20 mm should be recorded as the node measurement. All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be 
considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
 
Non-measurable disease.  
All other lesions are considered non-measurable, including small lesions (longest 
diameter < 10mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as 
well as truly non-measurable lesions. Lesions considered truly non-measurable 
include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
Target lesions.  
All measurable lesions up to a maximum of five lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified as 
target lesions. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the five target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions 
are not required, but the presence or absence of each should be noted throughout 
follow-up.  
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and not more than 28 days before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
CT of the abdomen and pelvis or MRI of the abdomen and CT chest (if indicated 
as determined by the Investigator) should be done every 8 weeks ± 1 week. 


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6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm (the sum may not be “0” if there are 
target nodes).  Determined by two separate observations conducted not 
less than 4 weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD. 
There can be no appearance of new lesions. 
 
Progressive Disease (PD): > 20% increase in the SLD taking as reference 
the smallest SLD recorded since the treatment started (nadir) and 
minimum 5 mm increase over the nadir.   
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. There can be no unequivocal new lesions. 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
 
(Non-CR/Non-PD): Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
6.1.4.3 Evaluation of Best Objective Response 
The best objective response is the best response recorded from the start 
of the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The subject’s best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Time point response: patients with target (+/– non-target) disease. 
Target lesions 
Non-target lesions 
New 
lesions 
Objective 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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CR = complete response, NE = not evaluable, PD = progressive disease, PR = 
partial response, SD = stable disease. 
 
Time point response: patients with non-target disease only. 
Non-target lesions 
New lesions 
Objective response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive 
disease 
 
6.1.5 
Duration of Response 
Duration of objective response: The duration of objective response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started.  
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
6.2 
Safety/Tolerability 
 
Analyses will be performed for all subjects having received at least one dose of study 
therapy. The study will use the CTCAE version 5.0 for reporting of adverse events.  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
A safety lead-in phase composed of the first six patients evaluable for dose-limiting 
toxicities as defined in Section 4.2 will be performed to ensure the safety and tolerability of 
this triplet regimen. 
7.0 
ADVERSE EVENTS 
7.1 
Axitinib 
For the most recent safety update, please refer to the current axitinib investigator’s 
brochure. 
7.1.1 
Contraindications 
None 


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7.1.2 
Special Warnings and Precautions for Use 
 
Aneurysms and artery dissections 
VEGF pathway inhibitors may promote the formation of aneurysms and/or artery 
dissections. Before initiating axitinib, this risk should be carefully considered in 
patients with risk factors such as hypertension or history of aneurysm. 
 
Elevation of Hemoglobin or Hematocrit 
Increases in hemoglobin or hematocrit, reflective of increases in red blood cell 
mass, may occur during treatment with axitinib. An increase in red blood cell mass 
may increase the risk of thromboembolic events. 
 
Hemoglobin or hematocrit should be monitored before initiation of, and periodically 
throughout, treatment with axitinib. If hemoglobin or hematocrit becomes elevated 
above the normal level, patients should be treated according to standard medical 
practice to decrease hemoglobin or hematocrit to an acceptable level. 
 
Gastrointestinal Perforation and Fistula Formation 
In pooled clinical studies with axitinib for the treatment of patients with renal cell 
carcinoma, gastrointestinal perforation and fistula were reported in 13/672 patients 
(2%) receiving axitinib. Monitor for symptoms of gastrointestinal perforation 
periodically throughout treatment with axitinib. 
 
Wound Healing Complications 
In the Phase 3 study A4061032 with axitinib for the treatment of patients with renal 
cell carcinoma, all-causality adverse events suggestive of wound healing 
complications were reported in 4/359 patients (1%). Treatment with axitinib should 
be stopped at least 24 hours prior to scheduled surgery. The decision to resume 
axitinib therapy after surgery should be based on clinical judgment of 
adequate wound healing. 
 
Reversible Posterior Leukoencephalopathy Syndrome 
In pooled clinical studies with axitinib for the treatment of patients with renal cell 
carcinoma, reversible posterior leukoencephalopathy syndrome was reported in 
2/672 patients (<1%) receiving axitinib. In patients with signs/symptoms of 
reversible 
posterior 
leukoencephalopathy 
syndrome, 
axitinib 
should 
be 
permanently discontinued. 
 
