Clinical trial NCT03376659
Conditions: Metastatic Colorectal Cancer Colorectal Adenocarcinoma Pancreatic Adenocarcinoma Metastatic Pancreatic Cancer
Keywords: PD-L1
Sponsor: Georgetown University
Start date: 2018-08-08; Completion date: 2023-08-01
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a dual arm, open label phase I/II study to evaluate the safety and clinical activity of the combination of durvalumab with CV301 in combination with maintenance chemotherapy for patients with metastatic colorectal or pancreatic cancer whose disease is stable on, or responding to 1st line therapy for metastatic disease. Patients with metastatic colorectal or pancreatic adenocarcinoma who still have an adequate performance status and normal hepatic and renal function will be eligible.

Detailed description:

Arms: arm 1: * MVA-BN-CV301 (prime) - Day 1 and Day 29.
* FPV-CV301 (boost) - Day 1 of Weeks 9, 13, 17, 21, 25, 37, and q24 weeks starting week 53.
* Durvalumab - q2 weeks
* Capecitabine - twice a day, Monday - Friday Weekly
* Bevacizumab - q2weeks (colorectal cancer patients only) arm 2: * MVA-BN-CV301 (prime) - Day 1 and Day 29.
* FPV-CV301 (boost) - Day 1 of Weeks 9, 13, 17, 21, 25, 37, and q24 weeks starting week 53.
* Durvalumab - q2 weeks
* Capecitabine - twice a day, Monday - Friday Weekly
* Bevacizumab - q2weeks arm 3: * MVA-BN-CV301 (prime) - Day 1 and Day 29.
* FPV-CV301 (boost) - Day 1 of Weeks 9, 13, 17, 21, 25, 37, and q24 weeks starting week 53.
* Durvalumab - q2 weeks
* Capecitabine - twice a day, Monday - Friday Weekly
Interventions: intervention 1: Durvalumab intervention 2: CV301 intervention 3: Capecitabine intervention 4: Bevacizumab
Intervention descriptions: intervention 1: 750mg IV q2 weeks intervention 2: MVA-BN-CV301 (prime) - two priming doses of 1.6 x 109 infectious units/0.5 mL (Inf.U) given subcutaneously (s.c.)

FPV-CV301 (boost) - dosed at 1 × 109 Inf.U/0.5 mL given s.c. intervention 3: 1000mg orally twice a day, Monday - Friday Weekly intervention 4: 5mg/kg IV q2weeks

Protocol documents:
Prot_SAP_000.pdf: 
Version 2.4 01-Oct2019 
 
 
 
1 
 
 
A Phase II Trial of the PD-L1 Inhibitor, Durvalumab (MEDI4736) plus 
CV301 in Combination with Maintenance Chemotherapy for Patients 
with Metastatic Colorectal or Pancreatic Adenocarcinoma 
 
 
 
Georgetown Protocol #:  
 
2017-1189 (CRC #072016-02) 
Clinicaltrials.gov #:  
 
 
NCT03376659 
IND #:  
 
 
 
 
 
 
17698 
Initial Concept Date:  
 
 
Version 1.0, July 31st, 2015 
Initial Protocol Version Date:  Version 1.0, November 18th, 2015 
Amended: 
 
 
 
 
 
Version 1.1, December 20th, 2015 
 
  
 
 
 
 
 
 
 
Version 1.2, December 26th, 2015 
 
  
 
 
 
 
 
 
 
Version 1.3, March 5th, 2016 
 
  
 
 
 
 
 
 
 
Version 1.4, May 22nd, 2016 
 
  
 
 
 
 
 
 
 
Version 2.0, March 10, 2017 
 
  
 
 
 
 
 
 
 
Version 2.1, July 23rd, 2017 
 
  
 
 
 
 
 
 
 
Version 2.2, November 11th, 2018 
 
  
 
 
 
 
 
 
 
Version 2.3, February 12th, 2019 
 
  
 
 
 
 
 
 
 
Version 2.4, October 1, 2019 
 
 
 
 
 
 
 
 
Study Chair:  
 
 
 
 
Michael J. Pishvaian, MD, PhD 
 
  
 
 
 
 
 
 
 
University of Texas, MD Anderson Cancer Center, Houston, TX 
 
  
 
 
 
 
 
 
 
 
Principal Investigator:  
 
Benjamin Weinberg, M.D. 
 
  
 
 
 
 
 
 
 
Lombardi Comprehensive Cancer Center 
 
  
 
 
 
 
 
 
 
Georgetown University Medical Center 
3800 Reservoir Road, NW 
Washington, DC 20057 
Telephone (202) 444-2223 
Fax (202) 444-9429 
E-Mail: Benjamin.A.Weinberg@gunet.georgetown.edu 
 
Associate Investigator(s):  
Tanios Bekaii-Saab, MD 
 
  
 
 
 
 
 
 
 
Mayo Clinic, Phoenix, AZ 
 
 
  
 
 
 
 
 
 
 
Bassel El’Rayes, MD 
 
  
 
 
 
 
 
 
 
Emory University 
 
Multicenter Project Managers: Eunice Shim, BS 
 
  
 
 
 
 
 
 
 
Nicole Swanson, BS, MFS 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
 


Version 2.4 01-Oct2019 
 
 
 
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Collaborators: 
 
 
 
 
James L. Gulley, M.D., Ph.D., F.A.C.P. 
 
  
 
 
 
 
 
 
 
Center for Cancer Research, NCI 
 
 
  
 
 
 
 
 
 
 
Jeffrey Schlom, Ph.D.  
 
  
 
 
 
 
 
 
 
Center for Cancer Research, NCI 
 
 
 
 
 
Chip Petricoin, PhD 
George Mason University 
 
 
  
 
 
 
 
 
 
 
Jonathan Brody, PhD 
 
  
 
 
 
 
 
 
 
Thomas Jefferson University 
 
 
 
Steve Byers, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
  
 
 
 
 
Corporate Collaborators: 
 
Medimmune, Inc (AstraZeneca) 
 
  
 
 
 
 
 
 
 
Bavarian Nordic, Inc 
 
Biostatistician:  
 
 
 
Hongkun Wang, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
Funding Source:  
 
 
 
Medimmune, Inc (AstraZeneca) 
 
  
 
 
 
 
 
 
 
Bavarian Nordic, Inc 
 
Study Drugs: 
 
 
Durvalumab (Medimmune/Astra Zeneca) 
 
 
 
 
 
CV301 (Bavarian Nordic) 
 
Clinical Phase: 
 
 
II 
 
Number of Subjects: 
 
Up to 52 Efficacy Evaluable Patients 
 
 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), 
with the Declaration of Helsinki, and with other applicable regulatory requirements including but not limited to 
Institutional Review Board/Ethics Committee (IRB/EC) approval. 
 
Confidentiality Statement 
All information contained in this document is privileged and confidential. Any distribution, copying, or 
disclosure is strictly prohibited without prior written approval by the Sponsor. 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title: A Phase II Trial of the PD-L1 Inhibitor, Durvalumab (MEDI4736) plus CV301 in Combination with 
Maintenance Chemotherapy for Patients with Metastatic Colorectal or Pancreatic Adenocarcinoma 
 
 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. The information 
it contains is consistent with the current risk/benefit evaluation of the investigational product as well as with 
the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki 
and the guidelines on Good Clinical Practice. 
 
 
_____________________________________  _____________________ 
Benjamin Weinberg, MD                    
       
Date 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
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INVESTIGATOR SIGNATURE PAGE 
 
Declaration of the Investigator 
 
Title: A Phase II Trial of the PD-L1 Inhibitor, Durvalumab (MEDI4736) plus CV301 in Combination with 
Maintenance Chemotherapy for Patients with Metastatic Colorectal or Pancreatic Adenocarcinoma 
 
 
 
I have read this study protocol, including all appendices. By signing this protocol, I agree to conduct the clinical 
study, following approval by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), in 
accordance with the study protocol, the current International Conference on Harmonisation (ICH) Guideline 
for Good Clinical Practice (GCP), and applicable regulatory requirements. I will ensure that all personnel 
involved in the study under my direction will be informed about the contents of this study protocol and will 
receive all necessary instructions for performing the study according to the study protocol. 
 
 
_____________________________________  _____________________ 
Benjamin Weinberg, MD                            
 Date 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
 


Version 2.4 01-Oct2019 
 
 
 
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Summary of Changes 
 
The full protocol was first reviewed by the Georgetown Scientific Review Committee (CRC) on 07/20/2016.  Since 
then updates and changes have been made, and summarized below (For each amendment, minor formatting, 
spelling and grammatical corrections, and pagination updates are not detailed below). 
 
Version 2.0, 03/10/2017 
1) The major change for this version involves the change from using PANVAC to CV301.  As detailed 
extensively in the protocol, CV301 (made up of two poxvirus vaccines, MVA-BN-CV301 and FPV-CV301) is 
an “updated” version of PANVAC (made up of the vaccinia virus, PANVAC-V; and the poxvirus, PANVAC-
F).  The updated CV301 harbors the same vaccine antigens, but the major updated benefit is that the priming 
vector, MVA-BN-CV301, is a non-replicating poxvirus (unlike the priming vector of PANVAC, which is a 
vaccinia virus), there is a significant reduction in the risk profile. The changes are reflected throughout the 
protocol, but the major sections include:  
a. The protocol title throughout this protocol, and the ICF 
b. The background was modified to incorporate information about CV301 
c. Much of Section 8.2 was modified, and many of the details of CV301 preparation and safety were 
deferred to the CV301 Investigator’s Brochure 
2) The dosing/schedule for CV301 differs from PANVAC 
a. There are two priming doses now - with a CV301 prime with MVA-BN-CV301 of 1.6 x 109 
infectious units/0.5 mL (Inf.U) given subcutaneously (s.c.) on Day 1 and Day 29.  
b. The boost with FPV-CV301, dosed at 1 × 109 Inf.U/0.5 mL will be given s.c. on Day 1 of Weeks 
9, 13, 17, and 21 (i.e. q4 weeks x 4); and then weeks 25 and 37 (i.e. q12 weeks X 2): and then 
starting week 53 q24 weeks continuously. There will be no stopping or restarting of the CV301. 
c. These changes are reflected in: 
i. The Synopsis 
ii. Figures 2 and 3 and 5 and 6 
iii. Section 4.1 
iv. Tables 4 and 5 
3) The schedule of the durvalumab was also clarified throughout the protocol 
a. In the synopsis 
b. Figures 2 and 3 and 5 and 6 
c. Section 4.1 
d. Table 4 and 5 
4) The schedule of events was clarified throughout the protocol to define the study activities as weeks, rather 
than cycles.  The studies activities table (Table 4) and checklist (Table 5) were also updated accordingly.   
5) The IRB # was updated to reflect IRB submission in 2017 and the CRC number was added.  This is reflected 
in the cover page and study synopsis and the informed consent 
6) Changes to the cover pages were made including: 
a. Removing the Study Co-Chair and one scientific collaborator 
b. Adding a collaborator 
c. Adding Bavarian Nordic as a second funding source 
d. Adding sponsor and PI signature pages 
7) The “On Study” Card in Appendix B was removed for HIPAA compliance 
8) The CRC raised the following concern.  
Consider revising hepatotoxicity management. Currently states to only administer steroids when 
AST/ALT >10x ULN. 
In response, the management of hepatotoxicity has been adjusted (which also parallels better the NIH CTC 
grading) to start steroids for AST/ALT >5X ULN.  Changes are reflected in: 
a. Table 7 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
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9) The tissue utilization plan has been updated.  Six cores will be requested with two samples that need to be 
collected as snap frozen samples; one sample now sent directly to Dr. Steve Byers at Georgetown; and one 
sample sent directly to Dr. Brody at Thomas Jefferson. These changes, as well as the sample labeling details, 
are reflected in: 
a. Section 4 
b. Section 9 
c. Appendix C 
10) There have been significant safety and toxicity management updates based on the updated Investigator’s 
brochure for Durvalumab (Version 10.0, 12 December 2016).  These changes are reflected in: 
a. The background on Durvalumab, including the sections on safety and efficacy 
b. The Informed Consent Form 
c. Appendix E 
 
Version 2.1, 07/23/2017 
1) The only major change for Version 2.1, 07/23/2017, as compared to Version 2.0, 03/10/2017 is that the 
Investigator’s Brochure for CV301 has now been updated to include the data from the Phase I trial of single 
agent CV301, and a Recommended Phase II Dose has now been confirmed.  The dosing included in Version 
2.0, 03/10/2017 as written was correct, but the provisional highlighting in that version was removed.    
a. Correspondingly, a section on the clinical experience of CV301 was added, Section 1.11.3.2.3 
2) One other minor point is that the NCI will not be participating as a clinical site (only as a scientific collaborative 
site), and thus Austin Duffy was removed as one of the co-investigators, and the NCI was removed as a 
clinical study center 
 
Version 2.2, 11/11/2018 
1) Information on the cover page and synopsis page was updated 
2) To clarify confusion over the details of the timing of enrollment, the inclusion criteria were updated to read: 
 
Stable on, or responding to 1st line therapy for metastatic disease 
o Radiographically (RECIST 1.1) confirmed stable or responding disease for at least 8, and not more 
than 16 weeks from the initiation of 1st line therapy for metastatic disease 
o Due to the timing of enrollment, patients who have completed a maximum of 16 weeks of 1st line 
chemotherapy may be enrolled >16 weeks after initiation of 1st line therapy if disease 
stability/response (without additional intervening therapy) can be documented within 4 weeks prior to 
first dose of CV301 
 
3) Windows of time (i.e. +/- X number of days) were added for study procedures throughout the protocol to 
accommodate patient schedules 
4) In Section 8, the dose and schedule of treatments were clarified: 
a. The dose and schedule of the capecitabine, and the dose, infusion time, and schedule of 
bevacizumab were clarified 
b. It was clarified that both MVA-BN-CV301 and FPV-CV301 should each be administered as a 
single syringe at each dosing timepoint. 
5) The order of administration of agents was added to section 4.1 
6) The patient and sample labelling schema was updated (Section 4.3 and Appendix C) 
7) The timing of the on treatment biopsy was corrected to Week 6 (Synopsis and Section 4.3.4 and Tables 4 
and 5, and Appendix C) 
8) The timing of the blood samples was pared down to before treatment and on weeks 9, 17, and 49 and at the 
off study visit (Synopsis and Section 4.3.4 and Tables 4 and 5, and Appendix C) 
9) The details of the collection and shipping for the lab samples were deferred to the Lab Manual (Section 4, 9, 
and Appendix C) 
10) Minor editorial/proofreading/typesetting corrections were made throughout the protocol 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
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Version 2.3, 02/12/2019 
1) Based on updated safety information, as detailed in Section 1.10.3, based on review and approval by the 
FDA and the Georgetown IRB, we have chosen to remove the Phase I lead in portion of the trial. Thus, this 
will be considered ONLY a two cohort, Phase II trial. Up to 46 efficacy evaluable patients will be enrolled 
(though assuming a 10% drop out rate, up to 52 patients may be enrolled).   
a. All references to Phase I have been removed 
b. All references to Phase II have been removed because the whole trial is now a Phase II trial 
c. All references to “Dose Limiting Toxicities” or “DLTs” have been removed 
2) The wording on the dosing of CV301 has been clarified to remove the volume of therapy, and focus on the 
Infectious Units as the dose: 
a. The CV301 prime with MVA-BN-CV301 now reads as “The CV301 prime with MVA-BN-CV301 is 
given subcutaneously (s.c.) on Day 1 and Day 29. One dose of MVA-BN-CV301 consists of 4 
injections of 4 X 108 Inf.U in 0.5mL (one in each arm, one in each leg). This results in a total 
administration of 1.6 x 109 infectious units (Inf.U) per dose.” 
b. The boost with FPV-CV301 now reads “dosed at 1 × 109 Inf.U will be given s.c. on Day 1 of Weeks 
9, 13, 17, and 21 (i.e. q4 weeks x 4); and then weeks 25 and 37 (i.e. q12 weeks X 2): and then 
starting week 53 q24 weeks continuously. One dose of FPV-CV301 consists of just one injection 
of 1.6 X 109 Inf.U per 0.5mL.  The vaccine will be injected subcutaneously into the thigh.  ” 
3) Additional minor corrections have been made: 
a. The study calendar made it appear as though the pre-treatment biopsy was to be performed within 
2 weeks of starting treatment Week 1. That was not the intention, and the calendar has been 
corrected accordingly 
b. The details of when the ECGs are obtained were clarified in Section 4.4.8 and in the Study 
Schedules (Tables 4 and 5) 
c. The timing of dosing of bevacizumab was clarified in Section 8 
d. Indiana University will no longer be participating in the trial and reference to the site, and associate 
staff have been removed accordingly 
4) Investigator’s Brochure for CV301 has now been updated and information about three new ongoing clinical 
trials with CV301 was added in Section 1.10.3.2.3. 
5) Minor editorial/proofreading/typesetting corrections were made throughout the protocol 
 
Version 2.4, 08/13/2019 
 
1) The Georgetown Principal Investigator was updated to Benjamin Weinberg, MD throughout protocol. 
2) University of Texas, MD Anderson Cancer Center was added as a site. 
3) Multicenter Trial Management information and the role of the Georgetown Multicenter Project 
Management Office was updated throughout the Protocol. 
4) References to Theradex were removed since they are not managing/auditng the trial. 
5) Updated enrollment procedures and Appendix B: Patient Registration Form to be consistent with 
Standard Patient Registration Procedures. 
6) The wording on the dosing of FPV-CV301 has been modified.  Per specifications from Bavarian Nordic, 
(as established in the Phase I trials) the FPV-CV301 must have a titer of at least 1 x 109 Inf.U.  This is 
given as a single injection in a volume of 0.5 mL.  However, the final dose may change slightly based on 
the lot of vaccine produced, and the flexibility in the wording at least will allow for some variation with the 
lots.   
a. Therefore, the boost with FPV-CV301 now reads as “One dose of FPV-CV301 consists of just 
one 0.5mL injection of at least 1x109 Inf.U per 0.5 mL.  The vaccine will be injected 
subcutaneously into the thigh.” 
b. Prior language referring to “1.6 X 109 Inf.U” for FPVCV301 has been removed. 
 


