Conditions: Platinum-Resistant Fallopian Tube Carcinoma Platinum-Resistant Ovarian Carcinoma Platinum-Resistant Primary Peritoneal Carcinoma Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Refractory Fallopian Tube Carcinoma Refractory Ovarian Carcinoma Refractory Primary Peritoneal Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
This trial studies the side effects and best dose of AVB-S6-500 when given together with durvalumab in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that is resistant to platinum therapy or has come back. Immunotherapy with AVB-S6-500 and durvalumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine toxicity profile of the combination of batiraxcept (AVB-S6-500) and durvalumab therapy.

SECONDARY OBJECTIVES:

I. To estimate objective response rate to combination AVB-S6-500 and durvalumab therapy.

II. To estimate the median immune-related progression free survival (irPFS) as well as overall survival (OS) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 after treatment with combination durvalumab and AVB-S6-500.

III. To investigate molecular and immunological changes associated with the combination of AVB-S6-500 and durvalumab; specifically to describe changes in T cell populations (including but not limited to CD3, CD8, CD4, FOXP3) and cell proliferation, as well as report changes in the proportion of macrophage phenotypes M1 and M2 (with phenotypic markers potentially including arginase1, CD11b, PDL-1, and CD206).

EXPLORATORY OBJECTIVES:

I. To evaluate blood and tissue based biomarkers for immune related adverse events and disease progression.

II. To investigate impact and possible sensitization of pretreatment with AVB-S6-500 monotherapy on subsequent combination of durvalumab and AVB-S6-500.

III. To evaluate for molecular and immunologic differences between pre-treatment with single agent AVB-S6-500 as compared to durvalumab.

OUTLINE: This is a phase I, dose-escalation of batiraxcept, followed by a phase II study. In Phase I, patients receive both batiraxcept (intravenously \[IV\] over 60 minutes on days 1 and 15) and durvalumab (IV over 60 minutes on day 1) every cycle.

In Phase II, patients are randomized to 1 of 2 arms.

ARM I: Patients receive batiraxcept IV over 60 minutes on days 1, 15, and 29 of cycle 0, and on days 1 and 15 of subsequent cycles. Beginning cycle 1, patients also receive durvalumab IV over 60 minutes on day 1. Cycle 0 continues for 6 weeks and subsequent cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive durvalumab IV over 60 minutes on days 1 and 22 of cycle 0 and on day 1 of subsequent cycles. Beginning cycle 1, patients also receive batiraxcept IV over 60 minutes on days 1 and 15. Cycle 0 continues for 6 weeks and subsequent cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 weeks for at least 90 days.

Arms:
arm 1: Patients receive batiraxcept IV over 60 minutes on days 1, 15, and 29 of cycle 0, and on days 1 and 15 of subsequent cycles. Beginning cycle 1, patients also receive durvalumab IV over 60 minutes on day 1. Cycle 0 continues for 6 weeks and subsequent cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive durvalumab IV over 60 minutes on days 1 and 22 of cycle 0 and on day 1 of subsequent cycles. Beginning cycle 1, patients also receive batiraxcept IV over 60 minutes on days 1 and 15. Cycle 0 continues for 6 weeks and subsequent cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Batiraxcept intervention 2: Durvalumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol document:
Prot_SAP_001.pdf: 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2019-0149 
Protocol Title 
Randomized Phase I/II study of AVB-S6-500 in Combination with 
Durvalumab (MEDI4736) in Patients with Platinum-resistant, Recurrent 
Epithelial Ovarian Cancer 
Protocol Version 
1.6 
Protocol Phase 
I/II 
Version Date 
04/06/2021 
 
Protocol PI 
Amir Jazaeri, MD 
Department 
Gynecologic Oncology and Reproductive Medicine 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
144133 
 
 
 


 
Randomized Phase I/II study of AVB-S6-500 in 
Combination with Durvalumab (MEDI4736) in Patients with 
Platinum-resistant, Recurrent Epithelial Ovarian Cancer 
 
MD Anderson Protocol Number: 2019-0149 
Aravive Study Number: AVB-OCIST-001 
AstraZeneca Study Number: 18-13852 
IND Number: 144133 
 
 
Version Number: 1.6 
Version Date:  April 6, 2021 
Sponsor: The University of Texas MD Anderson Cancer Center 
Supporting Companies: AstraZeneca, Aravive 
Investigational Drug Substances: Durvalumab (MEDI4736), AVB-S6-500 
 
 
Principal Investigator: Amir Jazaeri, MD 
Co-Investigator: Emily Hinchcliff, MD 
Statistician: Ying Yuan, PhD 
 
 


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TABLE OF CONTENTS 
 
Table of Contents ......................................................................................................................... 2 
Table of Tables ............................................................................................................................. 3 
Table of Figures ........................................................................................................................... 3 
Abbreviations and Definition of Terms ....................................................................................... 4 
1. 
Introduction ........................................................................................................................ 6 
1.1 Disease Background ......................................................................................................... 6 
1.2 Durvalumab: Non-clinical and Clinical Experience ........................................................... 8 
1.3 AVB-S6-500: Non-clinical and Clinical Experience .......................................................... 8 
1.4 Research Hypothesis ......................................................................................................... 9 
1.5 Rationale for Conducting this Study .................................................................................. 9 
1.6 Benefit/Risk and Ethical Assessment .............................................................................. 11 
2. 
Study Objectives ............................................................................................................... 12 
2.1 Primary ........................................................................................................................... 12 
2.2 Secondary ....................................................................................................................... 12 
2.3 Exploratory ..................................................................................................................... 13 
3. 
Study Design ..................................................................................................................... 13 
3.1 Safety Lead-in ................................................................................................................ 14 
3.2 Phase II .......................................................................................................................... 15 
4. 
Patient Selection ............................................................................................................... 15 
4.1 Inclusion Criteria ............................................................................................................ 15 
4.2 Exclusion Criteria ........................................................................................................... 16 
4.3 Withdrawal of Patients from Study Treatment and/or Study ............................................ 18 
5. 
Investigational Products ................................................................................................... 19 
5.1 Durvalumab .................................................................................................................... 19 
5.2 AVB-S6-500 ................................................................................................................... 21 
5.3 Accountability and Dispensation ..................................................................................... 22 
5.4 Disposition of Unused Investigational Study Drug .......................................................... 22 
6. 
Treatment Plan ................................................................................................................. 22 
6.1 Procedures for Randomization ........................................................................................ 22 
6.2 Definition of Dose-limiting Toxicities ............................................................................ 23 
6.3 Toxicity Management Guidelines .................................................................................... 24 
6.4 Restrictions During the Study and Concomitant Treatment(s) ......................................... 26 
6.5 Schedules of Study Assessments and Procedures ............................................................ 29 
6.6 Biological Sampling Procedures ..................................................................................... 38 
7. 
Disease Evaluation and Methods ...................................................................................... 39 
7.1 Modified RECIST v1.1 ................................................................................................... 39 
7.2 Response Criteria ............................................................................................................ 41 
8. 
Assessment of Safety ......................................................................................................... 43 
8.1 Safety Parameters ........................................................................................................... 43 
8.2 Assessment of Safety Parameters .................................................................................... 47 
8.3 Recording and Reporting of Adverse Events and Serious Adverse Events ....................... 48 
9. 
Statistical Methods and Sample Size Determination ....................................................... 51 
9.1 Description of Analysis Sets ........................................................................................... 55 
9.2 Methods of Statistical Analyses ...................................................................................... 55 
10. 
Ethical and Regulatory Requirements ............................................................................. 57 


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10.1
Ethical Conduct of the Study......................................................................................... 57
10.2
Ethics and Regulatory Review ...................................................................................... 57
10.3
Informed Consent .........................................................................................................57
10.4
Changes to the Protocol and Informed Consent Form .................................................... 58
11.
Study Management ...........................................................................................................58
11.1
Monitoring of the Study................................................................................................ 58
11.2
Data Management .........................................................................................................58
12.
List of References .............................................................................................................59
Dosing Modifications and Toxicity Management Guidelines for Immune-
mediated, Infusion-related, and Non-immune–mediated Reactions (Durvalumab and AVB-S6-
500) (CTCAE v5.0).....................................................................................................................63
ECOG Performance Status Criteria.................................................................. 86
Durvalumab Weight-based Dose Calculations.................................................. 87
TABLE OF TABLES
Table 1. Dosing for Dose Escalation
14
Table 2. Formulation of AVB-S6-500 Drug Product
21
Table 3. Highly Effective Methods of Contraception (<1% Failure Rate)
26
Table 4. Permitted Supportive Medications
27
Table 5. Prohibited Concomitant Medications
27
Table 6. Schedule of Assessments and Procedures: Safety Lead-in
29
Table 7. Schedule of Assessments and Procedures: Phase II, Durvalumab Monotherapy Cohort
32
Table 8. Schedule of Assessments and Procedures: Phase II, AVB-S6-500 Monotherapy Cohort
35
Table 9. Detailed Research Blood Collection Schedule
38
Table 10. Overall Responses for All Possible Combinations of Tumor Responses
42
Table 11. NCI Suggested AE recording criteria.
48
Table 12. Dose escalation/de-escalation rule for the BOIN design
52
Table 13. Operating Characteristics of the BOIN design
54
Table 14. Optimized stopping boundaries
56
Table 15. Operating characteristics of BOP2 design
57
Table 16. General Considerations
63
Table 17. Specific Immune-mediated Reactions
64
Table 18. Infusion-related Reactions
84
Table 19. Non-immune-mediated Reactions
85
Table 20. ECOG Performance Status Criteria
86
TABLE OF FIGURES
Figure 1. PK/PD for the 10 mg/kg Cohort.................................................................................................. 10
Figure 2. Study Schema .............................................................................................................................. 14
Figure 3. Flowchart for trial conduct using the BOIN design..................................................................... 53


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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BLQ 
Below level of quantification 
CBC 
Complete blood count 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Peak concentration 
CNS 
Central nervous system 
CR 
Complete response 
CT 
Computed tomography 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen-4 
DLS 
Discovery Life Sciences 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Disodium edetate dihydrate 
EGFR 
Epidermal growth factor receptor 
Fc 
Fragment crystallizable 
FDA 
Food and Drug Administration 
FFPE 
Formalin fixed paraffin embedded 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HBsAg 
Hepatitis B surface antigen 
HBsAb, HBcAb 
Hepatitis B surface antibody, Hepatitis B core antibody 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IFN 
Interferon 
IHC 
Immunohistochemistry  
IL 
Interleukin 
IP 
Investigational product(s) 
irAE 
Immune-related adverse event 


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IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
MAb 
Monoclonal antibody 
MDACC 
MD Anderson Cancer Center 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NSCLC 
Non-small cell lung cancer 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death 1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
Q12W 
Every 12 weeks 
QTc 
Time between the start of the Q wave and the end of the T wave corrected 
for heart rate 
QTcF 
QT interval on ECG corrected using the Frederica’s formula 
RCC 
Renal cell carcinoma 
RD 
Repeat dosing 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dosing 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SD 
Stable disease 
TEAE 
Treatment-emergent adverse event 
TIL 
Tumor infiltrating lymphocyte 
TMG 
Toxicity Management Guidelines 
TKI 
Tyrosine Kinase Inhibitor 
Tmax 
Time to peak concentration 
TMDD 
Target mediated drug disposition 
TMG 
Toxicity Management Guidelines 
TNF-Į 
Tumor necrosis factor alpha 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 


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1. 
INTRODUCTION 
1.1 
DISEASE BACKGROUND 
1.1.1 
EPITHELIAL OVARIAN CANCER 
Each year in the United States, over 22,000 women develop ovarian cancer and there are approximately 
14,240 attributed deaths annually, making ovarian cancer the deadliest of gynecologic malignancies [1]. 
Despite high rates of complete response to the combination of tumor reductive surgery and adjuvant 
platinum-taxane based chemotherapy, the vast majority of patients with stage III/IV EOC recur with a 
median progression free survival (PFS) of approximately 18 months. In those who recur, despite decades 
of clinical investigations, most cytotoxic and biological agents result in only modest rates of response and 
have a typical median PFS of 3 months [2], [3]. Therefore, a crucial unmet need is the development of 
new strategies that will ultimately improve the overall survival (OS) of patients with EOC. 
1.1.2 
IMMUNOTHERAPIES 
It is increasingly understood that cancers are recognized by the immune system, and, under some 
circumstances, the immune system may control or even eliminate tumors [4].  
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell 
activation. The PD-1 receptor (CD279) is expressed on the surface of activated T cells [5]. It has two 
known ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) [6]. The PD-1 and PD-L1/PD-L2 
belong to the family of immune checkpoint proteins that act as co-inhibitory factors, which can halt or 
limit the development of T cell response. When PD-L1 binds to PD-1, an inhibitory signal is transmitted 
into the T cell, which reduces cytokine production and suppresses T-cell proliferation. Tumor cells exploit 
this immune checkpoint pathway as a mechanism to evade detection and inhibit immune response. 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages. Importantly, PD-L1 is 
commonly over-expressed on tumor cells or on non-transformed cells in the tumor microenvironment[7]. 
PD-L1 expressed on the tumor cells binds to PD-1 receptors on the activated T-cells leading to the 
inhibition of cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment. 
The PD-1/PD-L1 pathway represents an adaptive immune resistance mechanism that is exerted by tumor 
cells in response to endogenous anti-tumor activity. 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of evading 
immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 receptor inhibits the 
interaction of PD-L1 with the PD-1 and CD80 receptors expressed on immune cells. This activity 
overcomes PD-L1-mediated inhibition of antitumor immunity. While functional blockade of PD-L1 
results in T-cell reactivation, this mechanism of action is different from direct agonism of a stimulatory 
receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody could 
be used therapeutically to enhance antitumor immune responses in patients with cancer. Results of non-
clinical and clinical studies of monoclonal antibodies (mAbs) targeting the PD-L1/PD-1 pathway have 
shown evidence of clinical activity and a manageable safety profile, supporting the hypothesis that an 
anti-PD-L1 antibody could be used to therapeutically enhance antitumor immune response in cancer 
patients [8]–[11]. Pre-clinical data have now been added to with a wealth of clinical data showing that 
blockade of negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) 
and PD-L1 has promising clinical activity. Ipilimumab was granted United States (US) Food and Drug 
Administration (FDA) approval for the treatment of metastatic melanoma and is currently under 
investigation for several other malignancies, whilst nivolumab and pembrolizumab, two anti-PD-1 agents, 


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and atezolizumab, an anti-PD-L1, agent have been granted approvals by agencies such as the US FDA 
and the European Medicines Agency approval for the treatment of a number of malignancies including 
metastatic melanoma, squamous and non-squamous cell non-small-cell lung cancer and urothelial 
carcinoma. In addition, there are data from agents in the anti-PD-1/PD-L1 class showing clinical activity 
in a wide range of tumor types. 
1.1.3 
POTENTIAL UTILITY OF IMMUNE CHECKPOINT INHIBITORS IN OVARIAN 
CANCER 
Immunogenicity of EOC has been well-documented, and there is extensive literature demonstrating the 
SUHVHQFHRIFORQDOO\DFWLYDWHG&'&'7&5Įȕ7-cells in ovarian tumors and their prognostic 
significance[12]–[18]. Tumor infiltrating lymphocytes (TIL) derived from patients with EOC demonstrate 
tumor specificity by a) clonal proliferation in response to low concentrations of IL2 in the presence of 
autologous tumor cells [19] and b) exhibit MHC restricted killing of EOC tumor cell lines as well as 
cloned autologous tumor cells [18] and c) cytokine production [12], [14], [20]. However, there is also 
strong evidence that EOC harbors an immune-suppressor environment that includes the presence of 
regulatory T Cells, CTLA4-positive TILs, monocyte/macrophages, and elevated intratumoral and plasma 
OHYHOVRILPPXQRVXSSUHVVLYHF\WRNLQHVVXFKDV,/,/DQG7*)ȕ[21]–[26]. Indeed, expression of 
PDL1 and PDL2 in EOC was shown to correlate with poorer OS[24], and both ascites and peripheral 
blood derived monocytes from patients with EOC showed upregulated PDL1 expression [26]. 
1.1.4 
POTENTIAL UTILITY OF AXL INHIBITION IN OVARIAN CANCER 
As a novel treatment, checkpoint blockade and immune modulation have demonstrated efficacy in heavily 
pretreated tumors with some durable responses, but only in a small fraction of patients. The emerging data 
on anti-PD1 / anti-PDL-1 therapies in ovarian cancer demonstrates response rates of 10-15%[8], [27]–
[29].  
While the mechanism for immune resistance to checkpoint inhibition remains poorly understood, a 
predictor of response to anti-PD1 therapy is the extent of CD8+ infiltration within the pretreated tumor 
[30]–[33]. Factors which contribute to T-cell exclusion, and thus resistance, within the tumor 
microenvironment include immune cell suppression via cytokines, aberrations in antigen presentation, or 
microenvironmental factors such as hypoxia. The receptor tyrosine kinase AXL has recently been 
identified as a possible mediator of T-cell exclusion and therapeutic resistance. In multiple tumor types, 
including uterine serous cancer, head and neck malignancy, and non-small cell lung cancers, AXL 
expression correlated with poor survival [34]–[37]. In ovarian cancer specifically, a meta-analysis of 
DNA microarray data and confirmatory cohort demonstrated that AXL ligand GAS6 was highly 
expressed and correlated to poor survival [38]–[40].  
An increasing body of evidence suggests that this survival difference may be due to AXL’s suppressive 
effect on the innate immune response by supporting maturation of natural killer cells and inhibiting 
macrophage-driven inflammation. AXL has been shown to redirect downstream signaling via STAT1 to 
result in activation of suppression cytokine signaling proteins [41], and activation of AXL in 
macrophages leads to a switch from M1 to M2 phenotype resulting in inability to activate CD8 T-cells 
[42]. Interestingly, AXL has been demonstrated to be induced together with the appearance of drug 
resistance to both targeted and conventional chemotherapy [34]–[37], [43]–[45]. Therefore, clinical trials 
utilizing AXL inhibition have been launched for both liquid and solid tumors (NCT02488408, 
NCT02729298, NCT03454243, NCT02424617).  
However, while this signaling axis represents an attractive target for therapeutic intervention, the strong 
picomolar binding affinity (~14-33 pM) between endogenous GAS6 and AXL and the promiscuity of 


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small molecule AXL inhibitors has historically presented a barrier to specific and potent inhibition of 
AXL. AVB-S6-500 is a highly sensitive and specific inhibitor of AXL, with apparent affinity of 93-324 
femtomolar to G AS6, which is approximately 200-fold higher affinity than wild-type (WT) AXL. AVB-
S6-500 binds GAS6, the sole ligand of AXL, inhibiting its interaction with AXL, thereby dramatically 
reducing AXL signaled invasion and migration of highly metastatic cells in vitro and inhibiting metastatic 
disease in nonclinical models of aggressive human cancers. 
1.1.5 
COMBINATION OF IMMUNE CHECKPOINT AND AXL INHIBITION 
There is the expectation of synergy between AXL and immune targeting agents[46]. A recent study 
investigated the genomic profile of anti-PD1 checkpoint-resistant melanoma, and demonstrated that AXL 
transcript levels were significantly correlated to resistance [47]. Subsequent literature further investigated 
the role of AXL in checkpoint sensitive and resistant clones and demonstrated that loss of AXL resulted 
in significantly greater TIL population and subsequent response to radiotherapy and checkpoint 
immunotherapy[43]. These findings have now been supported with translational mouse models of colon 
and breast cancer, with markedly decreased tumor growth with dual inhibition of AXL and immune 
checkpoint inhibition[48]–[50]. Trials utilizing this combination of immune checkpoint inhibition and 
AXL inhibitor have begun in other solid tumor types, including lung and breast cancer (NCT03184571, 
NCT03184558). 
1.2 
DURVALUMAB: NON-CLINICAL AND CLINICAL EXPERIENCE 
The non-clinical and clinical experience is fully described in the most current version of the durvalumab 
Investigator’s Brochure.  
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass 
that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the 
treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). The proposed 
mechanism of action (MOA) for durvalumab is interference in the interaction of PD-L1 with PD-1 and 
CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune 
responses, including those that may result in tumor elimination. In vitro studies demonstrate that 
durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored 
proliferation of IFN-Ȗ[51]. In vivo studies have shown that durvalumab inhibits tumor growth in 
xenograft models via a T-cell-dependent mechanism[51]. Based on these data, durvalumab is expected to 
stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward 
an antitumor response. Durvalumab has been engineered to reduce antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity.  
To date durvalumab has been given to more than 8000 patients as part of ongoing studies either as 
monotherapy or in combination with other anti-cancer agents. Refer to the current durvalumab 
Investigator’s Brochure for a complete summary of non-clinical and clinical information including safety, 
efficacy and pharmacokinetics.  
1.3 
AVB-S6-500: NON-CLINICAL AND CLINICAL EXPERIENCE 
AVB-S6-500, a GAS6-AXL pathway inhibitor, is an engineered receptor-Fc fusion protein therapeutic 
and is being developed by Aravive for use in the treatment of cancer. The proposed MOA for AVB-S6-
500 is the high affinity and highly specific binding to GAS6, the sole ligand for AXL, with 200 fold 
greater affinity compared to native AXL receptor. In vitro studies demonstrate that AVB-S6-500 has 
single agent efficacy in metastatic ovarian cancer models, decreasing both number of metastases and 


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tumor weight. While the exact mechanism requires further elucidation, prior data suggests that AXL 
inhibition stimulates a patient’s antitumor immune response by decreasing suppressive cytokine signaling 
and preventing the AXL mediating macrophage switch from the M1 to the M2 phenotype. Additionally, 
AVB-S6-500 proposed anti-fibrotic effects may benefit desmoplasia and drug penetrance.  
When directly compared in nonclinical models with the most advanced selective anti-AXL small 
molecules currently in clinical development, AVB-S6-500 achieved superior antitumor efficacy while 
displaying no toxicity in pharmacology studies [52]. AVB-S6-500 causes regression of tumor cells in 
vivo when dosing in these models commenced 4-7 days after tumor inoculation and establishment of 
small tumors in the mouse. However, AVB-S6-500 is not directly cytotoxic in vitro and under normal 
physiological (nonstressed) conditions, as the in vitro IC50 in cancer cells (with high levels of AXL on 
WKHFHOOVXUIDFHLV!ȝ00RGXODWLRQRI$;/VLJQDOLQJE\DSUHGHFHVVRU$;/GHFR\UHFHSWRU
protein, MYD1 Fc (AXL-S6-1 hIgG), increased expression of the epithelial marker E-cadherin, consistent 
with the AXL decoy protein causing a mesenchymal to epithelial phenotype transition in vivo [52]. 
Reversal of the mesenchymal phenotype has been reported to cause growth inhibition, suppression of 
spheroid forming capacity and induction of apoptosis[53], [54]. This is consistent with the combination 
treatment studies conducted with predecessor proteins, which demonstrated a relationship between AXL 
signaling and the cellular response to DNA damage in breast, pancreatic and ovarian cancer models. The 
damage was observed more so in combination with cytotoxic chemotherapies such as doxorubicin and 
gemcitabine[52]. Thus, inhibiting the AXL/GAS6 pathway in stressed cells (due to transition from 
mesenchymal to epithelial phenotype and/or in combination with cytotoxic agents) appears to lead to cell 
death in vivo. 
Safety data from the Phase 1 first-in-human study in healthy volunteers indicate that AVB-S6-500 was 
very well tolerated across all administered doses and a MTD was not reached. In addition to safety and 
tolerability, serum levels of AVB-S6-500 (pharmacokinetic [PK] data) and serum GAS6 levels 
(pharmacodynamics data) were used to identify the active doses of AVB-S6-500 that fully suppress serum 
GAS6 and guided selection of doses to be tested in combination with the standard-of-care (SOC) 
therapies in Phase 1b/2 studies in cancer patients. Refer to Investigational Brochure for complete details. 
1.4 
RESEARCH HYPOTHESIS 
Our overarching hypothesis is that the addition of AXL inhibition via the novel agent AVB-S6-500 to 
durvalumab (MEDI4736) therapy will produce clinically significant improvement in response rate 
compared to the currently achievable response rate with programmed cell death protein 1 (PD1) immune 
inhibition alone in patients with platinum resistant epithelial ovarian, fallopian tube and primary 
peritoneal cancers (that will be collectively referred to as EOC). We hypothesize that this combination 
will be associated with an acceptable toxicity profile. Additionally, dual targeting of programmed cell 
death protein ligand 1 (PDL1) and AXL in combination may synergistically prolong time to progression. 
In an exploratory analysis we will also compare translational objectives, to investigate molecular and 
immunologic changes associated with the combination of AVB-S6-500 and durvalumab. 
1.5 
RATIONALE FOR CONDUCTING THIS STUDY 
1.5.1 
AVB-S6-500 DOSE 
Based on available data from a recently completed First-in-Human, Phase 1 study in healthy volunteers 
(AVB500-HV-001), PK and pharmacodynamics data for AVB-S6-500 were evaluated in real time using 
validated enzyme linked immunosorbent assays (ELISA) in each cohort. As expected with an IV 
administered drug, Cmax increased proportionally to dose and Tmax was 1 h (the earliest time point 