Heart failure events 
In a controlled clinical study with axitinib for the treatment of patients with Renal 
Cell Carcinoma (RCC), heart failure events were reported in 1.7% of patients 
receiving axitinib. Grade 3/4 and 5 cardiac failure events were observed in 0.6% 
and 0.6% of patients receiving axitinib, respectively. Monitor for signs or symptoms 
of cardiac failure periodically throughout treatment with axitinib. 
 
Hypertension 
In pooled clinical studies with axitinib for the treatment of patients with renal cell 
carcinoma , hypertension was reported in 51% of patients receiving axitinib. Grade 
3 and 4 hypertension was reported in 22% and 1% of patients receiving axitinib, 
respectively. 
 
Blood pressure should be well-controlled prior to initiating axitinib. Patients should 
be monitored for hypertension and treated as needed with standard anti-
hypertensive therapy. For persistent hypertension despite use of anti- 
hypertensive medications, axitinib dose should be reduced. For severe 
hypertension, axitinib should be held and resumed at a lower dose level once 


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hypertension is improved. If axitinib is interrupted, patients receiving 
antihypertensive medications should be monitored for hypotension. 
 
Thyroid dysfunction 
In clinical studies with axitinib for the treatment of patients with Renal Cell 
Carcinoma (RCC), hypothyroidism was reported in 25% of patients receiving 
axitinib. Hyperthyroidism was reported in 2% of patients receiving axitinib. Monitor 
thyroid function before initiation of, and periodically throughout treatment with 
axitinib. Hypothyroidism and hyperthyroidism should be treated according to 
standard medical practice to maintain euthyroid state. 
 
Arterial thromboembolic events 
In clinical studies with axitinib for the treatment of patients with Renal Cell 
Carcinoma (RCC), arterial thromboembolic events were reported in 3% of patients 
receiving axitinib. Grade 3 events were reported in 1% and Grade 4 events were 
reported in 1% of patients.  
 
Axitinib should be used with caution in patients who are at risk for, or who have a 
history of these events. 
 
Venous  thromboembolic events 
In clinical studies with axitinib for the treatment of patients with Renal Cell 
Carcionma (RCC), venous thromboembolic events were reported in 3% of patients 
receiving axitinib. Grade 3 and 4 venous thromboembolic events were reported in 
2% of patients. 
 
Axitinib should be used with caution in patients who are at risk for, or who have a 
history of these events. 
 
Hemorrhage 
In clinical studies with axitinib for the treatment of patients with Renal Cell 
Carcinoma (RCC), hemorrhagic events were reported in 26% of patients receiving 
axitinib. Grade 3 and 4 hemorrhagic events were reported in 3% and 1% of 
patients. If any bleeding requires medical intervention, temporarily interrupt the 
axitinib dose. 
 
Proteinuria 
In clinical studies with axitinib for the treatment of patients with Renal Cell 
Carcinoma (RCC), proteinuria was reported in 21% of patients receiving axitinib. 
Grade 3 and 4 proteinuria were reported in 5% and <1% of patients receiving 
axitinib, respectively. Monitoring for proteinuria before initiation of, and 
periodically throughout, treatment with axitinib is recommended. For patients who 
develop moderate to severe proteinuria, reduce the dose or temporarily interrupt 
axitinib treatment. 
 
Hepatic impairment 
A dose decrease is recommended when administering axitinib to patients with 
moderate hepatic impairment (Child-Pugh class B). Axitinib has not been studied 
in patients with severe hepatic impairment (Child-Pugh class C). Monitor ALT, AST 
and bilirubin before initiation of and periodically throughout treatment with axitinib. 
7.1.3 
Interaction with other medications 
Axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, 
CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. Inhibitors 
of CYP3A4/5 such as ketoconazole, itraconazole, clarithromycin, atazanavir, 
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin may 


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increase axitinib plasma concentrations. Grapefruit may also increase axitinib 
plasma concentrations. Selection of concomitant medication with no or minimal 
CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor 
must be co-administered, a dose decrease of axitinib by approximately half is 
recommended. 
 