Version 2.4 01-Oct2019 
 
 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS………………………………………………………………………………………….8 
 
FIGURES AND TABLES ......................................................................................................................12 
 
LIST OF ABBREVIATION AND DEFINITION OF TERMS ...................................................................13 
 
STUDY SYNOPSIS ..............................................................................................................................15 
 
1. 
BACKGROUND AND RATIONALE .............................................................................................26 
1.1. An Unmet Need in Advanced GI cancers ...............................................................................26 
1.2. Maintenance Therapy in Colorectal Cancer ...........................................................................26 
1.3. Second line Therapy in Pancreatic Cancer ............................................................................26 
1.4. Checkpoint Inhibitors ..............................................................................................................26 
1.5. CV301 ........................................................................................................................................27 
1.5.1. 
PANVAC 
28 
1.5.1  
  CV301 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
  28 
1.5.3  
  PANVAC/CV301 plus Checkpoint Inhibitors  
 
 
 
 
 
 
 
 
     28 
1.6. Evaluation of Benefit in the Maintenance Setting ..................................................................29 
1.7. Immune Checkpoint Inhibitors plus Chemotherapy ..............................................................30 
1.8. Vaccines plus Chemotherapy .................................................................................................30 
1.9.Enhanced Immunogenicity with Bevacizumab ......................................................................30 
1.10.Study Agent Background and Associated Toxicities ..........................................................30 
1.10.1. 
Capecitabine 
30 
1.10.2. 
Bevacizumab 
31 
1.10.3. 
CV301 background 
31 
1.10.4. 
Durvalumab Background 
36 
1.10.5. 
Individual Drug Associated Toxicities 
40 
1.11.Hypothesis..............................................................................................................................43 
 
2. 
STUDY OBJECTIVES ..................................................................................................................44 
2.1. Primary Objectives ..................................................................................................................44 
2.2. Secondary Clinical Objectives (Both Arms) ...........................................................................44 
2.3. Secondary Scientific Objectives (Both Arms) ........................................................................44 
2.4. Exploratory Scientific Objectives (Both Arms) ......................................................................44 
 
3. 
SUBJECT POPULATION  (APPENDIX A - ELIGIBILITY CHECKLIST) ......................................45 
3.1. Subject Population, Number of Subjects and Feasibility ......................................................45 
3.1.1. 
Subject Population 
45 
3.1.2. 
Number of Subjects 
45 
3.1.3. 
Feasibility 
45 
3.2. Inclusion Criteria ......................................................................................................................45 
3.3. Exclusion Criteria ....................................................................................................................46 
3.4. Prior and concomitant therapies ............................................................................................48 
3.4.1. 
Prior Anticancer Therapy 
48 
3.4.2. 
Prior Surgery 
48 
3.4.3. 
Supportive Care 
49 
3.4.4        Permitted Concomitant Medications  
 
 
 
 
        
 
 
 
 
 
 49 
3.4.5        Excluded Concomitant Medications 
49 
3.5. Removal/replacement of Subjects from Therapy or Assessment ........................................49 
3.5.1. 
Screen Failures 
49 
3.5.2. 
Evaluable Patients 
50 
3.6. Multi-institutional trial coordination .......................................................................................50 


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3.6.1. 
Personnel 
50 
3.6.2. 
Patient enrollment 
51 
3.6.3. 
Data collection and management 
51 
3.6.4. 
Conference calls 
51 
3.6.5. 
Trial auditing 
51 
 
4. 
STUDY PROCEDURES ................................................................................................................52 
4.1. Study Overview ........................................................................................................................52 
4.2. Patient Screening .....................................................................................................................54 
4.2.1. 
Informed Consent 
54 
4.2.2. 
Medical history 
54 
4.2.3. 
Demographics 
55 
4.2.4. 
Review subject eligibility criteria 
55 
4.2.5. 
Review previous and concomitant medications 
55 
4.2.6. 
Physical exam including vital signs, height, and weight 
55 
4.2.7. 
Vital sign determinations 
55 
4.2.8. 
Hematology 
55 
4.2.9. 
Serum chemistries 
55 
4.2.10.     Urinalysis 
55 
4.2.11.     Pregnancy test and Pregnancy Prevention 
55 
4.2.12. 
Tumor assessment 
56 
         4.2.13.      Electrocardiogram                                           
 
 
 
     
 
    
       56 
4.2.14. 
Performance Status 
56 
4.2.15. 
Adverse event assessment 
57 
4.3. Patient enrollment ................................................................................................................... .57 
4.3.1. 
Patient study number assignment and sample labelling 
57 
4.3.2. 
Patient Study Number Assignment 
57 
4.3.3. 
Sample Labelling 
57 
4.3.4. 
Tumor Biopsies and Blood Collection 
58 
4.4. Detailed Patient Assessments ................................................................................................59 
4.4.1. 
Subject assessments 
59 
4.4.2. 
Physical Examinations 
59 
4.4.3. 
Updated Medical History 
59 
4.4.4. 
Vital Signs 
59 
4.4.5. 
Tumor Markers 
59 
4.4.6. 
Correlative Blood Samples 
59 
4.4.7. 
Clinical Laboratory Tests 
59 
         4.4.8  
  Electrocardiograms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       60 
         4.4.9  
  Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       60 
         4.4.10       Imaging and Response Evaluation 
 
 
 
 
 
 
 
 
 
 
 
       60 
         4.4.11     Adverse Event Evaluation  
 
 
 
 
 
 
 
 
 
 
 
 
 
       60 
         4.4.12 
  Final Visit and Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
       60 
4.5. Removal of Subjects from Study ............................................................................................61 
4.5.1. 
Discontinuation of Individual Subjects 
61 
4.5.2. 
Discontinuation of the Entire Study 
62 
 
5. 
SAFETY VARIABLES AND TOXICITY ASSESSMENT ...............................................................70 
5.1. Adverse events assessment ...................................................................................................70 
5.2. Study monitoring .....................................................................................................................70 
5.3. Adverse Events and Toxicity Definitions ...............................................................................71 
5.3.1. 
Adverse Event 
71 
5.3.2. 
Serious Adverse Events 
72 
5.3.3. 
Adverse Event severity 
72 
5.3.4. 
Relationship to Study Drugs 
73 


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5.3.5. 
Non-Serious Adverse Events of Special Interest 
73 
5.4 Recording of Adverse Events and Serious Adverse Events…………………………………...75
 
Adverse Event Collection Period ............................................................................................75 
5.6. Adverse Event Reporting ........................................................................................................76 
5.7. Pregnancy ................................................................................................................................77 
5.7.1. 
Maternal Exposure 
77 
5.7.2. 
Paternal Exposure 
77 
5.8. Overdose ..................................................................................................................................78 
5.9.Cardiac Events Management ..................................................................................................78 
5.10.Hepatic Function Abnormality ..............................................................................................78 
5.11.Protocol Deviations ...............................................................................................................78 
5.12.Definitions of Dose-Limiting Toxicities and Toxicity Management ....................................78 
5.12.1. 
Management of Toxicities Related to Capecitabine 
79 
5.12.2. 
Management of Toxicities Related to Bevacizumab 
79 
5.12.3. 
General Management of Immune-Related Toxicities 
80 
 
6. 
MEASUREMENT OF EFFECT .....................................................................................................85 
6.1. Assessment Parameters .........................................................................................................85 
6.1.1. 
Definitions 
85 
6.2. Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ................................................85 
6.2.1. 
Disease Parameters 
85 
6.2.2. 
Methods for Evaluation of Measurable Disease 
86 
6.2.3. 
Response Criteria 
86 
6.2.4. 
RECIST 1.1 Evaluation of Best Overall Response 
87 
6.3. Modified Response Evaluation Criteria in Solid Tumors (RECIST) ......................................88 
6.3.1. 
Impact of Non-target Lesion Response on Modified RECIST 
88 
6.3.2. 
Impact of New Lesions on Modified RECIST 
89 
6.4. Definition of Disease Progression ..........................................................................................89 
 
7. 
STATISTICAL CONSIDERATIONS ..............................................................................................90 
7.1. Study design ............................................................................................................................90 
7.2. Sample size considerations ....................................................................................................90 
7.3.Efficacy Endpoints ...................................................................................................................90 
7.3.1. 
Primary Endpoint 
90 
7.3.2. 
Secondary Endpoints 
90 
7.3.3. 
Exploratory Endpoints 
91 
7.4 Analysis Populations ...............................................................................................................91 
7.5. Analysis plan ............................................................................................................................91 
7.5.1  
  Demographics Characteristics 
 
 
 
 
 
 
 
 
 
 
 
 
        91 
7.5.2  
  Safety Analysis  
 
 
 
 
 
 
 
 
       
 
 
 
 
 
 
 
  91 
7.5.3  
  Efficacy Analysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        91 
7.5.4. 
Analysis for the Primary Endpoint 
91 
7.6.5. 
Analysis for the Secondary Endpoints 
91 
7.7.6. 
Analysis for the Exploratory Endpoints 
92 
 
8. 
DRUG INFORMATION, INCLUDING STORAGE AND DISPENSATION .....................................93 
8.1. Durvalumab ..............................................................................................................................93 
         8.1.1     Durvalumab Formulation, Packaging, and Storage 
 
 
 
 
 
 
 
       93 
 
   8.1.2     Study Drug Preparation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       93 
         8.1.3     Preparation of Durvalumab Doses for Administration with an IV Bag    
 
       93 
         8.1.4     Monitoring of Dose Administration  
 
 
 
 
 
 
 
 
 
 
 
       94 
8.2. CV301 ........................................................................................................................................95 


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         8.2.1   MVA-BN-CV301  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        
95 
         8.2.2   FPV-CV301   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
            
95 
         8.2.3   Patient Care Implications  
 
 
 
 
 
 
 
 
 
 
                             95 
 
9. 
CORRELATIVE SCIENTIFIC STUDIES .......................................................................................96 
9.1. Tissue Prioritization .................................................................................................................96 
 
  9.1.1     Biopsy Tissue Utilization and Prioritization 
 
 
 
 
 
 
  
 
         96 
 
  9.1.2     Serial Blood Collection 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
          96 
     9.1.3     Test Prioritization  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         97  
9.2. Immune Correlates – Methodology .........................................................................................97 
 
  9.2.1     Peripheral blood Antigen Specific T cell Immune Response  
 
 
 
        
97 
        9.2.2     Peripheral Blood Mononuclear Cell Subset Analysis  
 
 
 
 
 
        
98 
       9.2.3     Serum Cytokine and Soluble Factor Analysis  
 
 
        
        
 
 
 
98 
        9.2.4     T Cell Clonal Expansion Assay  
 
 
 
 
 
        
 
 
 
 
 
 
98 
        9.2.5    Tumor Immunohistochemistry Analysis  
 
 
 
 
        
 
 
 
 
 
98 
        9.2.6     Measurements of Serum indoleamine 2,3-dioxygenase (IDO) 
 
        
 
 
98 
        9.2.7     Immunohistochemistry for Detection of IDO in Tissue Samples  
 
        
 
98 
        9.2.8     Measurements of Serum Arginase-1 
 
 
 
 
 
        
 
 
 
 
 
99 
        9.2.9     Immunohistochemistry for Detection of Arginase-1 in Tissue Samples  
        
99 
        9.2.10   Reverse Phase Protein Microarray (RPPA)  
       
 
 
 
        
 
 
 
99 
        9.2.11   Ex Vivo Models 
 
 
 
 
 
 
 
 
 
        
 
 
 
 
 
 
 
102 
 
10. 
ETHICAL CONSIDERATIONS AND STUDY MANAGMENT ................................................... 106 
10.1. 
  Conflict of Interest ........................................................................................................ 106 
10.2. 
  Institutional Review Board (IRB) Approval and Consent ........................................... 106 
10.3. 
  Required Documentation.............................................................................................. 106 
10.4. 
  Record Retention .......................................................................................................... 106 
10.5. 
  Obligations of Investigators ......................................................................................... 107 
 
11. 
REFERENCES ......................................................................................................................... 108 
 
12. 
APPENDICES .......................................................................................................................... 113 
Appendix A. Study Eligibility Checklist ...................................................................................... 113 
Appendix B. Patient Registration Form ...................................................................................... 115 
Appendix C. Sample Collection and Shipping information ....................................................... 116 
Appendix D. Flow Cytometry Assays ......................................................................................... 121 
     Appendix E. Durvalumab Dosing Modification and Toxicity Management Guidelines……….124  
 
 
 


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FIGURES AND TABLES 
Figure 1: Trial Schema……………...………………………………………………………………………… 
17 
Figure 2: Durvalumab plus CV301 Treatment Schedule………………………………………………... 
18 
Figure 3: Phase II Schema (repeated)...……………………………………………………………………... 52 
Figure 4: Durvalumab plus CV301 Treatment Schedule (repeated)..………………………………...  
54 
Figure 5. Illustrated schematic of a typical RPPA slide configuration………………………………… 100 
 
 
Table 1: Prohibited and Rescue Medications……………………………………………………………….. 49 
Table 2. Effective methods of contraception……………………………………………………………….. 56   
Table 3: ECOG Performance Status…..…………………………………………………...….………........... 56 
Tables 4a – 4c: Study Activities…………………………………………...………………...……………........ 63 
Table 5: Study Activities Checklist.……………………………………...………………...……………........ 66 
Table 6: Capecitabine Dose Adjustments……………………………………………………………………. 79 
Table 7: Management of Hepatotoxicity…………………………………………………………………… 
82 
Table 8: Management of Pulmonary Toxicity………………………………………………………………. 84 
Table 9: Response Evaluation……………..……………….……..………………...…............................... 88 
Table 10:  Differences Between RECIST 1.1 and Modified RECIST……………………………………... 88 
Table 11. Outcome from 7/10 PDAC specimens collected by Indivumed-Georgetown…………….. 104 
Table 12: ECOG Performance Status (repeated)….……………………………………...….……….......... 114 
Table 13. Flow Cytometry Markers…………………………………………………………………………..… 121  
Table 14. Antibodies used for 5 panel stain to identify 123 peripheral immune cell subsets………. 122 
Table 15: Complete list of 123 peripheral immune cell subsets analyzed by flow cytometry….….. 123 