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collected) for all doses. Consistent with target mediated drug disposition (TMDD), the area under the 
curve (AUC) increased more than proportionally across doses and the half-life increased across doses. At 
the lowest dose tested, 1 mg/kg, serum GAS6 levels were suppressed (below level of quantitation [BLQ] 
of 2 ng/mL) for one-week post-dose in 4 out of 6 subjects. All 6 subjects in the 2.5 and 5 mg/kg groups 
had serum GAS6 levels BLQ 1-week post dose. All 6 subjects in the 5 mg/kg had serum GAS6 levels 
BLQ 2 weeks post dose. A single 10 mg/kg dose suppressed serum GAS6 for at least 3 weeks. Thus, all 
single doses tested had the desired pharmacological activity. In addition, GAS6 levels were suppressed 
for 3 weeks after the 4th dose of 5 mg/kg in the RD portion of the study. 
The dosing regimen that will be tested in the current trial is therefore 10 mg/kg every other week. The 
AVB-S6-500 concentrations vs the serum GAS6 levels are shown in the Figure 1 for this recommended 
dosing. This dose is anticipated to provide abrogation of serum GAS6 for at least 14 days and maintain 
the AVB-S6-500 levels in blood above those needed for 90% saturation of GAS6. Additionally, as above, 
subjects in the 5 mg/kg dosing also had serum GAS6 levels BLQ at 2 weeks post-dose. Thus, all doses 
intended during the current study, including dose de-escalation, had the desired pharmacological activity.  
In terms of safety, review of safety data from first-in-human study suggests that IV doses of up to 
10 mg/kg of AVB-S6-500 have been well tolerated. No serious adverse events (SAEs), deaths or 
withdrawals from study due to AEs have been reported. The incidence of treatment-emergent AEs 
(TEAE) does not appear to increase with dose. 
However, if tolerability issues unexpectedly arise for 
the AVB-S6-500 combination with Durvalumab, 
there is opportunity to adjust the AVB-S6-500 dose 
prior to enrolling the combination cohort. If, after 
review of the first cycle safety data from 3 subjects, 
the regimen of 10 mg/kg AVB-S6-500 every 2 
weeks (Q2W) is deemed not well-tolerated in 
combination with Durvalumab, 3 new subjects will 
be enrolled into a cohort with a lower AVB-S6-500 
dose of 5 mg/kg with weekly dosing (the 
durvalumab dose would remain unchanged). 
1.5.2 
DURVALUMAB DOSE 
A population PK model was developed for durvalumab using monotherapy data from a Phase I study 
(study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). Population PK 
analysis indicated only minor impact of body weight (WT) on the PK of durvalumab (coefficient of 0.5). 
The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab was 
evaluated by comparing predicted steady state PK concentrations (5th, median and 95th percentiles) using 
the population PK model. A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on 
median body WT of ~75 kg). A total of 1000 patients were simulated using body WT distribution of 40-
120 kg. Simulation results demonstrate that body WT-based and fixed dosing regimens yield similar 
median steady state PK concentrations with slightly less overall between-patient variability with fixed 
dosing regimen.  
Similar findings have been reported by others[55]–[58]. Wang and colleagues investigated 12 monoclonal 
antibodies and found that fixed and body size-based dosing perform similarly, with fixed dosing being 
better for 7 of 12 antibodies [56]. In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-patient 
variability in pharmacokinetic/pharmacodynamics parameters [57].  
Figure 1. PK/PD for the 10 mg/kg Cohort 


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A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing 
errors. Given expectation of similar pharmacokinetic exposure and variability, we considered it feasible to 
switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) is included in the combination therapy phases of the current 
study. Weight based dosing at 20 mg/kg will be utilized for any patient whose body weight drops below 
30 kg while on the combination treatment. 
For the monotherapy phase, Q3W dosing will be employed with fixed dose of 1120 mg, in order to 
accommodate the 6 week monotherapy lead-in timing. Patients randomized to durvalumab monotherapy 
will then transition to the Q4W dosing at initiation of combination phase, as above. 
1.6 
BENEFIT/RISK AND ETHICAL ASSESSMENT 
1.6.1 
 POTENTIAL BENEFITS 
Patients with platinum resistant ovarian cancer have a poor prognosis with typical response rates of 0-
20% and median PFS of approximately 3 months and OS ranging between 8 and 17 months across a large 
number of clinical trials employing cytotoxic and biological antineoplastic therapies[2], [3]. Emerging 
data from clinical trials investigating immune checkpoint inhibitors targeting PD1 pathways reveal that 
approximately 10-15% of patients with platinum resistant ovarian cancer respond to checkpoint inhibitor 
monotherapy[8]. Furthermore, many of the responses are durable in nature lasting many months. 
However, ongoing trials reveal that combination therapies are required in order to improve this low 
response rate. The expected synergy with AXL inhibition represents a valuable and important avenue of 
investigation in this patient population with no better alternative treatment options. 
1.6.2 
OVERALL RISKS 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell death 
ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or cytotoxic T-
lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses directed against tumor 
cells. By stimulating the immune system however, there is the potential for adverse effects on other 
tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are thought to be 
due to the effects of inflammatory cells on specific tissues. These risks are generally events with a 
potential inflammatory or immune mediated mechanism and may require more frequent monitoring 
and/or unique interventions such as immunosuppressants and/or endocrine therapy. These immune 
mediated effects can occur in nearly any organ system, and are most commonly seen as gastrointestinal 
AEs such as colitis and diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis 
and liver enzyme elevations, skin events such as rash and dermatitis and endocrinopathies including 
hypo- and hyper-thyroidism. 
1.6.2.1 AVB-S6-500 
AVB-S6-500 has been well tolerated across all doses trialed in initial healthy volunteer single ascending 
dose and repeat dose trial. There were no serious adverse events. There were no treatment-related changes 
noted in physical examinations or vital signs. None of the AEs based on laboratory values were deemed 
clinically significant, none required treatment, and all were asymptomatic. As per protocol, all laboratory 
values that met CTCAE v 4.03 criteria for subjects given active drug were considered possibly related. 
None were considered probably/likely or certainly related. Further information can be found in the 
Investigator’s Brochure. 
 


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However, the combination of AXL inhibition with durvalumab may result in exacerbation of immune-
related adverse effects. Therefore, the risks with the combination include, but are not limited to, the 
categories as listed within Section 1.6.2.2. 
1.6.2.2 DURVALUMAB 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus, hypophysitis 
and adrenal insufficiency) hepatitis/increases in transaminases, nephritis/increases in creatinine, 
pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, 
other rare or less frequent inflammatory events including neurotoxicities, infusion-related reactions, 
hypersensitivity reactions and infections/serious infections.  
For information on all identified and potential risks with durvalumab please always refer to the current 
version of the durvalumab IB. 
In mRQRWKHUDS\FOLQLFDOVWXGLHV$(VDOOJUDGHVUHSRUWHGYHU\FRPPRQO\15% of patients) are fatigue, 
nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, pyrexia, asthenia, 
anemia, arthralgia, peripheral edema, headache, rash, and pruritus. Approximately 9.4% of patients 
experienced an AE that resulted in permanent discontinuation of durvalumab and approximately 6.5% of 
patients experienced an SAE that was considered to be related to durvalumab by the study investigator. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic treatment, and in 
the case of events suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated adverse events (Section 6.3.1).  
1.6.3 
OVERALL BENEFIT-RISK 
Ovarian cancer is the deadliest gynecologic malignancy, with a short progression free interval and limited 
treatment options at time of recurrence. While checkpoint inhibition has showed exciting initial activity, 
the rates of response remain low. Therefore, further investigation of novel combinations where synergy is 
expected, such as with AXL inhibition, represents an essential approach to advancing the care of these 
women. Additionally, rapid expansion of the use of immunotherapies have demonstrated that the majority 
of immune-related adverse events are manageable and acceptable in such a patient group with few 
alternatives. Thus, overall, the risks-benefit ratio is in favor of further investigations to refine checkpoint 
and AXL inhibitor therapy combinations and their associated toxicities in this population. 
2. 
STUDY OBJECTIVES 
2.1 
PRIMARY 
To determine toxicity profile of the combination of AVB-S6-500 and durvalumab therapy  
2.2 
SECONDARY 
1. To estimate objective response rate to combination AVB-S6-500 and durvalumab therapy  
2. To estimate the median immune-related progression free survival (irPFS) as well as overall 
survival OS by RECIST 1.1 after treatment with combination durvalumab and AVB-S6-500 
3. To investigate molecular and immunological changes associated with the combination of AVB-
S6-500 and durvalumab; specifically to describe changes in T cell populations (including but not 
limited to CD3, CD8, CD4, FOXP3) and cell proliferation, as well as report changes in the 
proportion of macrophage phenotypes M1 and M2 (with phenotypic markers potentially 
including arginase1, CD11b, PDL-1, and CD206) 


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2.3 
EXPLORATORY 
1. To evaluate blood and tissue-based biomarkers for immune related adverse events and disease 
progression 
2. To investigate impact and possible sensitization of pretreatment with AVB-S6-500 monotherapy 
on subsequent combination of durvalumab and AVB-S6-500 
3. To evaluate for molecular and immunologic differences between pre-treatment with single agent 
AVB-S6-500 as compared to durvalumab 
3. 
ORIGINAL STUDY DESIGN 
This is a randomized phase I/II trial of the combination of immune checkpoint inhibitor therapy and AXL 
inhibition in patients with recurrent platinum resistant EOC. The design is based on the clinical rationale 
that the combination of durvalumab and AVB-S6-500 may have increased efficacy but at the risk of 
potentially greater toxicity. This trial will determine appropriate combination dosing and then, based on 
efficacy and safety assessments, allow for development of a superior suitable regimen for a follow-up 
phase III investigation based on these efficacy and toxicity tradeoffs. It will also be informative regarding 
response rates associated with this combination regimen and will generate key preliminary data to 
determine impact on irPFS and if pretreatment with either durvalumab or AVB-S6-500 impacts 
subsequent response to the combination of both therapies. Furthermore, translational correlative studies 
will include immune profiling and ribonucleic acid (RNA) expression analysis of tumor at enrollment, 
following monotherapy, and on combination treatment to investigate biological correlates for response, 
possible sensitization of immune microenvironment, and any indication of adverse event. Progression 
during investigational agent treatment cycles will be defined based on immune-related response criteria 
(irRC; including computed tomography (CT) confirmation at least 5 weeks apart to determine 
progression).  
 
3.1 
END OF STUDY ENROLLMENT 
In the first quarter of 2021, study supporters Aravive and AstraZeneca made the decision to end 
enrollment based on available data after the 5th evaluable subjected completed treatment on the safety 
lead-in.  


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Figure 2. Study Schema 
Dosing schedule as above demonstrates investigational product at week of administration, where A = 
AVB-S6-500 monotherapy, D= durvalumab monotherapy, and A+D = AVB-S6-500 + durvalumab 
combination therapy 
* Patients receiving the recommended Phase 2 dose (RP2D) will then be included in the primary analysis 
of the combination therapy. However, these patients will continue on the Safety Lead-in dosing schedule 
and will not participate in the Phase 2 monotherapy. See de-escalation dosing regimens below. 
‡ Sample size calculations account for predicted 8% dropout rate due to toxicity. 
† Dosing schedule shown reflects the starting dose for the dose escalation. This may be adjusted for the 
de-escalation schedule below and determination of the RP2D. 
Table 1. Dosing for Dose Escalation 
Dose Level 
Durvalumab + AVB-S6-500 
Dose Level 0 
(Initial dose) 
durvalumab (1500mg Q4W), AVB-S6-500 (10mg/kg Q2W) 
Dose level 1 
durvalumab (1500mg Q4W), AVB-S6-500 (15mg/kg Q2W) 
Dose level 2 
durvalumab (1500mg Q4W), AVB-S6-500 (20mg/kg Q2W) 
 
3.2 
SAFETY LEAD-IN 
The trial will begin with a dose escalation phase to determine the recommended Phase 2 dose (RP2D). 
The design for dose escalation is provided in Section 9. The dose level established in the dose escalation 
phase will define the recommended dosing for subsequent combination treatment. Those patients treated 
at the RP2D will continue on treatment and will contribute to primary analysis of combination therapy. 


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Of note, prior to receipt of any treatment, all patients will undergo a computed tomography (CT) scan to 
determine baseline volume of disease. An initial pre-treatment biopsy and blood samples will be obtained 
to measure immune function in both the pretreated tumor environment and systemically. 
To investigate translational aims, all patients participating in safety lead-in cohorts will undergo a biopsy 
and blood sampling after receiving 6 weeks of treatment.  
Refer to the Schedule of Assessments in Table 6 for complete details (Section 6.5).  
3.3 
PHASE II 
The Phase II portion of the study will begin after the RP2D is established in the Safety Lead-in. In Phase 
II, eligible subjects first will participate in a 6-week monotherapy cycle (Cycle 0) with either AVB-S6-50 
(ARM I) or durvalumab (ARM II) before proceeding to receive the combination therapy at the RP2D. We 
will randomize 3:1 to AVB-S6-500 and durvalumab monotherapy arms, respectively. Subjects 
randomized to Arm 1 will receive single agent AVB-S6-500 (Q2W), and subjects randomized to Arm 2 
will receive durvalumab (fixed Q3W dosing) during the monotherapy cycle. The monotherapy dose for 
each agent will be based on the combination RP2D established in the Safety Lead-in. Prior to receiving 
monotherapy treatment, all subjects will undergo a CT scan to determine initial volume of disease. An 
initial pre-treatment biopsy and blood samples will be obtained to measure immune function in both the 
pretreated tumor environment and systemically. 
Following 6 weeks of monotherapy treatment, a repeat CT scan will be performed and an additional 
biopsy will be obtained. Of note, this CT scan serves as the new baseline imaging from which response to 
combination will be compared. 
All patients who have completed monotherapy treatment without limiting toxicity will then be treated 
with combination therapy at the RP2D. Patients will receive treatment until progression or unacceptable 
toxicity with combination therapy. An additional biopsy will be obtained after 2 cycles of therapy, and CT 
scans will be performed every 8 weeks.  
Refer to the Schedules of Assessments in Table 7 and Table 8 for complete details (Section 6.5).  
4. 
PATIENT SELECTION  
4.1 
INCLUSION CRITERIA 
Inclusion criteria will be assessed within 28 days of starting study treatment: 
1. Ability to provide signed informed consent.  
2. Age  18 years at time of study entry. 
3. Patient is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
4. Histology (reviewed at MDACC) showing recurrent high grade epithelial ovarian, peritoneal, or 
fallopian tube cancer. 
5. Platinum resistant or refractory disease as defined by progression of disease on a platinum-
containing regimen or recurrence of disease within 180 days of previous platinum treatment. 
6. Have measurable disease based on modified RECIST 1.1. For the purposes of this study 
measurable disease is defined at least one "target lesion" that can be accurately measured in at 
least one dimension (longest dimension to be recorded). Each target lesion must be >20 mm when 
measured by conventional techniques, including palpation, plain x-ray, computed tomography 
(CT), and magnetic resonance imaging (MRI), or >10 mm when measured by spiral CT. The 


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target lesion must be distinct from other tumor areas selected for pre-treatment biopsies. Pre-
treatment imaging must be performed within 4 weeks of starting therapy. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
8. Life expectancy RI12 weeks. 
9. Body weight >30 kg. Note: if subject’s weight falls below 30 kg during study but the patient is 
otherwise eligible to continue investigational therapy the dose of durvalumab will be modified to 
be weight-based (20 mg/kg for the 1500 mg dose; modification is not required for 1120 mg dose). 
Refer to Section 5.1.2 and Appendix C for complete details. 
10. Adequate normal organ and marrow function as defined below.  
a. Hemoglobin 9.0 g/dL. 
b. Absolute neutrophil count (ANC) > 1500/mm3. 
c. Platelet count 100 x 109/L (>75,000/mm3). 
d. Serum bilirubin 1.5 x ULN. This will not apply to patients with confirmed Gilbert’s 
syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in 
the absence of hemolysis or hepatic pathology), who will be allowed only in consultation 
with their physician. 
e. AST (SGOT)/ALT (SGPT) 2.5 x ULN unless liver metastases are present, in which case it 
must be 5x ULN. 
f. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by 
the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for 
determination of creatinine clearance: 
Creatinine CL 
(mL/min) 
= 
   Weight (kg) x (140 - Age)  
x 0.85 
72 x serum creatinine (mg/dL) 
11. Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal 
patients. Women will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause. The following age-specific requirements apply:  
a. Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments 
and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-
menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
b. :RPHQ\HDUVRIDJHZRXOGEHFRQVLGHUHGSRVW-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
12.  Patients must have no currently available standard of care treatment options 
4.2 
EXCLUSION CRITERIA 
Exclusion criteria will be assessed within 28 days of starting study treatment: 
1. Participation in another clinical study with an investigational product during the last 28 days. 
2. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) 
clinical study or during the follow-up period of an interventional study. 
3. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, 
targeted therapy, biologic therapy, tumoUHPEROL]DWLRQPRQRFORQDODQWLERGLHV28 days prior to 


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the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or 
PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca, 
Aravive, and the investigator. 
4. $Q\XQUHVROYHGWR[LFLW\1&,&7&$(*UDGHIURPSUHYLRXVDQWLFDQFHUWKHUDS\ZLWh the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.  
a. Patients ZLWK*UDGHQHXURSDWK\ZLOOEHHYDOXDWHGRQDFDVH-by-case basis after 
consultation with the primary investigator. 
b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment 
with durvalumab may be included only after consultation with the primary investigator.  
5. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.  
6. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of 
IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 
7. History of allogenic organ transplantation. 
8. Active or prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], 
systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis 
with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following 
are exceptions to this criterion. 
a. Patients with vitiligo or alopecia. 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone 
replacement. 
c. Any chronic skin condition that does not require systemic therapy. 
d. Patients without active disease in the last 5 years may be included but only after consultation 
with the primary investigator. 
e. Patients with celiac disease controlled by diet alone. 
9. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated 
with diarrhea, or psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs or compromise the ability of the patient 
to give written informed consent. 
10. Any medical, social, or psychological condition that would interfere with evaluation of study 
treatment or interpretation of patient safety or study results.  
11. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and TB testing in line with local practice), hepatitis B 
(known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency 
virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients 
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative 
for HCV RNA. 
12. History of another primary malignancy except for the following histories. 
a. Malignancy treated ZLWKFXUDWLYHLQWHQWDQGZLWKQRNQRZQDFWLYHGLVHDVH\HDUVEHIRUHWKH
first dose of IP and of low potential risk for recurrence. 
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
c. Adequately treated carcinoma in situ without evidence of disease. 
13. History of leptomeningeal carcinomatosis. 


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14. Brain metastases or spinal cord compression. Patients with suspected brain metastases at 
screening should have a MRI (preferred) or CT each preferably with intravenous (IV) contrast of 
the brain prior to study entry.  
15. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) 470 ms.  
16. Current or prior use of immunosuppressive medication within 14 days before the first dose of 
durvalumab or AVB-S6-500. The following are exceptions to this criterion: 
a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) 
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its 
equivalent. 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). 
17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if 
enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose 
of IP. 
18. Female patients who are pregnant or breastfeeding or of reproductive potential who are not 
willing to employ effective birth control from screening to 180 days after the last dose of 
durvalumab + AVB-S6-500 combination therapy. 
19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 
20. Unresolved partial or complete small or large bowel obstruction 
21. Judgment by the investigator that the patient is unsuitable to participate in the study and the 
patient is unlikely to comply with study procedures, restrictions and requirements.  
4.3 
WITHDRAWAL OF PATIENTS FROM STUDY TREATMENT AND/OR STUDY 
4.3.1 
PERMANENT DISCONTINUATION OF DURVALUMAB + AVB-S6-500 
An individual subject will not receive any further investigational product if any of the following occur in 
the patient in question.  
1. Withdrawal of consent or lost to follow-up. 
2. Adverse event that, in the opinion of the investigator, contraindicates further dosing. 
3. Patient is determined to have met one or more of the exclusion criteria for study participation at 
study entry and continuing investigational therapy might constitute a safety risk. 
4. Pregnancy or intent to become pregnant. 
5. Any AE that meets criteria for discontinuation as defined in Section 6.3. 
6. Clinically significant dose-limiting toxicity (DLT) that is attributable to both drugs. Durvalumab 
or AVB-S6-500 may be held individually due to a DLT while dosing with the other drug 
continues if the DLT is attributable to only one drug (See Section 6.2 for definition of DLT and 
Section 6.3 for individual drug dose holds).  
7. Grade 3 infusion reaction. 
8. Patient noncompliance that, in the opinion of the investigator, warrants withdrawal; e.g., refusal 
to adhere to scheduled visits. 
9. Initiation of alternative anticancer therapy including another investigational agent. 
10. Confirmation, per irRC, of PD and investigator determination that the patient is no longer 
benefiting from treatment with durvalumab and AVB-S6-500. See Section 7.2. 
11. Subjects who are discontinued from further receipt of both investigational products, regardless of 
the reason (withdrawal of consent, due to an AE, other), will be identified as having permanently 
discontinued treatment. Patients who are permanently discontinued from receiving investigational 
product will be followed for safety per Schedule of Assessments, including the collection of any 
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up or enrolled in another clinical study. All patients will be followed for survival. Patients who 
decline to return to the site for evaluations will be offered follow-up by phone every 6 months as 
an alternative. 
4.3.2 
WITHDRAWAL OF CONSENT 
Patients are free to withdraw from the study at any time (treatment and assessments) without prejudice to 
further treatment. 
Patients who withdraw consent for further participation in the study will not receive any further IP or 
further study observation, with the exception of follow-up for survival, which will continue until the end 
of the study unless the patient has expressly withdrawn their consent to survival follow-up. Note that the 
patient may be offered additional tests or tapering of treatment to withdraw safely. 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and the 
presence of any AE. The Investigator will follow up AEs outside of the clinical study.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to: 
x 
all further participation in the study including any further follow up (e.g., survival contact 
telephone calls), 
x 
withdrawal of consent to the use of their study generated data, and/or 
x 
withdrawal to the use of any samples.  
4.3.3 
REPLACEMENT OF PATIENTS 
Subjects who withdraw consent or otherwise become ineligible prior to receiving the first dose of 
investigational regimen will be replaced. 
5. 
INVESTIGATIONAL PRODUCTS 
5.1 
DURVALUMAB 
5.1.1 
FORMULATION/PACKAGING/STORAGE 
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM histidine/ 
histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it 
has a pH of 6.0 and a density of 1.054 g/mL. The nominal fill volume is 10.0 mL. Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept in 
original packaging until use to prevent prolonged light exposure.季 
5.1.2 
PRODUCT PREPARATION AND DOSE ADMINISTRATION 
Patients in the durvalumab monotherapy treatment group will receive Q3W dosing of 1120 mg 
durvalumab during the monotherapy cycle (Cycle 0).  
In the Safety Lead-in Phase and during the combination treatments in Phase II, subjects will receive Q4W 
dosing of 1500 mg durvalumab (for patients >30kg in weight). Weight based dosing at 20 mg/kg will be 
utilized for any patient whose body weight drops below 30 kg while on the combination treatment. 
The dose of durvalumab (MEDI4736) for administration must be handled and prepared by the 
Investigator’s or site’s designated IP manager using aseptic technique according to institutional 
guidelines. Total time from needle puncture of the durvalumab vial to the start of administration should 
not exceed:季季


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x 
24 hours at 2°C to 8°C (36°F to 46°F) 
x 
4 hours at room temperature  
A dose of 1500 mg (for patients >30kg in weight) or 1120 mg will be administered using an intravenous 
(IV) bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set with a 0.2- or 
0.22-ȝPILOWHU Add 30.0 mL of durvalumab (MEDI4736) (i.e., 1500 mg of durvalumab [MEDI4736]) or 
22.4 mL (i.e., 1120 mg of durvalumab [MEDI4736]) to the IV bag. The IV bag size should be selected 
such that the final concentration is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
If patient weight falls to < 30 kg weight-based dosing at 20 mg/kg will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) concentration 
ranging from 1 to 15 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-ȝPILOWHU   
Standard infusion time is 1 hour, however if there are interruptions during infusion, the total and allowed 
infusion time should not exceed 8 hours at room temperature. If preparation time or infusion time exceeds 
the time limits a new dose must be prepared from new vials. Durvalumab does not contain preservatives, 
and any unused portion must be discarded. 
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the infusion set 
used after the contents of the IV bag are fully administered or complete the infusion according to 
institutional policy to ensure the full dose is administered. 
During combination treatment, durvalumab will be administered prior to AVB-S6-500. IV line flushing in 
between IP treatments will be performed per institutional policy.  
5.1.3 
MONITORING OF DOSE ADMINISTRATION 
Patients will be monitored before, during and after the infusion with assessment of vital signs at the times 
specified in the Schedule of Assessment. Patients are monitored (pulse rate, blood pressure) every 30 
minutes during the infusion period (including times where infusion rate is slowed or temporarily stopped). 
,QWKHHYHQWRID*UDGH 2 infusion-related reaction, the infusion rate of study drug may be decreased by 
50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate 
until completion of the infusion. For patients ZLWKD*UDGHLQIXVLRQ-related reaction, subsequent 
infusions may be administered at 50% of the initial rate. Acetaminophen and/or an antihistamine (e.g., 
diphenhydramine) or equivalent medications per institutional standard may be administered at the 
discretion of the investigator. If the infusion-related reaction is Grade 3 or higher in severity, study drug 
will be discontinued. However, a single occurrence of a Grade 3 reaction that resolves within 6 hours is 
permitted in the absence of prophylaxis. The standard infusion time is one hour, however if there are 
interruptions during infusion, the total allowed time from infusion start to completion of infusion should 
not exceed 8 hours at room temperature. For management of patients who experience an infusion 
reaction, please refer to the toxicity and management guidelines in Section 6.3. 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and 
medical equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis. The study site must have immediate access 
to emergency resuscitation teams and equipment in addition to the ability to admit patients to an intensive 
care unit if necessary. 
 


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5.2 
AVB-S6-500 
The AVB-S6-500 is an Fc fusion protein of the extracellular portion of the AXL receptor that has been 
engineered to have higher affinity to GAS6 by the substitution of five amino acids in the AXL 
extracellular domain. The molecule consists of one of the genetically modified AXL receptors fused to 
each arm of a human Fc molecule (CH2 & CH3), thereby creating a dimer of the genetically modified 
AXL receptor. 
5.2.1 
FORMULATION/PACKAGING/STORAGE 
AVB-S6-500 will be supplied by Aravive as a solution for injection with the composition of the 
formulated drug product (DP) shown in Table 1. AVB-S6-500 should be diluted in normal saline prior to 
infusion.  
AVB-S6-500 DP vials are filled with 10 mL at 20 mg /mL (±2 mg/mL) for a total of approximately 200 
mg/vial into 20 mL Schott USP Type I glass vials with rubber stoppers and aluminum-plastic flip caps. 
Vials are filled on an automated aseptic filling line and stored at -20°C. 
Vials of AVB-S6-500 drug product should be refrigerated in their box at 2-8Ԩ until ready to use. Refer to 
Investigator’s brochure and pharmacy manual for additional details. 
Table 2. Formulation of AVB-S6-500 Drug Product 
Components 
Function 
Amount 
AVB-S6-500 
Active 
20 mg/ml ± 2 mg/mL 
Polysorbate-80 
Stabilizer 
0.01% 
Mono and disodium phosphate 
Buffer to pH 7.0 
10 mM 
Sucrose 
Stabilizer 
9% 
 
5.2.2 
PRODUCT PREPARATION AND DOSE ADMINISTRATION 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit. AVB-S6-500 should be diluted in normal saline 
to a total volume of 150 mL (to achieve the desired dose in mg/kg) and administered as an i.v. infusion 
over 60 minutes.  
During combination treatment, durvalumab will be administered prior to AVB-S6-500. IV line flushing in 
between IP treatments will be performed per institutional policy.  
5.2.3 
 
PRE-MEDICATION FOR AVB-S6-500 DOSING 
All patients must be premedicated with anti-H1 and anti-H2 prior to first administration of AVB-S6-500 
(Cycle 0 in the AVB-S6-500 monotherapy group; Cycle 1 in the Safety Lead-In and durvalumab 
monotherapy groups) to reduce the risk and severity of infusion reaction.  
Premedication (or components thereof) could be optionally omitted for future cycles, if no infusion 
reaction was observed during or after the first AVB-S6-500 infusion.  
Steroids can be optionally included at the discretion of the treating physician, ideally administered the 
evening before and again the morning of dosing (for example, dexamethasone 12 mg PO the evening 
prior and 12 mg PO in the morning prior to dosing). If IV steroids are utilized on the morning of dosing, 
they should be administered at least 1 hour prior to dosing.  