Strong inducers of CYP3A4/5 including rifampin, dexamethasone, phenytoin, 
carbamazepine, rifabutin, rifapentine, phenobarbital, and Hypericum perforatum 
(St. John’s wort) may decrease axitinib plasma concentrations. Selection of 
concomitant medication with no or minimal CYP3A4/5 induction potential is 
recommended. If a strong CYP3A4/5 inducer must be co-administered, a dose 
adjustment of axitinib is recommended. 
7.1.4 
Adverse Reactions 
The following side effects are suspected to be related to axitinib treatment for 
reporting purposes: 
 
• 
Cardiac failure events (cardiac failure, cardiopulmonary failure, left 
ventricular dysfunction, and right ventricular failure) 
• 
Palmar-plantar erythrodysesthesia 
• 
Hypertension 
• 
Aneurysms and artery dissections 
• 
Thyroid dysfunction 
• 
Arterial thromboembolic events 
• 
Venous thromboembolic events 
• 
Increased Hemoglobin/hematocrit 
• 
Hemorrhage 
• 
Gastrointestinal perforation 
• 
Wound healing complications 
• 
Posterior reversible encephalopathy syndrome 
• 
Proteinuria 
• 
Diarrhea 
• 
Increased serum creatinine 
7.2 
Avelumab 
7.2.1 
Contraindications 
None 
7.2.2 
Special Warnings and Precautions for Use 
 
Infusion related reactions 
Avelumab can cause severe or life-threatening infusion reactions. Patients should 
be premedicated with antihistamine and acetaminophen prior to infusions. Monitor 
patients for signs and symptoms including pyrexia, chills, flushing, hypotension, 
dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the 
rate of infusion for mild or moderate Infusion-Related Reactions (IRRs). Stop the 
infusion and permanently discontinue avelumab for severe (Grade 3) or life-
threatening (Grade 4) infusion reactions.  
 
Immune related AEs (irAEs) 
Avelumab treatment may result in severe and rarely fatal immune-related 
toxicities. irAEs may affect any organ causing pneumonitis, hepatitis, colitis, 
dermatitis/rash, endocrinopathies, myalgias/arthralgias, or nephritis. Less 


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frequent irAEs include myositis, myocarditis, hypophysitis, uveitis, myasthenia 
gravis, and Guillan-Barre syndrome. For suspected immune-related adverse 
reactions, evaluation should include investigations to rule out non-immune 
causes of symptoms. Depending upon the severity of the adverse reaction, 
Avelumab may be delayed or permanently discontinued. Depending on the type 
of irAE, management may include hormone supplementation, corticosteroids, 
non-steroid immunosuppressants, or biologic agents. 
7.2.3 
Interaction with other medications 
 
 
No interaction studies have been conducted with avelumab in humans. 
7.2.4 
Adverse Reactions 
The following side effects are suspected to be related to avelumab treatment for 
reporting purposes: 
 
• 
Infusion reaction 
• 
Hypothyroidism 
• 
Adrenal insufficiency 
• 
Hyperthyroidism 
• 
Hypothyroidism 
• 
Hypopituitarism 
• 
Uveitis 
• 
Colitis 
• 
Autoimmune hepatitis 
• 
Pancreatitis 
• 
Type 1 diabetes mellitus 
• 
Myositis 
• 
Guillan-Barre syndrome 
• 
Nephritis 
• 
Pneumonitis 
• 
Rash/dermatitis 
7.3 
Bavituximab 
7.3.1 
Contraindications 
Known allergy or hypersensitivity to any component of the drug product or prior 
Grade ≥3 infusion reaction, hypersensitivity, or anaphylaxis after receiving any 
other monoclonal antibody therapy. 
7.3.2 
Special Warnings and Precautions for Use 
 