Version 2.4 01-Oct2019 
 
 
 
13 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse Event 
AESI 
adverse event of special interest 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ALP 
alkaline phosphatase 
AST 
Aspartate Aminotransferase 
AQUA 
automated quantitative analysis 
APC 
antigen-presenting cells 
BUN 
Blood Urea Nitrogen 
AUC 
area under the concentration-time curve 
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CI 
Continuous Infusion 
Cmax 
peak concentration 
Cmax,ss 
peak concentration at steady state 
Cmin 
trough concentration 
Cmin,ss 
trough concentration at steady state 
CMP 
Comprehensive Metabolic Panel 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen-4 
             DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DNA 
deoxyribonucleic acid 
DSMC 
Data Safety Monitoring Committee 
EBV 
Epstein-Barr Virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
Fc 
fragment crystallizable 
FFPE 
formalin fixed paraffin embedded 
FU 
Fluorouracil 
HIV 
human immunodeficiency virus 
HRPP 
Human Research Protections Program 
ICF 
informed consent form 
ICS 
Intracellular Cytokine Staining 
IDO 
Indoleamine 2,3-dioxygenase 
IFN 
interferon 
IGF 
insulin-like growth factor 
IgG1 
immunoglobulin G1 


Version 2.4 01-Oct2019 
 
 
 
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IgG2 
immunoglobulin G2 
IHC 
immunohistochemistry  
Inf.U 
infectious units 
IL 
interleukin 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
Mab 
Monoclonal Antibody 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events  
NOAEL 
no-observed-adverse-effect level 
ORR 
Overall Response Rate; Objective Response Rate  
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
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 
PFS4mos 
Progression Free Survival Rate at 4 Months 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
Q12W 
every 12 weeks 
QoL 
quality of life 
QTc 
QT interval on ECG corrected for heart rate 
QTcF 
QT interval on ECG corrected using the Fridericia’s formula 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
Recommended Phase II Dose 
s.c. 
subcutaneous 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
TAA 
Tumor-associated Antigens 
TCR 
T-Cell Receptor 
TIL 
tumor infiltrating lymphocyte 
Tmax 
time to peak concentration 
Tmax,ss 
time to peak concentration at steady state 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
USA 
United States of America 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cells 


Version 2.4 01-Oct2019 
 
 
 
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STUDY SYNOPSIS 
 
Title 
A Phase II trial of the PD-L1 inhibitor, Durvalumab (MEDI4736) plus CV301 in 
Combination with Maintenance Chemotherapy for Patients with Metastatic 
Colorectal or Pancreatic Adenocarcinoma 
Short Title 
Durvalumab plus CV301 with Maintenance Chemotherapy 
Protocol 
Number 
2017-1189 (CRC #072016-02) 
IND number and 
Clinicaltrials.gov 
number 
FDA IND: 17698 
Clinical Trials.gov: NCT03376659 
Phase 
Phase II 
Methodology 
Open label 
Study Duration 
30 – 36 months 
Study Center(s) 
 Georgetown University, Lombardi Comprehensive Cancer Center, 
Washington, DC 
 Mayo Clinic, Phoenix, AZ 
 Emory University, Atlanta, GA 
 University of Texas, MD Anderson Cancer Center, Houston, TX 
Objectives 
Primary Objectives: 
Colorectal Cancer (CRC) Arm 
To determine the 8.5 month progression free survival rate (PFS8.5mos) of 
durvalumab plus CV301 in combination with maintenance capecitabine and 
bevacizumab in patients with metastatic colorectal cancer, whose disease is 
stable on, or responding to 1st line therapy for metastatic disease 
 
Pancreatic Cancer Arm 
To determine the 4 month progression free survival rate (PFS4mos) of durvalumab 
plus CV301 in combination with maintenance capecitabine in patients with 
metastatic pancreatic cancer, whose disease is stable on, or responding to 1st 
line therapy for metastatic disease 
 
Secondary Clinical Objectives (Both Arms):  
To determine, in patients treated with durvalumab plus CV301 whose disease is 
stable on, or responding to 1st line therapy for metastatic colorectal or pancreatic 
cancer: 
1) Objective response rate (ORR) and duration of response 
2) Progression free survival  (PFS) 
3) Overall survival (OS) 
4) Disease control rate (DCR) (defined as ORR + rate of stable disease at 
4 months) 
5) Tolerability and safety of the combination  
 
Secondary Scientific Objectives (Both Arms): 
1) To assess the predictive value of immune-inhibitory proteins, including 
PD-1, PD-L1 (B7H1), B7H3, B7H4, IDO, and arginase; and to assess 
the characteristics of the infiltrating T-cells in tumor samples. 
2) Using a flow-based assay, to determine the number of immune cell 
subsets from peripheral blood mononuclear cell (PBMC) at baseline 
and during treatment and attempt to identify a pattern correlating with 
clinical benefit. 


Version 2.4 01-Oct2019 
 
 
 
16 
 
3) To evaluate the antigen-specific T-cell activation against the target 
antigens of the vaccine, MUC-1 and CEA as well as other potential 
cascade antigens, including but not limited to brachyury. 
4) To evaluate serum soluble factors and serum cytokine expression 
profiles at baseline and on treatment and determine correlates of 
clinical benefit. 
5) To evaluate the relationship between tumor mutation burden and 
clinical benefit. 
6) To evaluate the expansion of peripheral and, potentially, intratumoral T 
cell clones as correlates and identify correlation with clinical benefit. 
 
Exploratory Scientific Objectives (Both Arms): 
1) To assess, in patient tumor samples, the predictive value, and the 
changes in response to treatment of immune-inhibitory proteins and 
other cell signaling pathways as measured by reverse phase 
phosphoprotein pathway analysis of the laser capture microdissected 
tumor epithelium and tumor stroma/immune cell compartments. 
2) To develop ex vivo models of patient tumors derived from patient tumor 
samples  
 
Number of 
Subjects 
Minimum: 28 Maximum: 52 
 
It is estimated that a total of up to 52 patients will be enrolled in the study.  
Specifically, a minimum of 28 patients could be enrolled in the first Simon 
Minimax Stage of the two Phase II portions (14 in each cohort).  Each Phase II 
cohort will enroll a maximum of 23 evaluable patients, and allowing for a 10% 
dropout rate, up to 26 patients may be enrolled.  Thus, the absolute minimum 
number of patients for the trial is 28 and the absolute maximum number of 
patients for the trial is 52. 
 
Diagnosis and 
Main Inclusion 
Criteria 
Key Inclusion Criteria 
1) Histologically 
confirmed 
metastatic 
colorectal 
or 
pancreatic 
adenocarcinoma 
2) Stable on, or responding to 1st line therapy for metastatic disease 
o Radiographically (RECIST 1.1) confirmed stable or responding 
disease for at least 8, and not more than 16 weeks from the initiation 
of 1st line therapy for metastatic disease 
o Due to the timing of enrollment, patients who have completed a 
maximum of 16 weeks of 1st line chemotherapy may be enrolled  
>16 weeks after initiation of 1st line therapy if disease 
stability/response (without additional intervening therapy) can be 
documented within 4 weeks prior to first dose of CV301 
3) Radiographically measurable disease 
4) Disease that is amenable to serial biopsies 
5) Age ≥ 18 years 
6) ECOG performance status 0 or 1 
7) Adequate hepatic, bone marrow, and renal function. 
 
Key Exclusion Criteria 
1) No active severe infection, or known chronic infection with HIV or 
hepatitis B virus 
2) No cardiovascular disease problems including unstable angina, therapy 
for life-threatening ventricular arrhythmia, or myocardial infarction, 
stroke, or congestive heart failure within the last 6 months 


Version 2.4 01-Oct2019 
 
 
 
17 
 
3) No women who are pregnant or breastfeeding, and no women of 
childbearing potential without using dual forms of effective contraception 
4) Patients with known CNS metastases 
5) Anticipated patient survival under 2 months 
 
Study Design 
Basic Study Design 
This is a dual arm, open label phase II study to evaluate the safety and clinical 
activity of the combination of durvalumab with CV301 in combination with 
maintenance chemotherapy for patients with metastatic colorectal or pancreatic 
cancer whose disease is stable on, or responding to 1st line therapy for 
metastatic disease.  Patients with metastatic colorectal or pancreatic 
adenocarcinoma who still have an adequate performance status and normal 
hepatic and renal function will be eligible. 
 
The trial will consist of two parallel Phase II trials – one for patients with 
metastatic colorectal cancer, and one for patients with metastatic pancreatic 
cancer (Figure 1). Patients will be seen every two weeks through eight weeks, 
and then routinely every 4 weeks thereafter for as long as the patient is actively 
on study.  Adverse events will be monitored throughout the trial (safety tests will 
be performed every 2 weeks for the first 8 weeks, and then every 4 weeks 
thereafter) and graded in severity according to the guidelines outlined in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.   
 
Restaging studies will be performed every 8 weeks (+/- 5 days) (typically CT 
scans), by the calendar.  Patients whose tumors have not progressed at the time 
of restaging, and who continue to tolerate treatment will continue on study.  The 
study is estimated to last 36 months.  Patient treatment will continue until disease 
progression, death, or until the physician or patient request removal from the 
study for any reason. 
 
Figure 1: Trial Schema 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
18 
 
Study Product, Dose, Route, Regimen 
Please note that for all durvalumab and CV301 (and bevacizumab for the 
colorectal cancer patients), treatments may occur +/- 3 days to accommodate 
patient scheduling 
 
Patients will begin maintenance chemotherapy beginning Week 1.  This will be 
dosed as capecitabine 1000mg orally twice a day given Monday – Friday every 
week [3]. In addition colorectal cancer patients will receive maintenance 
bevacizumab, dosed at 5mg/kg IV q2weeks [4].  
 
Patients first receive two priming doses with CV301 prime with MVA-BN-CV301 
which is given subcutaneously (s.c.) on Day 1 and Day 29. One dose of MVA-
BN-CV301 consists of 4 injections of 4 X 108 Infectious Units (Inf.U) in 0.5mL 
(one in each arm, one in each leg). This results in a total administration of 1.6 x 
109 Inf.U per dose.  Then, starting week 9, patients will begin therapy with FPV-
CV301.  One dose of FPV-CV301 consists of just one 0.5mL injection of at least 
1x109 Inf.U per 0.5 mL.  The vaccine will be injected subcutaneously into the 
thigh on Day 1 of Weeks 9, 13, 17, and 21; and then weeks 25 and 37: and then 
starting week 53 q24 weeks continuously until progression.      
 
Week 3, Day 1, patients will also begin therapy with durvalumab, which will be 
subsequently given every two weeks until progression (or intolerance).  
 
Figure 2: Durvalumab plus CV301 Treatment Schedule.   
Durval = durvalumab.   
Duration of administration 
Durvalumab and FPV-CV 301 will continue until disease progression (or 
intolerance).  Maintenance chemotherapy (capecitabine (+ bevacizumab for 
CRC)) will also continue until disease progression (or intolerance).  However, in 
the event of a complete response, patients may stop the maintenance 
chemotherapy and continue the durvalumab and FPV-CV301 alone after 52 
weeks (one year).  Patients who stop maintenance chemotherapy after 52 
weeks, and whose disease then begins to progress/recur may be restarted on 
the maintenance chemotherapy until further disease progression.   
 
Response Assessment 
The primary efficacy objective is to determine the PFS8.5mos in the colorectal 
cancer arm, and the PFS4mos in the pancreatic cancer arm.  Disease 
response/progression will be assessed according to RECIST 1.1.  However, 
RECIST 1.1 will be adapted to account for the potential of pseudoprogression, 
in which immune-mediated tumor infiltration may lead to an initial increase in the 
size of the tumors, and can lead to a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions.  Therefore, standard 
RECIST 1.1 criteria may not provide an accurate response assessment of 
immunotherapeutic agents such as durvalumab and FPV-CV301.   Therefore, 
RECIST 1.1 will be used with the following adaptations, and as detailed in 
Section 6 of the full protocol: 
 


Version 2.4 01-Oct2019 
 
 
 
19 
 
If radiologic imaging shows initial progressive disease (PD), but patients are 
adequately tolerating therapy, patients may continue therapy until the next 
restaging while awaiting radiologic confirmation of progression.  The decision to 
continue therapy should be based on the subject’s overall clinical condition, 
including performance status, clinical symptoms, and laboratory data.  Subjects 
may receive treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention 
 
When feasible, subjects should not be discontinued until progression is 
confirmed.  Subjects that are deemed clinically unstable are not required to have 
repeat imaging for confirmation of progressive disease:  
• If repeat imaging shows a reduction in the tumor burden compared to the 
initial scan demonstrating PD, treatment may be continued.  If repeat imaging 
confirms progressive disease, subjects will be discontinued from study 
therapy.   
 
Multicenter Trial 
Management 
Personnel 
At each site, personnel dedicated to this protocol will be: 
 
- A site PI 
 
- A research coordinator and data manager 
 
In addition, Georgetown University’s Multicenter Project Management Office will 
oversee the conduct of the trial at Lombardi-Georgetown and additional sites.  
Georgetown University’s Multicenter Project Management Office will be the main 
point of contact for the study chair, Dr. Pishvaian and the other site PIs for any 
study related concerns, including data management and regulatory.  
 
Patient Enrollment 
Enrollment at the sites will be competitive.  If a patient is being screened for 
enrollment, the local research coordinator must send an email within 24 hours 
containing the patient’s screening number and initials, to the site PI, Dr. 
Pishvaian, and to Georgetown University Multicenter Project Management 
Office. If a patient is successfully screened, the local research coordinator must 
send all supporting documentation to Georgetown University’s Quality 
Assurance Office (QAO) by secure email or fax to confirm eligibility.  
 
Patients should not start therapy until Dr. Pishvaian and Georgetown University’s 
QAO have reviewed the patient’s records and confirmed that the patient is 
indeed eligible for enrollment. 
 
Data Collection and Management  
Patient data will be entered into the on-line accessible database (the database 
will be built with case report forms (CRFs) at Georgetown upon trial approval).  
This database is housed at Lombardi-Georgetown, but is accessible anywhere 
there is internet access.  The data manager and research coordinator at each 
site will attend an on-line training session so that they may learn how to enroll 
data into the data base.  All screening data should be entered prior to initiating 
any study related activities, and all ongoing patient data should be entered within 
one week of each patient visit.   


Version 2.4 01-Oct2019 
 
 
 
20 
 
 
Trial Auditing 
Georgetown University’s Multicenter Project Management Office will provide 
annual trial auditing for this study. Georgetown University’s Multicenter Project 
Management Office will arrange all primary source documents for the patients 
from all sites to be audited.  Auditing of the study will occur at Lombardi-
Georgetown, and will be performed on a random sampling of the patients 
selected from any site. 
 
Conference Calls 
A monthly conference call will be held between Lombardi-Georgetown and the 
other sites to review patient enrollment, toxicity, and response assessment. 
Study Product, 
Dose, Route, 
Regimen 
1) MVA-BN-CV301 (prime) - two priming doses given s.c. on Day 1 and Day 
29. One dose of MVA-BN-CV301 consists of 4 injections of 4 X 108 Inf.U in 
0.5mL (one in each arm, one in each leg). This results in a total 
administration of 1.6 x 109 Inf.U per dose. 
2) FPV-CV301 (boost) - One dose of FPV-CV301 consists of just one 0.5mL 
injection of at least 1x109 Inf.U per 0.5 mL.  The vaccine will be injected 
subcutaneously into the thigh on Day 1 of Weeks 9, 13, 17, 21, 25, 37, and 
q24 weeks starting week 53.  
3) Durvalumab – 750mg IV q2 weeks 
4) Capecitabine – 1000mg orally twice a day, Monday – Friday Weekly 
5) Bevacizumab (colorectal cancer only) – 5mg/kg (Based on weight at 
screening unless 10% change) IV q2weeks 
 
Importantly, the dose of capecitabine parallels the dose used in the 
“maintenance” setting for pancreatic cancer[3].  However, for colorectal cancer, 
the dose of capecitabine in the CAIRO 3 trial was higher – 625mg/m2 
continuously daily [4]. In our experience, that dose given chronically can lead to 
significant toxicities and is not ideally suited for the “maintenance” setting. 
Duration of 
administration 
1) MVA-BN-CV301 (prime) – two doses 
2) FPV-CV301 (boost) – until progression (or intolerance) 
3) Durvalumab – until progression (or intolerance) 
4) Capecitabine (+ bevacizumab for colorectal cancer) – until progression 
(unless patients achieve a CR, in which case capecitabine (+ bevacizumab 
for colorectal cancer) may be stopped after 52 weeks (1 year) 
Reference 
therapy 
Reference therapy 
For metastatic colorectal cancer, patients enrolled in the capecitabine plus 
bevacizumab arm of the CAIRO3 study had a median PFS of 8.5 months, which 
roughly translates to a PFS8.5mos of 50% [4]. 
 