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Most infusion reactions occur toward the end of the infusion, or after the infusion has been completed, 
and patients must be observed for at least 45 minutes after their first AVB-S6-500 infusion.  
Any patient who experiences a reaction DURING the infusion and is deemed by the Investigator to be 
acceptable for same day rechallenge, should be premedicated prior to rechallenge, and the remainder of 
the infusion should be administered at one-half of the previous infusion rate.  
Any patient who experiences a reaction AFTER the infusion and is deemed by the Investigator to be 
acceptable for rechallenge with the next dose, should be premedicated with an anti-H1, anti-H2, and 
steroid-containing regimen prior to rechallenge, and the duration of AVB-S6-500 at rechallenge should be 
2 hours (instead of 1 hour).  
If the patient tolerates AVB-S6-500 upon rechallenge, the premedication regimen and infusion duration 
should remain the same for subsequent dosing.  
Infusion reactions should be managed symptomatically. Meperidine should be considered for treatment of 
rigors. 
5.2.4 
MONITORING OF DOSE ADMINISTRATION 
Patients will be monitored before, during, and after the infusion with assessment of vital signs at the times 
specified in the Schedule of Assessment and as per Section 5.1.3. After the first AVB-S6-500 infusion, a 
45-minute observation will be required for all patients (Cycle 0 in the AVB-S6-500 monotherapy group; 
Cycle 1 in the Safety Lead-In and durvalumab monotherapy groups). After the first infusion, observation 
will only be needed as clinically indicated. 
5.3 
ACCOUNTABILITY AND DISPENSATION  
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent. The Velos IData System will be utilized by the MD Anderson 
Investigational Pharmacy services for accountability.  
5.4 
DISPOSITION OF UNUSED INVESTIGATIONAL STUDY DRUG 
The site will account for all investigational study drug dispensed and also for appropriate destruction. 
Certificates of delivery and destruction must be signed. 
6. 
TREATMENT PLAN 
6.1 
PROCEDURES FOR RANDOMIZATION 
Subjects will be recruited from the Department of Gynecologic Oncology and Reproductive Medicine at 
The University of Texas MD Anderson Cancer Center. Patients with platinum resistant high grade 
ovarian, primary peritoneal, or fallopian tube cancers will be screened by the designated research staff 
and/or study investigators for eligibility. Interested patients will be approached and provided information 
regarding the study and potential eligibility and participation. After informed consent, screening 
evaluation will be performed to determine eligibility. Patients may elect to leave the study at any time.  
We will enroll up to 30 evaluable subjects with platinum-resistant EOC at an expected rate of 3 subjects 
per month. Subjects will be evaluable for the primary objective once they have completed one cycle of 
combination therapy at the RP2D. Up to 12 evaluable subjects will be enrolled into the dose de-escalation 
combination phase (Safety Lead-in) to determine the RP2D. Once the RP2D is determined, subsequent 
subjects will be randomized to monotherapy arms as described below. To replace patients that are 
registered but do not proceed to treatment (e.g. screen failures), an additional 15 patients may be 


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registered; however, a maximum of 30 evaluable patients will be treated as per the protocol. Subjects will 
be treated until disease progression or until unacceptable toxicity. We will follow all patients for at least 
12 months, and we will employ safety and efficacy monitoring rules as described in Section 9.2.1 and 
Section 9.2.2.  
Following RP2D determination, we will randomly assign patients to one of two monotherapy treatment 
arms (durvalumab or AVB-S6-500) at a ratio of 1 (durvalumab) to 3 (AVB-S6-500). All patients, with the 
exception of any who meet discontinuation criteria, will then receive combination treatment regimen.  
Randomization will be carried out using CORe. 
Subjects who are incorrectly enrolled but have not been initiated on treatment will be withdrawn from the 
study. Such subjects will be replaced. Any subjects who are incorrectly enrolled and randomized and 
initiated on therapy will be reported to the IRB as a protocol violation. Such subjects will be evaluated on 
an individual basis by the PI and the decision to continue treatment or withdraw will be based on an 
analysis of risk/benefit for the subject. 
6.2 
DEFINITION OF DOSE-LIMITING TOXICITIES 
DLTs will be evaluated during the safety lead-in (dose de-escalation phase) of the trial. The period for 
evaluating DLTs will be from the time of first administration of study drug until 6 weeks (1.5 cycles). 
Any treatment-related toxicities that first occurred during the DLT period must be followed for resolution 
to determine if the event qualifies as a DLT as specified in the DLT criteria below. Patients who do not 
remain on the study up to this time for reasons other than DLT will be replaced with another patient at the 
same dose level. Grading of DLTs will follow the guidelines provided in the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  
To be considered a DLT, an AE must be at least possibly related to the investigational product or regimen 
and meet the criteria listed below. Toxicity that is clearly and directly related to the primary disease or to 
another etiology is excluded from this definition. The DLT criteria are specified in the following lists. 
Hematologic toxicity: 
x 
*UDGHQHXWURSHQLDFRPSOLFDWHGE\IHYHU!& 
x 
GraGHQHXWURSHQLD that does not improve *UDGHwithin 7 days  
x 
Grade 4 neutropenia (lasting more than 7 days) 
x 
*UDGHWKURPERF\WRSHQLDZLWKVLJQLILFDQWEOHHGLQJ 
x 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding and does not 
improve by at least 1 grade within 7 days 
x 
Grade 4 thrombocytopenia (regardless of duration) 
x 
Grade 4 anemia (regardless of duration) 
Non-hematologic toxicity:  
x 
Any Grade 4 non-immune-mediated AE 
x 
Any Grade 4 immune-mediated AE, excluding endocrinopathies 
x 
Any Grade 3 non-immune mediated AE, including fatigue, WKDWGRHVQRWUHVROYHWR*UDGHRU
baseline within 30 days with optimal medical management 
x 
Any Grade 3 immune-mediated AE – excluding diarrhea/colitis, pneumonitis, hepatitis, rash, 
neurotoxicity, myocarditis, myositis/polymyositis, endocrinopathies and nephritis – that does not 
UHVROYHWR*UDGH2 or baseline within 15 days DQGWR*UDGHZLWKLQGD\Vafter onset of the 
event, despite optimal medical management including systemic corticosteroids 


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x
Grade 3 diarrhea or colitis 
x
Grade 3 noninfectious pneumonitis
x
Grade 2 noninfectious pneumonitis WKDWGRHVQRWUHVROYHWR*UDGHZLWKLQGD\VRIWKH
initiation of maximal supportive care
x
Aspartate aminotransferase (AST) or alanine DPLQRWUDQVIHUDVH$/7î8/1ZLWKFRQFXUUHQW
LQFUHDVHLQWRWDOELOLUXELQ7%/î8/1ZLWKRXWHYLGHQFHRIFKROHVWDVLVRUDOWHUQDWLYH
explanations (e.g., viral hepatitis, disease progression in the liver; i.e., “Hy’s Law”)
x
$/7RU$67!î8/1RU7%/!î8/1
x
Grade 3 immune-PHGLDWHGUDVKWKDWGRHVQRWUHVROYHWR*UDGHRUEDVHOLQHZLWKLQGD\V
x
Grade 2 rash covering > 30% BSA WKDWGRHVQRWUHVROYHWR*UDGHRUEDVHOLQHZLWKLQGD\V
x
Any grade of immune-mediated rash with bullous formation
x
Grade 3 immune-mediated neurotoxicity (excluding Guillain-Barre and myasthenia gravis) that 
GRHVQRWUHVROYHWR*UDGHZLWKLQGD\V
x
Grade 2 or 3 immune-mediated peripheral neuromotor syndrome (such as Guillain-Barre and 
P\DVWKHQLDJUDYLVWKDWGRHVQRWUHVROYHWR*UDGHZLWKLQGD\VRUWKDWH[KLELWVVLJQVRI
respiratory insufficiency or autonomic instability
x
Grade 3 immune-mediated myocarditis
x
Any symptomatic immune-mediated myocarditis that does not become asymptomatic within 3 
days of initiating optimal medical management including systemic corticosteroids
x
Grade 2 or 3 immune-PHGLDWHGP\RVLWLVSRO\P\RVLWLVWKDWGRHVQRWUHVROYHWR*UDGHZLWKLQ
days of initiating optimal medical management including systemic corticosteroids or that exhibits 
signs of respiratory insufficiency regardless of optimal medical management
x
Immune-PHGLDWHGLQFUHDVHLQFUHDWLQLQH!î8/1RU!îEDVHOLQHIRUSDWLHQWVZLWKDEDVHOLQH
creatinine elevated above ULN
The DLT definition excludes the conditions listed below.
x
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed with 
or without systemic corticosteroid therapy and/or hormone replacement therapy and the patient is 
asymptomatic
x
Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc.)
x
Concurrent vitiligo or alopecia of any AE grade
x
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) that 
resolves within 6 hours with appropriate clinical management
x
Grade 3 or 4 lymphopenia
x
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or symptoms 
and are reversed with appropriate maximal medical intervention within 14 days
In the absence of a clinically significant abnormality, repeat laboratory testing will be conducted to 
confirm significant laboratory findings prior to designation as a DLT. 
6.3
TOXICITY MANAGEMENT GUIDELINES
It is possible only one of the investigational agents is deemed attributed to causality of an AE, in this 
instance, only the attributed study drug may be held. Per principal investigator discretion, the treating 
investigator may elect to hold the study drug they deem attributable to the experienced AE.
It is possible only one of the investigational agents is deemed attributed to causality of an AE, in this
instance, only the attributed study drug may be held. Per principal investigator discretion, the treating
investigator may elect to hold the study drug they deem attributable to the experienced AE.


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6.3.1
DURVALUMAB
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and non-
immune-mediated reactions for durvalumab are provided in the durvalumab Toxicity Management 
Guidelines (TMGs). Please see Section 6.3 and Appendix A. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the irAE. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis. In the absence of a clear 
alternative etiology, events should be considered potentially immune related.
In addition, there are certain circumstances in which durvalumab should be permanently discontinued 
(Appendix A). Following the first dose of investigational product, subsequent administration of 
durvalumab and AVB-S6-500 can be modified based on toxicities observed. These guidelines have been 
prepared to assist the Investigator in the exercise of his/her clinical judgment in treating these types of 
toxicities. These guidelines apply to AEs considered causally related to durvalumab monotherapy and the 
durvalumab + AVB-S6-500 regimen by the reporting investigator
Following determination of RP2D, dose reductions are not permitted. 
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the irAE. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an irAE diagnosis. In the absence of a clear 
alternative etiology, events should be considered potentially immune related.
All toxicities will be graded according to NCI CTCAE, Version 5.0. 
6.3.2
AVB-S6-500
The safety, pharmacokinetic and pharmacodynamic profile of AVB-S6-500 has been evaluated in healthy 
volunteers in a single-ascending dose (SAD) and repeat-dose (RD) Phase 1 clinical study (AVB500-HV-
001). AVB-S6-500 was well tolerated at all doses evaluated in healthy volunteers.
Following the establishment of RP2D, dose reductions are not permitted. In addition, there are certain 
circumstances in which AVB-S6-500 should be permanently discontinued (see Appendix A).
6.3.3
COMBINATION TREATMENT REGIMEN
In addition to the individual toxicity management guidelines for durvalumab and AVB-S6-500 described 
above management of any potential overlapping toxicities that may occur following treatment with this 
combination must be considered. For AEs that are considered at least partly due to administration of 
durvalumab or AVB-S6-500, treat each of the toxicities with maximum supportive care (including 
holding the agent suspected of causing the toxicity where required). If the symptoms promptly resolve 
with supportive care, consideration should be given to continuing the same dose of durvalumab or AVB-
S6-500 along with appropriate continuing supportive care. 
For these subjects, once the AE resolves to permit resumption of the investigational combination, if the 
AE recurs at a dose-limiting severity, AVB-S6-500 and durvalumab dosing should be held until the 
recurrence until the AE resolves to Grade 1 or baseline. The AE should resolve to Grade 1 or baseline 
within 21 days for the subject to be considered for continued treatment. If the AE does not resolve to 
Grade 1 or baseline within 21 days, the investigator should consult the MDACC IND Office to determine 
feasibility of continued treatment with AVB-S6-500 and durvalumab.
Following the first dose of investigational product, subsequent administration of 
durvalumab and AVB-S6-500 can be modified based on toxicities observed. T
 For AEs that are considered at least partly due to administration of 
durvalumab or AVB-S6-500, treat each of the toxicities with maximum supportive care (including
holding the agent suspected of causing the toxicity where required)
 AVB-S6-500 and durvalumab dosing shoul
d
d be held until the
recurrence until the AE resolves to Grade 1 or baseline. The AE should resolve to Grade 1 or baseline
 
within 21 days for the subject to be considered for continued treatment. I


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6.4 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT TREATMENT(S) 
6.4.1 
SUBJECTS OF CHILD-BEARING POTENTIAL 
Female subjects of childbearing potential who are not abstinent and intend to be sexually active with a 
non-sterilized male partner must use at least 1 highly effective method of contraception (Table 3) from 
the time of screening throughout the total duration of the drug treatment and the drug washout period (90 
days after the last dose of study drug). Non-sterilized male partners of a female patient of childbearing 
potential must use a male condom plus spermicide throughout this period. Cessation of birth control after 
this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and 
the withdrawal method are not acceptable methods of birth control. Female patients should also refrain 
from breastfeeding throughout this period.  
Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months without an 
alternative medical cause. The following age-specific requirements apply:  
x 
Women <50 years of age would be considered post-menopausal if they have been amenorrheic 
for 12 months or more following cessation of exogenous hormonal treatments and if they have 
luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the 
institution. 
x 
:RPHQ\HDUVRIDJHZRXOGEHFRQVLGHUHGSRVW-menopausal if they have been amenorrheic 
for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-
induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with 
last menses >1 year ago. 
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e. less than 
1% per year) when used consistently and correctly are described in Table 3. Note that some contraception 
methods are not considered highly effective (e.g. male or female condom with or without spermicide; 
female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; 
progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode 
of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined 
oral contraceptive pills). 
Table 3. Highly Effective Methods of Contraception (<1% Failure Rate) 
Barrier/Intrauterine methods 
Hormonal Methods 
x Copper T intrauterine 
device 
x Levonorgestrel-releasing 
intrauterine system (e.g., 
Mirena®)a 
x Implants: Etonogestrel-releasing implants: e.g. Implanon® or Norplant®  
x Intravaginal: Ethinylestradiol/etonogestrel-releasing intravaginal 
devices: e.g. NuvaRing®  
x Injection: Medroxyprogesterone injection: e.g. Depo-Provera®  
x Combined Pill: Normal and low dose combined oral contraceptive pill 
x Patch: Norelgestromin/ethinylestradiol-releasing transdermal system: 
e.g. Ortho Evra®  
x Minipillc: Progesterone based oral contraceptive pill using desogestrel: 
Cerazette® is currently the only highly effective progesterone-based  
a 
This is also considered a hormonal method 
 


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6.4.2 
BLOOD DONATION 
Patients should not donate blood while participating in this study or for at least 90 days following the last 
infusion of durvalumab or AVB-S6-500. 
6.4.3 
CONCOMITANT TREATMENT(S) 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary, as briefly listed in Table 3, to provide adequate prophylactic or 
supportive care except for those medications identified as “excluded” as listed in Table 4. The Principal 
Investigator must be informed as soon as possible about any medication taken from the time of screening 
until the end of the clinical phase of the study (final study visit). Any concomitant medication(s), 
including herbal preparations, taken during the study will be recorded in the medical record. 
Table 4. Permitted Supportive Medications 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications identified 
as “prohibited,” as listed above  
To be administered as prescribed by the 
Investigator or alternate treating physician in 
consultation with Investigator 
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to non-target lesions, etc]) 
Should be used, when necessary, for all 
patients 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
Table 5. Prohibited Concomitant Medications 
Prohibited medication/class of drug: 
Usage: 
Any investigational anticancer therapy other 
than those under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment. (Concurrent use of hormones for 
non-cancer-related 
conditions 
[e.g., insulin 
for 
diabetes and hormone replacement therapy] is 
acceptable. Local treatment of isolated lesions, 
excluding target lesions, for palliative intent is 
acceptable [e.g., by local surgery or radiotherapy]) 


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Prohibited medication/class of drug: 
Usage: 
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-ĮEORFNHUV 
Should not be given concomitantly or used for 
premedication prior to the I-O infusions. The 
following are allowed exceptions: 
x 
Use of immunosuppressive medications for 
the management of IP-related AEs,  
x 
Use in patients with contrast allergies.  
x 
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 
  
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related events 
experienced by the patient (e.g., chronic obstructive 
pulmonary disease, radiation, nausea, etc). 
Drugs with laxative properties and herbal or 
natural remedies for constipation 
Should be used with caution through to 90 days after 
the last dose of durvalumab during the study 
EGFR TKIs  
Should not be given concomitantly. 
Should be used with caution in the 90 days post last 
dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly. 
Live attenuated vaccines 
Should not be given through 90 days after the last dose 
of IP (including SoC) 
Herbal and natural remedies which may have 
immune-modulating effects 
Should not be given concomitantly unless agreed by 
Aravive and AstraZeneca 
 
 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number:  1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 29 
 
6.5 
SCHEDULES OF STUDY ASSESSMENTS AND PROCEDURES 
Table 6. Schedule of Assessments and Procedures: Safety Lead-in  
 
 
 
Cycle 1 
(4 weeks) 
Cycle 2 
(4 weeks) 
Cycle 3+a 
(4 weeks) 
EOTb 
Follow-upc 
 
Screening 
1 
Screening 
2 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
N/A 
30 
Days 
90 Days 
Assessment/Procedure 
Days 
-28 to -1 
Days 
-28 to -1 
N/A 
±7 Days 
±3 
Days 
±7 Days 
Written Informed Consent 
Xd 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exame 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/Diffh 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Paneli 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Beta hCGj 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Thyroid Functionk 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Urinalysisl 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Coagulationm 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV Screeningn 
X 
 
 
 
 
 
 
 
 
 
 
ECGo 
X 
 
 
 
 
 
 
 
 
 
 
Tumor Imagingp 
Xq 
 
 
 
 
Xr 
 
 
 
 
 
RECISTs 
X 
 
 
 
 
X 
 
 
 
 
 
Biopsyt 
Xu 
Xv 
 
 
 
Xw 
 
 
 
 
 
CA125 
 
 
X 
 
X 
 
X 
 
X 
 
 
Research Bloodx 
 
 
Xy 
 
X 
 
Xz 
 
 
 
X 
AVB-S6-500 dosingaa 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Durvalumab dosingbb 
 
 
X 
 
X 
 
X 
 
 
 
 
a The procedures/assessments including treatment will continue until intolerable toxicity or confirmed progression.  
b End of treatment (EOT) is defined as the last visit where the decision is made to discontinue protocol directed 
treatment, including confirmed progression of disease. All required procedure may be completed within ± 7 days of 
the end of treatment visit. Repeat disease assessment is not required if performed within 35 days prior to the EOT 
visit. 
c For subjects who end treatment de to progression, follow-up visits will occur every 6 weeks for at least 90 days or 
until initiation of subsequent treatment or alternative trial. For subjects who are no longer receiving study drug(s) 
but have not had confirmed progression, follow-up with clinical and laboratory evaluation will occur every 6 weeks 
with imaging assessment every 12 weeks (unless more frequent assessment is clinically indicated) for at least 90 
days or until progression, whichever occurs later. All patients should have further chemistry profiles performed at 30 
days (±3 days) and 90 days (±1 week) after permanent discontinuation of IP. All patients will be followed for 
survival. Patients who decline to return to the site for evaluations will be offered follow-up by phone every 6 months 
as an alternative. 
d Informed consent of study procedures and pretreatment tumor biopsy sample may be obtained prior to the 28-day 
screening window, if necessary, in order to permit tumor biopsy sample acquisition and analysis prior to 
randomization. If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, 
 
 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number:  1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 30 
 
 
these can be used for screening purposes with consent of the patient. However, all screening laboratory and imaging 
results must have been obtained within 28 days of randomization. 
e Full physical exam will be performed at screening, with targeted physical exam at all other time points. Body 
weight is recorded at each visit. Height to be performed at screening only. 
f Routine vital signs to be performed at each visit, and these should occur prior to infusion on treatment days. On 
treatment days, BP and pulse will be collected from patients prior to the beginning of the infusion (measured once 
from approximately 30 minutes before up to 0 minutes [i.e., the beginning of the infusion]), approximately 30 
minutes during the infusion (halfway through infusion), and at the end of the infusion (approximately 60 minutes ±5 
minutes). If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the principles 
as described above or be taken more frequently if clinically indicated. 
g A 1-hour observation period is recommended after the first dose of combination therapy. 
h May be performed more frequently than noted in the schedule if clinically indicated. CBC with differential 
includes: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, monocytes, neutrophils, platelet count, red blood 
cell count, and total white cell count. 
i May be performed more frequently than noted in the schedule if clinically indicated. Chemistry Panel includes: 
albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, calcium, 
chloride, creatinine, gamma glutamyltransferase, glucose, lactate dehydrogenase, lipase, magnesium, potassium, 
sodiumWRWDOELOLUXELQWRWDOSURWHLQ%81DQGXULFDFLG,IWRWDOELOLUXELQLVî8/1DQGQRHYLGHQFHRI*LOEHUW¶V
syndrome) then fractionate into direct and indirect bilirubin. Amylase and lipase are to be performed at screening, 
Day 1 of each cycle, and at EOT. It is preferable that both amylase and lipase parameters are assessed. For sites 
where only 1 of these parameters is routinely measured then either lipase or amylase is acceptable. Bicarbonate, 
chloride, creatinine clearance, and magnesium testing are to be performed at screening, on Day 0 (if required), and if 
FOLQLFDOO\LQGLFDWHG,IDSDWLHQWVKRZVDQ$67RU$/7[8/1WRJHWKHUZLWKWRWDOELOLUXELQ[8/1UHIHUWR
Section 6.3 for further instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law. Gamma 
glutamyltransferase may be included at any time if clinically indicated. 
j Serum B-HCG within 72 hours prior to the first dose of therapy and as clinically indicated prior to day 1 of each 
subsequent cycle and at end of treatment only in women of childbearing potential (women who are not surgically-
sterile or post-menopausal). 
k Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related to 
the endocrine system. 
l Urinalysis includes: bilirubin, blood, glucose, ketones, pH, protein, specific gravity, color, and appearance. 
Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for red blood 
cells 
m May be performed more frequently than noted in the schedule if clinically indicated. Coagulation testing includes: 
PT, aPTT, and INR. 
n Hepatitis screening tests include: HCV-Ab, HBsAg, HBcAb, and HBsAb. 
o Resting 12-lead ECG on which QTcF must be <470 ms. ECGs should be obtained after the patient has been in a 
supine position for 5 minutes and recorded while the patient remains in that position. In case of clinically significant 
ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief 
period (e.g., 30 minutes) to confirm the finding. ECGs may be performed more frequently than noted in the schedule 
if clinically indicated. 
p Imaging to occur Q8W (±7 days) and should continue unless the subject has confirmed progression, death or 
unacceptable toxicity. If progression is identified, then a confirmatory scan should be obtained 6 weeks (±7 days) 
after the first positive scan. As long as treatment is being well-tolerated and the investigator believes that the patient 
may derive benefit, the patient should continue regularly scheduled visits and receive additional treatment until the 
confirmatory scan results have been reviewed. 
q Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with 
intravenous (IV) contrast of the brain. 
 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number:  1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 31 
 
 
r To occur during the final week of the marked Cycle, prior to initiating treatment in the following Cycle. 
s RECIST measurements will be performed in line with imaging. Refer to Section 7.1. 
t Refer to Section 6.6.2 for details regarding Tumor sample. 
u %LRSV\FDQEHQHZO\DFTXLUHGRUDUFKLYDO\HDUVROG5HIHUWR Section 6.6.2 for details regarding tumor sample. 
v If subjects are not required to have a diagnostic biopsy (i.e. tumor recurrence/progression has been already 
histologically confirmed), tissue acquisition will occur during a research-only biopsy procedure. Refer to Section 
6.6.2 for details regarding tumor sample. 
w To occur immediately prior to Cycle 3 where possible. Refer to Section 6.6.2 for details regarding tumor sample. 
x Sample will be taken within 45 minutes before dosing. Additional post-dose time points will be collected only on 
Day 1 of Cycle 1. See note “y” below. Refer to Section 6.6.1. A blood sample will be collected and processed for 
serum at the 90-day follow up visit to analyze for the presence of anti-drug antibodies for AVB-S6-500. 
y Samples will be taken within 45 minutes before dosing begins and at 1 and 4 hours after the completion of 
treatment. Refer to Section 6.6.1. 
z Cycles 3 and 4 only. 
aa Refer to Section 5.2. 
bb Refer to Section 5.1. 
 