Infusion related reactions 
Bavituximab can cause infusion reactions. Monitor patients for signs and 
symptoms including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, 
back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for 
mild or moderate IRRs. Stop the infusion and permanently discontinue bavituximab 
for severe (Grade 3) or life-threatening (Grade 4) infusion reactions.  
7.3.3 
Interaction with other medications 
Potential drug-drug interactions between bavituximab and docetaxel were 
investigated in 17 patients, which showed no significant differences in PK 
parameters when bavituximab was administered with or without docetaxel.42 


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7.3.4 
Adverse Reactions 
No adverse reactions are known to be specifically attributable to bavituximab. All 
serious adverse events will be reported to the Sponsor.  
7.4 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies. Adverse events are assessed in a routine manner at scheduled 
times during a trial. Additionally, certain adverse events must be reported in an expedited 
manner to allow for optimal monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study therapy, 
will be monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline or is stable in the opinion of the investigator;  
➢ there is a satisfactory explanation other than the study therapy for the changes 
observed; or 
➢ death. 
 
7.4.1 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam, imaging finding or clinically significant laboratory finding), symptom, clinical 
event, or disease, temporally associated with the subject’s participation in the research, 
whether or not it is considered related to the subject’s participation in the research. 
Adverse events encompass clinical, physical, and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Adverse events not 
specifically defined in the NCI CTCAE will be scored on the Adverse Event log according 
to the general guidelines provided by the NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
OHRP and UTSW HRPP define serious adverse events as those events, occurring at any 
dose, which meets any of the following criteria:  
• 
results in death; 
• 
is life-threatening (places the subject at immediate risk of death from the event as 
it occurred); 
• 
results in inpatient hospitalization1,2 or prolongation of existing hospitalization; 
• 
results in a persistent or significant disability/incapacity; 


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• 
results in a congenital anomaly/birth defect; or 
• 
based upon appropriate medical judgment, may jeopardize the subject’s health, 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
 
 
Note: A “Serious adverse event” is, by definition, an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and events 
that are expected in the context of the condition under study may be serious adverse 
events, independent of relatedness to the study itself. As examples, a car accident 
requiring >24-hour inpatient admission to the hospital would be a serious adverse event 
for any research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death which occurs during the protocol-specified period of monitoring for 
adverse and serious adverse events would be a serious adverse event, even if the event 
observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE truly 
fits this definition and NOT for hospitalizations associated with less serious events. For 
example: a hospital visit where a patient is admitted for observation or minor treatment 
(e.g. hydration) and released in less than 24 hours. Furthermore, hospitalization for 
pharmacokinetic sampling is not an AE and therefore is not to be reported either as a 
routine AE or in an expedited report. 
7.4.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term unanticipated 
adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from the regulatory 
agencies considers unanticipated problems to include any incident, experience, or 
outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 


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Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.5 
Expedited Reporting to the SCCC DSMC 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and is 
attributed (possibly, probably, or definitely) to the agent(s) must also be reported as 
indicated in the sections below. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
• 
the drug package insert (if applicable); 
• 
the current Investigator’s Brochure (if applicable) 
• 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
 
7.5.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
SAEs and UPIRSOs at all sites, which occur in research subjects on protocols for which 
the SCCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. All SAEs occurring during the protocol-specified monitoring period 
and all UPIRSOs should be submitted to the SCCC DSMC within 5 business days of the 
study team members awareness of the event(s). In addition, for participating centers other 
than UTSW, local IRB guidance should be followed for local reporting of serious adverse 
events or unanticipated problems. 
 
The UTSW study PI is responsible for ensuring SAEs/UPIRSOs are submitted to the SCCC 
DSMC Coordinator. This may be facilitated by the IIT project manager, study team, sub-
site or other designee. Hardcopies or electronic versions of the eIRB Reportable Event 
report; FDA Form #3500A forms, or other sponsor forms, if applicable; and/or any other 
supporting documentation available should be submitted to the DSMC Coordinator.  The 
DSMC Coordinator forwards the information to the DSMC Chairman who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE or UPIRSO 
documentation that is available are also submitted to the DSMC Chair who determines if 