For pancreatic cancer, there is no direct comparator, but for second-line therapy 
(by analogy), multiple regimens have resulted in a median PFS of 3-5 months 
(average of 4 months) which roughly translates to a PFS4mos of 50% [5]. 
 
Statistical 
Design 
This trial will assess the efficacy of the combination of durvalumab plus CV301 
in combination with maintenance chemotherapy for patients with metastatic 
colorectal and pancreatic cancer whose disease is stable on or responding to 
1st line therapy for metastatic disease.  The trial is divided into two arms, 
colorectal cancer and pancreatic cancer.  The median progression-free survival 
(PFS) reported for patients receiving capecitabine plus bevacizumab in the 
maintenance setting for colorectal cancer is 8.5 months [4]; for patients with 
metastatic pancreatic cancer, the median PFS with second-line therapy is 


Version 2.4 01-Oct2019 
 
 
 
21 
 
around 4 months [5].  Alternatively stated, the estimated 8.5 month PFS 
(colorectal cancer) and the estimated 4 month PFS (pancreatic cancer) is 
approximately 50%.  The addition of the combination of durvalumab plus CV301 
to maintenance chemotherapy would be of great interest in these patient 
populations if it could increase the 8.5 month PFS rate (colorectal cancer) and 4 
months PFS rate (pancreatic cancer) to 75% or higher.  Thus, the primary 
endpoints of this trial are the 8.5 months PFS rate in the colorectal cancer arm, 
and the 4-month PFS rate in the pancreatic cancer arm. 
 
We will use a two-stage Simon Minimax Phase II design [6] in each arm.  All 
patients meeting the eligibility criteria who have signed a consent form, begun 
treatment, and are not lost to follow-up or who are not taken off study for reasons 
other than progression or death will be considered evaluable.  The statistical 
design for both the colorectal cancer arm and the pancreatic cancer arm is the 
same, despite the fact that the estimated PFS timing is different. We will assume 
a one-sided alpha level of 0.05 and a power of 80% to test the null hypothesis of 
PFS rate (at 8.5 months for colorectal cancer and 4 months for pancreatic 
cancer) is at most 50% vs. the alternative hypothesis of PFS rate of at least 75% 
for each parallel arm. In the first stage, 14 patients will be needed. If 7 or fewer 
of the 14 patients are alive and progression-free (at 8.5 months for colorectal 
cancer and 4 months for pancreatic cancer), we will conclude that this treatment 
is insufficiently active in this population and terminate the study. If 8 or more of 
these 14 patients are alive and progression-free (at 8.5 months for colorectal 
cancer and 4 months for pancreatic cancer), we will continue the study to the 
second stage and accrue a total of 23 evaluable patients. If 15 or fewer of these 
23 patients are alive and progression-free (at 8.5 months for colorectal cancer 
and 4 months for pancreatic cancer), we will conclude that this treatment is 
insufficiently active in this population.  If 16 or more of these 23 patients are alive 
and progression-free (at 8.5 months for colorectal cancer and 4 months for 
pancreatic cancer), this will be considered adequate evidence of efficacy of this 
treatment and may be recommended for further testing in subsequent studies.  
Assuming a drop-out rate of 10%, a total of 26 patients for each arm will be 
accrued. 
  
Study Feasibility 
Across our centers, more than 400 new cases of pancreatic cancer and 800 
cases of colorectal cancer are seen yearly, at least half of whom have metastatic 
disease.    Since at least 50% of patients with metastatic colon cancer and 
pancreatic cancer achieve stable disease on first line therapy, we anticipate that 
across our centers, at least 100 patients per year will be eligible for this trial.  
Nevertheless, given the barriers for recruiting any patient to a clinical trial, we 
conservatively estimate that recruitment will take 24 – 30 months.  With each 
patient followed for a minimum of 8 weeks, the anticipated time to complete 
follow-up of all patients will be 30 – 36 months. 
 
The team at the NIH led by Dr. Gulley and Dr. Schlom have years to decades of 
experience in understanding and harnessing the immune response to cancer.  
They have published using the techniques proposed herein.  Thus completion of 
the correlative studies is highly feasible.  
 
Correlative 
Research 
Correlative Research  
Serial tumor biopsies will be taken before treatment and during week 6.  Blood 
samples will be taken before the initiation of study treatment and on weeks 9, 
17, and 49, and at the off study visit.  The characteristics of the tumor cells, the 


Version 2.4 01-Oct2019 
 
 
 
22 
 
tumor stroma, and of the infiltrating T-cells in the tumor samples and in the blood 
will be analyzed. 
 
This trial will be conducted in conjunction with Dr. Jeffrey Schlom, Chief of the 
Laboratory of Tumor Immunology and Biology and Dr. James Gulley, Chief of 
the Genitourinary Malignancies Branch (Head, Immunotherapy Section) in the  
Center for Cancer Research, NCI, NIH, along Dr. Steve Byers at Georgetown, 
Dr. Jonathan Brody at Thomas Jefferson University, and Dr. Chip Petricoin at 
George Mason University. 
 
Immune Correlates – Methodology 
Tumor Immunohistochemistry Analysis 
We will employ digital immunohistochemistry using MAbs against targets 
including CD3, CD4, CD8, PD-1, PD-L1 along with isotype control MAbs to 
examine the extent of immune infiltrate in any biopsies collected before 
treatment and during week 8 on study. If enough tissue is available, we may also 
stain for FoxP3, IDO, arginase, TIM3, LAG3 MHC and other markers related to 
immune activation and inhibition.  Reverse Phase Protein Microarray analysis 
will also be used to quantitatively measure these proteins (CD3, CD4, CD8, PD-
1, PD-L1, FoxP3, IDO, arginase, TIM3, LAG3 MHC) along with activated ZAP70, 
T cell receptor, JAK-STAT signaling in the laser capture microdissected stroma 
and tumor epithelium, when appropriate 
 
Peripheral Blood Antigen Specific T cell Immune Response 
Analysis of antigen-specific responses will be assessed by intracellular cytokine 
staining (ICS) following a period of in vitro stimulation with overlapping 15-mer 
peptide pools encoding the tumor-associated antigens (TAAs) CEA, MUC-1, and 
brachyury. The TAA peptide pools have been designed to contain agonist 
epitopes that have been previously identified [7-9]; peptide pools encoding for 
HLA and CEFT (a mixture of CMV, EBV, Flu, and Tetanus toxin) will serve as 
negative and positive controls, respectively. Peptide mixes will be purchased 
from JPT (Berlin, Germany), reconstituted in DMSO, and utilized immediately. 
Cryopreserved PBMC from patients before therapy and at specified time points 
will be thawed and rested overnight at 37oC, 5% CO2 in complete media (IMDM 
supplemented with 10% Human AB, 2mM glutamine, 100 units/ml penicillin, and 
100 μg/ml streptomycin). The next day (Day 0), PBMC will be seeded in 12 well 
plates (2.5 x106 in 1 mL), and stimulated with peptide mixes (0.1μg/mL per 
peptide); cultures will be supplemented on days 3 and 5 with cytokines (IL7 and 
IL15, 10 ng/mL, PeproTech, Rocky Hill, NJ) and fresh media, and on day 7 will 
be rested (with removal of cytokines and peptide). On day 11, 1x106 cells will be 
restimulated for 24 hours in 96 well plates with peptide mixes in the presence of 
anti-CD107a-APC (clone H4A3, BD Biosciences); brefeldin A (1μl/mL) and 
monensin (0.7μl/mL) (BD Biosciences) will be added to cultures 2 hours after the 
start of the restimulation and incubated for the final 22 hours. PBMC will then be 
stained with anti-CD4-PerCP-Cy5.5 (clone OKT4, Biolegend), anti-CD8-AF700 
(clone OKT8, Ebioscience), and anti-TNF-PE (clone MAb11), anti-IFNg-PE-Cy7 
(clone 4SB3), and anti-IL-2-BV521 (clone 5344.111) (BD Biosciences).  
 
For all flow cytometry experiments, at least 3x105 events in the live gate will 
be acquired with a BD LSR-II flow cytometer equipped with a UV, violet, blue, 
and red laser. FCS files will be imported and analyzed with FlowJo V.9.7 for 
Macintosh (TreeStar, Ashland, OR). Fluorescence minus one (FMO) controls will 
be used for gating, and non-viable cells will be excluded. For ICS experiments, 
the absolute number of CD4+ or CD8+ lymphocytes producing cytokine or 
positive for CD107a will be calculated per 1x106 cells plated at the start of the in 


Version 2.4 01-Oct2019 
 
 
 
23 
 
vitro stimulation (IVS). [10] The background signal (obtained with the HLA 
peptide pool), and values obtained prior to therapy will be subtracted from those 
obtained post-therapy. Values >250 will be scored as positive for TAA-specific 
immune response following therapy. 
 
Peripheral Blood Mononuclear Cell Subset Analysis 
Multicolor flow cytometry will be performed on frozen peripheral blood 
mononuclear cells (PBMC) as previously described [11]. Staining will be 
performed using 5 panels (Appendix D, table 1) to identify markers involved in 
PD-1 signaling (Appendix D, table 2, panel 1), CD4+ T cells, CD8+ T cells, and 
B cells (Appendix D, table 2, panel 2), Tregs (Appendix D, table 2, panel 3), NKs, 
NK-T, cDCs, and pDCs (Appendix D, table 2, panel 4), and MDSCs (Appendix 
D, table 2, panel 5). These panels will identify a total of 123 peripheral immune 
cell subsets (Appendix D, Table 3), which include 9 parental immune cell types 
and 114 subsets relating to maturation and function within the parental types. 
Optimal amounts of antibodies for staining were determined by previous titration 
experiments. Briefly, 1 million PBMCs per test will be incubated for 15 minutes 
at 4°C with 2 µL of human TruStain FcX (Biolegend, San Diego, CA) and Live 
Dead Fixable Stain Blue (Invitrogen, Waltham, MA). Surface antibodies will be 
added for 30 minutes at 4°C. Cells will then be washed, permeabilized 
(eBioscience, San Diego, CA), and stained with intracellular antibodies for 30 
minutes at room temperature. Samples will be acquired on an LSRII flow 
cytometer (BD Biosciences, San Jose, CA) equipped with a UV, violet, blue, and 
red laser, and analyzed using FlowJo V9.7 for Macintosh (Treestar, Ashland, 
OR). The gating strategy will identify 123 peripheral immune cell subsets, with 
non-viable cells excluded, and negative gates set based on fluorescence minus 
one controls. All values will be reported as % of PBMCs in order to help eliminate 
the bias that could occur in the smaller populations with fluctuations in leukocyte 
subpopulations [12]. 
 
Serum Cytokine and Soluble Factor Analysis 
Serum cytokines and soluble factors related to immune regulation will be 
analyzed using standard ELISA kits for soluble factors, as previously described 
[13] and cytokines (available via the Inglefield Laboratory, NCI, Frederick using 
the MesoScale platform (Rockville, MD), V-plex kit).  
 
T Cell Clonal Expansion Assay 
cDNA from PBMC will be amplified using locus specific primers for TCR-β.  
Previously described methods will be used to map the V region and identify the 
J region [14] and identify clonal sequences of interest. Analytics tools will be 
used to sort and identify clonal populations of interest in the post- versus pre-
treatment samples.  Correlation of expansion of a clonal TCR population post 
treatment will be correlated with clinical outcomes. 
 
 
Measurements of Serum indoleamine 2,3-dioxygenase (IDO) 
Tryptophan is catabolized by IDO to N-formylkynurenine which is rapidly 
converted to kynurenine. Measurement of serum levels of kynurenine and 
tryptophan can provide evidence of functional IDO activity. Because kynurenine 
can be further metabolized to downstream products, this assay is not entirely 
quantitative, but the ratio of tryptophan/kynurenine can provide a relative 
indication of IDO functional activity. Serum samples from patient taken before 
treatment and prior to the 2nd dosing of CV301 with durvalumab will be analyzed 


Version 2.4 01-Oct2019 
 
 
 
24 
 
for kynurenine and tryptophan levels by HPLC. HPLC will be performed 
according to the method described by Yong, et al [15].  
 
Immunohistochemistry for Detection of IDO in Tissue Samples 
Immunohistochemical staining will be performed on 10% formalin fixed, paraffin-
embedded tissue sections (4μm). After deparaffinization and rehydration, the 
sections will be treated with 0.3% hydrogen peroxide and incubated with 10% 
bovine serum albumin to block nonspecific staining. The sections will be 
incubated for 15 minutes at 37°C with proteinase for antigen-retrieval. The 
sections will be incubated at room temperature with anti-IDO monoclonal 
antibody. The sections will then be rinsed and incubated with the biotinylated 
second antibody. After washing, the sections will be incubated with horseradish 
peroxidase-conjugated 
streptavidin, 
and 
finally 
treated 
with 
3,3’ 
diaminobenzidine tetrahydrochloride. The slides will counter stain with Meyer’s 
Hematoxylin [16]. 
 
Double immunohistochemical analysis for the detection of CD3+ T-cells in the 
IDO-stained tissue sections will also be performed using mouse anti-CD3 
monoclonal antibodies.  
 
All these analyses will be done on samples taken before treatment and after 8 
weeks on therapy with CV301 with durvalumab. 
 
Genotyping IDO2 of Constitutional gDNA (unpublished and confidential data) 
Indoleamine 2,3-dioxygenase 2 (IDO2) is a family member of IDO and related to 
the same pathway that is involved in an immune regulatory mechanism.   Two 
functional IDO2 single polymorphisms (SNPs) are known to result in complete 
or 
partial 
inactivation 
(rs10109853:R248W 
– 
Catalytic 
inactivation, 
rs4503083:Y325X = stop Codon) were sequenced in 64 pancreatic tumor 
samples from 43 patients operated for resectable pancreatic cancer (41 PDA, 2 
periampullary adenoca.). Genotypes were considered germline. Genotypes 
considered as resulting in complete inactivation (Y325X Homozygous, R248W 
homozygous) were grouped as a homozygous group, all the other genotypes 
were grouped as WT and/or Heterozygous. Histopathological features and 
overall survival (OS) were analyzed.  A total of 43 pancreatic tumor patients were 
analyzed. Twenty-six patients (62.8%) were WT/Heterozygous homozygous and 
16 patients (37.2%) were Homozygous. Patients in the homozygous group had 
considerably higher rates of Familial PDA (OR 15.6, 95% CI 1.7-146.4, 
P=0.007). These findings remained consistent in a sub-analysis for smoking 
status. Interestingly, the familial PDAs were limited to male patients 
(n/N=7/19,P=0.002). In a gender based sub-analysis (N=19), the homozygous 
patients retained their high proportion of familial PDAs (OR 18.0, 95% CI 1.5-
216.6, P=0.02). A multivariate Cox hazard-model paradoxically indicated that 
patients in the homozygous group, while more prone to familial PDA, had a more 
favorable long term outcome than the WT/Hetero counterparts (HR 0.34, 
P=0.02). 
 