 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number:  1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 32 
 
Table 7. Schedule of Assessments and Procedures: Phase II, Durvalumab Monotherapy Cohort 
 
 
 
Cycle 0 
(6 Weeks) 
Cycle 1 
(4 Weeks) 
Cycle 2 
(4 Weeks) 
Cycle 3+a 
(4 Weeks) 
EOTb 
Follow-upc 
 
Screening 
1 
Screening 
2 
Day 
1 
Day 
22 
Day 
29 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
N/A 
30 
Days 
90 
Days 
Assessment/Procedure 
Days 
-28 to -1 
Days 
-28 to -1 
N/A 
±7 Days 
±3 
Days 
±7 
Days 
Written Informed Consent 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exame 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
 
Xg 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Evaluation 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/Diffi 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panelj 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Beta hCGk 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Thyroid Functionl 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Urinalysism 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Coagulationn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV Screeningo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imagingq 
Xr 
 
 
 
Xs 
 
 
 
Xs 
 
 
 
 
 
RECISTt 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Biopsyu 
Xv 
Xw 
 
 
Xx 
 
 
 
Xy 
 
 
 
 
 
CA125 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Research Bloodz 
 
 
X 
 
 
X 
 
X 
 
Xaa 
 
 
 
X 
AVB-S6-500 dosingbb 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Durvalumab dosingcc 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
a The procedures/assessments including treatment will continue until intolerable toxicity or confirmed progression.  
b End of treatment (EOT) is defined as the last visit where the decision is made to discontinue protocol directed 
treatment, including confirmed progression of disease. All required procedure may be completed within ± 7 days of 
the end of treatment visit. Repeat disease assessment is not required if performed within 35 days prior to the EOT 
visit. 
c For subjects who end treatment due to progression, follow-up visits will occur every 6 weeks for at least 90 days or 
until initiation of subsequent treatment or alternative trial. For subjects who are no longer receiving study drug(s) 
but have not had confirmed progression, follow-up with clinical and laboratory evaluation will occur every 6 weeks 
with imaging assessment every 12 weeks (unless more frequent assessment is clinically indicated) for at least 90 
days or until progression, whichever occurs later. All patients should have further chemistry profiles performed at 30 
days (±3 days) and 90 days (±1 week) after permanent discontinuation of IP. All patients will be followed for 
survival. Patients who decline to return to the site for evaluations will be offered follow-up by phone every 6 months 
as an alternative. 
d Informed consent of study procedures and pretreatment tumor biopsy sample may be obtained prior to the 28-day 
screening window, if necessary, in order to permit tumor biopsy sample acquisition and analysis prior to 
 
 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number:  1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 33 
 
 
randomization. If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, 
these can be used for screening purposes with consent of the patient. However, all screening laboratory and imaging 
results must have been obtained within 28 days of randomization. 
e Full physical exam will be performed at screening, with targeted physical exam at all other time points. Body 
weight is recorded at each visit. Height to be performed at screening only. 
f Routine vital signs at each visit and should occur prior to infusion on treatment days. On treatment days, BP and 
pulse will be collected from patients prior to the beginning of the infusion (measured once from approximately 30 
minutes before up to 0 minutes [i.e., the beginning of the infusion]), approximately 30 minutes during the infusion 
(halfway through infusion), and at the end of the infusion (approximately 60 minutes ±5 minutes). If the infusion 
takes longer than 60 minutes, then BP and pulse measurements should follow the principles as described above or be 
taken more frequently if clinically indicated. 
g A 1-hour observation period is recommended after the first infusion of durvalumab. 
h A 1-hour observation period is recommended after the first dose of combination therapy. 
i May be performed more frequently than noted in the schedule if clinically indicated. CBC with differential 
includes: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, monocytes, neutrophils, platelet count, red blood 
cell count, and total white cell count. 
j May be performed more frequently than noted in the schedule if clinically indicated. Chemistry Panel includes: 
albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, calcium, 
chloride, creatinine, gamma glutamyltransferase, glucose, lactate dehydrogenase, lipase, magnesium, potassium, 
sodium, total bilirubin total protein, BUN, and uric acid. ,IWRWDOELOLUXELQLVîULN (and no evidence of Gilbert’s 
syndrome) then fractionate into direct and indirect bilirubin. Amylase and lipase are to be performed at screening, 
Day 1 of each cycle, and at EOT. It is preferable that both amylase and lipase parameters are assessed. For sites 
where only 1 of these parameters is routinely measured then either lipase or amylase is acceptable. Bicarbonate, 
chloride, creatinine clearance, and magnesium testing are to be performed at screening, on Day 0 (if required), and if 
clinically indicated. ,IDSDWLHQWVKRZVDQ$67RU$/7[8/1WRJHWKHUZLWKWRWDOELOLUXELQ[8/1UHIHUWR 
Section 6.3 for further instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law. Gamma 
glutamyltransferase may be included at any time if clinically indicated. 
k Serum B-HCG within 72 hours prior to the first dose of therapy and as clinically indicated prior to day 1 of each 
subsequent cycle and at end of treatment only in women of childbearing potential (women who are not surgically-
sterile or post-menopausal). 
l Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related to 
the endocrine system. 
m Urinalysis includes: bilirubin, blood, glucose, ketones, pH, protein, specific gravity, color, and appearance. 
Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for red blood 
cells. 
n May be performed more frequently than noted in the schedule if clinically indicated. Coagulation testing includes: 
PT, aPTT, and INR. 
o Hepatitis screening tests include: HCV-Ab, HBsAg, HBcAb, and HBsAb. 
p Resting 12-lead ECG on which QTcF must be <470 ms. ECGs should be obtained after the patient has been in a 
supine position for 5 minutes and recorded while the patient remains in that position. In case of clinically significant 
ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief 
period (e.g., 30 minutes) to confirm the finding. ECGs may be performed more frequently than noted in the schedule 
if clinically indicated. 
q Imaging to occur Q8W (±7 days) and should continue as long as the subject has not had confirmed progression, 
death or unacceptable toxicity. If progression is identified, then a confirmatory scan should be obtained 6 weeks (±7 
days) after the first positive scan. As long as treatment is being well-tolerated and the investigator believes patient 
may derive benefit, the patient should continue regularly scheduled visits and receive additional treatment until the 
confirmatory scan results have been reviewed. 
 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number:  1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 34 
 
 
r Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with 
intravenous (IV) contrast of the brain. 
s To occur during the final week of the marked Cycle, prior to initiating treatment in the following Cycle. 
t RECIST measurements will be performed in line with imaging. Refer to Section 7.1. 
u Refer to Section 6.6.2. 
v Biopsy can be newly acquired (standard-of-care) or arcKLYDO\HDUVROG5HIHUWRSection 6.6.2 for details 
regarding tumor sample. 
w If subjects are not required to have a diagnostic biopsy (i.e. tumor recurrence/progression has been already 
histologically confirmed), tissue acquisition will occur during a research-only biopsy procedure. Refer to Section 
6.6.2 for details regarding tumor sample. 
x To occur immediately prior to initiation of combination therapy. Refer to Section 6.6.2 for details regarding tumor 
sample. 
y To occur immediately prior to initiation of Cycle 3 where possible. Refer to Section 6.6.2 for details regarding 
Tumor sample. 
z Sample will be taken within 45 minutes before dosing. Refer to Section 6.6.1. A blood sample will be collected 
and processed for serum at the 90-day follow up visit to analyze for the presence of anti-drug antibodies for AVB-
S6-500. 
aa Cycles 3 and 4 only. 
bb Refer to Section 5.2. 
cc Refer to Section 5.1. 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number:  1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 35 
 
Table 8. Schedule of Assessments and Procedures: Phase II, AVB-S6-500 Monotherapy Cohort 
 
 
 
Cycle 0 
(6 Weeks) 
Cycle 1 
(4 Weeks) 
Cycle 2 
(4 Weeks) 
Cycle 3+a 
(4 Weeks) 
EOTb 
Follow-upc 
 
Screening 
1 
Screening 
2 
Day 
1 
Day 
15 
Day 
29 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
N/A 
30 
Days 
90 
Days 
Assessment/Procedure 
Days 
-28 to -1 
Days 
-28 to -1 
N/A 
±7 Days 
±3 
Days 
±7 
Days 
Written Informed Consent 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exame 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
 
Xg 
Xg 
Xg 
Xh 
Xo 
Xo 
Xo 
Xo 
Xo 
X 
X 
X 
ECOG PS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/Diffi 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panelj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Beta hCGk 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Thyroid Functionl 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Urinalysism 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Coagulationn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis/HIV Screeningo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imagingq 
Xr 
 
 
 
Xs 
 
 
 
Xs 
 
 
 
 
 
RECISTt 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Biopsyu 
Xv 
Xw 
 
 
Xx 
 
 
 
Xy 
 
 
 
 
 
CA125 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Research Bloodz 
 
 
X 
 
 
X 
 
X 
 
Xaa 
 
 
 
X 
AVB-S6-500 dosingbb 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Durvalumab dosingcc 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
a The procedures/assessments including treatment will continue until intolerable toxicity or confirmed progression.  
b End of treatment (EOT) is defined as the last visit where the decision is made to discontinue protocol directed 
treatment, including confirmed progression of disease. All required procedure may be completed within ± 7 days of 
the end of treatment visit. Repeat disease assessment is not required if performed within 35 days prior to the EOT 
visit. 
c For subjects who end treatment due to progression, follow-up visits will occur every 6 weeks for at least 90 days or 
until initiation of subsequent treatment or alternative trial. For subjects who are no longer receiving study drug(s) 
but have not had confirmed progression, follow-up with clinical and laboratory evaluation will occur every 6 weeks 
with imaging assessment every 12 weeks (unless more frequent assessment is clinically indicated) for at least 90 
days or until progression, whichever occurs later. All patients should have further chemistry profiles performed at 30 
days (±3 days) and 90 days (±1 week) after permanent discontinuation of IP. All patients will be followed for 
survival. Patients who decline to return to the site for evaluations will be offered follow-up by phone every 6 months 
as an alternative. 
d Informed consent of study procedures and pretreatment tumor biopsy sample may be obtained prior to the 28-day 
screening window, if necessary, in order to permit tumor biopsy sample acquisition and analysis prior to 
randomization. If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, 
 
 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number:  1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 36 
 
 
these can be used for screening purposes with consent of the patient. However, all screening laboratory and imaging 
results must have been obtained within 28 days of randomization. 
e Full physical exam will be performed at screening, with targeted physical exam at all other time points. Body 
weight is recorded at each visit. Height to be performed at screening only. 
f Routine vital signs to be performed at each visit, and these should occur prior to infusion on treatment days. 
g During administration of monotherapy AVB-S6-500: BP and pulse will be collected from patients prior to the 
beginning of the infusion (measured once from approximately 30 minutes before up to 0 minutes [i.e., the beginning 
of the infusion]), approximately 15 minutes during the infusion (halfway through infusion), and at the end of the 
infusion (approximately 30 minutes ±5 minutes). If the infusion takes longer than 30 minutes, then BP and pulse 
measurements should follow the principles as described above or be taken more frequently if clinically indicated. A 
1-hour observation period is recommended after the first infusion of AVB-S6-500.  
h During administration of combination therapy: BP and pulse will be collected from patients prior to the beginning 
of the infusion (measured once from approximately 30 minutes before up to 0 minutes [i.e., the beginning of the 
infusion]), approximately 30 minutes during the infusion (halfway through infusion), and at the end of the infusion 
(approximately 60 minutes ±5 minutes). If the infusion takes longer than 60 minutes, then BP and pulse 
measurements should follow the principles as described above or be taken more frequently if clinically indicated. A 
1-hour observation period is recommended after the first dose of combination therapy. 
i May be performed more frequently than noted in the schedule if clinically indicated. CBC with differential 
includes: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, monocytes, neutrophils, platelet count, red blood 
cell count, and total white cell count. 
j May be performed more frequently than noted in the schedule if clinically indicated. Chemistry Panel includes: 
albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, calcium, 
chloride, creatinine, gamma glutamyltransferase, glucose, lactate dehydrogenase, lipase, magnesium, potassium, 
sodium, total bilirubin total protein, BUN, and uric acid. ,IWRWDOELOLUXELQLVîULN (and no evidence of Gilbert’s 
syndrome) then fractionate into direct and indirect bilirubin. Amylase and lipase are to be performed at screening, 
Day 1 of each cycle, and at EOT. It is preferable that both amylase and lipase parameters are assessed. For sites 
where only 1 of these parameters is routinely measured then either lipase or amylase is acceptable. Bicarbonate, 
chloride, creatinine clearance, and magnesium testing are to be performed at screening, on Day 0 (if required), and if 
clinically indicated. ,IDSDWLHQWVKRZVDQ$67RU$/7[8/1WRJHWKHUZLWKWRWDOELOLUXELQ[8/1UHIHUWR 
Section 6.3 for further instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law. Gamma 
glutamyltransferase may be included at any time if clinically indicated. 
k Serum B-HCG within 72 hours prior to the first dose of therapy and as clinically indicated prior to day 1 of each 
subsequent cycle and at end of treatment only in women of childbearing potential (women who are not surgically-
sterile or post-menopausal). 
l Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related to 
the endocrine system. 
m Urinalysis includes: bilirubin, blood, glucose, ketones, pH, protein, specific gravity, color, and appearance. 
Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for red blood 
cells 
n May be performed more frequently than noted in the schedule if clinically indicated. Coagulation testing includes: 
PT, aPTT, and INR. 
o Hepatitis screening tests include: HCV-Ab, HBsAg, HBcAb, and HBsAb. 
p Resting 12-lead ECG on which QTcF must be <470 ms. ECGs should be obtained after the patient has been in a 
supine position for 5 minutes and recorded while the patient remains in that position. In case of clinically significant 
ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief 
period (e.g., 30 minutes) to confirm the finding. ECGs may be performed more frequently than noted in the schedule 
if clinically indicated. 
q Imaging to occur Q8W (±7 days) and should continue as long as the subject has confirmed progression, death or 
 


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acceptable toxicity. If progression is identified, then a confirmatory scan should be obtained 5 weeks (±7 days) after 
the first positive scan. As long as treatment is being well-tolerated and the investigator believes patient may derive 
benefit, the patient should continue regularly scheduled visits and receive additional treatment until the confirmatory 
scan results have been reviewed. 
r Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with 
intravenous (IV) contrast of the brain. 
s To occur during the final week of the marked Cycle, prior to initiating treatment in the following Cycle. 
t RECIST measurements will be performed in line with imaging. Refer to Section 7.1. 
u Refer to Section 6.6.2. 
v %LRSV\FDQEHQHZO\DFTXLUHGRUDUFKLYDO\HDUVROG,IVXEMHFWVDUHQRWUHTXLUHGWRKDYHDGLDJQRVWLFELRSV\LH
tumor recurrence/progression has been already histologically confirmed), tissue acquisition will occur during a 
research-only biopsy procedure. Refer to Section 6.6.2 for details regarding tumor sample. 
w If subjects are not required to have a diagnostic biopsy (i.e. tumor recurrence/progression has been already 
histologically confirmed), tissue acquisition will occur during a research-only biopsy procedure. Refer to Section 
6.6.2 for details regarding tumor sample. 
x To occur immediately prior to initiation of combination therapy. Refer to Section 6.6.2 for details regarding tumor 
sample. 
y To occur immediately prior to initiation of Cycle 3 where possible. Refer to Section 6.6.2 for details regarding 
tumor sample. 
z Samples will be taken within 45 minutes before dosing. Refer to Section 6.6.1. A blood sample will be collected 
and processed for serum at the 90-day follow up visit to analyze for the presence of anti-drug antibodies for AVB-
S6-500. 
aa Cycles 3 and 4 only. 
bb Refer to Section 5.2. 
cc Refer to Section 5.1. 
 


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6.6 
BIOLOGICAL SAMPLING PROCEDURES 
6.6.1 
RESEARCH BLOOD 
A pharmacokinetics/pharmacodynamics (AVB-S6-500 plasma concentration/GAS6 suppression) model 
was developed from non-human primate (monkey) data, scaled to humans, and used to predict human 
AVB-S6-500 exposure and GAS6 suppression (refer to AVB-S6-500 Investigator Brochure for more 
complete details). In healthy volunteer studies, GAS6 was demonstrated to be suppressed for at least 3 
weeks post-dose administration. Therefore, in the current study we will collect blood to evaluate GAS6 
levels as a relevant biomarker at cycles 1 and 2, immediately prior to dose administration. 
Blood will be collected on the days noted in the Schedules of Assessments in Section 6.5.  Sample 
collection specifics are detailed below.  
Table 9. Detailed Research Blood Collection Schedule 
Phase of Study 
Safety Lead-in 
Phase II: 
Durvalumab 
Phase II: 
AVB-S6-500 
Time point 
Serum 
Plasma/ 
PBMC 
Serum 
Plasma/ 
PBMC 
Serum 
Plasma/ 
PBMC 
Cycle 0 Day 1: Pre-treatment 
N/A 
 
X 
X 
X 
Cycle 1 Day 1: Pre-treatment 
X 
X 
X 
X 
X 
X 
Cycle 1 Day 1: 1 hour after treatment 
X 
 
 
 
 
 
Cycle 1 Day 1: 4 hours after treatment 
X 
 
 
 
 
 
Cycle 2 Day 1: Pre-treatment 
X 
X 
X 
X 
X 
X 
Cycle 3 Day 1: Pre-treatment 
 
X 
 
X 
 
X 
Cycle 4 Day 1: Pre-treatment 
 
X 
 
X 
 
X 
90-day Follow-Up 
X 
 
Xa 
 
X 
 
a Only for patients who have received at least one dose of AVB-S6-500. 
 
Serum fractions will be isolated from blood samples collected in EDTA-free tubes and will be used to 
measure 1) PK: AVB-S6-500 concentrations in serum, 2) Pharmacodynamics: GAS6 suppression, which 
will be analyzed by Altasciences, and 3) Anti-drug Antibody (ADA): immunogenicity of AVB-S6-500, 
which will be analyzed by Charles River Labs.  Blood will be collected and processed for serum for 
analysis of AVB-S6-500 ADA at the 90 day Follow Up visit.  
Plasma and PBMCs will be extracted from blood samples collected in EDTA-containing tubes and will be 
used for planned translational analysis, including gene expression analysis, functional proteomics, and 
immune profiling using a variety of complementary platforms. It is important to note that assays available 
for analysis of trial specimens are continuously evolving, thus the final method/platform used will be 
selected by primary investigators and translational collaborators at the time of specimen analysis.  
6.6.2 
TUMOR BIOPSIES 
Pre- and on-treatment biopsies will be performed as part of this clinical investigation. To avoid putting 
patients in undue risk, procedures more invasive than a core biopsy will not be used. Pretreatment 
biopsies will be collected prior to the first dose of study drug regimen. On-treatment biopsies include 
sampling after monotherapy treatment and then after combination treatment with Durvalumab and AVB-


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S6-500 when there is a lesion amenable to biopsy as assessed by imaging study by MDACC Radiologist. 
The time points for each Phase and Arm are noted in the Schedules of Assessments in Section 6.5.  
When possible, on-treatment biopsies will be obtained from the same area of tumor as the pre-treatment 
biopsy. 
At all biopsy time points and when deemed clinically safe, up to 10 core biopsies will be collected by 
Radiology faculty through an image-guided procedure. When feasible and depending on the tumor 
volume, 1-3 cores will be processed as formalin-fixed, paraffin-embedded blocks (FFPE) and 1-3 cores 
will be flash frozen, and remaining cores will be kept fresh in media. In cases where only limited amounts 
of tumor can be obtained, the FFPE samples will be prioritized. Samples will be collected, labeled, 
processed, and stored by the MDACC Gynecologic Oncology Tumor Bank. Sample identification and 
associated collection data will be entered into a secure database. 
Translational studies including tumor immune and gene expression profiling will be performed with 
collaborators at MD Anderson group and Discovery Life Sciences (DLS). This assessment may include, 
but is not limited to, fresh flow cytometry, tissue cyTOF, and multiplex immunofluorescence. Exploratory 
analyses may include sequencing platforms and, given that assays for these evaluations are rapidly 
evolving in the laboratories at MDACC, other assays will be performed with the current state of the art 
technology available at the time of analysis. Aliquots may be stored and used for exploratory and future 
translational immunology research. 
6.6.3 
WITHDRAWAL OF INFORMED CONSENT FOR DONATED BIOLOGICAL SAMPLES 
If a patient withdraws consent to the use of donated samples, the samples will be disposed of/destroyed, 
and the action documented. However, any data that was previously generated from the sample will be 
retained. Such subjects may still continue with the therapeutic portion of the investigation. 
The Principal Investigator: 
x 
Ensures that biological samples from that patient, if stored at the study site, are immediately 
identified, disposed of /destroyed, and the action documented 
x 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn consent 
immediately and that samples are disposed/destroyed, the action documented and the signed 
document returned to the study site 
x 
Ensures that the patient is informed about the sample disposal 
7. 
DISEASE EVALUATION AND METHODS 
7.1 
MODIFIED RECIST V1.1  
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy. These difference include the following [59], [60]: 
x 
Response to immunotherapy may be delayed, 
x 
Response to immunotherapy may occur after PD by conventional criteria, 
x 
The appearance of new lesions may not represent PD with immunotherapy, and 
x 
SD while on immunotherapy may be durable and represent clinical benefit. 
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anticancer 
medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating anticancer compounds, 
we will implement the following modifications in addition to standard RECIST 1.1 criteria. 


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x 
RECIST will be modified so that PD must be confirmed at the next scheduled visit, preferably, 
and no earlier than 5 weeks after the initial assessment of PD in the absence of clinically 
significant deterioration. Treatment with durvalumab and AVB-S6-500 would continue between 
the initial assessment of progression and confirmation for progression.  
x 
In addition, patients may continue to receive durvalumab and AVB-S6-500 beyond confirmed PD 
in the absence of clinically significant deterioration and if investigators consider that patients 
continue to receive benefit from treatment.  
Modification of RECIST as described may discourage the early discontinuation of durvalumab and AVB-
S6-500 and provide a more complete evaluation of its antitumor activity than would be seen with 
conventional response criteria. Nonetheless, the efficacy analysis will be conducted by programmatically 
deriving each efficacy endpoint based on RECIST 1.1 criteria. 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that necessitates 
treatment with anticancer therapy other than durvalumab or with symptomatic progression that requires 
urgent medical intervention (e.g., central nervous system metastasis, respiratory failure due to tumor 
compression, spinal cord compression). 
7.1.1 
PHYSICAL EXAMINATION 
Lesions detected by physical examination will only be considered measurable if superficial, e.g., skin 
nodules and palpable lymph nodes. Documentation by color photography including ruler is recommended 
for estimating the size of skin lesions. 
7.1.2 
CT SCAN WITH CONTRAST OF THE CHEST, ABDOMEN, AND PELVIS 
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. Spiral CT should 
be performed using a 5-mm contiguous reconstruction algorithm. 
7.1.3 
MRI SCANS 
MRI of the abdomen and pelvis is acceptable for measurement of lesions provided that the same 
anatomical plane is used for serial assessments. If possible, the same imaging device should be used for 
serial evaluations. In case of MRI, measurements will be preferably performed in the axial (transverse) 
plane on contrast-enhanced T1-weight 
7.1.4 
MEASURABILITY OF TUMOR LESIONS 
Tumor lesions will be categorized as follows. 
7.1.4.1 MEASURABLE LESIONS 
Measurable 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: 
x 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness 
and a minimum of 10 mm). 
x 
10 mm caliper measurement by clinical exam (when superficial). 
Malignant lymph nodes are considered pathologically enlarged and measurable, a lymph nodHPXVWEH
15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). 
 
 


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7.1.4.2 NONMEASURABLE LESIONS 
Nonmeasurable lesions are defined as all other lesions (or sites of disease), including small lesions 
(longest diameter < 10 mm or SDWKRORJLFDOO\PSKQRGHVZLWK10 to < 15 mm short axis). Lesions 
considered truly nonmeasurable include the following: leptomeningeal disease, ascites, pleural/pericardial 
effusion, lymphangitic involvement of skin or lung, abdominal masses/abdominal or organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
7.1.4.3 TARGET LESIONS 
All lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of 
all involved organs should be identified as target lesions. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
7.1.4.4 NON-TARGET LESIONS 
It is possible to record multiple nontarget lesions involving the same organ as a single item on the case 
record form (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).Patients who 
have disease control following completion of 12 months of treatment or patients who are withdrawn from 
durvalumab + AVB-S6-500 treatment for reasons other than confirmed PD will continue to have 
objective tumor assessments (see Schedule of Assessments).  
7.2 
RESPONSE CRITERIA 
7.2.1 
EVALUATION OF TARGET LESIONS 
x 
Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may not be 
“0” if there are target nodes). 
x 
Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
x 
Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression.) 
x 
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum of diameters while on study. 
7.2.2 
EVALUATION OF NON-TARGET LESIONS 
x 
Complete Response - 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). 
x 
Non-complete response/Non-progressive disease - Persistence of 1 or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits. 
x 
Progressive Disease - Unequivocal progression of existing non-target lesions will be defined as 
the overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. In the absence of measurable disease, change in non-measurable 
disease comparable in magnitude to the increase that would be required to declare PD for 


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measurable disease. Examples include an increase in a pleural effusion from ‘trace’ to ‘large,’ an 
increase in lymphangitic disease from localized to widespread. 
7.2.3 
APPEARANCE OF NEW LESIONS 
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. However, 
considering the unique response kinetics that have been observed with immunotherapy, new lesions may 
not represent true disease progression. In the absence of rapid clinical deterioration, subjects may 
continue to receive the study regimen if investigators consider that subjects continue to benefit from 
treatment. A confirmatory radiologic assessment should be performed at least 5 weeks from the original 
study suggesting PD. 
7.2.4 
EVALUATION OF OVERALL RESPONSE WITH MODIFICATIONS 
Confirmation of CR, PR, as well as PD is required by a repeat, consecutive assessment no less than 5 
weeks from the date of first documentation. Treatment with study regimen will continue between the 
initial assessment of PD and confirmation for PD. If PD is confirmed by the second confirmatory scan, 
the associated time of progression will be reported as that of the initial imaging study revealing 
progression. In the absence of clinical deterioration, such modifications to the RECIST criteria may 
discourage the early discontinuation of the study regimens and provide a more complete evaluation of its 
antitumor activity than would be seen with conventional response criteria.  
Table 10 provides overall responses for all possible combinations of tumor responses in target and non-
target lesions with or without the appearance of new lesions. 
Table 10. Overall Responses for All Possible Combinations of Tumor Responses 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response (or no non-
target lesion) 
No 
Complete response 
Complete response 
Not evaluablea 
No 
Partial response 
Complete response 
Non-complete response/non-
progressive 
No 
Partial response 
Partial response 
Non-progressive and non-evaluablea 
No 
Partial response 
Stable disease 
Non-progressive and non-evaluablea No 
Stable disease 
Not all evaluated 
Non-progressive 
No 
Not evaluable 
Progressive disease 
Any 
Yes/No 
Progressive diseaseb 
Any 
Progressive disease 
Yes/No 
Progressive diseaseb 
Any 
Any 
Yes 
Progressive diseaseb 
a Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment 
b Disease progression requires confirmatory radiologic assessment 
Confirmation of progression guidelines are set for the following reasons:  
x 
for patient management and treatment decisions and 
x 
in the absence of significant clinical deterioration, to promote the collection of additional scans 
after the first radiologic RECIST 1.1 assessment of progressive disease (PD) in order to 
distinguish pseudoprogression from true radiologic progression, also known as RECIST 1.1 
modified for confirmation of progression. 