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further action is required. (See Appendix III of the SCCC DSMC Plan for a template Serious 
Adverse Event Form which may be utilized). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the IIT Project Manager or designee ensures that all 
participating sites are notified of the event and resulting action, according to FDA guidance 
for expedited reporting. DSMC Chairperson reviews all SAEs and UPIRSOs upon receipt 
from the DSMC Coordinator.  The DSMC Chairperson determines whether action is 
required and either takes action immediately, convenes a special DSMC session (physical 
or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
 
Telephone reports to: 
 
Investigator: David Hsieh 
Phone: 214-648-4180 
 
Research Manager: Ellen Siglinsky 
Phone: 214-648-7031 
 
Written reports to: 
 
Investigator: David Hsieh 
Email:  david.hsieh@UTSouthwestern.edu 
Fax: 214-648-8146 
 
Research Manager: Ellen Siglinsky 
Email:  ellen.siglinsky@UTSouthwestern.edu  
Fax: 214-648-1906 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
 
According to UTSW HRPP policy, UPIRSOs are incidents, experiences, outcomes, etc. 
that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a subject’s 
underlying condition or not expected as a risk of the study; therefore, not included in 
the investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 


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For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW HRPP within 5 working days of study 
team awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of study team awareness. Investigators must 
report to their relying IRB according to the relying IRB’s policy. In addition, the external 
IRB’s responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, and 
submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/hrpp/quality-assurance/ 
7.6 
Stopping Rules 
This study utilizes a two-stage design which allows stopping for futility which minimizes the 
expected sample size when the true response is low. In the first stage, 14 evaluable 
patients will be accrued. The study will procced to the second stage only if 2 or greater 
responses are observed. If less than 2 responses are observed among the first 14 
evaluable patients, the study will be terminated. 
8.0 
DRUG/TREATMENT INFORMATION 
8.1 
Axitinib 
• 
Other names for the drug(s): Inlyta  
 
• 
Classification - type of agent: Targeted therapy  
 
• 
Mode of action: Selective inhibitor of VEGFR-1, 2, and 3 
 
• 
Storage and stability: Axitinib must be stored at controlled room temperature (between 
15-30 C) or as specified in the product label. 
 
• 
Protocol dose: 5 mg BID at approximately the same time in the morning and evening 
on a continuous dosing schedule. Axitinib tablets are to be taken approximately 12 
hours apart and may be administered without regard to meals. Tablets must not be 
crushed, split, or dissolved, and patients should be instructed to swallow the study 
medication whole without manipulation or chewing of the medication prior to 
swallowing. A dosing card will be provided to the patients to provide guidance for the 
correct use of axitinib. 
 
• 
Route of administration for this study: oral 
 
• 
Availability: provided by Pfizer 


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• 
Side effects: The most common (≥20%) adverse reactions observed following 
treatment with axitinib were diarrhea, hypertension, fatigue, decreased appetite, 
nausea, weight decreased, dysphonia, palmar-plantar erythrodysesthsia, hemorrhage, 
hypothyroidism, vomiting, proteinuria, cough, and constipation. See Section 7.1.4 and 
the axitinib Investigator’s Brochure for additional information on expected treatment 
related AEs. 
 
8.1.1 
Return and Retention of Study Drug 
Patients will be required to return to the investigational site all bottles of axitinib 
every 4 weeks (at the end of each cycle) during the planned visit at the site. The 
number of remaining axitinib tablets will be documented and recorded at each 
clinic visit. The patient diary may also be used to support this part of the axitinib 
accountability process.  
 
The sponsor or designee will provide guidance on the destruction of unused 
investigational product. If destruction is authorized to take place at the study site, 
the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special 
instructions provided by Pfizer, and all destruction must be adequately 
documented. 
 