Based on these data that strongly suggests that the presence of the IDO2 SNP 
has function, we will sequence the IDO2 gene for the presence of these SNPs 
from the blood from patients from this protocol.  Specifically, we will determine if 
a correlation exists between the presence of an IDO2 SNP and patient response 
within this clinical trial.  
Measurements of Serum arginase-1 


Version 2.4 01-Oct2019 
 
 
 
25 
 
Arginase is a hydrolase mostly found in liver. It catalyzes the amino acid L-
arginine to ornithine and urea. There are two isoforms of arginases, cytoplasmic 
arginase I and mitochondrial arginase II. Myeloid-derived suppressor cells 
(MDSC) expressing arginase I deplete L-arginine and profoundly inhibit T-cell 
functions. Increased levels of MDSC on cancer patients correlated with low L-
arginase and high ornithine levels in plasma and T-cell dysfunction.  
 
Serum level of arginase I will be determined by two assays. (a) ELISA kit 
(BioVendor) using monoclonal antibody to arginase [17] and (b) The function of 
arginase will be determined by measuring the serum levels of L-arginase and L-
ornithine by HPLC [18].  These analyses will be done on samples taken before 
treatment and after 8 weeks on therapy with CV301 with durvalumab. 
 
Immunohistochemistry for Detection of arginase-1 in Tissue Samples 
Four μm thick sections of the formalin-fixed paraffin-embedded tissue will be 
stained 
with 
polyclonal 
antibody 
against 
arginase 
I. 
Double 
immunohistochemical analysis for the detection of MDSC (CD11b+/CD14- and 
CD11b+/CD14+) MDSC in the arginase stained tissue sections will also be 
performed [19]. 
 
Reverse Phase Phospoprotein MicroArray Analysis 
The Reverse Phase Protein Microarray (RPPA) technology has been developed 
to address the analytical challenges of the sandwich and forward phase protein 
arrays (e.g. mismatch of sandwich antibody affinity, imprecision within and 
between analytes, and poor sensitivity).  The platform has been designed to 
enable non-subjective, quantitative, multiplexed analysis of specific forms of 
cellular proteins (e.g. phosphorylated, unphosphorylated, and cleaved) from a 
limited amount of starting sample, such as with a fine needle aspirate or laser 
capture microdissected (LCM) cellular material to procure pure populations of 
the target cells of interest. Particularly suited for clinical tissue samples, RPPA 
uses a single antibody directed against the epitope of interest.  A key attribute of 
the RPPA is the ability to quantitatively measure hundreds of signaling proteins 
concomitantly from only a few thousand cells, thus providing a critical means of 
broad-scale cell signaling analysis directly from tissue samples, cell culture 
models, and animal tissues from pre-clinical studies. The RPPA technology, 
invented in the lab of Drs. Liotta and Petricoin at George Mason University and 
now optimized for routine clinical sample analysis [20-27], is currently being 
employed within the CAP/CLIA complaint proteomics laboratory within the 
Center for Applied Proteomics and Molecular Medicine at George Mason 
University. No other technology can measure the activity of as many signaling 
proteins at once from such small amounts of input material. 
 
Ex Vivo Models of Patient Tumors 
Several models of ex vivo tumor propagation are currently being explored, 
including organoids and zebrafish avatars.  Pre-treatment tumor samples will be 
used to develop an ex vivo model from each individual patient. 
 
 


Version 2.4 01-Oct2019 
 
 
 
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1. BACKGROUND AND RATIONALE 
1.1. An Unmet Need in Advanced GI cancers  
We have made significant advancements in the treatment of advanced gastrointestinal cancers over the 
last two decades.  Patients with metastatic colon cancer are now living, on average over 30 months; 
while in pancreatic cancer, new combinations are leading to median overall survivals that for the first 
time ever are approaching 12 months.  But to achieve these gains, patients must be exposed to 
chemotherapy continuously; and despite these gains, over 100,000 patients in the United States die 
each year as a result of advanced GI cancers [28].  Thus, novel therapies, particularly those with minimal 
toxicities are desperately needed. An immune-based approach to treating colorectal and pancreatic 
cancer may provide a mechanism to fight cancer with a novel approach, with the aim of extending 
survival but with fewer toxicities than chemotherapy.  CV301 is capable of inducing a tumor-specific T-
cell response against antigens significantly expressed in colorectal and pancreatic adenocarcinomas.  
There is great potential for synergistic anti-tumor activity with the combination of CV301 and an immune 
checkpoint inhibitor, allowing possible anti-tumor responses together that each agent alone could not 
provide. 
1.2. Maintenance Therapy in Colorectal Cancer  
Combination chemotherapy (e.g. FOLFOX or FOLFIRI) typically with anti-VEGF or anti-EGFR 
monoclonal antibodies have improved survival to 30+ months in patients with newly diagnosed 
metastatic colorectal cancer [29, 30]. Moreover, in patients for whom chemotherapy has led to a control 
of their disease, manifest as either stable disease, or a response, transitioning to “maintenance” therapy 
with 5FU/Capecitabine and bevacizumab improves progression-free AND overall survival compared to 
no chemotherapy (i.e. compared to a chemotherapy free holiday) [31]. In the CAIRO-3 trial, the median 
progression-free survival for patients receiving 5FU and bevacizumab was 8.5 months, compared with 
4.1 months for patients who received placebo [4].  
1.3. Second Line Therapy in Pancreatic Cancer 
Significant improvements have also been made in just the last few years for patients with metastatic 
pancreatic cancer. In 2011, the combination of 5-FU, oxaliplatin and irinotecan (FOLFIRINOX) was 
compared against gemcitabine in a phase III trial with promising results, and FOLFIRINOX is considered 
the standard first-line treatment option in patients with a good performance status (PS 0-1). [32] The 
median overall survival (mOS) was 11.1 months in the FOLFIRINOX group as compared with 6.8 months 
in the gemcitabine group. The mPFS was 6.4 months in the FOLFIRINOX group as compared with 3.3 
months in the gemcitabine group.  More recently, in 2013, in a Phase III trial, the combination of 
gemcitabine and nab-paclitaxel was also demonstrated to be superior over gemcitabine alone. [33] The 
median overall survival of gemcitabine + nab-paclitaxel was 8.5 months, which was statistically superior 
to the 6.7-month survival seen with single agent gemcitabine. The mPFS was 5.5 months in the 
gemcitabine plus nab-paclitaxel group as compared with 3.7 months in the gemcitabine group. 
 
Nevertheless, the progression-free survival times in patients with metastatic pancreatic cancer have 
been too short to effectively pursue the concept of “maintenance” therapy.  But as patients are living 
longer, the prospect of continuing chemotherapy with a fair degree of toxicity becomes unappealing, and 
a therapy that could control the disease, with little toxicity could be very appealing. The only comparator 
for efficacy would be for second-line therapy, and the median progression-free survival time for several 
Phase II second line trials ranges from 2.5 to 5.7 months (typically around 4 months) [5]. 
1.4. Checkpoint Inhibitors 
Anti-tumor immune activation requires a variety of immunomodulatory signals, and both costimulatory 
and coinhibitory signals are needed to orchestrate an optimal antigen-specific immune response.  
Tumors can evade immune detection by expressing the programmed cell death ligand 1 (PD-L1).  
Blockade of PD-L1 may help overcome immunosuppressive effects and restore T-cell activity against 
tumors. [34-39] PD-L1 is found on the surface of many cancer cells and impairs the immune system’s 


Version 2.4 01-Oct2019 
 
 
 
27 
 
ability to fight cancer.  As the T cells come close to the tumor, they are engaged by PD-L1, which starts 
a signal inside the T-cell that blocks the T-cell’s ability to kill the cancer cell.  Inhibition of PD-L1 has 
been shown to produce durable antitumor activity as a single agent and in combination with other 
therapies.   However, not all patients treated respond to anti-PD-L1 therapy alone, prompting the 
suggestion that induction of an immune stimulatory response is required in conjunction with blockade of 
the inhibitory signals to illicit robust anti-tumor activity. Immune responses directed against tumors are 
one of the body’s natural defenses against the growth and proliferation of cancer cells. However, over 
time and under pressure from immune attack, cancers develop strategies to evade immune-mediated 
killing allowing them to develop unchecked. One such mechanism involves upregulation of surface 
proteins that deliver inhibitory signals to cytotoxic T cells. PD-L1 is one such protein, and is upregulated 
in a broad range of cancers with a high frequency, with up to 88% expression in some tumor types. In a 
number of these cancers, including lung [40], renal [41-43], pancreatic [44-46], ovarian cancer [47], and 
hematologic malignancies [48, 49] tumor cell expression of PD-L1 is associated with reduced survival 
and an unfavorable prognosis. PD-L1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help regulate normal 
immune responses and is utilized by tumors to help evade detection and elimination by the host immune 
system tumor response. In the lymph nodes, PD-L1 on antigen-presenting cells binds to PD-1 or CD80 
on activated T cells and delivers an inhibitory signal to the T cell [50, 51]. This results in reduced T-cell 
activation and fewer activated T cells in circulation. In the tumor microenvironment, PD-L1 expressed 
on tumor cells binds to PD-1 and CD80 on activated T cells reaching the tumor. This delivers an inhibitory 
signal to those T cells, preventing them from killing target cancer cells and protecting the tumor from 
immune elimination [52]. 
1.5. CV301 [53] 
Garnett, et al discuss that stimulation and activation of T-cells is essential for a successful adaptive 
immune response to an antigen [54]; a sufficient immune response to a tumor associated antigen (TAA), 
such as CEA, may result in direct attack of the tumor. The carcinoembryonic antigen (CEA) is an oncofetal 
antigen that is expressed at high levels in most colorectal and pancreatic carcinomas.  The mucin, MUC-
1, is a highly glycosylated protein that is also overexpressed in many adenocarcinomas, including those 
of colorectal and pancreatic origin. T-cells from normal donors and cancer patients have been shown to 
recognize HLA-restricted epitopes derived from CEA and non-HLA-restricted epitopes encoded by MUC-
1 [55, 56]. Targeting two distinct tumor antigens in a single vaccine may induce better anti-tumor effects 
because the generation of polyclonal T-cell responses may prevent tumor escape through antigen loss.  
 
CV301 comprises two recombinant poxviral vectors to be used together in a prime-boost vaccination 
regimen. The priming vector is a highly attenuated, non-replicating vaccinia virus Modified Vaccinia 
Ankara-Bavarian Nordic-CV301 (MVA-BN-CV301) and the boost is a recombinant fowlpox virus (FPV-
CV301). Collectively, the regimen is referred to as CV301. CV301 has been designed to consist of five 
human transgenes to elicit a specific and robust immune response to a variety of cancers. Both viral 
vectors for CV301 co-express two human tumor-associated antigens (TAA): carcinoembryonic antigen 
(CEA) and mucin-1 (MUC-1), and three human costimulatory molecules: B7.1, intercellular adhesion 
molecule-1 (ICAM-1), and leukocyte function-associated antigen-3 (LFA-3) (or TRIad of COstimulatory 
Molecules, TRICOM™). The three costimulatory molecules are included to maximize the immune 
response to the TAAs. 
 
The proposed anti-tumor mechanism of action for CV301 poxvirus-based immunotherapy is to induce 
the generation of tumor antigen-specific killer T cells capable of infiltrating the tumor. This tumor-specific 
T cell immune response is aimed to target and kill antigen-expressing tumor cells throughout the patient’s 
body.  
 
CV301 consists of the same five transgenes as the earlier poxviral vaccine known as PANVAC, which 
was the subject of two Investigational New Drug Application (IND) clinical development programs. As 


Version 2.4 01-Oct2019 
 
 
 
28 
 
such, much of the nonclinical and clinical data for PANVAC are supportive of CV301. A summary of these 
results are provided below. 
 
1.5.1 PANVAC 
Vaccinia vector expressing CEA, MUC-1, and TRICOM® (TRIad of COstimulatory Molecules; a 
vaccine containing three costimulatory molecules: B7.1, ICAM-1 and LFA-3) was named PANVAC-
V, and fowlpox vector expressing CEA, MUC-1, TRICOM was named PANVAC-F [1, 57].  In the initial 
Phase I study using PANVAC in patients with advanced pancreatic cancer, ten patients received 
priming with PANVAC-V followed by three booster vaccinations with PANVAC-F.  GM-CSF 
(granulocyte-macrophage colony-stimulating factor) was also used as a local adjuvant after each 
vaccination and for 3 consecutive days thereafter. Monthly booster was given if a patient had no 
disease progression. There was no significant toxicity; the majority of side effects were low grade 
injection site reactions or constitutional symptoms. Anti-CEA specific antibody was detected in 50% 
of patients and a heightened antigen-specific T-cell response was observed in 63% of patients [57].  
The PANVAC recombinant vaccinia expresses 2 TAAs: CEA and MUC-1. For those patients who had 
an anti-TAA specific response, a significant increase in overall survival was noted compared with 
those who did not have such a response. A randomized Phase II trial was conducted in patients with 
colorectal cancer with completely resected hepatic or pulmonary metastases [58].  Seventy-four 
patients received adjuvant vaccine therapy comprising PANVAC-V and PANVAC-F, administered 
with autologous dendritic cells (Arm 1) or with sargramostim (GM-CSF) (Arm 2). The recurrence-free 
survival at 2 years was similar in the two arms, at an impressive rate of ~50% for both (47% and 55% 
for PANVAC with dendritic cells and PANVAC/GM-CSF, respectively). The rate and magnitude of T-
cell responses against CEA was statistically similar between study arms. As a group, vaccinated 
patients had superior survival compared with a contemporary group of patients with metastatic 
colorectal cancer who had undergone resection of metastases, but who had not received adjuvant 
vaccine therapy [58].  
 
1.5.2 CV301 
CV301 is composed of two new constructs that were generated to replace the former PANVAC 
(PANVAC-V and PANVAC-F). For CV301, MVA-BN-CV301 replaced PANVAC-V, and FPV-CV301 
replaced PANVAC-F. These constructs are designed to express the same five transgenes with similar 
expression profiles as the previous PANVAC vectors but using the non-replicating MVA-BN® vector 
instead of a replicating vaccinia virus vector as priming vaccine. Furthermore, changes were made 
to increase the genetic stability of the inserted transgenes to enhance manufacturability. The new 
constructs encode each of the transgenes (CEA, MUC-1, B7.1, ICAM-1 and LFA-3) with amino acid 
sequences that are identical to the original vectors, except for MUC-1 where additional agonistic 
epitopes are included. Additionally, changes were made to the DNA sequences of MUC-1, CEA, B7.1, 
ICAM-1 and LFA-3 to reduce homologies and optimize codon expression.  
 
As CV301 consists of the same five transgenes as the earlier generation PANVAC, the CV301 IB 
relies on the available data for CV301 and the extensive nonclinical and clinical data that exists for 
PANVAC.  However, safety data with the use of CV301 has been updated, as detailed below 
 
 
1.5.3 PANVAC/CV301 plus Checkpoint Inhibitors 
A clinical trial of single agent PANVAC in patients with pancreatic cancer was a negative trial, and 
did not improve survival compared to placebo alone [59].  Additionally, in multiple ongoing, and 
recently completed trials of anti-PD-1/PD-L1 therapies, there have been no consistent responses 
induced by single agent therapy [37]. However, mechanistically, there is great promise, as described 
above in the combination of a vaccine therapy with an immune checkpoint inhibitor. 
 