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Confirmed objective disease progression refers to either of the following scenarios: 1. clinical 
progression/deterioration followed by a radiologic verification scan (PD by RECIST 1.1); or 2. in the 
absence of significant clinical deterioration, radiologic PD by RECIST 1.1 followed by a second 
radiologic confirmation scan with PD assessed according to the specific confirmation of progression 
criteria listed below. RECIST 1.1 modified for confirmation of progression refers to the second scenario 
above. The confirmatory scan should occur preferably at the next scheduled imaging visit and no earlier 
than 5 weeks following the date of the immediate prior assessment of RECIST 1.1 PD. 
Immediate prior radiologic progression would be considered confirmed if any the following criteria are 
met in the confirmatory scan: 
x 
LQFUHDVHLQWKHVXPGLDPHWHUVRIWDUJHWOHVLRQV7/VFRPSDUHGZLWKWKHQDGLUDW
consecutive visits, with an absolute increase of at least 5 mm in sum of diameters compared to 
nadir, 
x 
and/or significant progression (worsening) of non-target lesions (NTLs) and/or of pre-existing 
new lesions at the confirmatory scan time-point compared with the immediate prior time-point 
(Note: Pre-existing new lesions are evaluated as NTLs at the confirmatory scan time-point), 
and/or 
x 
additional new unequivocal lesions at the confirmatory scan time-point. 
To have confirmed objective disease progression, there should be two consecutive assessments meeting 
the PD definition: the first PD by RECIST 1.1 and the second PD using the confirmation of progression 
criteria (above). If the first assessment fulfilling the PD definition by RECIST 1.1 is not confirmed, 
continue with assessments until the next PD by RECIST 1.1, which in turn will need its own immediate 
subsequent confirmation scan. In the absence of significant clinical deterioration, treatment with study 
drug may continue between the initial assessment of progression and the scan to confirm progression. 
If the confirmation scan confirms progression, then the date of the prior scan with PD should be declared 
as the date of progression. 
If progression is not confirmed, in the absence of significant clinical deterioration, then the patient should 
continue study drug and on-treatment assessments until the next PD which will also require a follow-up 
confirmation scan. If the first PD is not confirmed by the immediate next scan, then the Investigator 
should change the PD assessment of the first scan. 
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to radiologic 
progression, then the patient should still continue to be followed until confirmed objective disease 
progression. 
Following confirmed progression, patients should continue to be followed up for survival as outlined in 
the follow-up schedules of assessments. 
8. 
ASSESSMENT OF SAFETY 
The Principal Investigator is responsible for ensuring that all staff members involved in the study are 
familiar with the content of this section. 
8.1 
SAFETY PARAMETERS 
8.1.1 
DEFINITION OF ADVERSE EVENTS 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) 
E6(R1) defines an AE as: 


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Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a patient’s pre-existing 
condition. An abnormal laboratory finding (including ECG finding) that requires an action or intervention 
by the investigator, or a finding judged by the investigator to represent a change beyond the range of 
normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be TEAE (i.e., occurring after initial receipt of investigational product) or non-
treatment emergent. A non-TEAE is any new sign or symptom, disease, or other untoward medical event 
that begins after written informed consent has been obtained but before the patient has received 
investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the patient 
being enrolled into the study) for a documented pre-existing condition, that did not worsen from baseline, 
is not considered an AE (serious or nonserious). An untoward medical event occurring during the 
prescheduled elective procedure or routinely scheduled treatment should be recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator, MDACC IND Office, or supporting companies, it results in any of the following outcomes: 
x 
Death 
x 
A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. 
It does not include an adverse experience that, had it occurred in a more severe form, might have 
caused death. 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
x 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug experience when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
1. Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. All AEs that do not meet any of the 
criteria for serious will be regarded as non-serious AEs. 
2. All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 


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University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”. Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of relatedness to study drug (within 5 working days of knowledge of the event).
3.
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have 
a written report submitted within 24 hours (next working day) of knowledge of the event to the 
Safety Project Manager in the IND Office. 
4.
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety
reporting to the IND Office and MDACC IRB. 
5.
Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 30 days after the last dose of drug, unless the participant withdraws consent. Serious adverse 
events must be followed until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been acceptable resolution of the 
event.
6.
Additionally, any serious adverse events that occur after the 30 day time period that are related to 
the study treatment must be reported to the IND Office. This may include the development of a 
secondary malignancy.
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager IND 
Office) according to 21 CFR 312.32.
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the IND 
sponsor’s guidelines, and Institutional Review Board policy.
8.1.3
DEFINITION OF ADVERSE EVENTS OF SPECIAL INTEREST
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be serious 
or non-serious. 
If the treatment team has any questions in regards to an event being an irAE, the primary investigator 
should promptly contacted.
AESIs for this study include:
x
Diarrhea / Colitis and intestinal perforation
x
Pneumonitis / ILD
x
hepatitis / transaminase increases
x
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and 
hypothyroidism and type I diabetes mellitus)
x
Rash / Dermatitis
x
Nephritis / Blood creatinine increases
x
Pancreatitis / serum lipase and amylase increases
x
Myocarditis
x
Myositis / Polymyositis
x
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)
x
Other inflammatory responses that are rare / less frequent with a potential immune-mediated 
aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events 
involving the eye, skin, haematological and rheumatological events.
hepatitis / transaminase increases
Pneumonitis / ILD


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In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological aetiology are also considered AESIs.
Further information on these risks (e.g. presenting symptoms) can be found in the current versions of the 
durvalumab Investigator’s Brochures. More specific guidelines for their evaluation and treatment are 
described in detail in the Dosing Modification and Toxicity Management Guidelines (TMG, please see 
Appendix A). These guidelines have been prepared by AstraZeneca and agreed upon by Aravive to assist 
the Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. These 
guidelines apply to AEs considered causally related to the study drug/study regimen by the reporting 
investigator.
8.1.3.1 INFUSION REACTIONS
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to AstraZeneca 
and Aravive and are defined, for the purpose of this protocol, as all AEs occurring from the start of IP 
infusion up to 48 hours after the infusion start time. All infusion reactions should be reported to 
AstraZeneca Patient safety and to Aravive as AESI’s. The electronic SAE application (eSAE) will be 
utilized for reporting to the IND Office and MDACC IRB, as well as AstraZeneca Patient safety and 
Aravive. If the AESI does not meet the criteria of an SAE, this should be clearly indicated on the eSAE 
form. These AESI’s should be reported to all parties within five working days. If an AESI also meets the 
criteria of an SAE, then they should be reported as an SAE as described in Section 8.1.2.
8.1.3.2 HYPERSENSITIVITY REACTIONS
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti PDL1 and 
anti-PD-1 therapy. As with the administration of any foreign protein and/or other biologic agents, 
reactions following the infusion of mAbs can be caused by various mechanisms, including acute 
anaphylactic (IgE-mediated) and anaphylactoid reactions against the mAbs and serum sickness. Acute 
allergic reactions may occur, may be severe, and may result in death. Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, arthralgia, 
bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, vomiting, and 
unresponsiveness. Guidelines on management can be found in Appendix A.
8.1.3.3 PNEUMONITIS
AEs of pneumonitis are also of interest for AstraZeneca and Aravive, as pneumonitis has been observed 
with use of anti-PD-1 mAbs (but not with anti-PDL1 mAbs). Initial work-up should include a high-
resolution CT scan, ruling out infection, and pulse oximetry. Pulmonary consultation is highly 
recommended. 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality suggestive of 
pneumonitis/interstitial lung disease is observed, toxicity management as described in detail in the Dosing 
Modification and TMG will be applied. Refer to Appendix A for details. 
8.1.3.4 HEPATIC FUNCTION ABNORMALITIES (HEPATOTOXICITY)
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from a single blood draw or from separate blood draws taken within 8 days of each other. Follow-up 
investigations and inquiries will be initiated promptly by the investigational site to determine whether the 
findings are reproducible and/or whether there is objective evidence that clearly supports causation by a 
disease (e.g., cholelithiasis and bile duct obstruction with distended gallbladder) or an agent other than the 
IP. Guidelines on management can be found in Appendix A.
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8.1.3.5 GASTROINTESTINAL DISORDERS 
Diarrhea/colitis is a commonly observed treatment emergent SAE when durvalumab is used as 
monotherapy. In rare cases, colon perforation may occur that requires surgery (colectomy) or can lead to a 
fatal outcome if not properly managed. Guidelines on management can be found in Appendix A. 
8.1.3.6 ENDOCRINE DISORDERS 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism. Guidelines for the management of patients with immune-mediated endocrine events can 
be found in Appendix A. 
8.1.3.7 PANCREATIC DISORDERS 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase elevation. 
Guidelines for the management of patients with immune-mediated pancreatic disorders are provided in 
Appendix A. 
8.1.3.8 NEUROTOXICITY 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis. Guidelines for the management of patients with 
immune-mediated neurotoxic events are provided in Appendix A. 
8.1.3.9 NEPHRITIS 
Monitor for signs and symptoms that may be related to changes in renal function (e.g. routine urinalysis, 
elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in 
urine output, proteinuria, etc). Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, infections etc.) and consultation with nephrologist is recommended. Guidelines 
for the management of patients with immune-mediated renal events are provided in Appendix A. 
8.2 
ASSESSMENT OF SAFETY PARAMETERS 
8.2.1 
ASSESSMENT OF SEVERITY 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs and 
SAEs. Severity will be graded according to the NCI CTCAE v5.0. The determination of severity for all 
other events not listed in the CTCAE should be made by the investigator based upon medical judgment 
and the severity categories of Grade 1 to 5 as defined below. 
x 
Grade 1 (mild): An event that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
x 
Grade 2 (moderate): An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the patient. 
x 
Grade 3 (severe): An event that requires intensive therapeutic intervention. The event interrupts 
usual activities of daily living, or significantly affects the clinical status of the patient. 
x 
Grade 4 (life-threatening): An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that affect or limit the ability of the 
patient to perform activities of daily living (eating, ambulation, toileting, etc). 
x 
Grade 5 (fatal): Death (loss of life) as a result of an event. 


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It is important to distinguish between serious criteria and severity of an AE. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 8.1.2. A Grade 3 AE need not 
necessarily be considered an SAE. For example, a Grade 3 headache that persists for several hours may 
not meet the regulatory definition of an SAE and would be considered a nonserious event, whereas a 
Grade 2 seizure resulting in a hospital admission would be considered an SAE. 
8.2.2 
ASSESSMENT OF RELATIONSHIP 
The investigator (or physician designee) will provide an assessment of relationship of AEs and SAEs to 
the investigational product.  
An event will be considered “not related” to use of the investigational product if any of the following tests 
are met. 
x 
An unreasonable temporal relationship between administration of the investigational product and 
the onset of the event (e.g., the event occurred either before, or too long after, administration of 
the investigational product for it to be considered product-related). 
x 
A causal relationship between the investigational product and the event is biologically 
implausible (e.g., death as a passenger in an automobile accident). 
x 
A clearly more likely alternative explanation for the event is present (e.g., typical adverse 
reaction to a concomitant drug and/or typical disease-related event). 
Individual AE/SAE reports will be considered “related” to use of the investigational product if the “not 
related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” meaning that 
there is “a reasonable possibility” that the event may have been caused by the product under investigation 
(i.e., there are facts, evidence, or arguments to suggest possible causation). 
8.3 
RECORDING AND REPORTING OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
AEs and SAEs will be recorded according to the NCI suggested criteria as listed below. 
Table 11. NCI Suggested AE recording criteria. 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II  
Phase I 
Phase II  
Phase III 
Phase I  
Phase II  
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II  
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Possible 
Phase I 
Phase II  
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Probable 
Phase I 
Phase II  
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Definitive 
Phase I 
Phase II  
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II  
Phase III 
 


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8.3.1 
STUDY RECORDING PERIOD AND FOLLOW-UP FOR ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS 
AEs and SAEs will be collected from the time of the first protocol-specific procedure until the follow-up 
period is completed (30 days after the last dose of durvalumab ±AVB-S6-500). If an event that starts post 
the defined safety follow up period noted above is considered to be due to a late onset toxicity to study 
drug then it should be reported as an AE or SAE as applicable. Investigator will instruct subjects to report 
to the investigator any subsequent SAEs; these events’ relatedness to investigational regimen will be 
determined by the investigator and if felt to be related will be reported to the IND office as per Section 
8.3 Definition of Serious Adverse Events.  
During the course of the study, all AEs and SAEs should be proactively followed up for each patient for 
as long as the event is ongoing. Every effort should be made to obtain a resolution for all events, even if 
the events continue after the patient has discontinued study drug or the study has completed. 
8.3.2 
FOLLOW-UP OF UNRESOLVED ADVERSE EVENTS 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the Investigator for 
as long as medically indicated, but without further recording in the eCRF. AstraZeneca and Aravive shall 
retain the right to request additional information for any patient with ongoing AE(s)/SAE(s) at the end of 
the study, if judged necessary. 
8.3.3 
INVESTIGATOR COMMUNICATIONS WITH ASTRAZENECA AND ARAVIVE 
SAE report forms should be forwarded with supporting relevant source documents (e.g. history and 
physical [H&P], hospital discharge summary, autopsy report when available, results of relevant 
diagnostic tests completed to evaluate the event) to AstraZeneca for AEs related to durvalumab and to 
Aravive for AE related to AVB-S6-500. 
AstraZeneca’s designated mailbox is AEMailboxClinicalTrialTCS@astrazeneca.com. 
Aravive’s designated mailbox is laura@aravive.com, and ISTAEs@aravive.com. 
Transmission of the SAE report Form should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should also be 
reported to the appropriate supporting company (i.e. AstraZeneca for durvalumab-related AEs or Aravive 
for AVB-S6-500-related AEs) as soon as it is available; these reports can be submitted using the MD 
Anderson eSAE Report Form. If a non-serious AE becomes serious, this and other relevant follow-up 
information must also be provided to AstraZeneca and Aravive. Serious adverse events that do not require 
expedited reporting to the FDA still need to be reported to AstraZeneca and Aravive for serious adverse 
events. This information should be reported on a monthly basis and under no circumstance less frequently 
than quarterly.  
8.3.3.1 OVERDOSE 
An overdose is defined as a patient receiving a dose of durvalumab or AVB-S6-500 in excess of that 
specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study patient with durvalumab and/or AVB-S6-500, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to the MDACC IND 
Office, Aravive, and AstraZeneca Patient Safety or designee (see Section 8.3.3 for reporting information). 
If the overdose results in an AE, the AE must also be recorded as an AE (see Section 8.1.2). Overdose 
does not automatically make an AE serious, but if the consequences of the overdose are serious, for 
example death or hospitalization, the event is serious and must be recorded and reported as an SAE (see 


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Section 8.1.2 and Section 8.3.3). There is currently no specific treatment in the event of an overdose of 
durvalumab or AVB-S6-500.
The investigator will use clinical judgment to treat any overdose.
8.3.3.2 NEW CANCERS
The development of a new cancer should be regarded as an SAE. New primary cancers are those that are 
not the primary reason for the administration of the IP and have been identified after the patient’s 
inclusion in this study.
8.3.3.3 HEPATIC FUNCTION ABNORMALITY
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case in a study 
patient, with or without associated clinical manifestations, is required to be reported as “hepatic function 
abnormal” within 24 hours of knowledge of the event to the MDACC IND Office, Aravive, and 
AstraZeneca Patient Safety (see Section 8.1.2 for SAE reporting information), unless a definitive 
underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed. The criteria for a potential Hy’s Law case is Aspartate 
Aminotransferase (AST) or Alanine Aminotransferase (ALT) 3x Upper Limit of Normal (ULN) together 
with Total Bilirubin (TBL) 2xULN at any point during the study following the start of study medication
irrespective of an increase in Alkaline Phosphatase (ALP).
x
If the definitive underlying diagnosis for the abnormality has been established and is unrelated to 
investigational product, the decision to continue dosing of the study patient will be based on the 
clinical judgment of the investigator.
x
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
patient must be interrupted immediately. Follow-up investigations and inquiries must be initiated 
by the investigational site without delay.
Each reported event of hepatic function abnormality will be followed by the investigator and evaluated by
the MDACC IND Office, Aravive, and AstraZeneca. 
8.3.3.4 MATERNAL EXPOSURE
If a patient becomes pregnant during the course of the study, the IPs should be discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may have 
interfered with the effectiveness of a contraceptive medication. Congenital abnormalities or birth defects 
and spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up 
and documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel should 
inform the appropriate Aravive and AstraZeneca representatives per reporting guidelines (Section 8.3.3).
The designated Aravive and AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the Aravive and AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
 The criteria for a potential Hy’s Law case is Aspartate
Aminotransferase (AST) or Alanine Aminotransferase (ALT)
f
3x Upper Limit of Normal (ULN) together 
with Total Bilirubin (TBL) 2xULN at any point during the study following the start of study medication
irrespective of an increase in Alkaline Phosphatase (ALP).


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8.3.3.5 MEDICATION ERROR 
For the purposes of this clinical study a medication error is an unintended failure or mistake in the 
treatment process for an AstraZeneca or Aravive study drug that either causes harm to the patient or has 
the potential to cause harm to the patient.  
A medication error is not lack of efficacy of the drug, but rather a human or process related failure while 
the drug is in control of the study site staff or patient. 
Medication error includes situations where an error:  
x 
Occurred, 
x 
Was identified and intercepted before the patient received the drug, and/or 
x 
Did not occur, but circumstances were recognized that could have led to an error. 
Examples of events to be reported in clinical studies as medication errors: 
x 
Drug name confusion 
x 
Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to the 
patient 
x 
Drug not administered as indicated, for example, wrong route or wrong site of administration 
x 
Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a solid tablet  
x 
Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature  
x 
Wrong patient received the medication  
x 
Wrong drug administered to patient  
Examples of events that do not require reporting as medication errors in clinical studies: 
x 
Patient accidentally missed drug dose(s) e.g. forgot to take medication 
x 
Accidental overdose (will be captured as an overdose) 
x 
Patient failed to return unused medication or empty packaging 
x 
Errors related to background and rescue medication, or standard of care medication in open label 
studies, even if an AZ or Aravive product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the medication error.  
If a medication error occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate Aravive and AstraZeneca representatives within 1 day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated Aravive and AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated with the 
medication error (see Section 8.3.3 for reporting details) and within 30 days for all other medication 
errors. 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
We will employ the Bayesian optimal interval (BOIN) design (Yuan et al., 2016) to find the MTD. The 
target toxicit\UDWHIRUWKH07'LV݊ DQGWKHPD[LPXPVDPSOHVL]HLVWe will enroll and treat 
patients in cohorts of size 3. DLTs are defined in Section 6.2, and only those DLTs that occur within the 
first 6 weeks will be used for dose finding. To guide dose-escalation decisions, if the observed DLT rate 
DWWKHFXUUHQWGRVHLVWKHQH[WFRKRUWRISDWLHQWVZLOOEHWUHDWHGDWWKHQH[WKLJKHUGRVHOHYHOLILW
LVWKHQH[WFRKRUWRISDWLHQWVZLOOEHWUHDWHGDWWKHQH[WORZHUGRVHOHYel. For the purpose of 
overdose control, doses j and higher levels will be eliminated from further examination if Pr(pj > 0.25 | 


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data) > 0.95, where pj is the true DLT rate of dose level j, j = 1, 2, 3. When the lowest dose is eliminated, 
stop the trial for safety. The trial design is illustrated in Figure 3 and described as follows: 
1. Patients in the first cohort are treated at dose level 1. 
2. To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to 
the rule displayed in Table 12, which minimizes the probability of incorrect dose assignment. 
When using Table 12, please note the following:  
a. “Eliminate” means eliminate the current and higher doses from the trial to prevent 
treating any future patients at these doses because they are overly toxic.  
b. When we eliminate a dose, automatically de-escalate the dose to the next lower level. 
When the lowest dose is eliminated, stop the trial for safety. In this case, no dose should 
be selected as the MTD.  
c. If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, treat the 
new patients at the current dose.  
d. If the current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new patients at the lowest dose unless the number of DLTs reaches the elimination 
boundary, at which point terminate the trial for safety.  
e. If the current dose is the highest dose and the rule indicates dose escalation, treat the new 
patients at the highest dose.  
3. Repeat step 2 until the maximum of 5 evaluable patients are treated on the highest dose, or 
maximum sample size of 15 is reached or end enrollment  when the number of patients treated at 
the current dose >= 9 and the decision based on Table 12 is to stay at the current dose.  
Table 12. Dose escalation/de-escalation rule for the BOIN design 
Actions 
The number of patients treated at the current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Escalate if  
# of DLT <=  
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
2 
2 
De-escalate if  
# of DLT >= 
1 
1 
1 
2 
2 
2 
3 
3 
3 
3 
4 
4 
Eliminate if  
# of DLT >= 
NA 
NA 
3 
3 
3 
4 
4 
4 
5 
5 
6 
6 


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Figure 3. Flowchart for trial conduct using the BOIN design 
After the trial is completed, select the MTD based on isotonic regression as specified in Liu and Yuan 
(2015). This computation is implemented by the "Estimate MTD" tab of the BOIN Design Desktop 
Program (Venier et al., 2017). Specifically, select as the MTD the dose for which the isotonic estimate of 
the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the 
isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic 
estimate is greater than or equal to the target toxicity rate. In general, the MTD will be used as the R2PD 
for phase II part, but might be adjusted based on the PK/PD and total evidence.  
Table 13 shows the operating characteristics of the trial design based on 1000 simulations of the trial 
using the BOIN Design Desktop Program (Venier et al., 2018). The operating characteristics show that 
the design selects the true MTD, if any, with high probability and allocates more patients to the dose 
levels with the DLT rate closest to the target of 0.25.  
 
 
 


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Table 13. Operating Characteristics of the BOIN design 
  
Dose Level 
Number of 
Patients 
% Early 
Stopping 
  
1 
2 
3 
Scenario 1 
True DLT Rate 
0.25 
0.42 
0.59 
11.75 
6.3 
Selection % 
73.4 
19.1 
1.2 
# Pts Treated 
8.2 
3.0 
0.6 
Scenario 2 
True DLT Rate 
0.10 
0.25 
0.40 
14.08 
0.0 
Selection % 
28.9 
56.6 
14.5 
# Pts Treated 
6.7 
5.0 
2.4 
Scenario 3 
True DLT Rate 
0.05 
0.12 
0.25 
14.75 
0.0 
Selection % 
6.0 
40.0 
54.0 
# Pts Treated 
4.8 
5.1 
4.9 
 
The trial will be completed after the RP2D is determined as described above.  The section below is 
maintained in the protocol in order to reference the original design and will no longer apply. 
After the RP2D is determined, subsequent patients will be randomized in a 3:1 manner for enrollment into 
the respective AVB-S6-500 and Durvalumab monotherapy arms. We estimate accrual rate of 3 patients 
per month. We anticipate a dropout rate of approximately 8-10% due to possible toxicity as seen in prior 
literature of checkpoint inhibitor therapy [61], [62], and subsequent inability to proceed to combination 
treatment. All patients who complete the monotherapy treatment phase will proceed to combination 
treatment, at which time receipt of at least one dose of combination therapy at the final determined dosing 
defines evaluable patients. As mentioned above, should the safety lead-in phase in the combination 
treatment require dose adjustment, only those patients who received the RP2D and completed one cycle 
of combination treatment will be considered evaluable for the primary outcome of response rate to 
combination therapy and used for making go/no-go decision as described below.  
In terms of outcome assessment of response rate and toxicity to combination therapy, the Bayesian 
optimal phase 2 (BOP2) design is utilized to jointly monitor toxicity and efficacy [63]. The first 12 
patients to receive combination treatment constitutes the first stage. Of these N=12 patients, if 1 or more 
responses are detected and no more than 5 DLTs are observed, the trial will proceed to the second-stage 
and enroll an additional 15 patients. Of note, more than 3 responses and fewer than 10 DLTs in the total 
study cohort will indicate statistically significant improvement in response and toxicity.  


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Thus, the total number of evaluable patients following the second-stage will be N=27, in order to have 
93% power to detect an improvement in response rate from 10% based on prior literature in this patient 
population to 30% with novel combination treatment and a toxicity of less than 40%. The rationale to 
design the study to detect this rate of improvement was that 10 to 30% is felt by the investigators to 
represent a clinically meaningful increase in response rate. Given the sample size of 27, a two-sided 90% 
confidence interval for a single proportion of ORR will extend 0.145 from the observed proportion for an 
expected proportion of 0.30. Similarly, the confidence interval for toxicity will extend 0.127 from the 
observed proportion for an expected proportion of 0.20. 
We anticipate enrollment of a maximum of 39 patients: this includes the 27 total evaluable patients at 
RP2D; correction for an unevaluable, i.e., dropout rate of 8-10% after monotherapy (3 patients); and the 
dose-finding requirement of up to 9 additional patients should dose adjustment be needed due to toxicity. 
Further details of the statistical methods and operating characteristics of this Bayesian monitoring are 
found in Section 9.2. 
9.1 
DESCRIPTION OF ANALYSIS SETS 
9.1.1 
SAFETY ANALYSIS SET 
Subjects who have received at least one dose of Durvalumab + AVB-S6-500 combination treatment will 
be included in the Safety Analysis Set. Safety will be monitored in the monotherapy phase and in the 
combination therapy phase.  
9.1.2 
EFFICACY ANALYSIS SET 
Subjects who have received at least one dose of Durvalumab + AVB-S6-500 combination treatment will 
be included in the Efficacy Analysis Set. Efficacy will be monitored in the combination therapy phase.  
9.2 
METHODS OF STATISTICAL ANALYSES 
We will use descriptive statistics to summarize the demographic and clinical characteristics of the 
subjects. We will estimate the objective response rate (ORR) along with a 90% confidence interval. 
Response is defined in Section 7.2. We will estimate the median immune-related progression free 
survival (irPFS) after treatment with combination durvalumab and AVB-S6-500 using the product-limit 
estimator of Kaplan and Meier. When appropriate, we will model irPFS using Cox proportional hazards 
regression as an exploratory analysis because of the small sample size. Immune-related PFS is defined as 
the time from the date of dual therapy treatment initiation to the date of initial radiologic evidence of 
progressive disease (Section 7.2) or death. Those who are immune-related progression-free and alive will 
have irPFS censored at their last clinic visit.  
Molecular and immunological changes will be summarized with standard descriptive statistics. Changes 
in T cell populations and proliferation will be calculated along with 95% confidence intervals and 
compared between pre and posttreatment biopsies using two sample t-test. Similar summaries will be 
used to compare proportions of macrophage phenotypes. We will tabulate adverse events by grade, and 
by relationship to study drug. We will estimate the proportion of subjects that discontinue treatment due 
to adverse events with 90% confidence intervals. We will estimate the unacceptable toxicity rate with a 
90% confidence interval.  
9.2.1 
SAFETY ANALYSES 
We will tabulate adverse events by grade, and relationship to study drug. We will estimate the proportion 
of subjects that discontinue treatment due to treatment-related adverse events with 90% confidence 
intervals. We will estimate the unacceptable toxicity rate with a 90% confidence interval.  