8.1.2 
A dosing card will be provided to the patients to provide guidance for the correct 
use of axitinib. Patients must be instructed that if they miss a dose or vomit any 
time after taking a dose, they must not “make it up” with an extra dose, but instead 
resume subsequent doses as prescribed. Any missed dose may be taken late, up 
to 3 hours before the next scheduled dose of that day, otherwise, it should be 
skipped and dosing resumed with subsequent doses as prescribed. Patient must 
be instructed to record all doses (missed or vomited doses or extra doses) in a 
dosing diary supplied by the site. 
8.2 
Avelumab 
• 
Other names for the drug(s): Bavencio 
 
• 
Classification - type of agent: Immunotherapy 
 
• 
Mode of action: anti-PD-L1 antibody 
 
• 
Storage and stability: Store at 2°C to 8°C and protected from light until use. Avelumab 
drug product must not be frozen. Rough shaking of the solution must be avoided. 
 
• 
Protocol dose: 10 mg/kg every 2 weeks (maximum dose of 2000) 
 
• 
Route of administration for this study: intravenous 
 
• 
Avelumab will be dosed at the investigational site. Avelumab will be administered as a 
1-hour (no longer than 2 hours) IV infusion on Day 1 and Day 15 of each 28-day cycle. 
Avelumab may be administered up to 3 days before or after the scheduled Day 1 of 
each dose due to administrative reasons. Avelumab should be administered at least 
30 minutes after the bavituximab infusion (on days when both are administered). In 
order to mitigate infusion-related reactions, a required premedication regimen of 25 to 
50 mg IV or oral equivalent diphenhydramine and 650 mg IV or oral equivalent 
acetaminophen will be administered immediately prior to administration of avelumab. 


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• 
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives. Any spills that occur should be cleaned up using the 
facility’s standard cleanup procedures for biologic products. Avelumab drug product 
must be diluted with preferably 250 mL 0.9% saline solution (sodium chloride injection) 
supplied in an infusion bag; alternatively, a 0.45% saline solution can be used if 
needed. If not used immediately, the diluted drug product can be stored up to 8 hours 
at room temperature or up to 24 hours at 2°C to 8°C. The storage conditions may be 
limited to up to 4 hours at room temperature depending on the approved avelumab 
label in the country. No other drugs should be added to the solution for infusion 
containing avelumab. 
 
Detailed information on infusion bags and medical devices to be used for the 
preparation of the dilutions and subsequent administration will be provided in the 
Dosage and Administration Instruction contained in the Investigational Product Manual 
(IP Manual). 
 
• 
Availability: provided by Pfizer 
 
• 
Side effects: The most frequent AEs attributable to avelumab include infusion reactions 
and irAEs. See Section 7.2.4 and the avelumab Investigator’s Brochure for additional 
information on expected treatment related AEs. 
8.2.1 
Return and Retention of Study Drug 
The sponsor or designee will provide guidance on the destruction of unused 
investigational product. If destruction is authorized to take place at the study site, 
the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special 
instructions provided by Pfizer, and all destruction must be adequately 
documented. 
8.3 
Bavituximab 
• 
Other names for the drug(s): none 
 
• 
Classification - type of agent: Immunotherapy 
 
• 
Mode of action: anti-phosphatidylserine antibody 
 
• 
Storage and stability: Store at 2°C to 8°C. Once diluted, it should be stored at room 
temperature and used within 8 hours.   
 
• 
Protocol dose: 3 mg/kg every week 
 
• 
Route of administration for this study: intravenous 
 
• 
Bavituximab will be dosed at the investigational site. Infusion preparation and 
administration are to be performed as follows: 
 
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used). Fill 
treatment into a sterile glass bottle or plastic IV bag. 
2. Using aseptic techniques, repeat procedure until the calculated volume has 
been put into the container. Bring the final volume to 100 mL using 0.9% 
Sodium Chloride Injection, USP. 


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3. Administer through a low protein binding 0.2-micrometer in-line filter (placed 
as proximal to the patient as practical). 
4. Affix the infusion line and prime it with infusate before starting the infusion. 
Infuse the solution intravenously over 90 (± 10) minutes. No reduction in 
infusion time will be permitted. Flush the line with normal saline after infusion. 
 