The combination of a vaccine and an immune checkpoint inhibitor appears to be safe, as 
demonstrated by a study in which patients received a similar pox-viral vector platform incorporating 
multiple costimulatory molecules (TRICOM) in combination with an immune checkpoint inhibitor. 
Results of that study suggested that there was no obvious increase in adverse events over that 


Version 2.4 01-Oct2019 
 
 
 
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expected with immune checkpoint inhibitor alone [60]. To our knowledge, there has been no study to 
date combining CV301 with an immune check point inhibitor. The safety of this combination will be 
evaluated in the phase I part of the protocol. 
1.6. Evaluation of Benefit in the Maintenance Setting 
The choice to explore the benefits of the combination of durvalumab and CV301 in the maintenance 
setting is intended to balance several key factors.  While there is great theoretical promise with this 
combination, there is no guarantee of benefit, and there is concern about offering this combination to 
patients who are in desperate need of additional treatment in the face of progressing disease. In fact, 
patients whose disease progresses despite this immunotherapy approach would have the opportunity to 
restart the first line chemotherapy that was providing benefit prior to enrollment. Moreover, understanding 
the effects on the immune response in tumors is a critical part of this trial – so enrolling patients whose 
performance status enables serial correlative marker assessment is also critical. 
1.7. Immune Checkpoint Inhibitors plus Chemotherapy 
There is now a vastly growing body of data demonstrating the safety and efficacy of the combination of 
immune checkpoint inhibitors plus chemotherapy. Most relevant to the current study, Georgetown 
University has been one of the lead accruing institutions for an ongoing trial of MPDL3280A (Anti-PD-L1) 
in combination with bevacizumab and/or FOLFOX (5-FU and oxaliplatin) in patients with metastatic 
colorectal cancer [61].  This trial demonstrated no safety signal of concern over the addition of 
MPDL3280A in combination with chemotherapy AND bevacizumab, and in fact, as part of this trial, 
patients who stopped oxaliplatin (after a maximum of 8 doses), were allowed to continue on maintenance 
capecitabine and bevacizumab (exactly paralleling the current proposal).  Multiple ongoing trials with 
other immune checkpoint inhibitors, including durvalumab, nivolumab and pembrolizumab in combination 
with chemotherapy or targeted agents have repeatedly demonstrated no additional safety concerns 
above and beyond that seen with either the immune checkpoint inhibitors or the chemotherapy/targeted 
therapy alone 
 
Combining anti-PD-L1 with standard of care provides multiple advantages that may allow for improved 
clinical outcomes compared with either agent alone.  5-FU and oxaliplatin have been identified as agents 
which can induced immunogenic cell death and/or decrease the number of regulatory T cells [62], which 
increases T cell activation via immunogenic cell death and antigen presentation on tumor cells resulting 
in increased T cell mediated killing of tumor cells.  Immunogenic cell death induced by oxaliplatin is known 
to be capable of inducing an anti-tumor immune response [63-67]. There is also evidence that 
immunotherapy in combination with 5-FU is capable of increasing the immune response against tumor 
cells.   
 
T cell activation and resultant production of IFN-gamma and type 1 cytokines results in PD-L1 induction 
in the tumor tissue. PD-L1 expression has been correlated with the likelihood of PD-1 – PD-L1 blockade 
to induce anti-tumor immune response and cause tumor volume reduction and clinical benefit.    
Another mechanism by which the underlying anti-tumor immune response may be improved when 
patients are exposed to the standard of care regimen is through a process known as immunogenic 
modulation.  Hodge and colleagues in the LTIB have demonstrated immunogenic modulation resulting in 
upregulation of MHC, tumor associated antigens, and FAS resulting in T cell mediated killing with 
chemotherapeutics, including 5-FU and oxaliplatin [68, 69].  
 
Finally, the decreased tumor burden induced by standard of care therapy may allow better immune 
response by debulking the tumor and improving the microenvironment for immunologic killing [70-75].  
The addition of standard of care therapy also provides ample time for an immune response to occur, 
which may be important considering the occasional delayed responses and prolonged stable disease 
findings that have been described with anti-PD-1 and anti-PD-L1 targeting agents.  Given the findings 
with ipilimumab improving overall survival while not necessarily improving PFS [76], it may be that 
delayed immunologic effects create long term clinical benefit in some populations despite lack of 


Version 2.4 01-Oct2019 
 
 
 
30 
 
immediate tumor volume reduction.  By using a therapy in combination with standard agents known to 
induce tumor volume reduction, we may be able to capture that long term benefit. 
1.8. Vaccines plus Chemotherapy 
To our knowledge, there have been no published reports of the combination of CV301 plus 
chemotherapy.  But several clinical trials have demonstrated the safety of combining a vaccine plus 
chemotherapy.  Most notably, GVAX (a “vaccine” consisting of irradiated, GM-CSF-secreting allogeneic 
pancreatic cell lines given intradermally to elicit a broad antigenic response) has been combined with 
safely with FOLFIRINOX in patients with pancreatic cancer(NCT01595321).  This trial has not been 
published, but in personal communication with the Principal Investigator, there have been no signals of 
safety concerns of the combination.  In addition, the yeast vaccine GI-4000 has been safely combined 
with gemcitabine in pancreatic cancer(NCT00300950), and with FOLFOX/FOLFIRI plus bevacizumab in 
colorectal cancer (NCT01322815) without safety concerns.  
1.9. Enhanced Immunogenicity with Bevacizumab 
Preclinical evidence indicates that vascular endothelial growth factor (VEGF) signaling in the tumor 
microenvironment causes disorganized perfusion, resulting in poor T cell trafficking to the tumor site, 
increased hypoxia, and an immunosuppressive microenvironment.  Rakesh Jain’s group has 
demonstrated significant improvement in T cell infiltration with the addition of VEGF inhibition in 
preclinical models [77]. In this study, VEGF inhibition increased the efficacy of a vaccine to induce T cell 
infiltration into the tumor, resulting in better anti-tumor effect.  Similarly, Dr. Hwu’s group has found VEFG 
blockade to result in greater T cell infiltration in adoptively transferred T cells in a murine model [78].  
Alfaro, et al., found VEGF inhibition to be valuable for dendtritic cell differentiation and T cell activation 
[79]. Taken together, these data indicate a potential synergy between VEGF inhibition and 
immunotherapy, supportive of combining these agents in patients.  
1.10. Study Agent(s) Background and Associated Toxicities 
 
1.10.1. Capecitabine (Package insert) [80] 
5-Fluorouracil (5-FU) is an inactive agent in its parent form, and requires intracellular activation for its 
anti-cancer effects.  In the cell, thymidine phosphorylase converts 5-FU to FUDR, which is then 
phosphorylated by thymidine kinase to generate the active metabolite, FdUMP which then covalently 
binds to and inhibits thymidylate synthase, leading to a depletion of dTTP and preventing DNA 
synthesis and repair.  A metabolite, FUTP is also generated, interfering with RNA synthesis as well. 
The most common mechanism of resistance to 5-FU is overexpression of or mutation in the 
thymidylate synthase gene.  5-FU is administered intravenously, and metabolism is rapid, with a half-
life of only minutes, for the parent compound.   
 
Oral capecitabine is a 5-FU prodrug that is highly bioavailable.  It undergoes successive 
transformation to its active metabolite, 5-FU.  Conversion begins in the liver, but the final step is 
mediated in cells by thymidine phosphorylase.  Of great importance, thymidine phosphorylase is 
expressed at much higher levels in tumor tissues, making capecitabine much more tumor specific.  
Peak levels of capecitabine occur 2 hours after ingestion, and elimination is primarily through the 
kidneys. 
 
Toxicities of 5-FU/capecitabine are dependent upon the dose, and also the route and schedule of 
administration.  IV 5-FU can be given as a rapid bolus, or as a continuous infusion.  Bolus 
administration is more associated with myelosuppression while continuous infusion and oral 
capecitabine are more associated with the development of hand-foot syndrome.  Both routes can 
lead to nausea, vomiting, diarrhea, mucositis, fatigue, and rarely coronary vasospasm. 


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1.10.2. Bevacizumab (Package Insert) [81] 
Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) and 
prevents binding of VEGF to its receptor (VEGF-R). This prevents activation of a key pathway 
involved in the angiogenesis tumors require for establishing a blood supply to sustain further growth. 
Bevacizumab is indicated for the first- or second-line treatment of patients with metastatic carcinoma 
of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.  
bevacizumab is dosed at 5mg/kg every two weeks.  
1.10.3. CV301 Background  [53] 
1.10.3.1. Summary of Non-clinical Experience 
CV301 comprises two recombinant poxviral vectors to be used together in a prime-boost 
vaccination regimen. The priming vector is a highly attenuated, non-replicating vaccinia virus 
Modified Vaccinia Ankara-Bavarian Nordic-CV301 (MVA-BN-CV301) and the boost is a 
recombinant fowlpox virus (FPV-CV301). Collectively, the regimen is referred to as CV301. 
CV301 has been designed to consist of five human transgenes to elicit a specific and robust 
immune response to a variety of cancers. Both viral vectors for CV301 co-express two human 
tumor-associated antigens (TAA): carcinoembryonic antigen (CEA) and mucin-1 (MUC-1), 
and three human costimulatory molecules: B7.1, intercellular adhesion molecule-1 (ICAM-1), 
and leukocyte function-associated antigen-3 (LFA-3) (or TRIad of COstimulatory Molecules, 
TRICOM™). The three costimulatory molecules are included to maximize the immune 
response to the TAAs.  The proposed anti-tumor mechanism of action for CV301 poxvirus-
based immunotherapy is to induce the generation of tumor antigen-specific killer T cells 
capable of infiltrating the tumor. This tumor-specific T cell immune response is aimed to target 
and kill antigen-expressing tumor cells throughout the patient’s body. 
 
CV301 consists of the same five transgenes as the earlier poxviral vaccine known as 
PANVAC, which was the subject of two Investigational New Drug Application (IND) clinical 
development programs. As such, much of the nonclinical and clinical data for PANVAC are 
supportive of CV301.  
 
In vitro studies demonstrated that antigen-presenting cells incubated with PANVAC led to the 
activation of CEA and MUC-1 specific cytotoxic T cells that likely target tumor cells 
overexpressing CEA and/or MUC-1. The responses were optimal when the 3 costimulatory 
molecules of TRICOM were co-expressed. Humoral and cellular responses specific to CEA 
have also been demonstrated in mice. 
 
It was hypothesized that poxvirus-based active immunotherapy could provide even greater 
improvements to patient outcome when used in combination with immune checkpoint 
inhibitors (ICIs) by reactivating functionally inhibited tumor-specific T cells and inducing new 
productive tumor-specific responses. Thus, a nonclinical proof-of-principle combination 
therapy study with anti-PD-1 was performed using a precursor to MVA-BN-CV301. Antitumor 
efficacy of poxvirus-based immunotherapy was significantly improved when combined with 
monoclonal antibodies that block the activity of PD-1, and worked through different (and 
complementary) mechanisms of action. Therefore, combination therapy of reduced-dose ICIs 
with poxvirus-based active immunotherapy showed improved benefit in preclinical models 
over ICI therapy alone. 
1.10.3.2. Summary of Clinical Experience 
Four clinical trials with CV301 are currently ongoing, with updated details presented in section 
1.10.3.2.3 below. 
 


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To date, CV301’s predecessor product PANVAC has been evaluated in approximately 300 
subjects (138 subjects in the clinical trials sponsored by Therion and 164 subjects in the 
National Cancer Institute (NCI) -sponsored trials) in the following 7 clinical trials: 
 
• TBC-PAN-002 (completed): Phase 1, single-arm, clinical trial of PANVAC in combination 
with granulocyte macrophage colony-stimulating factor (GM-CSF) in subjects with 
unresectable adenocarcinoma of the pancreas 
 
• TBC-PAN-003 (completed): Phase 3, 2-arm, clinical trial of PANVAC in combination with 
GM-CSF versus best supportive care or palliative chemotherapy in subjects with metastatic 
(Stage IV) adenocarcinoma of the pancreas who have failed a gemcitabine-containing 
chemotherapy regimen 
 
• CTEP No. 6536 (completed): Phase 1, 4-arm, clinical trial of PANVAC in combination with 
GM-CSF in subjects with metastatic colorectal, non-colorectal, breast, or ovarian cancer 
 
• CTEP No. 7606 (ongoing; enrollment and treatment phase completed): Phase 1, single-arm, 
clinical trial of PANVAC in combination with GM-CSF in subjects with incurable pancreatic 
cancer 
 
• CTEP No. 6977 (completed): Phase 2, 2-arm, clinical trial of PANVAC + docetaxel compared 
with docetaxel alone in subjects with metastatic breast cancer 
 
• CTEP No. 8087 (completed): Phase 2, 2-arm, clinical trial of DCs + PANVAC compared with 
GM-CSF + PANVAC in subjects with hepatic or pulmonary metastases secondary to 
adenocarcinoma of the colon and rectum 
 
• CTEP No. 9539 (ongoing): Phase 2, 2-arm, clinical trial of PANVAC + Bacillus Calmette-
Guerin (BCG) compared with BCG alone in subjects with high grade non-muscle invasive 
bladder cancer (NMIBC) who failed at least 1 induction course of BCG 
 
1.10.3.2.1. Safety 
CV301 will be administered in a heterologous prime-boost regimen consisting of 
recombinant MVA-BN-CV301 followed by recombinant FPV-CV301. Since the vaccine 
constructs encode the same five transgenes as the earlier generation PANVAC, but 
using non-replicating MVA-BN as priming vector instead of replicating vaccinia virus, 
the proposed development program for CV301 is supported by existing nonclinical 
data for PANVAC. 
 
The pilot study 6536 “An Open-Label Pilot Study to Evaluate the Safety and Tolerability 
of PANVAC™-V (Vaccinia) and PANVAC™-F (Fowlpox) in Combination with 
Sargramostim in Adults with Metastatic Carcinoma,” was closed to accrual as of 
5/27/2008. As of May 2013, 51 patients have been treated and the highest grade, 
therapy-related AEs reported are two instances of grade 3 syncope (fainting). Grade 
1 or 2 injection site reaction/extravasation changes, flu-like symptoms, fever, and 
fatigue have been the most commonly reported events. 
 
The phase 1 study 7606, “Immunotherapy for Unresectable Pancreas Cancer: A 
Phase 1 Study of Intratumoral Recombinant Fowlpox PANVAC (PANVACTM-F) Plus 
Subcutaneous Recombinant Vaccinia PANVAC (PANVACTM-V), PANVACTM-F and 
Recombinant Granulocyte-Macrophage Colony Stimulating Factor (rH-GM-CSF),” 
was closed to accrual and treatment on 4/20/2013. As of May 2013, 14 patients have 
been treated on this trial. Two grade 4 therapy-related AEs included increased lipase 
and increased serum amylase. Six grade 3 therapy-related AEs included colitis, 


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diarrhea, pancreatitis, increased lipase, and decreased lymphocyte count. Injection 
site reaction was the most frequently reported therapy related AE (all grade 1).  
 
The phase 2 pilot study 6977, “Randomized Pilot Phase II Study of Docetaxel Alone 
or in Combination with PANVAC™-V (Vaccinia) and PANVAC™-F (Fowlpox) in Adults 
with Metastatic Breast Cancer,” was closed to accrual and treatment on 2/4/2013. No 
grade 5 therapy-related events have been reported for this study. Grade 4 therapy-
related AEs included pericardial effusion, pleural effusion and a thromboembolic 
event. Grade 3 therapy-related AEs included decreased neutrophils, lymphopenia, 
leukopenia, increased alanine aminotransferase, abdominal pain, dyspnea, and 
injection site reaction. Injection site reaction, leukopenia, and fatigue were the most 
commonly reported therapy-related AEs (grades 1-3). 
 
PANVAC has been well-tolerated in all clinical trials. The most frequent treatment-
related adverse events (AEs) were injection site reaction, myalgia, fatigue, vomiting, 
nausea, and abdominal pain. Most treatment-related AEs were Grade 1 or 2 in 
severity. Serious adverse events (SAEs) related to study treatment, discontinuations 
due to AE, and deaths related to study treatment were rare (only 1 death due to Grade 
5 pulmonary infiltrate was assessed as possibly related to study drug). 
1.10.3.2.2. Efficacy 
Early nonclinical studies demonstrated CV301’s safety, along with its ability to activate 
antigen-specific T-cell responses. Murine (mu) dendritic cells (DCs) infected with 
rVmuTRICOMTM or rF-muTRICOMTM were shown to significantly enhance naive T-
cell, allogenic T-cell, and peptide-specific T-cell proliferation in vitro. Following weekly 
vaccination for 4 weeks with rV-muCEA/TRlCOMTM plus murine granulocyte-
macrophage colony-stimulating factor (muGM-CSF) and interleukin (IL)-2, 9 of 16 
treated CEA-transgenic (Tg) mice with established CEA-positive hepatic carcinoma 
metastases mice, remained alive through 25 weeks. By contrast, in the control group 
(which received non-rV plus cytokines), only 1 of 19 (5%) survived past 16 weeks. 
 