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9.2.2 
EXPLORATORY ANALYSES 
Two-sample t test or chi-squared test will be used to compare continuous and binary variables for 
molecular and immunologic differences between pre-treatment with single agent AVB-S6-500 as 
compared to durvalumab.  
The maximum of 6 patients who enroll directly into the safety-lead in phase of combination therapy will 
be separately analyzed for exploratory outcomes of response rate to combination alone. Similarly, 
pretreatment monotherapy arms will be compared for safety and signal of monotherapy response, as well 
as for impact on subsequent response rate in combination treatment. 
9.2.3 
INTERIM ANALYSES 
We will conduct an interim analysis for efficacy and safety once 12 subjects have been evaluated for dual 
therapy. As stated in Section 6.2, DLTs will be evaluated from the time of first drug administration until 6 
weeks. ORR will be determined at 8-week scan, but as stated in Table 10, disease progression will require 
a confirmatory scan. Based on Table 10, we will stop the trial if 0 responses are detected or 6 or more 
toxicities are observed. 
We simultaneously monitor efficacy and safety endpoints using the Bayesian optimal phase 2 (BOP2) 
design [63]. Specifically, let ݊ denote the interim sample size and ܰ denote the maximum sample size. 
Let ܻ௘௙௙ and ܻ௧௢௫ respectively denote the efficacy and toxic endpoints, with ܻ௘௙௙= 1 and ܻ௧௢௫= 1 
respectively indicating that patients experience efficacy and toxicity. We assume that the joint distribution 
of (ܻ௘௙௙, ܻ௧௢௫) follows a multinomial distribution with 4 elementary outcomes: (ܻ௘௙௙, ܻ௧௢௫) = (1, 1), (1, 0), 
(0, 1) and (0, 0). Let ݌௘௙௙= ܲݎ(ܻ௘௙௙= 1) and ݌௧௢௫= ܲݎ(ܻ௧௢௫= 1). The treatment is deemed as 
unacceptable if ݌௘௙௙൑0.1 or ݌௧௢௫> 0.4. Thus, we will stop enrolling patients and claim that the 
treatment is unacceptable if 
ܲݎ(݌௘௙௙> 0.1|݀ܽݐܽ) < ߣ(݊
ܰ)ఈ, 
or 
ܲݎ(݌௧௢௫൑0.4|݀ܽݐܽ) < ߣ(݊
ܰ)ఈ, 
where ߣ=0.65 and ߙ=0.9 are design parameters optimized to maximize the probability of correctly 
concluding an efficacious and safe treatment as acceptable when ݌௘௙௙= 0.3, ݌௧௢௫= 0.2 and ݌௘௙௙௧௢௫=
0.06, while controlling that the probability of incorrectly claiming an inefficacious and toxic treatment, 
with ݌௘௙௙= 0.1, ݌௧௢௫= 0.4 and ݌௘௙௙௧௢௫= 0.04, as acceptable is less than 10%. Assuming a Dirichlet 
prior distribution ܦ݅ݎ(0.04,0.06,0.36,0.54) for the treatment effect, the above decision rule corresponds 
to the following stopping boundaries and yields a statistical power of 0.9245 under ܪଵ: 
Table 14. Optimized stopping boundaries 
# patients treated Stop if # response <= OR # toxicity >= 
12 
0 
6 
27 
3 
10 
Based on Table 10, we will perform the interim analysis when the number of evaluable patients reaches 
12. When the total number of evaluable patients reaches the maximum sample size of 27, we reject the 
null hypothesis and conclude that the treatment is acceptable if the number of responses in the efficacy 


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endpoint are > 3, and the number of toxicities are < 10; otherwise we conclude that the treatment is 
unacceptable. 
Below are the operating characteristics of the design based on 10000 simulations using the BOP2 web 
application, which is available at http://www.trialdesign.org. 
Table 15. Operating characteristics of BOP2 design 
Pr(Eff) Pr(Tox) Pr(Eff & Tox) Early stopping (%) Claim acceptable (%) Sample size 
0.1 
0.4 
0.04 
51.51 
7.58 
19.3 
0.3 
0.2 
0.08 
3.67 
92.27 
26.4 
0.4 
0.1 
0.06 
0.28 
99.61 
27.0 
0.3 
0.5 
0.20 
61.65 
5.40 
17.8 
0.1 
0.1 
0.03 
28.11 
26.04 
22.8 
The Investigator is responsible for completing safety/efficacy summary reports and submitting them to 
the IND office Medical Affairs and Safety Group for review and approval. These should be submitted as 
follows:  
Lead-In Phase: After the first 3 evaluable patients, complete 6 weeks of study treatment, and every 3 
evaluable subjects thereafter, IND Office approval must be obtained prior to advancing/changing dose 
levels. 
Phase II: After the first 12 evaluable subjects, and again after the first 27 evaluable subjects complete the 
first cycle of the combination treatment.  
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under “sponsor 
correspondence”. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
ETHICAL CONDUCT OF THE STUDY 
The study will be performed in accordance with ethical principles that have their origin in the Declaration 
of Helsinki and are consistent with ICH/GCP, and applicable regulatory requirements Patient data 
protection. 
10.2 
ETHICS AND REGULATORY REVIEW 
This study will be subject to subject to local IRB and federal oversight. 
10.3 
INFORMED CONSENT 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. The 
formal consent of a participant, using the IRB approved consent form, must be obtained before the 
participant is involved in any study-related procedure. The consent form must be signed and dated by the 
participant or the participant’s legally authorized representative, and by the person obtaining the consent. 
The participant must be given a copy of the signed and dated consent document. The original signed copy 
of the consent document must be retained in the medical record or research file. 
 
 


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10.4 
CHANGES TO THE PROTOCOL AND INFORMED CONSENT FORM 
This protocol, the proposed informed consent and all forms of participant information related to the study 
(e.g., advertisements used to recruit participants) and any other necessary documents must be submitted, 
reviewed and approved by the IRB, Aravive, and AstraZeneca. Any changes made to the protocol must be 
submitted as amendments and must be approved by the IRB and Aravive and AstraZeneca prior to 
implementation. Any changes in study conduct must be reported to the IRB, Aravive, and AstraZeneca. 
11. 
STUDY MANAGEMENT 
11.1 
MONITORING OF THE STUDY 
The study will be monitored by the M.D. Anderson IND office and a protocol specific monitoring plan 
will be followed. We will monitor unacceptable toxicity (defined as grade 3 or greater treatment-related 
AEs or discontinuation of the study regimen due to side effects) independently in each monotherapy 
treatment arm and in subsequent combination treatment, guarding against an unacceptable toxicity rate of 
40% or higher (based on published studies employing combination of other Anti-PD1/PDL1 agents), 
using the methods of Thall et al.[64]. 
11.2 
DATA MANAGEMENT 
Clinical study data for this trial will be collected and managed using the Prometheus database system.  
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other records 
transmitted outside the clinical site will be identified by a subject’s identification number or coded 
number and age. All study records, source medical records, and code sheets or logs linking a subject’s 
name to an SID number will be kept in a secure location. Study records such as CRFs may be maintained 
electronically and require the same security and confidentiality as paper. Clinical information will not be 
released without written permission of the subject/legal representative, except as specified in the ICF(s) 
(e.g., necessary for monitoring by regulatory authorities or the sponsor of the clinical study). The 
investigator must also comply with all applicable privacy regulations (e.g., HIPAA 1996, EU Data 
Protection Directive 95/46/EC). Study documents (including subject records, copies of data submitted to 
the MDACC IND Office, study notebook, and pharmacy records) must be kept secured in accordance 
with the specific data retention periods that are described in the clinical study site agreement and based 
upon local requirements. Study documents must not be destroyed without prior written approval of the 
sponsor study governance and oversight. 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by AstraZeneca 
representatives in consultation with Patient Safety. Similarly, safety of clinical studies with Aravive are 
monitored on an ongoing basis by Aravive representatives. Issues identified will be addressed; for 
instance, this could involve amendments to the study protocol and letters to Investigators. 
 


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Dosing Modifications and Toxicity Management Guidelines for Durvalumab and AVB-S6-500
Table 16. General Considerations regarding Immune-Mediated Reactions
These guidelines are provided as a recommendation to support investigators in the management of potential immune-mediated adverse events (imAEs). 
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-mediated reactions. Investigators are 
advised to take into consideration the appropriate practice guidelines and other society guidelines (e.g., NCCN, ESMO) in the management of these events.  Refer to the section 
of the table titled “Other -Immune-Mediated Reactions” for general guidance on imAEs not noted in the “Specific Immune-Mediated Reactions” section.
Early identification and management of immune-mediated adverse events (imAEs) are essential to ensure safe use of the study drug.  Monitor patients closely for symptoms and 
signs that may be clinical manifestations of underlying immune-mediated adverse events. Patients with suspected imAEs  should be thoroughly evaluated to rule out any 
alternative etiologies (e.g., disease progression, concomitant medications, infections). In the absence of a clear alternative etiology, all such events should be managed as if they 
were immune-mediated.  Institute medical management promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen for severe 
(Grade 3) imAEs. Permanently discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic 
immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. 
Based on the severity of the imAE, durvalumab VKRXOGEHZLWKKHOGDQGFRUWLFRVWHURLGVDGPLQLVWHUHG8SRQLPSURYHPHQWWR*UDGHFRUWLFRVWHURLGVKRXOGEHWDSHUHGRYHU28 
days.  More potent immunosuppressive agents such as TNF inhibitors (e.g., infliximab) should be considered for events not responding to systemic steroids. Alternative 
immunosuppressive agents not listed in this guideline may be considered at the discretion of the investigator based on clinical practice and relevant guidelines. With long-term 
steroid and other immunosuppressive use, consider need for Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii pneumonia) prophylaxis, 
gastrointestinal protection, and glucose monitoring.
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI CTCAE version in the applicable study protocol.
í
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; irAE immune-related adverse event; NCI National Cancer 
Institute.
Pediatric Considerations regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteURLG a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks of the start initiating corticosteroids.
í
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended.
í
The recommendations for steroid dosing (i.e., mg/kg/day) provided for adult 
patients should also be used for pediatric patients.
í
The recommendations for IVIG and plasmapheresis use provided for adult
patients may be considered for pediatric patients.
í
The infliximab 5 mg/kg IV one time dose recommended for adults is the 
VDPHDVUHFRPPHQGHGIRUSHGLDWULFSDWLHQWV\HDUVROG)RUsubsequent 
dosing in children  6 years old, consult a pediatric specialist.
í
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist.
gy,
g
In general, withhold study drug/study regimen for severe
g
p
p y,
g p
y
pp
p
g
,
y
g
y
g
(Grade 3) imAEs. Permanently discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic
(
)
y
y
g
y
g
g (
)
,
(
)
q
y
immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. 
Based on the severity of the imAE, durvalumab VKRXOGEHZLWKKHOGDQGFRUWLFRVWHURLGVDGPLQLVWHUHG8


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Dose Modifications
Toxicity Management
í
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring.
Table 17. Specific Immune-mediated Reactions
Adverse Events
Severity Grade of 
the Event
Dose Modifications
Toxicity Management
Pneumonitis/
Interstitial Lung 
Disease (ILD)
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade
í
Monitor patients for signs and symptoms of pneumonitis or ILD (new 
onset or worsening shortness of breath or cough). Patients should be 
evaluated with imaging and pulmonary function tests, including other 
diagnostic procedures as described below.
í
Suspected pneumonitis should be confirmed with radiographic imaging 
and other infectious and disease-related aetiologies excluded, and 
managed as described below.
í
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), laboratory work-
up, and high- resolution CT scan.
í
Consider Pulmonary and Infectious Diseases consults.
Grade 1
No dose modifications required. However, 
consider holding study drug/study regimen 
dose as clinically appropriate and during 
diagnostic work-up for other etiologies.
For Grade 1
í
Monitor and closely follow up in 2 to 4 days for clinical symptoms, pulse 
oximetry (resting and exertion), and laboratory work-up and then as 
clinically indicated.
í
Grade 2
Hold study drug/study regimen dose until 
*UDGHUHVROXWLRQWR*UDGH
x
If toxicity worsens, then treat as Grade 3 
or Grade 4.
x
,IWR[LFLW\LPSURYHVWR*UDGHWKHQ
the decision to reinitiate study 
drug/study regimen will be based upon 
treating physician’s clinical judgment 
and after completion of steroid taper.
For Grade 2
í
Monitor symptoms daily and consider hospitalization.
í
Promptly start systemic steroids (e.g., prednisone 1 to 2 mg/kg/day PO or 
IV equivalent).
í
Reimage as clinically indicated, consider chest CT with contrast and 
repeat in 3-4 weeks.
í
If no improvement within 2 to 3 days, additional workup should be 
considered and prompt treatment with IV methylprednisolone 2 to 
4 mg/kg/day started
í
If no improvement within 2 to 3 days despite IV methylprednisolone at 2 
to 4 mg/kg/day, promptly start immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV once, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the treating provider). Caution: 
It is important to rule out sepsis and refer to infliximab label for general 
guidance before using infliximab.
 Specific Immune-mediated Reactions
Pneumonitis/
Interstitial Lung
Disease (ILD)


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Version Date: April 6, 2021
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Adverse Events
Severity Grade of 
the Event
Dose Modifications
Toxicity Management
í
í
Consider, as necessary, discussing with study physician.
Grade 3 or 4
Permanently discontinue study drug/study 
regimen.
For Grade 3 or 4
í
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or 
equivalent.
í
Obtain Pulmonary and Infectious Diseases Consults; consider 
discussing with study physician as needed.
í
Hospitalize the patient.
í
Supportive care (e.g., oxygen).
í
If no improvement within 2 to 3 days, additional workup should be 
considered and prompt treatment with additional immunosuppressive 
therapy such as TNF inhibitors (e.g., infliximab at 5 mg/kg IV may be 
repeated at 2 and 6 weeks after initial dose at the discretion of the 
treating provider). Caution: rule out sepsis and refer to infliximab 
label for general guidance before using infliximab.
Diarrhea/Colitis
Any Grade
General Guidance
For Any Grade
í
Monitor for symptoms that may be related to diarrhea/enterocolitis 
(abdominal pain, cramping, or changes in bowel habits such as 
increased frequency over baseline or blood in stool) or related to 
bowel perforation (such as sepsis, peritoneal signs, and ileus).
孰
WHEN SYMPTOMS OR EVALUATION INDICATE A 
PERFORATION IS SUSPECTED, CONSULT A SURGEON 
EXPERIENCED IN ABDOMINAL SURGERY IMMEDIATELY 
WITHOUT ANY DELAY.
孰
PERMANENTLY DISCONTINUE STUDY DRUG FOR ANY 
GRADE OF INTESTINAL PERFORATION.
í
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections), 
including testing for clostridium difficile toxin, etc.
í
Steroids should be considered in the absence of clear alternative 
etiology, even for low-grade events, in order to prevent potential 
progression to higher grade event, including intestinal perforation.
í
Use analgesics carefully; they can mask symptoms of perforation and 
peritonitis.
Grade 1
No dose modifications.
For Grade 1
í
Monitor closely for worsening symptoms.
Diarrhea/Colitis


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number: 1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 66 
 
Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
í 
Consider symptomatic treatment, including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association 
colitis diet), loperamide, and other supportive care measures. Use 
probiotics as per treating physician’s clinical judgment. 
í 
If symptoms persist, consider checking lactoferrin; if positive, treat as 
Grade 2 below. If negative and no infection, continue Grade 1 
management. 
Grade 2 
 
 
Hold study drug/study regimen until 
UHVROXWLRQWR*UDGH 
x 
If toxicity worsens, then treat as Grade 3 
or Grade 4. 
x 
If toxicity LPSURYHVWR*UDGHWKHQ
study drug/study regimen can be 
resumed after completion of steroid 
taper. 
For Grade 2 
í 
Consider symptomatic treatment, including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or budesonide. 
í 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
í 
If event is not responsive within 2 to 3 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, consult a GI 
specialist for consideration of further workup, such as imaging and/or 
colonoscopy, to confirm colitis and rule out perforation. 
í 
If still no improvement within 2 to 3 days despite 1 to 2 mg/kg IV 
methylprednisolone, promptly start immunosuppressant agents such 
as infliximab at 5 mg/kg IV, may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the treating provider.. Caution: it is 
important to rule out bowel perforation and refer to infliximab label 
for general guidance before using infliximab. 
í 
Consider, as necessary, discussing with study physician if no 
UHVROXWLRQWR*UDGHLQWR days. 
Grade 3 or 4 
 
Grade 3 
x 
 For patient treated with PDL-1 
inhibitors, hold study drug/study 
regimen until resolution to Grade 
VWXG\GUXJVWXG\UHJLPHQFDQ
be resumed after completion of 
steroid taper. Permanently 
discontinue study drug/study 
regimen for Grade 3 if toxicity 
GRHVQRWLPSURYHWR*UDGH
within 14 days. 
x 
Permanently discontinue study 
For Grade 3 or 4: 
í 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
í 
Monitor stool frequency and volume and maintain hydration. 
í 
Urgent GI consult and imaging and/or colonoscopy as appropriate. 
í 
If still no improvement within 2 to 3 days, promptly add further 
immunosuppressants (e.g., infliximab at 5 mg/kg IV, may be repeated 
at 2 and 6 weeks after initial dose at the discretion of the treating 
provider). Caution: Ensure GI consult to rule out bowel perforation 
and refer to infliximab label for general guidance before using 
infliximab. If perforation is suspected, consult a surgeon experienced 
in abdominal surgery immediately without any delay. 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer
Version Number: 1.6
Protocol: 2019-0149
Version Date: April 6, 2021
Page 67
Adverse Events
Severity Grade of 
the Event
Dose Modifications
Toxicity Management
drug for 1) Grade 3 colitis in 
patients treated with CTLA-4 
inhibitors or 2) Any grade of 
intestinal perforation in any patient 
treated with ICI.  
Grade 4
Permanently discontinue 
study drug/study regimen. 
í
If perforation is suspected, consult a surgeon experienced in 
abdominal surgery immediately without any delay.
Hepatitis 
(elevated LFTs)
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis.
Any Grade
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade
í
Monitor and evaluate liver function test: AST, ALT, ALP, and TB.
í
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications).
Grade 1
x
No dose modifications.
x
If it worsens, then treat as Grade 2. 
For Grade 1
í
Continue LFT monitoring per protocol.
Grade 2
í
Hold study drug/study regimen 
dose until resolution to Grade
í
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
í
If toxicity improves to Grade or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper.
í
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (AST 
and/or ALT >3 î8/1ELOLUXELQ
>2 î8/1ZLWKRXWLQLWLDOILQGLQJV
of cholestasis (i.e., elevated 
alkaline P04) and in the absence of 
any alternative cause.b
For Grade 2:
í
Regular and frequent checking of LFTs (e.g., every 1 to 2 days) until 
LFT elevations improve or resolve.
í
If no resolution to *UDGH1 in 1 to 2 days, consider discussing with 
study physician as needed.
í
If event is persistent (>2 to 3 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent.
í
Grade 3 or 4
)RUHOHYDWLRQVLQWUDQVDPLQDVHVîULN, or 
HOHYDWLRQVLQ7%îULN:
For Grade 3 or 4:
PLEASE SEE 
shaded area 
immediately below
this section to find
guidance for
management of
“Hepatitis (elevated 
LFTS)” in HCC 
patients
Hepatitis 
(elevated LFTs)


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer
Version Number: 1.6
Protocol: 2019-0149
Version Date: April 6, 2021
Page 68
Adverse Events
Severity Grade of 
the Event
Dose Modifications
Toxicity Management
x
Hold study drug/study regimen dose 
until resolution to Grade or baseline
x
Resume study drug/study regimen if 
elevations downgrade to Grade or 
baseline within 14 days and after 
completion of steroid taper.
x
Permanently discontinue study 
drug/study regimen if the elevations do 
not downgrade to Grade1 or baseline
within 14 days.
í
Promptly initiate empiric IV methylprednisolone at 1 to 2 mg/kg/day 
or equivalent.
í
If still no improvement within 2 to 3 days despite 1 to 2 mg/kg/day 
methylprednisolone IV or equivalent, promptly start treatment with an
immunosuppressant therapy (i.e., mycophenolate mofetil 0.5 – 1 g 
every 12 hours then taper in consultation with hepatology consult). 
Discuss with study physician if mycophenolate is not available. 
Infliximab should NOT be used.
í
Perform Hepatology Consult, perform abdominal workup, and 
imaging as appropriate.
Hepatitis 
(elevated LFTs)
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis.
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
Any Elevations of 
AST, ALT, or TB as 
Described Below
General Guidance
For Any Elevations Described:
í
Monitor and evaluate liver function test: AST, ALT, ALP, and TB.
í
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of liver cirrhosis 
[e.g., portal vein thrombosis]).
í
For HBV+ patients: evaluate quantitative HBV viral load, quantitative 
HBsAg, or HBeAg
í
For HCV+ patients: evaluate quantitative HCV viral load
í
Consider consulting Hepatology or Infectious Diseases specialists
regarding changing or starting antiviral HBV medications for any 
patient if HBV viral load is >2000 IU/ml.
í
Consider consulting Hepatology or Infectious Diseases specialists
regarding changing or starting HCV medications if HCV viral load 
LQFUHDVHGE\-fold
í
For HCV+ with HBcAb+: Evaluate for both HBV and HCV as above
THIS shaded area 
is guidance only for
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients
Any Elevations of 
AST, ALT, or TB as 
Described Below
Hepatitis 
(elevated LFTs)
Infliximab should 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number: 1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 69 
 
Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
 
Isolated AST or 
ALT >ULN and 
î8/1ZKHWKHU
normal or elevated 
at baseline  
x 
No dose modifications. 
x 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as 
described for elevations in the row 
below. 
For all transaminase elevations, see 
instructions at bottom of shaded area if 
transaminase rise is not isolated but (at any 
time) occurs in setting of either increasing 
bilirubin or signs of DILI/liver 
decompensation 
 
 
 
Isolated AST or ALT 
!î8/1DQG
î8/1LIQRUPDO
at baseline 
 
Isolated AST or ALT 
!îEDVHOLQHDQG
î8/1LI
elevated >ULN at 
baseline 
x 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
î8/1 
x 
If toxicity worsens, then treat as 
described for elevations in the rows 
below. 
x 
If toxicity improves to AST or ALT 
î8/1UHVXPHVWXG\GUXJVWXG\
regimen after completion of steroid 
taper. 
x 
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria, in the absence of any 
alternative cause.b 
í 
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) until 
elevations of these are improving or resolved. 
í 
Recommend consult hepatologist; consider abdominal ultrasound, 
including Doppler assessment of liver perfusion. 
í 
Consider, as necessary, discussing with study physician. 
í 
If event is persistent (>2 to 3 days) or worsens, and investigator 
suspects toxicity to be im AE, start prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. 
í 
If still no improvement within 2 to 3 days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, consider additional workup. If still 
no improvement within 2 to 3 days despite 1 to 2 mg/kg/day of IV 
methylprednisolone, consider additional abdominal workup (including 
liver biopsy) and imaging (i.e., liver ultrasound), and consider starting 
immunosuppressants (i.e., mycophenolate mofetil 0.5 – 1 g every 12 
hours then taper in consultation with hepatology consult).a Discuss 
with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
 
 
Isolated AST or ALT 
!î8/1DQG
î8/1LI
normal at baseline 
 
x 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
î8/1 
x Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
í 
Regular and frequent checking of LFTs (e.g., every 1-2 days) until 
elevations of these are improving or resolved. 
í 
Consult hepatologist (unless investigator is hepatologist); obtain 
abdominal ultrasound, including Doppler assessment of liver 
perfusion; and consider liver biopsy. 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number: 1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 70 
 
Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
Isolated AST or ALT 
!î8/1DQG
î8/1LI
elevated >ULN at 
baseline 
î8/1ZLWKLQ days and after 
completion of steroid taper. 
x Permanently discontinue study 
drug/study regimen if the elevations do 
not downgrade to AST or ALT 
î8/1ZLWKLQ days 
Permanently discontinue study 
drug/study regimen for any case meeting 
Hy’s law criteria, in the absence of any 
alternative cause.b 
í 
Consider discussing with study physician as needed. 
í 
If investigator suspects toxicity to be immune-mediated, promptly 
initiate empiric IV methylprednisolone at 1 to 2 mg/kg/day or 
equivalent. 
í 
If no improvement within 2 to 3 days despite 1 to 2 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it has not 
been done already) and promptly start treatment with an 
immunosuppressive therapy (mycophenolate mofetil 0.5 – 1 g every 
12 hours then taper in consultation with hepatology consult). Discuss 
with study physician if mycophenolate is not available. Infliximab 
should NOT be used. 
 