• 
Availability: provided by OncXerna 
 
• 
Side effects: The most frequent AEs attributable to bavituximab include decreased 
appetite, fatigue, constipation, nausea, and diarrhea. See Section 7.3.4 for additional 
information on expected treatment related AEs. 
8.3.1 
Return and Retention of Study Drug 
The sponsor or designee will provide guidance on the destruction of unused 
investigational product. If destruction is authorized to take place at the study site, 
the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special 
instructions provided by OncXerna, and all destruction must be adequately 
documented. 
9.0 
CORRELATIVES/SPECIAL STUDIES 
 
The goal of the planned laboratory correlative studies is to assess genetic mechanisms of 
immunotherapy resistance. Analyses will be performed on tissue specimens collected as a 
component of routine clinical practice, and thus no additional specimen collection solely for 
research purposes is required. 
 
Archival or baseline tumor tissue will be genomically characterized by MI Profile (Caris Life 
Sciences). This will allow us to assess whether mutations, copy number alterations, and RNA 
signatures may be associated with different clinical outcomes.  
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
The study is an open-label, non-randomized single-arm, multi-center phase II therapeutic 
clinical trial with a safety lead-in. The study population will be patients with advanced HCC. 
 
Combination treatment with axitinib, avelumab, and bavituximab will be tested in a safety 
lead-in of the first 6 patients evaluable for dose-limiting toxicities in this study (see 
definitions for evaluable patients and dose-limiting toxicities in Section 4.2) to ensure the 
safety and tolerability of this triplet regimen. 
 
A two-stage design is used to limit the maximum sample size required to determine 
efficacy. Objective response requires confirmation imaging greater than or equal to 4 
weeks after initial best response. Patients who attain a complete response, partial 
response, or stable disease but do not have two imaging assessments to confirm response 
will be replaced. Patients who have progressive disease at any imaging assessment do 
not require subsequent confirmation. 
10.2 
Sample Size and Accrual 
We will use a minimax two-stage design method to compare the objective response rate 
of 34% (alternative hypothesis) for the treatment cohort versus 14% (null hypothesis) for 
the historical control. The basis of the null response rate is based on the previously reported 
objective response rate of 14% for axitinib plus avelumab in advanced HCC. This design 


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requires a sample size of 29 evaluable patients to yield a type I error rate of 0.10 and power 
of 0.9 when the true response rate is 34%. In the first stage 14 evaluable patients will be 
accrued. If there are 2 or more responses, then 15 additional evaluable patients will be 
accrued. Thus, the total enrollment for this study will be up to 29 evaluable patients. The 
null hypothesis will be rejected if 7 or more responses are observed in 29 patients. 
Objective response rate is defined as number of responders (either complete or partial 
response as the best objective response) of eligible patients. Patients who attain a 
complete response, partial response, or stable disease but do not have two imaging 
assessments to confirm response will be replaced. 
10.3 
Data Analyses 
Objective response rate, and disease control rate with corresponding 2-sided 95% CIs will 
be estimated using the Clopper-Pearson method. Kaplan-Meier methods will be used to 
estimate medians and 95% CIs for duration of response, overall survival, and progression-
free survival. Survival outcomes will be calculated from Day 1 of Cycle 1. Descriptive 
statistics will be used to analyze AEs described according to the NCI CTCAE v5.0. 
Clinically significant laboratory abnormalities will be described as well. Serious adverse 
events will be summarized, including a causality assessment. The number of treatment 
cycles and doses administered will be summarized using descriptive statistics.  
 
Associations between molecular features and tumor response will be analyzed using the 
Fisher-exact test with Benjamini-Hochberg multiple-testing correction. Cox regression 
models will be used to assess for associations between overall survival or progression-free 
survival and exploratory and correlative measures. 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy on 
Conflicts of Interest.  All investigators will follow the University conflict of interest policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. 


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11.3 
Required Documentation (for multi-site studies) 
Before the study can be initiated at any sub-site, the following documentation must be 
provided to the UTSW Clinical Research Office. 
 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list or Federal-wide Assurance letter 
• 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
(NOTE: this is required if UTSW holds the IND. Otherwise, the affiliate Investigator’s 
signature on the protocol is sufficient to ensure compliance) 
• 
A copy of the IRB-approved consent form 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Executed clinical research contract 
• 
Signed Monitoring Plan 
 
11.4 
Data Management and Monitoring/Auditing 
 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic case 
report forms in accordance with Simmons Comprehensive Cancer Center requirements, 
as appropriate for the project 
 
In order to facilitate remote source to case report form verification, the Simmons 
Comprehensive Cancer Center study team will require other institutions participating in this 
trial as sub-sites to enter data into the selected EDC system and upload selected de-
identified source materials when instructed.  
 