Successful protection by vaccines comprised of combinations of costimulatory 
molecules was evaluated. C57BL/6 mice were vaccinated subcutaneously (SC) with 
either rV-CEA or rV-CEA/muTRICOMTM, then challenged 100 days later with MC-38 
colon carcinoma cells. All mice vaccinated with rV-CEA succumbed to tumors while all 
mice vaccinated with rV-CEA/muTRICOMTM survived tumor challenge. T-cell 
responses were also significantly higher in animals vaccinated with rV-
CEA/muTRICOMTM.  
 
In CEA-Tg mice bearing CEA-positive peripancreatic tumors, 80–100% of animals 
died within 12 weeks without treatment. A CEA/TRICOMTM vaccination regimen 
induced a therapeutic antitumor response as demonstrated by a 60% increase in 
survival through a 25-week observation period, without evidence of tumor. In CEA-
Tg/MIN mice that express human CEA as a result of a transgenic insertion and develop 
numerous intestinal neoplasms due to a mutation in the adenomatosis polyposis coli 
(APC) gene, there was a spontaneous onset of intestinal tumorigenesis with strong 
CEA expression in all tumor cells as well as in normal gastrointestinal tissues. 
Vaccination with rV-CEA/TRICOMTM and GM-CSF, followed by rF-CEA/TRICOMTM 
and rF-GM-CSF, resulted in a reduction in the number of intestinal tumors, improved 
overall survival (OS), and no histologic evidence of autoimmune-related pathology 
directed against normal tissues expressing CEA.    
 
In clinical trials TBC-PAN-002 and CTEP No. 8087, the development of a CEA-specific 
T cell response was observed following treatment with PANVAC. As demonstrated in 


Version 2.4 01-Oct2019 
 
 
 
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clinical trial TBC-PAN-002, this response could be detected 2 to 6 weeks after initial 
treatment, and although variable, generally increased with repeated boosting 
immunizations. 
 
Though TBC-PAN-003 did not meet the primary endpoint of overall survival (OS), 
cancer immunotherapies such as PANVAC require time for an effective immune 
response to develop before a clinical response can be observed (approximately 4-6 
months). For example, the randomized Phase 2 trial of the poxvirus immunotherapy 
PROSTVAC® in metastatic castration-resistant prostate cancer (mCRPC), which 
resulted in a significant difference in OS (25.1 months vs. 16.6 months; hazard ratio 
[HR] = 0.56; p = 0.0061), did not demonstrate a significant difference in progression-
free survival (PFS) (3.8 months vs 3.7 months) [88].  Similarly, the Phase 3 trial of the 
therapeutic cancer vaccine sipuleucel-T demonstrated a significant improvement in 
OS when there was not a significant difference in the shorter term endpoint of PFS 
[89,90].  At the time this Phase 3 trial was conducted, the median time to progression 
in patients with advanced metastatic pancreatic cancer who failed gemcitabine therapy 
was less than 10 weeks. Therefore, the clinical course of pancreatic cancer is too rapid 
for the clinical benefits of immunotherapy to be seen in this trial, and it was unlikely 
that PANVAC would improve survival as a single-agent in this patient population. 
 
Supporting this hypothesis, in subjects with unresectable adenocarcinoma of the 
pancreas (clinical trial TBC-PAN-002), the median OS was 6.3 months, which is 
notably higher than the median OS observed in clinical trial TBC-PAN-003. 
Furthermore, in subjects with histologically confirmed hepatic or pulmonary 
metastases secondary to adenocarcinoma of the colon and rectum (clinical trial CTEP 
No. 8087) the median OS was significantly longer in subjects who received PANVAC 
compared with the contemporary control group (> 75 months in both PANVAC arms 
and 44.1 months in the contemporary control group; p < 0.0001). Additionally, some 
subjects with metastatic colorectal, non-colorectal, breast, or ovarian cancer (clinical 
trial CTEP No. 6536) had a positive clinical response to PANVAC treatment, with a 
number of subjects experiencing prolonged survival after coming off trial. In subjects 
with metastatic breast cancer (clinical trial CTEP No. 6977), PFS was higher in the 
PANVAC plus docetaxel arm compared with the docetaxel alone arm (7.9 months and 
3.9 months, respectively [p = 0.09]). These results demonstrate the potential clinical 
benefit of PANVAC treatment in a variety of metastatic carcinomas. 
1.10.3.2.3. Clinical Experience with CV301 
CV301-2015-201 
To date, CV301 has been evaluated in 12 subjects in the phase I part of the CV301-
2015-201 trial sponsored by Bavarian Nordic.  Clinical Trial CV301-2015-201 is an 
ongoing, BN-sponsored Phase 1/2 Trial of CV301 in Combination with nivolumab 
versus nivolumab in Subjects with Previously Treated Non-Small Cell Lung Cancer.  
The safety data originating from the phase I part of trial CV301-2015-201, with 12 
subjects enrolled and treated, suggests that CV301 is safe and well tolerated, showing 
a similar safety profile as compared to the previous experience with MVA-BN-based 
and FPV-based vaccines. 
 
In the phase I part of this trial, 12 subjects with various CEA/MUC-1 positive cancers 
have been enrolled, 6 male and 6 female subjects, aged between 39 and 77 years. Of 
these 12 subjects, 3 have received MVA-BN-CV301 at the lowest dose level, 4 x 108 
Inf.U, 3 have received the second dose level, 8 x 108 Inf.U, and 6 have received the 
highest dose level, 1.6 x 109 Inf.U.  At the cut-off date for assessment of the initial 
phase I safety data, 3 of the subjects had also received at least one dose of FPV-
CV301, at a dose of 1 x 109 Inf.U/0.5 mL.  Initial safety data from the phase I part of 


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this trial involving 12 subjects dosed in three different dose levels show that the most 
frequently occurring treatment-related AEs were temporary and self-limiting, grade 1 
or 2 in severity and included injection site reactions (injection site erythema, pruritus, 
pain, induration and swelling) and general symptoms including fever/chills, flu-like 
symptoms, headache, fatigue/weakness, nausea/vomiting, myalgia and arthralgia.. 
There was no occurrence of any of the pre-specified adverse events of special interest 
(immune-related events and cardiac events). There were no related SAEs. There were 
no dose limiting toxicities at all three investigated dose levels. Based on this initial 
safety information, the trial has moved into the phase Ib part, which includes 
combination treatment of CV301 and nivolumab or pembrolizumab. The selected dose 
level for the further course of the trial was 1.6 x 109 Inf.U (i.e. 4 injections of 4 x 108 
Inf.U/0.5 mL) of MVA-BN-CV301. 
 
In the ongoing Phase 1b part of the trial, another 12 subjects (nine females and three 
males between 48 and 74 years) were enrolled: four subjects in cohort 1 received up 
to 15 combination doses of CV301 and nivolumab over a period of up to approximately 
16 months. In cohort 2, eight subjects received up to nine combination doses of CV301 
and pembrolizumab over a period of up to nine months. 
 
During Phase 1b, preliminary data showed that the local injection site reactions and 
general symptoms were in line with the experience during monotherapy in Phase 1. In 
total, 12 SAEs in five patients were reported. Five SAEs in two patients and four non-
serious AEs in two patients led to permanent treatment discontinuation. In both Phase 
1b cohorts (CV301 plus nivolumab and CV301 plus pembrolizumab), safety of the 
combination regimen was established. Overall, DLT and IMAE were below the pre-
specified threshold to continue the trial based on the known safety profile of PD-1 
inhibition. In conclusion, there appears to be no increased toxicity of the combination 
regimens CV301 plus pembrolizumab or nivolumab as compared to Immune 
Checkpoint Inhibitors alone (per Immune Checkpoint Inhibitors prescribing 
information). 
 
Serious Adverse Events 
One unexpected related SAE case was classified as a dose limiting toxicity (DLT) 
during combination treatment of CV301 and nivolumab. The subject had started 
treatment on 28-MAR-2018. During administration of the 2nd dose of nivolumab on 
11-APR-2018, the infusion was interrupted due to infusion reaction. On 25-APR-2018, 
she complained of continuing cough and dyspnea, CT scan was indicative of 
pneumonitis, and the patient was started on prednisone. On 21-MAY-2018 she was 
hospitalized for management of ongoing shortness of breath due to pneumonitis grade 
3 (meeting seriousness criteria). On 25-MAY-2018 there was onset of disseminated 
intravascular coagulation (DIC) while hospitalized, on 26-MAY-2018 she was 
diagnosed with vasculitis while hospitalized. The patient died on 31-MAY-2018 due to 
multi-organ failure.  This case was discussed in the safety management team. The 
relationship was most probably to the anti-PD1 treatment, as such events are known 
reactions for immune checkpoint inhibitors, but for the pneumonitis also possibly 
related to CV301.  
 
Four other subjects reported eight SAEs unrelated or unlikely related to CV301 
(autoimmune hepatitis with liver enzyme elevations, obstructive pneumonia; 
intracranial vascular stroke; dysarthria and memory impairment). The overall 
frequency of immune mediated events under combination treatment of CV301 plus 
anti-PD1 seems to be in line with previously published experience for anti-PD1 alone. 
 
 


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CV301-BLD-001 
This is an ongoing, BN-sponsored Phase 2, multicenter, single-arm trial of CV301 in 
combination with PD-1/L1 blockade in patients with locally advanced or metastatic 
urothelial bladder cancer. As of December 31st, 2018, seven patients were dosed with 
CV301 in combination with atezolizumab). Data is still preliminary.  
 
18-C-0005 / BN-IST-013 
This is an ongoing, NCI-sponsored Phase 2, single center, open lable, single-arm trial 
of CV301 and PROSTVAC in combination with PD-1/L1 blockade in patients with 
confirmed adenocarcinoma of the prostate and with a PSA over 0.8 ng/mL (following 
radical prostatectomy) or rise in PSA of ≥ 2 ng/mL above the nadir (definitive following 
radiation therapy). As of December 31st, 2018, six patients were dosed with the IMPs. 
Data is still preliminary.  
 
HCRN GI16-288 / BN-IST-016 
This is an ongoing, Investigator-sponsored Phase 2, multicenter, open label, 
randomized, two-arm trial with PD-1/L1 blockade in patients with hepatic-limited 
metastatic colorectal cancer foreseen for perioperative chemotherapy and surgical 
resection. As of December 31st, 2018, two patients were enrolled, and one patient 
dosed with CV301. Data is still preliminary.  
 
1.10.4. Durvalumab Background (From the Durvalumab IB, v10.0) [2] 
Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid 
tumors. Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa (IgG1κ) 
subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], 
cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). 
Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an overall 
molecular weight of approximately 149 kDa. Durvalumab contains a triple mutation in the constant 
domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein C1q 
and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function.  
1.10.4.1. Summary of Non-clinical Experience 
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory 
effect of PD-L1 on primary human T cells, resulting in their restored proliferation and release 
of interferon gamma (IFN-γ). Additionally, durvalumab demonstrated a lack of antibody-
dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) 
in cell-based functional assays. In vivo studies show that durvalumab inhibits tumor growth in 
a xenograft model via a T lymphocyte (T-cell) dependent mechanism. Moreover, an anti-
mouse PD-L1 antibody demonstrated improved survival in a syngeneic tumor model when 
given as monotherapy and resulted in complete tumor regression in > 50% of treated mice 
when given in combination with chemotherapy. Combination therapy (dual targeting of PD-L1 
and cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) resulted in tumor regression in a 
mouse model of colorectal cancer.  
 
Cynomolgus monkeys were selected as the only relevant species for evaluation of the 
pharmacokinetics (PK)/pharmacodynamics and potential toxicity of durvalumab. Following 
intravenous (IV) administration, the PK of durvalumab in cynomolgus monkeys was nonlinear. 
Systemic clearance (CL) decreased and concentration half-life (t1/2) increased with increasing 
doses, suggesting saturable target binding-mediated clearance of durvalumab. No apparent 
gender differences in PK profiles were observed for durvalumab. In general, treatment of 
cynomolgus monkeys with durvalumab was not associated with any durvalumab-related 
adverse effects that were considered to be of relevance to humans. Adverse findings in the 
non-Good Laboratory Practice (GLP) PK/pharmacodynamics and dose range-finding study, 


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and a GLP 4-week repeat-dose toxicity study were consistent with antidrug antibody (ADA)-
associated morbidity and mortality in individual animals. The death of a single animal in the 
non-GLP, PK/pharmacodynamics, and dose range-finding study was consistent with an ADA-
associated acute anaphylactic reaction. The spectrum of findings, especially the clinical signs 
and microscopic pathology, in a single animal in the GLP, 4-week, repeat-dose study was also 
consistent with ADA immune complex deposition, and ADA: Durvalumab immune complexes 
were identified in a subsequent non-GLP, investigative immunohistochemistry study. Similar 
observations were reported in cynomolgus monkeys administered human mAbs unrelated to 
durvalumab. Given that immunogenicity of human mAbs in nonclinical species is generally 
not predictive of responses in humans, the ADA-associated morbidity and mortality were not 
considered for the determination of the no-observed-adverse-effect level (NOAEL) of 
durvalumab. Finally, data from the pivotal 3-month GLP toxicity study with durvalumab in 
cynomolgus monkeys showed that subchronic dosing of durvalumab was not associated with 
any adverse effects. Therefore, the NOAEL of durvalumab in all the general toxicity studies 
was considered to be 100 mg/kg, the highest dose tested in these studies. In addition to the 
in vivo toxicology data, no unexpected membrane binding of durvalumab to human or 
cynomolgus monkey tissues was observed in GLP tissue cross-reactivity studies using normal 
human and cynomolgus monkey tissues.  
1.10.4.2. Summary of Clinical Experience 
As of the data cut-off date of 12 July 2016 [2], more than 6,900 subjects have been exposed 
to one or more doses of durvalumab either as monotherapy, or in combination.   This includes 
808 patients who received durvalumab in combination with tremelimumab, and 140 who 
received durvalumab in combination with other investigational anticancer agents, and 186 
who received durvalumab in combination with other FDA approved anticancer agents. No 
studies have been completed or terminated prematurely due to toxicity. 
 
1.11.4.2.1 Pharmacokinetics and Product Metabolism  
As of 24 July 2016, PK data were available for 977 patients in the dose-escalation and 
dose-expansion phases of Study CD-ON-MEDI4736-1108 following treatment with 
durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W), 15 mg/kg every 3 weeks (Q3W), 
or 20 mg/kg every 4 weeks (Q4W). The maximum observed concentration (Cmax) 
increased in an approximately dose-proportional manner over the dose range of 0.1 
to 20 mg/kg. The area under the concentration-time curve from 0 to 14 days (AUC0-14) 
increased in a greater than dose proportional manner over the dose range of 0.1 to 3 
mg/kg and increased dose-proportionally at ≥3 mg/kg. These results suggest 
durvalumab exhibits nonlinear PK likely due to saturable target-mediated CL at doses 
<3 mg/kg and approaches linearity at doses ≥3 mg/kg. Near complete target saturation 
(soluble programmed cell death ligand 1 [sPD L1] and membrane bound) is expected 
with durvalumab ≥3 mg/kg Q2W. Exposures after multiple doses showed 
accumulation consistent with PK parameters estimated from the first dose. In addition, 
PK simulations indicate that following durvalumab 10 mg/kg Q2W dosing, >90% of 
subjects are expected to maintain PK exposure ≥40 µg/mL throughout the dosing 
interval.  As of 24 July 2016, a total of 790 subjects provided samples for ADA analysis. 
Overall, 25 of 790 patients (3.2%) tested positive for treatment emergent ADAs in the 
ADA evaluable population; 19 (2.4%) patients were persistently positive for the 
presence of ADA.  Three patients (0.4%, in 3/790 patients) were neutralising ADA 
(nAb) positive. Based on population PK covariate analysis, ADA positive status was 
not associated with a clinically relevant reduction of exposure to durvalumab. There 
was no apparent effect of immunogenicity on the PK profile. At the 10 mg/kg Q2W 
dose, sPD-L1 suppression in ADA positive patients was similar to that observed in 
ADA negative patients. 
 