Isolated AST or ALT 
!î8/1ZKHWKHU
normal or elevated at 
baseline 
Permanently discontinue study 
drug/study regimen. 
Same as above  
(except would recommend obtaining liver biopsy early) 
í 
 
If transaminase rise is not isolated but (at any time) occurs in seWWLQJRIHLWKHULQFUHDVLQJWRWDOGLUHFWELOLUXELQî8/1LIQRUPDODWEDVHOLQHRUîEDVHOLQHLI!8/1
at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase rise 
- 
For example, manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0î8/1DQGî8/1, if normal at baseline, or AST or ALT 
>2.0îEDVHOLQHDQGî8/1LI elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0î8/1DQGî8/1
LIQRUPDODWEDVHOLQHRU$67RU$/7!î8/1DQGî8/1LI elevated >ULN at baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
í 
Consult a nephrologist. 
í 
Monitor for signs and symptoms that may be related to changes in 
renal function (e.g., routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, electrolyte imbalance, 
decrease in urine output, or proteinuria). 
í 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, recent IV contract, 
medications, fluid status). 
Consider using steroids in the absence of clear alternative etiology even for low-
grade events (Grade 2), in order to prevent potential progression to higher grade 
event. 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number: 1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 71 
 
Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
Grade 1 
No dose modifications. 
For Grade 1: 
í 
Monitor serum creatinine weekly and any accompanying symptoms. 
x 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
x 
If creatinine worsens, depending on the severity, treat as 
Grade 2, 3, or 4. 
í 
Consider symptomatic treatment, including hydration, electrolyte 
replacement, and diuretics. 
í 
If baseline serum creatinine is elevated above normal, and there is a 
rise to > WRîEDVHOLQHFRQVLGHUIROORZLQJUHFRPPHQGDWLRQVLQ
this row.  
Grade 2 
Hold study drug/study regimen until 
UHVROXWLRQWR*UDGHRUEDVHOLQH 
x 
If toxicity worsens, then treat as Grade 3 
or 4. 
x 
,IWR[LFLW\LPSURYHVWR*UDGHRU
baseline, then resume study drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
í 
Consider symptomatic treatment, including hydration, electrolyte 
replacement, and diuretics. 
í 
Carefully monitor serum creatinine every 2 to 3 days and as clinically 
warranted. 
í 
Consult nephrologist and consider renal biopsy if clinically indicated. 
í 
If event is persistent beyond 3 to 5 days or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
í 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, consider 
additional workup   . 
í 
When event returns to baseline, resume study drug/study regimen and 
routine serum creatinine monitoring per study protocol. 
Grade 3 or 4 
  
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
í 
Carefully monitor serum creatinine. 
í 
Consult nephrologist and consider renal biopsy if clinically indicated. 
í 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
í 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, consider 
additional workup and prompt treatment with an immunosuppressant 
in consultation with a nephrologist. 
Rash or Dermatitis 
Any Grade 
General Guidance 
For Any Grade: 
í 
Monitor for signs and symptoms of dermatitis (rash and pruritus). 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number: 1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 72 
 
Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
(including 
Pemphigoid) 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
definition of 
severity/grade 
depending on type of 
skin rash)  
í 
HOLD STUDY DRUG IF STEVENS-JOHNSON SYNDROME 
(SJS), TOXIC EPIDERMAL NECROLYSIS (TEN), OR OTHER 
SEVERE CUTANEOUS ADVERSE REACTION (SCAR) IS 
SUSPECTED.  
í 
PERMANENTLY DISCONTINUE STUDY DRUG IF SJS, TEN, 
OR SCAR IS CONFIRMED. 
Grade 1 
No dose modifications. 
For Grade 1: 
í 
Consider symptomatic treatment, including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., emollient, 
lotion, or institutional standard). 
Grade 2 
For persistent (>1 week) Grade 2 events, 
hold scheduled study drug/study regimen 
XQWLOUHVROXWLRQWR*UDGHRUEDVHOLQH 
x 
If toxicity worsens, then treat as 
Grade 3. 
x 
,IWR[LFLW\LPSURYHVWR*UDGHRU
baseline, then resume drug/study 
regimen after completion of steroid 
taper. 
For Grade 2 
í 
Obtain Dermatology consult. 
í 
Consider symptomatic treatment, including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy. 
í 
Consider moderate-strength topical steroid. 
í 
If no improvement of rash/skin lesions occurs within 3 days or is 
worsening despite symptomatic treatment and/or use of moderate 
strength topical steroid, consider discussing with study physician, as 
needed, and promptly start systemic steroids such as prednisone 1 to 2 
mg/kg/day PO or IV equivalent. If > 30% body surface area is 
involved, consider initiation of systemic steroids promptly. 
í 
Consider skin biopsy if the event persists for >1 week or recurs. 
Grade 3 or 4 
For Grade 3 
x 
Hold study drug/study regimen until 
UHVROXWLRQWR*UDGHRUEDVHOLQH 
x 
,IWR[LFLW\LPSURYHVWR*UDGHRU
baseline, then resume drug/study 
regimen after completion of steroid 
taper. 
For Grade 3 or 4 
í 
Consult Dermatology. 
í 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
í 
Consider hospitalization. 
í 
Monitor extent of rash [Rule of Nines]. 
í 
Consider skin biopsy (preferably more than 1) as clinically feasible. 
í 
Consider, as necessary, discussing with study physician. 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number: 1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 73 
 
Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
x 
If toxicity worsens, then treat as Grade 
4. 
 
For Grade 4 
Permanently discontinue study drug/study 
regimen. 
 
Endocrinopathy 
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, type 
1 diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency) 
 
Any Grade 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
applicable version in 
study protocol for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
í 
Consider consulting an endocrinologist for endocrine events. 
í 
Consider discussing with study physician as needed. 
í 
Monitor patients for signs and symptoms of endocrinopathies. Non-
specific symptoms include headache, fatigue, behavior changes, 
mental status changes, photophobia, visual field cuts, vertigo, 
abdominal pain, unusual bowel habits, polydipsia, polyuria, 
hypotension, and weakness. 
í 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression including brain metastases, or 
infections). 
í 
Depending on the suspected endocrinopathy, monitor and evaluate 
thyroid function tests: TSH, free T3 and free T4 and other relevant 
endocrine and related labs (e.g., blood glucose and ketone levels, 
HgA1c). 
í 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, or 
diabetes insipidus), the investigator should send a blood sample for 
appropriate autoimmune antibody testing. 
í 
Investigators should ask subjects with endocrinopathies who may 
require prolonged or continued hormonal replacement, to consult their 
primary care physicians or endocrinologists about further monitoring 
and treatment after completion of the study. 
 
Grade 1 
No dose modifications. 
For Grade 1 
í 
Monitor patient with appropriate endocrine function tests. 
í 
For suspected hypophysitis/hypopituitarism, consider consultation of 
an endocrinologist to guide assessment of early-morning ACTH, 
cortisol, TSH and free T4; also consider gonadotropins, sex hormones, 
and prolactin levels, as well as cosyntropin stimulation test (though it 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
Version Number: 1.6 
Protocol: 2019-0149 
 
Version Date: April 6, 2021 
Page 74 
 
Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
may not be useful in diagnosing early secondary adrenal 
insufficiency). 
í 
,I76+î//1RU76+!î8/1RUFRQVLVWHQWO\RXWRIUDQJH
in 2 subsequent measurements, include free T4 at subsequent cycles as 
clinically indicated and consider consultation of an endocrinologist. 
Grade 2, 3, or 4 
x 
For Grade 2-4 endocrinopathies 
other than hypothyroidism and 
Type 1 diabetes mellitus, consider 
holding study drug/study regimen 
dose until acute symptoms resolve. 
x 
Study drug/study regimen can be 
resumed once patient stabilizes and 
after completion of steroid taper. 
x 
Patients with endocrinopathies who 
may require prolonged or 
continued steroid replacement 
(e.g., adrenal insufficiency) can be 
retreated with study drug/study 
regimen patient is clinically stable 
as per investigator or treating 
physician’s clinical judgement. 
x 
If toxicity worsens, then treat based 
on severity. 
For Grade 2, 3, or 4 
í 
Consult endocrinologist to guide evaluation of endocrine function and, 
as indicated by suspected endocrinopathy and as clinically indicated, 
consider pituitary scan. 
í 
For all patients with abnormal endocrine work up, except those with 
isolated hypothyroidism or type 1 DM, and as guided by an 
endocrinologist, consider short-term corticosteroids (e.g., 1 to 
2 mg/kg/day methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone replacement (e.g., 
hydrocortisone, sex hormones). 
í 
Isolated hypothyroidism may be treated with replacement therapy, 
without study drug/study regimen interruption, and without 
corticosteroids. 
í 
Isolated type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, and without corticosteroids. Only hold 
study drug/study regimen in setting of hyperglycemia when 
diagnostic workup is positive for diabetic ketoacidosis. 
í 
For patients with normal endocrine workup (laboratory assessment or 
MRI scans), repeat laboratory assessments/MRI as clinically 
indicated. 
 
1. 
 
 
Amylase/Lipase 
increased 
 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity) 
General Guidance 
For Any Grade 
í 
For modest asymptomatic elevations in serum amylase and lipase, 
corticosteroid treatment is not indicated as long as there are no other 
signs or symptoms of pancreatic inflammation.  
í 
Assess for signs/symptoms of pancreatitis  
í 
Consider appropriate diagnostic testing (e.g., abdominal CT with 
contrast, MRCP if clinical suspicion of pancreatitis and no radiologic 
evidence on CT) 
í 
If isolated elevation of enzymes without evidence of pancreatitis, 
continue immunotherapy.  Consider other causes of elevated 
amylase/lipase 


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Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
í 
If evidence of pancreatitis, manage according to pancreatitis 
recommendations  
 
Grade 1 
No dose modifications. 
 
 
Grade 2, 3, or 4 
For Grade 2, 3, or 4 
In consultation with relevant pancreatic 
specialist consider continuing study 
drug/study regimen if no clinical/radiologic 
evidence of pancreatitis ± improvement in 
amylase/lipase. 
 
Acute Pancreatitis 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity) 
General Guidance 
For Any Grade 
í 
Consider Gastroenterology referral  
 
Grade 1 
No dose modifications. 
For Grade 1 
í 
IV hydration 
í 
Manage as per amylase/lipase increased (asymptomatic) 
 
Grade 2, 3, or 4 
For Grade 2 
Hold study drug/study regimen dose until 
UHVROXWLRQWR*UDGH 
For Grade 3 or 4 
Permanently discontinue study drug/study 
regimen. 
For Grade 2, 3, or 4 
í 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
í 
IV hydration 
Neurotoxicity 
(to include but not be 
limited to non-
infectious meningitis, 
non-infectious 
encephalitis and 
Any Grade 
(Depending on the 
type of neurotoxicity, 
refer to NCI CTCAE 
applicable version in 
study protocol for 
General Guidance 
For Any Grade: 
í 
Patients should be evaluated to rule out any alternative etiology (e.g., 
disease progression, infections, metabolic syndromes, or medications). 
í 
Monitor patient for general symptoms (headache, nausea, vertigo, 
behavior change, or weakness). 
í 
Consider appropriate diagnostic testing (e.g., electromyogram and 
nerve conduction investigations). 


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Adverse Events 
Severity Grade of 
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Dose Modifications 
Toxicity Management 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
defining the CTC 
grade/severity) 
í 
Perform symptomatic treatment with Neurology consult as 
appropriate. 
í 
FOR TRANSVERSE MYELITIS, PERMANENTLY 
DISCONTINUE FOR ANY GRADE. 
Grade 1 
No dose modifications. 
For Grade 1 
í 
See “Any Grade” recommendations above. 
í 
Treat mild signs/symptoms as Grade 1 (e.g.  loss of deep tendon 
reflexes or paresthesia) 
Grade 2 
x 
For acute motor neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose until 
UHVROXWLRQWR*UDGH 
x 
For sensory 
neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to 
*UDGH 
x 
Permanently discontinue study 
drug/study regimen if Grade 2 
imAE does not resolve to *UDGH
within 30 days. 
x 
If toxicity worsens, then treat as 
Grade 3 or 4. 
For Grade 2 
í 
Consider, as necessary, discussing with the study physician. 
í 
Obtain Neurology consult. 
í 
Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin or duloxetine). 
í 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. 
í 
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup and 
promptly treat with additional immunosuppressive therapy (e.g., IV 
IG). 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 
í 
Consider, as necessary, discussing with study physician. 
í 
Obtain Neurology consult. 
í 
Consider hospitalization. 
í 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
í 
If no improvement within 2 to 3 days despite IV corticosteroids, 
consider additional workup and promptly treat with an additional 


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Version Date: April 6, 2021 
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Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
immunosuppressant (e.g., IV IG or other immunosuppressant 
depending on the specific imAE). 
í 
2QFHVWDEOHJUDGXDOO\WDSHUVWHURLGVRYHUGD\V 
Peripheral 
neuromotor 
syndromes 
(such as Guillain-
Barre and myasthenia 
gravis) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
í 
The prompt diagnosis of immune-mediated peripheral neuromotor 
syndromes is important, since certain patients may unpredictably 
experience acute decompensations that can result in substantial 
morbidity or in the worst case, death. Special care should be taken for 
certain sentinel symptoms that may predict a more severe outcome, 
such as prominent dysphagia, rapidly progressive weakness, and signs 
of respiratory insufficiency or autonomic instability. 
í 
Patients should be evaluated to rule out any alternative etiology (e.g., 
disease progression, infections, metabolic syndromes or medications). 
It should be noted that the diagnosis of immune-mediated peripheral 
neuromotor syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding effects of 
cancer (and its treatments) throughout the neuraxis. Given the 
importance of prompt and accurate diagnosis, it is essential to have a 
low threshold to obtain a Neurology consult. 
í 
Neurophysiologic diagnostic testing (e.g., electromyogram and nerve 
conduction investigations, and “repetitive stimulation” if myasthenia 
is suspected) are routinely indicated upon suspicion of such conditions 
and may be best facilitated by means of a Neurology consultation. 
í 
It is important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered effective. 
Patients requiring treatment should be started with IV IG and followed 
by plasmapheresis if not responsive to IV IG. 
 
Grade 1 
    
No dose modifications. 
For Grade 1 
í 
Consider discussing with the study physician as needed. 
í 
Care should be taken to monitor patients for sentinel symptoms of a 
potential decompensation as described above. 
í 
Consult a neurologist. 
Grade 2 
x 
Hold study drug/study regimen 
GRVHXQWLOUHVROXWLRQWR*UDGH 
x 
Permanently discontinue study 
drug/study regimen if it does not 
For Grade 2 
í 
Consider discussing with the study physician as needed. 
í 
Care should be taken to monitor patients for sentinel symptoms of a 
potential decompensation as described above. 


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Adverse Events 
Severity Grade of 
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Dose Modifications 
Toxicity Management 
UHVROYHWR*UDGHZLWKLQGD\V
or if there are signs of respiratory 
insufficiency or autonomic 
instability. 
í 
Consult a neurologist. 
í 
Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision of a 
consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IV IG. Such decisions are 
best made in consultation with a neurologist, taking into 
account the unique needs of each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, consider 
starting AChE inhibitor therapy in addition to steroids. Such 
therapy, if successful, can also serve to reinforce the 
diagnosis. 
o 
Avoid medications that can worsen myasthenia gravis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. 
o 
Patients requiring treatment should be started with IV IG 
and followed by plasmapheresis if not responsive to IV IG. 
 
Grade 3 or 4 
For Grade 3 
x 
Hold study drug/study regimen 
GRVHXQWLOUHVROXWLRQWR*UDGH 
x 
Permanently discontinue study 
drug/study regimen if Grade 3 
LP$(GRHVQRWUHVROYHWR*UDGH
within 30 days or if there are signs 
of respiratory insufficiency or 
autonomic instability. 
 
For Grade 3 or 4 
í 
Consider discussing with study physician as needed. 
í 
Recommend hospitalization. 
í 
Monitor symptoms and obtain Neurology consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IV IG. 


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Protocol: 2019-0149 
 
Version Date: April 6, 2021 
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Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
 
For Grade 4 
Permanently discontinue study drug/study 
regimen. 
o 
If myasthenia gravis-like neurotoxicity present, consider 
starting AChE inhibitor therapy in addition to steroids. Such 
therapy, if successful, can also serve to reinforce the 
diagnosis. 
o 
Avoid medications that can worsen myasthenia gravis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. 
o 
Patients requiring treatment should be started with IV IG 
and followed by plasmapheresis if not responsive to IV IG. 
Myocarditis 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity) 
General Guidance 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis. 
For Any Grade 
í 
The prompt diagnosis of immune-mediated myocarditis is important, 
particularly in patients with baseline cardiopulmonary disease and 
reduced cardiac function.  
í 
Consider discussing with the study physician as needed. 
í 
Monitor patients for signs and symptoms of myocarditis (new onset or 
worsening chest pain, arrhythmia, shortness of breath, peripheral 
edema). As some symptoms can overlap with lung toxicities, 
simultaneously evaluate for and rule out pulmonary toxicity as well as 
other causes (e.g., pulmonary embolism, congestive heart failure, 
malignant pericardial effusion). Consult a cardiologist early to 
promptly assess whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
í 
Initial work-up should include clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram (ECHO), monitoring of oxygenation 
via pulse oximetry (resting and exertion), and additional laboratory 
work-up as indicated. Spiral CT or cardiac MRI can complement 
ECHO to assess wall motion abnormalities when needed. 
í 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections) 
 
Grade 1 
 
No dose modifications required unless 
clinical suspicion is high, in which case hold 
study drug/study regimen dose during 
diagnostic work-up for other etiologies. If 
study drug/study regimen is held, resume 
after complete resolution to Grade 0. 
 
For Grade 1 
- 
Monitor and closely follow up in 2 to 4 days for clinical symptoms, 
BNP, cardiac enzymes, ECG, ECHO, pulse oximetry (resting and 
exertion), and laboratory work-up as clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 


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Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
 
Grade 2, 3 or 4 
 
x 
If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly 
improves to Grade 0, then the 
decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study 
regimen. 
x 
If Grade 3-4, permanently 
discontinue study drug/study 
regimen. 
For Grade 2-4 
í 
Monitor symptoms daily, hospitalize. 
í 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or equivalent 
after Cardiology consultation has determined whether and when to 
complete diagnostic procedures including a cardiac biopsy. 
í 
Supportive care (e.g., oxygen). 
í 
If no improvement within 2 to 3 days despite IV methylprednisolone 
at 2 to 4 mg/kg/day, promptly start immunosuppressive therapy such 
as TNF inhibitors (e.g., infliximab at 5 mg/kg IV, may be repeated at 
2 and 6 weeks after initial dose at the discretion of the treating 
provider). Caution: It is important to rule out sepsis and refer to 
infliximab label for general guidance before using infliximab. 
Infliximab is contraindicated for patients who have heart failure. 
í 
2QFHWKHSDWLHQWLVLPSURYLQJJUDGXDOO\WDSHUVWHURLGVRYHUGD\V
and consider prophylactic antibiotics, antifungals, or anti-PJP 
treatment (refer to current NCCN guidelines for treatment of cancer-
related infections).a 
Myositis/Polymyositis 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for defining 
the CTC 
grade/severity) 
General Guidance 
For Any Grade 
í 
Monitor patients for signs and symptoms of poly/myositis. Typically, 
muscle weakness/pain occurs in proximal muscles including upper 
arms, thighs, shoulders, hips, neck and back, but rarely affects the 
extremities including hands and fingers; also difficulty breathing 
and/or trouble swallowing can occur and progress rapidly. Increased 
general feelings of tiredness and fatigue may occur, and there can be 
new-onset falling, difficulty getting up from a fall, and trouble 
climbing stairs, standing up from a seated position, and/or reaching 
up. 
í 
If poly/myositis is suspected, a Neurology consultation should be 
obtained early, with prompt guidance on diagnostic procedures. 
Myocarditis may co-occur with poly/myositis; refer to guidance under 
Myocarditis. Given breathing complications, refer to guidance under 
Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation. 
í 
Consider, as necessary, discussing with the study physician. 
í 
Initial work-up should include clinical evaluation, creatine kinase, 
aldolase, LDH, BUN/creatinine, erythrocyte sedimentation rate or C-
reactive protein level, urine myoglobin, and additional laboratory 


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Version Date: April 6, 2021 
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Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
work-up as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider whether a 
rheumatologist consultation is indicated and could guide need for 
rheumatoid factor, antinuclear antibody, anti-smooth muscle, 
antisynthetase [such as anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include electromyography, 
nerve conduction studies, MRI of the muscles, and/or a muscle 
biopsy. Consider Barium swallow for evaluation of dysphagia or 
dysphonia. 
í 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
 
Grade 1 
x 
No dose modifications. 
For Grade 1 
í 
Monitor and closely follow up in 2 to 4 days for clinical symptoms 
and initiate evaluation as clinically indicated. 
í 
Consider Neurology consult. 
í 
Consider, as necessary, discussing with the study physician. 
 
Grade 2 
x 
Hold study drug/study regimen 
GRVHXQWLOUHVROXWLRQWR*UDGH 
x 
Permanently discontinue study 
drug/study regimen if it does not 
resolve to *UDGHZLWKLQGD\V
or if there are signs of respiratory 
insufficiency. 
For Grade 2 
í 
Monitor symptoms daily and consider hospitalization. 
í 
Obtain Neurology consult, and initiate evaluation. 
í 
Consider, as necessary, discussing with the study physician. 
í 
If clinical course is rapidly progressive (particularly if difficulty 
breathing and/or trouble swallowing), promptly start IV 
methylprednisolone 2 to 4 mg/kg/day systemic steroids along with 
receiving input from Neurology consultant  
í 
If clinical course is not rapidly progressive, start systemic steroids 
(e.g., prednisone 1 to 2 mg/kg/day PO or IV equivalent); if no 
improvement within 2 to 3 days, continue additional work up and start 
treatment with IV methylprednisolone 2 to 4 mg/kg/day 
í 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no 
improvement within 2 to 3 days, consider starting  another 
immunosuppressive therapy such as TNF inhibitors (e.g., infliximab 
at 5 mg/kg IV, may be repeated at 2 and 6 weeks after initial dose at 
the discretion of the treating provider). Caution: It is important to 
rule out sepsis and refer to infliximab label for general guidance 
before using infliximab. 
 
Grade 3 or 4 
For Grade 3 
x 
Hold study drug/study regimen 
For Grade 3 or 4 
í 
Monitor symptoms closely; recommend hospitalization. 
í 
Obtain Neurology consult. 


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Adverse Events 
Severity Grade of 
the Event 
Dose Modifications 
Toxicity Management 
GRVHXQWLOUHVROXWLRQWR*UDGH 
x 
Permanently discontinue study 
drug/study regimen if Grade 3 
LP$(GRHVQRWUHVROYHWR*UDGH
within 30 days or if there are signs 
of respiratory insufficiency. 
 
For Grade 4 
x 
Permanently discontinue study 
drug/study regimen. 
í 
Consider discussing with the study physician as needed. 
í 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from Neurology consultant. 
í 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day there is no 
improvement within 2 to 3 days, consider starting another 
immunosuppressive therapy such as TNF inhibitors (e.g., infliximab 
at 5 mg/kg IV, may be repeated at 2 and 6 weeks after initial dose at 
the discretion of the treating provider). Caution: It is important to 
rule out sepsis and refer to infliximab label for general guidance 
before using infliximab. 
í 
Consider whether patient may require IV IG, plasmapheresis. 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
cNCCN Clinical Practice Guidelines in Oncology “Management of Immunotherapy-Related Toxicities” Version 1.2020 – December  2019 
 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; 
BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  
National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); 
PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 
 


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Table 18. Other–Immune-Mediated Reactions
Severity Grade of the Event 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity)
Dose Modifications
Toxicity Management
Any Grade
Note: It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all 
organs, some of them are not noted specifically in these 
guidelines (e.g. immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis).
í
The study physician may be contacted for immune-mediated 
reactions not listed in the “specific immune-mediated 
reactions” section
í
Thorough evaluation to rule out any alternative etiology 
(e.g., disease progression, concomitant medications, and 
infections)
í
Consultation with relevant specialist
í
Treat accordingly, as per institutional standard.
Grade 1
No dose modifications.
Monitor as clinically indicated
Grade 2
x
Hold study drug/study regimen until resolution to 
*UDGHRUEDVHOLQH
x
If toxicity worsens, then treat as Grade 3 or Grade 4.
x
Study drug/study regimen can be resumed once event 
VWDELOL]HVWR*UDGHDIWHUFRPSOHWLRQRIVWHURLG
taper.
x
Consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality when they 
do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper
For Grade 2, 3, or 4
Treat accordingly, as per institutional standard, appropriate 
clinical practice guidelines, and other society guidelines 
(e.g., NCCN, ESMO) 
Grade 3
Hold study drug/study regimen 
Grade 4
Permanently discontinue study drug/study regimen 
Other–Immune-Mediated Reactions
Table 18.


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
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Protocol: 2019-0149 
 
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Table 19. Infusion-related Reactions 
Severity Grade of the Event 
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the CTC 
grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade 
í 
Manage per institutional standard at the discretion of investigator. 
í 
Monitor patients for signs and symptoms of infusion-related reactions 
(e.g., fever and/or shaking chills, flushing and/or itching, alterations in 
heart rate and blood pressure, dyspnea or chest discomfort, or skin 
rashes) and anaphylaxis (e.g., generalized urticaria, angioedema, 
wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1 
The infusion rate of study drug/study regimen may be decreased by 
50% or temporarily interrupted until resolution of the event. 
 
For Grade 2 
The infusion rate of study drug/study regimen may be decreased 50% 
or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial infusion rate. 
For Grade 1 or 2 
í 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
í 
Consider premedication per institutional standard prior to subsequent 
doses. 
í 
6WHURLGVVKRXOGQRWEHXVHGIRUURXWLQHSUHPHGLFDWLRQRI*UDGH
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4 
í 
Manage severe infusion-related reactions per institutional standards 
(e.g., IM epinephrine, followed by IV diphenhydramine and famotidine, 
and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 
 
 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer 
 
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Table 20. Non-immune-mediated Reactions 
Severity Grade of the Event  
(Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTC grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to be related to study treatment 
(i.e., events due to underlying disease) or for laboratory abnormalities not deemed to be clinically 
significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
+ROGVWXG\GUXJVWXG\UHJLPHQXQWLOUHVROXWLRQWR*UDGHRUEDVHOLQH 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold VWXG\GUXJVWXG\UHJLPHQXQWLOUHVROXWLRQWR*UDGHRUEDVHOLQH 
)RU$(VWKDWGRZQJUDGHWR*UDGHZLWKLQGD\VRUUHVROYHWR*UDGHRUEDVHOLQHZLWKLQ
days, resume study drug/study regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
Discontinue study drug/study regimen (Note: For Grade 4 labs, decision to discontinue should be 
based on accompanying clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the MDACC IND Office and supporting companies.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with primary investigator.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer
Version Number: 1.6
Protocol: 2019-0149
Version Date: April 6, 2021
Page 86
ECOG Performance Status Criteria
Table 21. ECOG Performance Status Criteria
Status
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.


AVB-S6-500 and Durvalumab in Recurrent Ovarian Cancer
Version Number: 1.6
Protocol: 2019-0149
Version Date: April 6, 2021
Page 87
Durvalumab Weight-based Dose Calculations
Durvalumab Dosing
For patients weighing < 30 kg, durvalumab should be dosed at 20 mg/kg. There is no 
modification to the durvalumab regimen in dose de-escalation, therefore this weight based 
dosing applies for any patient who falls below this cut off of < 30 kg (in the combination therapy 
portion of the trial with durvalumab + AVB-S6-500).
Example: 
1. Cohort dose: 20 mg/kg
2. Patient weight: 29 kg
3. Dose for patient: 580 mg = 2PJNJî29 (kg)
4. Dose to be added into infusion bag: [rounded to the nearest tenth mL (0.1 mL)]:
Dose (mL) = 580 mg / 50 (mg/mL) = 11.6 mL
5. The number of vials required for dose preparation: 
Number of vials = 11.6 (mL) / 10.0 (mL/vial) = 2 vials

ICF_000.pdf: 
Protocol 2019-0149 
May 19, 2021 
Page 1 of 14 
 
 
Informed Consent 
 
 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN 
RESEARCH 
 
Randomized Phase I/II study of AVB-S6-500 in Combination with 
Durvalumab (MEDI4736) in Patients with Platinum-resistant, Recurrent 
Epithelial Ovarian Cancer 
2019-0149 
 
 
Study Chair: 
Amir A. Jazaeri 
 
_________________________ 
_____________________ 
Participant’s Name  
 
Medical Record Number  
 
This is an informed consent and authorization form for a research study. It includes a 
summary about the study. A more detailed description of procedures and risks is 
provided after the summary.  
 