Trial monitoring will be conducted according to the study specific monitoring plan. This will 
be conducted no less than annually and refers to a regular interval review of trial related 
activity and documentation performed by the UTSW Simmons Cancer Center 
Gastrointestinal Disease-Oriented Teams (GI DOT), which includes but is not limited to 
accuracy of case report forms, protocol compliance, timeless and accuracy of Velos entries 
and AE/SAE management and reporting. Documentation of trial monitoring will be 
maintained along with other protocol related documents and will be reviewed during 
internal audit.    
  
Toxicity and dose escalation reviews will be performed in real-time by the GI DOT and 
DSMC.  These reviews will be documented by distributing reports of the findings to the 
members of the GI DOT and investigators. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all serious 
adverse events and UPIRSOs in real time as they are reported and reviews adverse events 
on a quarterly basis.  The quality assurance activity for the Clinical Research Office 
provides for periodic auditing of clinical research documents to ensure data integrity and 
regulatory compliance.  A copy of the DSMC plan is available upon request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The Quality Assurance 
Coordinator (QAC) works as part of the DSMC to conduct regular audits based on the level 


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of risk. Audit findings are reviewed at the next available DSMC meeting.  In this way, 
frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is determined 
by the DSMC Chairman and a number of factors such as the phase of the study; the type 
of investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles.  
11.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
11.5.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an emergency 
and is: 
• intentional on part of the investigator; or 
• in the investigator’s control; or 
• not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 Reporting requirement*: Exceptions are non-emergency deviations that 
require prospective IRB approval before being implemented. Call the IRB if 
your request is urgent. If IRB approval is not obtained beforehand, this 
constitutes a major deviation. For eligibility waivers, studies which utilize the 
SCCC-DSMC as the DSMC of record must also obtain approval from the 
DSMC prior to submitting to IRB for approval.  
11.5.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
• 
avoid immediate apparent harm, or 
• 
protect the life or physical well-being of subjects or others 
 Reporting requirement*: Emergency deviations must be promptly 
reported to the IRB within 5 working days of occurrence. 
11.5.3 Serious Noncompliance (formerly called major deviations or violations): 
include any departure from IRB-approved research that: 
• 
Increase risk of harm to subjects; and/or 
• 
adversely affects the rights, safety, or welfare of subjects (any of which may 
also be an unanticipated problem); and/or  
• 
adversely affects the integrity of the data and research (i.e., substantially 
compromises the integrity, reliability, or validity of the research) 
 Reporting requirement*: Serious Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
11.5.4 Continuing Noncompliance: includes a pattern of repeated noncompliance 
which continues after initial discovery, including inadequate efforts to take or 
implement corrective or preventive action within a reasonable time frame. 
 Reporting requirement*: Continuing Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
 


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11.5.5 Noncompliance (that is neither serious nor continuing; formerly called 
minor deviations) any departure from IRB-approved research that: 
• 
Does not meet the definition of serious noncompliance or continuing 
noncompliance 
 Reporting requirement*: Noncompliance that is neither serious nor 
continuing should be tracked and summarized the next IRB continuing review, 
or the notice of study closure- whichever comes first. 
 
*Reporting Requirements reflect UTSW HRPP/IRB guidelines; participating sites should follow the 
reporting guidelines for their IRB of record. 
11.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with 
a drug seeking regulatory approval and marketing, these documents shall be retained for 
at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region. In all other cases, study documents should be 
kept on file until three years after the completion and final study report of this investigational 
study. 
11.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 


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12.0 
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Makker, V. et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: 
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40 
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13.0 
APPENDICES 
 
 
Appendix A: Drug diary 
 


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