STUDY SUMMARY 
 
This study has 2 phases: Phase 1 (dose finding) and Phase 2 (dose expansion).  
 
The goal of Phase 1 of this clinical research study is to find the highest tolerable dose 
of AVB-S6-500 that can be given in combination with durvalumab to patients with 
platinum-resistant epithelial, ovarian, peritoneal, or fallopian tube cancer that is 
recurrent (has returned after treatment). 
 
The goal of Phase 2 of this clinical research study is to learn if the highest tolerable 
dose combination of AVB-S6-500 and durvalumab found in Phase 1 can help to 
control these cancer types.  
 
The safety of this drug combination will also be studied in both parts. 
 
This is an investigational study.  AVB-S6-500 is not FDA approved or commercially 
available. It is currently being used for research purposes only. Durvalumab is FDA 
approved and commercially available for the treatment for certain types of urothelial 
cancer, but not for the types of cancer in this study. The use of the study drug 
combination in these disease types is investigational. The study doctor can explain 
how the study drugs are designed to work. 
 


Protocol 2019-0149 
May 19, 2021 
Page 2 of 14 
 
The study drugs may help to control the disease. Future patients may benefit from 
what is learned. There may be no benefits for you in this study. 
 
Your participation is completely voluntary. Before choosing to take part in this study, 
you should discuss with the study team any concerns you may have, including side 
effects, potential expenses, and time commitment. If you take part in this study, you 
may experience side effects, some of which may be severe or fatal. 
 
You can read a list of potential side effects below in the Possible Risks section of this 
consent. 
 
You may continue taking the study drugs for as long as the doctor thinks it is in your 
best interest. 
 
While you are on study, AVB-S6-500 and durvalumab will be provided at no cost to 
you. 
 
You may choose not to take part in this study. Instead of taking part in this study, you 
may choose to have tumor reduction surgery and/or laparoscopy. You may choose to 
receive standard of care treatments outside of this study. You may choose to receive 
other investigational therapy, if available. The doctor will talk to you to make sure you 
have considered all standard of care and investigational treatments available. You 
may choose not to have treatment for cancer at all. In all cases, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer. 
 
1.  STUDY DETAILS 
 
Screening Tests 
Signing this consent form does not mean that you will be able to take part in this study. 
The following screening tests will be performed within 28 days before your first study 
drug dose to help the doctor decide if you are eligible: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests and test for viruses 
such as hepatitis and HIV (the AIDS virus). If you can become pregnant, part of 
this blood sample will be used for a pregnancy test. To take part in this study, you 
must not be pregnant. 
• Urine will be collected for routine tests. 
• You will have an EKG to check your heart function. 
• You will have an MRI or a CT scan to check the status of the disease. If the 
doctor thinks the disease may have spread to the brain, your brain will also be 
scanned. 
• Tumor tissue from a previous biopsy will be collected for biomarker testing, which 
may include genetic biomarkers. Biomarkers are found in the blood/tissue and 
may be related to your reaction to the study drug. If this tissue is not available, 
you will have a core tumor biopsy performed for biomarker testing. To collect a 
tumor biopsy, the affected area may be numbed with anesthetic and a small 


Protocol 2019-0149 
May 19, 2021 
Page 3 of 14 
 
amount of tissue is removed with a large needle or a small cut, depending on the 
location of the tumor. 
 
The study doctor will discuss the screening test results with you. If the screening tests 
show that you are not eligible to take part in the study, you will not be enrolled. 
Other treatment options will be discussed with you. 
 
Study Groups 
If you are found to be eligible to take part in this study, you will be assigned to a phase 
depending on when you join the study. Up to 12 participants will be enrolled in 
Phase 1, and up to 24 participants will be enrolled in Phase 2.  
 
If you are enrolled in Phase 1, the dose of the study drugs you receive will depend on 
when you join this study. Up to 2 dose levels of AVB-S6-500 will be tested in 
combination with durvalumab. The first group of participants will receive the highest 
dose level of AVB-S6-500. If intolerable side effects are seen, the next group will 
receive a lower dose level.  
 
If you are enrolled in Phase 2, you will be randomly assigned (as in a roll of the dice) 
to 1 of 2 study groups: 
• If you are assigned to the AVB-S6-500 Cycle 0 Group, you will receive 6 weeks 
of AVB-S6-500 before you receive the study drug combination. 
• If you are assigned to the Durvalumab Cycle 0 Group, you will receive 6 weeks 
of durvalumab before you receive the study drug combination. 
 
You will have a 75% (3 in 4) chance of being assigned to the AVB-S6-500 Cycle 0 
Group. You will have a 25% (1 in 4) chance of being assigned to the Durvalumab 
Cycle 0 Group. 
 
Up to 11 participants will be enrolled in this study. All will take part at MD Anderson. 
 
Study Drug Administration 
Each study cycle (except Cycle 0 for Phase 2, described below) will be 4 weeks long. 
You will receive AVB-S6-500 by vein over about 1 hour on Days 1 and 15 of each 
cycle. You will receive durvalumab by vein over about 60 minutes on Day 1 of each 
cycle. 
 
If you are in Phase 2, your first cycle (Cycle 0) will be 6 weeks long. If you are in the 
Durvalumab Cycle 0 Group, you will receive durvalumab on Days 1 and 22 of this 
cycle only. If you are in the AVB-S6-500 Cycle 0 Group, you will receive it on Days 1, 
15, and 29. 
 
All participants will be given antihistamines before their first dose of AVB-S6-500 to 
prevent or reduce the chance of side effects. You will also be watched for 45 minutes 
after your infusion to watch for side effects. After the first dose, antihistamines and 
other drugs will only be given prior to dosing if you experienced side effects with the 
first dose. 


Protocol 2019-0149 
May 19, 2021 
Page 4 of 14 
 
 
You will no longer be able to take the study drugs if the disease gets worse, if 
intolerable side effects occur, or if you are unable to follow study directions. 
 
Study Visits 
 
Phase 2 – Cycle 0 Visits 
On Day 1 of Cycle 0: 
• You will have a physical exam. 
• Blood (about 3 ½ tablespoons) will be drawn for routine tests. Some of this blood 
will also be used for biomarker and pharmacokinetic (PK) testing. PK testing 
measures the amount of study drug in the body at different time points. 
• Urine will be collected for routine tests. 
• If you can become pregnant, part of the above blood sample will be used for a 
pregnancy test. To take part in this study, you must not be pregnant. 
 
If you are in the AVB-S6-500 Cycle 0 Group, on Day 15 of Cycle 0: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests.  
 
If you are in the Durvalumab Cycle 0 Group, on Day 22 of Cycle 0: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests.  
 
For both study groups, on Day 29 of Cycle 0: 
• You will have an MRI or a CT scan to check the status of the disease. 
• You will have a core tumor biopsy for biomarker testing.  
• If you are in the AVB-S6-500 Cycle 0 Group, you will also have a physical exam 
and blood (about 3 tablespoons) will be drawn for routine tests. 
 
All Participants – Cycles 1 and beyond 
 
On Day 1 of Cycle 1: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests and biomarker testing. 
If you can become pregnant, part of this blood sample will be used for a 
pregnancy test.  
• Urine will be collected for routine tests. 
• Right before your dose, additional blood (about 3 ½ tablespoons) will be drawn 
for PK testing. 
• If you are in Phase 1, additional blood (about 1 ½ tablespoons) will be drawn for 
PK testing about 1 and 4 hours after the dose.  
 
On Day 15 of Cycle 1: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests.  


Protocol 2019-0149 
May 19, 2021 
Page 5 of 14 
 
 
On Day 1 of Cycle 2: 
• You will have a physical exam. 
• Blood (about 3 ½ tablespoons) and urine will be collected for routine tests. If you 
can become pregnant, part of this blood sample will be used for a pregnancy test. 
• Right before your dose, additional blood (about 3 tablespoons) will be drawn for 
PK testing. 
 
On Day 15 of Cycle 2: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests. 
 
Starting on Day 15 of Cycle 2, you will have an MRI or a CT scan to check the status 
of the disease every 8 weeks. 
 
Just before Cycle 3, you will have a core tumor biopsy. 
 
On Day 1 of Cycle 3 and beyond: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests and (at some of these 
visits) biomarker testing. If you can become pregnant, part of this blood sample 
will be used for a pregnancy test.  
• Urine will be collected for routine tests. 
• At Cycles 3 and 4 only, right before your dose, additional blood (about 3 ½ 
tablespoons) will be drawn for PK testing. 
 
On Day 15 of Cycle 3 and beyond: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests.  
 
End of Treatment Visit 
Within 7 days after the last dose of study drug(s): 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests and biomarker testing. 
If you can become pregnant, part of this blood sample will be used for a 
pregnancy test.  
• Urine will be collected for routine tests. 
 
Follow-up 
If you are taken off study for any reason other than the disease getting worse, you will 
have follow-up visits every 6 weeks for at least 90 days or until you start another 
treatment: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) and urine will be collected for routine tests. 
• Every 12 weeks, you will also have an MRI or a CT scan to check the status of 
the disease. 


Protocol 2019-0149 
May 19, 2021 
Page 6 of 14 
 
 
If you are taken off study because the disease gets worse, about 30 and 90 days 
after the last dose of study drug(s): 
• You will have a physical exam. 
• Blood (about 3 tablespoons) and urine will be collected for routine tests.  
• On Day 90 after the last dose of study drug, additional blood (about 1½ 
tablespoons) will be drawn for antibody testing. Antibodies are created by the 
immune system and may attack foreign cells or substances, such as the study 
drug. 
 
Other Instructions 
You should not donate blood or receive a live vaccine while taking part in this study or 
for at least 90 days following the last dose of durvalumab or AVB-S6-500. 
 
 
2.  POSSIBLE RISKS 
 
While on this study, you are at risk for side effects. You should discuss these with the 
study doctor. The more commonly occurring side effects are listed in this form, as are 
rare but serious side effects. You may also want to ask about uncommon side effects 
that have been observed in small numbers of patients but are not listed in this form. 
Many side effects go away shortly after treatment is stopped, but in some cases side 
effects may be serious, long-lasting or permanent, and may even result in 
hospitalization and/or death. 
 
Side effects will vary from person to person, and some may occur after you have 
stopped receiving treatment. Tell the study staff about any side effects you may have, 
even if you do not think they are related to the study drugs/procedures. 
 
This is an early study of AVB-S6-500, so the side effects are not well known. 
Based on early human studies, AVB-S6-500 may cause the following side effects. 
  
• facial flushing/and or 
swelling 
• fast heart rate 
• low blood pressure 
(possible dizziness 
and/or fainting) 
• fever 
• chills and/or cold 
sweats 
• headache 
• sweating 
 
• abdominal pain 
• chest/back pain 
• difficulty breathing 
• tightness in the chest 
and throat 
 
 
Durvalumab Side Effects 
 
Durvalumab may cause side effects that are unknown. In previous studies people 
have had the side effects listed below. You may get none, some, or all of these. If you 
suffer any side effects or injuries, or your condition gets worse, it is important to tell 
your study doctor right away so you can receive appropriate care. 
 


Protocol 2019-0149 
May 19, 2021 
Page 7 of 14 
 
The study drug durvalumab works by boosting the immune system. Side effects as a 
result of stimulating the immune system have been reported in patients being given 
durvalumab. These immune system side effects are included in the risks outlined 
below. Durvalumab may cause unknown side effects resulting from your immune 
system attacking your organs. This may cause inflammation and inflammation-related 
side effects in any organ or tissue. 
 
Common (occurring in more than 20% of patients) 
 
• fatigue 
• skin rash 
• high blood sugar 
(possible diabetes) 
• abnormal salts, 
minerals, and/or acids in 
the blood (which may 
cause weakness, 
swelling, fatigue, low 
blood pressure, organ 
failure, heart problems, 
changes in mental 
status, and/or seizure)  
• constipation 
• abnormal liver tests 
(possible liver damage 
and/or yellowing of the 
skin and/or eyes)  
• pain (such as 
muscle/joint)  
• lung inflammation 
(possible difficulty 
breathing) 
• cough 
• infections (upper 
respiratory infections, 
pneumonia, influenza, 
dental and oral soft 
tissue infections, oral 
thrush) 
 
Occasional (occurring in 3-20% of patients) 
 
• swelling (arms/legs) 
• fever 
• voice disorder/hoarse 
voice 
• night sweats 
• itching 
• underactive thyroid 
gland (possible weight 
gain, heart failure, 
and/or constipation) 
• overactive thyroid gland 
(possible weight loss, 
heart rate changes, 
and/or sweating) 
• loss of appetite 
• inflammation of the 
intestines 
• diarrhea 
• abdominal pain 
• nausea/vomiting 
• dehydration 
• difficult and/or painful 
urination 
• low blood cell count (red, 
white) 
• liver 
damage/inflammation 
(hepatitis) 
• kidney inflammation or 
injury (possible kidney 
failure or decreased 
kidney function) 
• difficulty breathing 
Durvalumab may occasionally cause a low blood cell count (red and/or white blood 
cells): 
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. 
You may need a blood transfusion.  
• A low white blood cell count increases your risk of infection (such as pneumonia 
and/or severe blood infection). Infections may occur anywhere and become life-


Protocol 2019-0149 
May 19, 2021 
Page 8 of 14 
 
threatening.  Symptoms of infection may include fever, pain, redness, and 
difficulty breathing. 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
• inflammation of the heart 
(or the membrane 
surrounding the heart) 
• inflammation of the brain 
or membranes around 
the spinal cord and brain 
(possible headache 
and/or coma) 
• immune system damage 
to the nervous system 
(causing weakness, 
numbness and/or 
paralysis) 
• inflammation of blood 
vessels 
• hardening/tightening of 
the skin and connective 
tissue 
• inflammation of skin 
(dermatitis) or patches of 
skin color loss 
• skin blisters 
• decreased production of 
adrenal hormones 
(possible weakness 
and/or low blood 
pressure)  
• pituitary gland 
failure/inflammation 
(possible headaches, 
thirst, and/or irregular 
periods in women) 
• imbalance of body fluids 
and electrolytes 
(diabetes insipidus) 
• type 1 diabetes which 
requires insulin 
• high blood sugar  
• hole in the intestines 
(possibly leaking 
contents into the 
abdomen) 
• inflammation of the 
pancreas (possible 
abdominal pain) 
• anemia due to 
destruction of red blood 
cells 
• low platelet count 
• immune response 
(causing joint, tissue, 
and/or organ damage) 
• inflammation and 
weakness of multiple 
muscles  
• inflammation 
inside/around the eye 
(possible vision 
problems) 
• immune reaction 
(possible loss of drug 
function) 
• lung damage 
• infusion reaction 
(possible chills, fever, 
difficulty breathing, 
and/or change in blood 
pressure) 
• multi-organ disease 
causing lesions, most 
often in the lungs 
(sarcoidosis) 
• allergic reaction or over-
activated immune 
system causing swelling 
of face, lips, or throat, 
fever, or shortness of 
breath 
Durvalumab may rarely cause a low platelet cell count. A low platelet count increases 
your risk of bleeding (such as nosebleeds, bruising, stroke, and/or digestive system 
bleeding). You may need a platelet transfusion.   
 
Patients with head and neck cancer may have an increased risk of bleeding. Tell the 
study doctor right away if you experience any bleeding and about any drugs you are 
taking that may increase your risk of bleeding (such as aspirin, blood thinners, or 
NSAIDs). 
 
Other Risks 
 
Having biopsies performed may cause pain, bruising, bleeding, redness, low blood 
pressure, swelling, and/or infection at the site of the biopsies.  An allergic reaction to 
the anesthetic may occur.  A scar may form at the biopsy site. 


Protocol 2019-0149 
May 19, 2021 
Page 9 of 14 
 
 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or 
develop an infection with redness and irritation of the vein at the site where blood is 
drawn.  Frequent blood collection may cause anemia (low red blood cell count), which 
may create a need for blood transfusions. 
 
This study may involve unpredictable risks to the participants. 
 
Pregnancy Related Risks 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you 
should not become pregnant or breastfeed a baby while on this study. You must use 
birth control during the study if you are sexually active. 
 
Birth Control Specifications:  If you can become pregnant, you must use at least 1 
effective method of birth control from the time of screening until 180 days after your 
last dose of study drug(s). Stopping birth control after this point should be discussed 
with the study doctor. Your male must use a condom plus spermicide throughout this 
period. 
 
Effective methods of birth control include barrier methods (male condom plus 
spermicide, cap plus spermicide, or diaphragm with spermicide), intrauterine device 
methods (Copper T, progesterone T, or levonorgestrel-releasing intrauterine system 
[e.g., Mirena®]), or hormonal methods (implants, hormonal shot or injection, combined 
pill, minipill, or patch). 
 
Females:  If you are pregnant, you will not be enrolled on this study. If you become 
pregnant or suspect that you are pregnant, you must tell your doctor right away. 
 
Getting pregnant will result in your removal from this study. 
 
3. COSTS AND COMPENSATION  
 
If you suffer injury as a direct result of taking part in this study, MD Anderson health 
providers will provide medical care. However, this medical care will be billed to your 
insurance provider or you in the ordinary manner. You will not be reimbursed for 
expenses or compensated financially by MD Anderson, Aravive, or AstraZeneca for 
this injury. You may also contact the Chair of MD Anderson’s IRB at 713-792-6477 
with questions about study-related injuries. By signing this consent form, you are not 
giving up any of your legal rights. 
 
Certain tests, procedures, and/or drugs that you may receive as part of this study 
may be without cost to you because they are for research purposes only. However, 
your insurance provider and/or you may be financially responsible for the cost of 
care and treatment of any complications resulting from the research tests, 
procedures, and/or drugs. Standard medical care that you receive under this 
research study will be billed to your insurance provider and/or you in the ordinary 
manner. Before taking part in this study, you may ask about which parts of the 


Protocol 2019-0149 
May 19, 2021 
Page 10 of 14 
 
research-related care may be provided without charge, which costs your insurance 
provider may pay for, and which costs may be your responsibility. You may ask that 
a financial counselor be made available to you to talk about the costs of this study. 
 
Samples that are collected from you in this study may be used for the development 
of treatments, devices, new drugs, or patentable procedures that may result in 
commercial profit. 
 
There are no plans to compensate you for any patents or discoveries that may result 
from your participation in this research.  
 
You will receive no compensation for taking part in this study.  
 
Additional Information  
 
4. 
You may ask the study chair (Dr. Amir A. Jazaeri, at 713-745-1613) any questions 
you have about this study. You may also contact the Chair of MD Anderson's 
Institutional Review Board (IRB - a committee that reviews research studies) at 
713-792-6477 with any questions that have to do with this study or your rights as a 
study participant. 
 
5. 
You may choose not to take part in this study without any penalty or loss of 
benefits to which you are otherwise entitled. You may also withdraw from 
participation in this study at any time without any penalty or loss of benefits. If you 
decide you want to stop taking part in the study, it is recommended for your safety 
that you first talk to your doctor. If you withdraw from this study, you can still 
choose to be treated at MD Anderson. 
 
6. 
This study or your participation in it may be changed or stopped without your 
consent at any time by the study chair, Aravive, AstraZeneca, the U.S. Food and 
Drug Administration (FDA), the Office for Human Research Protections (OHRP), or 
the IRB of MD Anderson. 
 
7. 
You will be informed of any new findings or information that might affect your 
willingness to continue taking part in the study, and you may be asked to sign 
another informed consent and authorization form stating your continued willingness 
to participate in this study. 
 
8. 
MD Anderson may benefit from your participation and/or what is learned in this 
study. 
 
9.  This study is sponsored and/or supported by: Aravive and AstraZeneca. 
 
10.  In a medical emergency, you may be cared for by someone who has a financial 
interest with the study sponsor(s)/supporter. If you have any questions about this, you 
may call the IRB at 713-792-6477. 
 


Protocol 2019-0149 
May 19, 2021 
Page 11 of 14 
 
 
Future Research 
 
Your personal information and/or samples are being collected as part of this study. 
These data and/or samples may be used by researchers at MD Anderson or shared 
with other researchers and/or institutions for use in future research.  
 
Before being shared for future research, every effort will be made to remove your 
identifying information from any data and/or samples. If all identifying information is 
removed, you will not be asked for additional permission before future research is 
performed.  
 
In some cases, all of your identifying information may not be removed before your 
data or samples are used for future research. If this research is performed at MD 
Anderson, the researchers must get approval from the Institutional Review Board 
(IRB) of MD Anderson before your data and/or samples can be used. At that time, 
the IRB will decide whether or not further permission from you is required. The IRB is 
a committee of doctors, researchers, and community members that is responsible for 
protecting study participants and making sure all research is safe and ethical.  
 
If this research is not performed at MD Anderson, MD Anderson will not have 
oversight of any data and/or samples. 
 
Genetic Research 
 
Samples collected from you as part of this study will be used for genetic research, 
which may include whole genome sequencing. Whole genome sequencing is a type 
of testing in which researchers study your entire genetic makeup (DNA). This may 
help researchers learn how changes in the ordering of genes may affect a disease or 
response to treatment. 
 
Conflict of Interest 
Dr. Amir Jazaeri (Study Chair) has received compensation from Aravive Biologics as 
a consultant.  The financial interests are within the limits of the conflict of interest 
policy. 
 
 
Authorization for Use and Disclosure of Protected Health Information (PHI): 
 
A.  During the course of this study, MD Anderson will be collecting and using your 
PHI, including identifying information, information from your medical record, and 
study results. For legal, ethical, research, and safety-related reasons, your doctor 
and the research team may share your PHI with: 
• 
Federal agencies that require reporting of clinical study data (such as the 
FDA, National Cancer Institute [NCI], and OHRP) 
• 
The IRB and officials of MD Anderson 


Protocol 2019-0149 
May 19, 2021 
Page 12 of 14 
 
• 
Aravive and AstraZeneca, who are sponsors or supporters of this study, 
and/or any future sponsors and/or licensees of the study technology 
• 
Study monitors and auditors who verify the accuracy of the information 
• 
Individuals who put all the study information together in report form 
 
Study sponsors and/or supporters receive limited amounts of PHI. They may also 
view additional PHI in study records during the monitoring process. MD Anderson’s 
contracts require sponsors/supporters to protect this information and limit how they 
may use it.  
 
B. 
Signing this consent and authorization form is optional but you cannot take part in 
this study or receive study-related treatment if you do not agree and sign. 
 
C. 
MD Anderson will keep your PHI confidential when possible (according to state 
and federal law). However, in some situations, the FDA could be required to reveal 
the names of participants. 
 
Once disclosed outside of MD Anderson, federal privacy laws may no longer 
protect your PHI. 
 
D.  The permission to use your PHI will continue indefinitely unless you withdraw your 
authorization in writing. Instructions on how to do this can be found in the MD 
Anderson Notice of Privacy Practices (NPP) or you may contact the Chief Privacy 
Officer at 713-745-6636. If you withdraw your authorization, you will be removed 
from the study and the data collected about you up to that point can be used and 
included in data analysis. However, no further information about you will be 
collected. 
 
 E.  A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can identify 
you. At most, the Web site will include a summary of the results. You can search 
this Web site at any time. 
 
 
 


Protocol 2019-0149 
May 19, 2021 
Page 13 of 14 
 
CONSENT/AUTHORIZATION 
I understand the information in this consent form.  I have had a chance to read the 
consent form for this study, or have had it read to me. I have had a chance to think 
about it, ask questions, and talk about it with others as needed. I give the study chair 
permission to enroll me on this study.  By signing this consent form, I am not giving up 
any of my legal rights. I will be given a signed copy of this consent document. 
 
________________________________________ 
_______ 
SIGNATURE OF PARTICIPANT 
DATE 
 
_________________________________         
PRINTED NAME OF PARTICIPANT                 
 
LEGALLY AUTHORIZED REPRESENTATIVE (LAR) 
The following signature line should only be filled out when the participant does not have 
the capacity to legally consent to take part in the study and/or sign this document on his 
or her own behalf. 
_____________________________________________________ 
_________ 
SIGNATURE OF LAR 
DATE 
 
 
 
PRINTED NAME and RELATIONSHIP TO PARTICIPANT 
 
WITNESS TO CONSENT 
I was present during the explanation of the research to be performed under Protocol 
2019-0149. 
_____________________________________________________  
_________ 
SIGNATURE OF WITNESS TO THE VERBAL CONSENT  
  
DATE  
PRESENTATION (OTHER THAN PHYSICIAN OR STUDY CHAIR) 
A witness signature is only required for vulnerable adult participants. If witnessing the assent of a 
pediatric participant, leave this line blank and sign on the witness to assent page instead. 
 
 
PRINTED NAME OF WITNESS TO THE VERBAL CONSENT 
 
PERSON OBTAINING CONSENT 
I have discussed this research study with the participant and/or his or her authorized 
representative, using language that is understandable and appropriate.  I believe that I 
have fully informed this participant of the nature of this study and its possible benefits 
and risks and that the participant understood this explanation. 
 
______________________________________________ 
  
_________ 
PERSON OBTAINING CONSENT  
 
 
 
 
 
DATE 
 
______________________________________________ 
PRINTED NAME OF PERSON OBTAINING CONSENT 
 


Protocol 2019-0149 
May 19, 2021 
Page 14 of 14 
 
TRANSLATOR 
I have translated the above informed consent as written (without additions or 
subtractions) into 
and assisted the people 
(Name of Language) 
obtaining and providing consent by translating all questions and responses during the 
consent process for this participant. 
 
 
_____________________       _______________________________    
___________ 
NAME OF TRANSLATOR       SIGNATURE OF TRANSLATOR 
 DATE 
 
   Please check here if the translator was a member of the research team.  (If checked, 
a witness, other than the translator, must sign the witness line below.) 
 
____________________________________________________   
___________ 
SIGNATURE OF WITNESS TO THE VERBAL TRANSLATION  
  
DATE  
(OTHER THAN TRANSLATOR, PARENT/GUARDIAN,  
OR STUDY CHAIR) 
 
_____________________________________________________ 
PRINTED NAME OF WITNESS TO THE VERBAL TRANSLATION