 


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1.11.4.2.2 Safety  
The safety profile of durvalumab as monotherapy and combined with other anticancer 
agents was consistent with the pharmacology of the target and other agents in the 
immune checkpoint inhibitor class. No tumor types appeared to be associated with 
unique AEs. Immune-related AEs (irAEs), which are important risks of immune 
checkpoint inhibitors, have been observed with durvalumab and include colitis and 
diarrhea, pancreatitis, pneumonitis/interstitial lung disease (ILD), hepatic adverse 
events such as hepatitis and liver enzyme elevations, neurotoxicities such as 
myasthenia gravis and Guillain-Barre syndrome., endocrinopathies such as hypo- and 
hyper-thyroidism, hyophysitis, adrenal insufficiency and type I diabetes mellitus, 
dermatitis/rash, and renal adverse events such as nephritis and increase in creatinine. 
These events are manageable by available/established treatment guidelines as 
described in the study protocols. 
 
AEs reported with durvalumab monotherapy in key clinical studies are described 
below.  Safety data have been pooled for 4 durvalumab monotherapy studies (CD-
ON-MEDI4736-1108, D4190C00002, ATLANTIC and D4193C00001 [HAWK]) for 
patients who received a durvalumab dose of 10 mg/kg Q2W; a total of 1645 patients 
are included in this pooled data set. 
 AEs reported in ≥10% of patients were fatigue (31.1%), decreased appetite 
(22.5%), nausea (20.5%), dyspnea (17.9%), constipation (17.8%), cough (17.4%), 
diarrhea (16.0%), anemia (15.3%), pyrexia (15.0%), vomiting (13.4%), back pain 
(12.5%), pruritus (11.0%), arthralgia (10.6%) and abdominal pain (10.2%). 
 AEs that were considered by the investigator as related to durvalumab in ≥5% of 
patients were fatigue (14.5%); nausea (7.3%); diarrhea (6.9%); hypothyroidism 
(6.6%); pruritus (6.4%); decreased appetite (6.0%) and rash (5.2%). 
 A total of 820 patients (49.8%) reported Grade 3 or higher AEs: of these, 487 
patients (29.6%) had events of Grade 3, 63 patients (3.8%) had events of Grade 
4 and 270 patients (16.4%) had Grade 5 (fatal) events. AEs of Grade 3 or higher 
considered related to durvalumab were reported in 164 patients (10.0%): of these, 
144 patients (8.8%) had events of Grade 3, 12 patients (0.7%) had events of Grade 
4 and 8 patients (0.5%) had Grade 5 (fatal) events. 
 Grade 3 events occurring in ≥1% of patients were: anemia (5.5%); dyspnea (4.4%); 
hyponatremia (4.1%); fatigue (2.9%); GGT increased (2.7%); abdominal pain 
(2.0%); decreased appetite and back pain (1.9% each); pneumonia (1.8%); AST 
increased, and dehydration (1.6% each); hypertension (1.3%); alkaline 
phosphatase increased, hypokalaemia, urinary tract infection and vomiting (1.2% 
each); ALT increased and pleural effusion (1.1% each); bilirubin increased, 
asthenia, nausea and pulmonary embolism (1.0% each). Grade 3 events 
considered related to durvalumab occurring in ≥0.5% patients were fatigue (1.2%), 
GGT increased (0.8%) and AST increased (0.6%). 
 The most commonly reported Grade 4 event was sepsis (0.9%), GGT increased 
(0.5%), dyspnea, hypercalcemia and respiratory failure (0.4%), and pneumonia 
(0.3%). All other Grade 4 events were reported in less than 5 patients each. Grade 
4 events considered related to durvalumab occurring in ≥2 patients were GGT 
increased and pneumonitis (0.1% each). 
 Grade 5 events occurred in the system organ class (SOC) of ‘neoplasms benign, 
malignant and unspecified (including cysts and polyps), with the most common 
Grade 5 events being general physical health deterioration (12 patients), 
respiratory failure (8 patients); Grade 5 events of pneumonia and sepsis occurred 
in 5 patients each with the remainder of the Grade 5 events occurring in ≤4 patients 
for each event. The only Grade 5 event considered related to durvalumab 
occurring in ≥2 patients was pneumonitis (0.1%). 


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 A total of 134 patients (8.1%) discontinued from study treatment due to an AE. The 
most common events leading to treatment discontinuation were: general physical 
health deterioration (10 patients); pneumonitis (7 patients); pneumonia (6 
patients); dyspnea and NSCLC (5 patients each); all other discontinuation events 
occurred in ≤4 patients. 
 A total of 89 patients (5.4%) had serious treatment-emergent AEs (TEAEs) that 
were considered by the investigator as related to durvalumab. The most common 
were: pneumonitis (0.7%); fatigue (0.3%); colitis, infusion related reaction and ILD 
(0.2% each); dehydration, diarrhea, nausea and nervous system disorder (0.2% 
each); abdominal pain, acute kidney injury, adrenal insufficiency, AST increased, 
bilirubin increased, dyspnea, hepatic function abnormal, nephritis, transaminases 
increased, tumor haemorrhage and vomiting (0.1% each). 
 A total of 854 patients (51.9%) experienced an AESI during the study. The most 
common grouped term AESI was diarrhea (16.0%, of whom 0.7% had events of 
Grade ≥3). Other common AESIs were: selected hepatic events (15.1%, of whom 
6.9% had events of Grade ≥3); dermatitis (14.4%, of whom 0.2% had events of 
Grade ≥3); rash (12.1%, of whom 0.4% had events of Grade ≥3); hypothyroidism 
(10.3%, of whom 0.1% had events of Grade ≥3); hyperthyroidism (5.7%, of whom 
<0.1% had events of Grade ≥3); and select renal events (5.3%, of whom 1.0% had 
events of Grade ≥3). There were 6 patients who had AESIs of CTCAE Grade 5 
(fatal events): three patients had hepatic events (autoimmune hepatitis; hepatic 
failure and hyperbilirubinemia); two patients had pneumonitis and 1 patient had 
immune thrombocytopenic purpura. 
 
1.11.4.2.4 Efficacy  
Efficacy data are available for three monotherapy studies (Advanced solid tumors; 
Myelodysplastic syndrome (MDS); and Non-small cell lung cancer (NSCLC)), and two 
combination therapy studies (durvalumab + dabrafenib ± trametinib in melanoma; and 
durvalumab + tremelimumab in NSCLC). Clinical activity has been observed across 5 
studies. 
 
Study CD-ON-MEDI4736-1108: 
Patients with tumours defined as PD-L1 high (defined as tumor tissue samples that 
had ≥25% of tumor cells (TC) with membrane staining for PD-L1 (TC≥25%); 
low/negative (defined as TC<25%).  In 304 NSCLC patients, the ORR, was 25% and 
6% in patients with PD-L1 high and low/negative tumors, respectively and 18% in the 
overall population regardless of PD-L1 expression. The 12-month OS rate was 71% 
and 44% in patients with PD-L1 high and low/negative tumors, respectively (1st line).  
In 62 patients with squamous cell carcinoma of the head and neck (SCCHN), ORR 
was 11% across all patients, 18% in patients with PD-L1 high tumors and 8% in PD-
L1 low/negative tumors. In the 61 patients with urothelial carcinoma, the ORR was 
46% in the PD-L1+ subgroup compared to 0% in the PD-L1– subgroup. For other 
indications: In PD-L1 unselected patients, the ORR ranged from 0% in uveal 
melanoma to 17.4% in advanced cutaneous melanoma.   
 
Study D4190C00007:  
40 patients with MDS treated with durvalumab as a single agent in Study 
D4190C00007, the best overall responses were marrow complete remission (mCR) in 
13 patients (32.5%); stable disease (SD) in 6 patients (15.0%); and progressive 
disease (PD) in 12 patients (30.0%).   
 
ATLANTIC (NSCLC monotherapy): 
In patients with locally advanced or metastatic NSCLC who had received at least 2 
prior systemic treatment regimens, in the PD-L1 unselected patients (regardless of 


Version 2.4 01-Oct2019 
 
 
 
40 
 
PD-L1 TC expression) in the epidermal growth factor receptor (EGFR) wild 
type/unknown Cohort 2, the ORR was 10.4% (95% confidence interval [CI]: 6.2, 16.2). 
The response rate was similar between the non-squamous patients and the full 
population with the same PD-L1 expression cut off. The median OS was highest in the 
PD-L1 high (TC ≥25%) patients with the OS rate at 6 and 12 months of 67.4% and 
47.7%, respectively. For the PD-L1 unselected patients, the OS rate at 6 and 12 
months was 58.4% and 37.9%, respectively. For the patients with PD-L1 low/negative 
tumours, the OS rate at 6 and 12 months was 60.3% and 34.5%, respectively.  
 
Durvalumab + BRAFi/MEKi (Study CD-ON-MEDI4736-1161): 
Of the 68 patients with metastatic or unresectable melanoma treated with the 
combination of durvalumab and BRAF inhibitor (BRAFi; dabrafenib)/MEK inhibitor 
(MEKi; trametinib), 65 patients were evaluable for response. The ORR was 54.4%. 
The disease control rate (DCR; CR + PR + SD ≥12 weeks) was 73.5%. 
 
Durvalumab + tremelimumab (Study D4190C00006): 
Among the 75 patients with non-squamous EGFR/ALK wild type, or unknown, NSCLC, 
the ORR was 24.0% (18/75); for patients with PD-L1 high NSCLC it was 35.0% (7/20) 
and for patients with PD-L1 low/negative NSCLC ORR was 22.0% (9/14).  
 
1.10.4.3. Fixed Dosing 
A population PK model was developed for durvalumab using monotherapy data from a Phase 
1 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 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-subject variability with fixed 
dosing regimen. 
 
Similar findings have been reported by others [82-85]. 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 [83]. 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-subject variability in pharmacokinetic/pharmacodynamics 
parameters [82].  
 
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 750 mg Q2W durvalumab (equivalent to 10 mg/kg Q2W), 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) is included in the current study. Fixed dosing of 
durvalumab is recommend only for subjects with > 30kg body weight due to endotoxin 
exposure.  Patients with a body weight less than or equal to 30 kg should be dosed using a 
weight-based dosing schedule.  
1.10.5. Individual Drug Associated Toxicities 
1.10.5.1. Capecitabine [80] 
Very Common (more than 1 in 10 patients) 
 
Fatigue 


Version 2.4 01-Oct2019 
 
 
 
41 
 
 
Insomnia 
 
Fever  
 
Headache  
 
Diarrhea 
 
Hand-foot syndrome 
 
Stomatitis 
       Less Common (less than 5 in 100 patients) 
 
Increased liver enzymes  
 
Anemia 
 
Dehydration 
 
Abdominal pain 
 
Decrease in appetite 
 
Darkening of the fingers and toes 
 
Myelosuppression 
 
Acute kidney injury 
Rare but serious toxicities 
 
Coronary vasospasm 
1.10.5.2. Bevacizumab [81] 
Very Common (more than 1 in 10 patients) 
 
Surgery and Wound Healing Complications 
 
Hypertension 
Less Common (less than 5 in 100 patients) 
 
Gastrointestinal Perforations and Fistulae 
 
Non-Gastrointestinal Fistulae 
 
Hemorrhage 
 
Arterial Thromboembolic Events 
 
Venous Thromboembolic Events 
 
Proteinuria 
 
Worsening thrombocytopenia 
Rare but serious toxicities 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
 
Infusion Reactions 
1.10.5.3. PANVAC (As a surrogate to CV301) [1] 
Very Common (more than 1 in 10 patients) 
 
Injection site reaction 
 
Fatigue  
 
Fever  
 
Flu like symptoms  
Rare but Serious toxicities 
 
Pericardial effusion 
 
Abdominal pain 
 
Colitis 
 
Diarrhea 
 
Pancreatitis 
 
Alanine aminotransferase increased 
 
Lipase increased 
 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 
Serum amylase increased 
 
White blood cell decreased 


Version 2.4 01-Oct2019 
 
 
 
42 
 
 
Syncope 
 
Dyspnea 
 
Pleural effusion 
 
Thromboembolic events 
1.10.5.4. Durvalumab [2]  
Very Common (more than 1 in 10 patients) 
 
Diarrhea 
 
Fatigue 
 
Nausea and vomiting 
 
Dyspnea 
 
Decreased appetite 
 
Constipation 
 
Cough 
 
Pyrexia  
 
Pain in muscles and joints 
 
Dermatitis/Rash 
 
Hepatitis/Increased liver enzymes 
 
Anemia 
 
Pruritus 
Less Common (>1 but <10 in 100 patients) 
 
Pneumonitis 
 
General physical health deterioration (asthenia) 
 
Dehydration 
 
Abdominal pain 
 
Hypertension 
 
Endocrinopathies including hypo- or hyperthyroidism 
 
Hyponatremia 
 
Hypokalemia 
 
Nephritis 
 
Neurotoxicities 
 
Infusion-related reactions 
 
Colitis 
Rare but serious toxicities (<1 in 100 patients) 
 
Pancreatitis 
 
Type I Diabetes 
 
Allergic reactions 
 
Adrenal insufficiency 
 
Hypopituitarism 
 
 
 
 
 
 
 
 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
43 
 
1.11. Hypothesis 
As CV301 is capable of inducing a tumor-specific T-cell response against antigens significantly 
expressed in colorectal and pancreatic adenocarcinomas, and immune checkpoint inhibition can 
enhance the anti-tumor effect, it is hypothesized that durvalumab and CV301 will act synergistically to 
improve the progression-free survival rate (at 8.5 months for colorectal cancer, and 4 months for 
pancreatic cancer) when combined with maintenance chemotherapy from a historical 50% to a 
hypothesized rate of 75% or higher.  
 
Correlative Science Hypotheses 
Additionally, it is hypothesized that serial biopsies of tumor specimens will reveal the predictive value of 
the expression of the immune-inhibitory proteins, including PD-1, PD-L1 (B7H1), B7H3, B7H4, IDO, and 
arginase, and demonstrate a robust anti-tumor T-cell response in patients for whom the combination is 
active.  
 
 


Version 2.4 01-Oct2019 
 
 
 
44 
 
2. STUDY OBJECTIVES  
 
2.1. Primary Objectives 
 
 
Colorectal Cancer (CRC) Arm 
To determine the 8.5 month progression free survival rate (PFS8.5mos) of durvalumab plus CV301 in 
combination with maintenance capecitabine and bevacizumab in patients with metastatic colorectal 
cancer, whose disease is stable on, or responding to 1st line therapy for metastatic disease 
 
 
 
Pancreatic Cancer Arm 
To determine the progression free survival rate (PFS4mos) of durvalumab plus CV301 in combination with 
maintenance capecitabine in patients with metastatic pancreatic cancer, whose disease is stable on, or 
responding to 1st line therapy for metastatic disease 
2.2. Secondary Clinical Objectives (Both Arms) 
To determine, in patients treated with durvalumab plus CV301 whose disease is stable on, or responding 
to 1st line therapy for metastatic colorectal or pancreatic cancer: 
a. Objective response rate (ORR) and duration of response 
b. Progression free survival (PFS) 
c. Overall survival (OS) 
d. Disease control rate (DCR) (defined as ORR + rate of stable disease at 4 months) 
e. Tolerability and safety of the combination 
2.3. Secondary Scientific Objectives (Both Arms) 
1) To assess the predictive value of immune-inhibitory proteins, including PD-1, PD-L1 (B7H1), B7H3, 
B7H4, IDO, and arginase; and to assess the characteristics of the infiltrating T-cells in tumor 
samples. 
2) Using a flow-based assay, to determine the number of immune cell subsets from peripheral blood 
mononuclear cell (PBMC) at baseline and during treatment and attempt to identify a pattern 
correlating with clinical benefit. 
3) To evaluate the antigen-specific T-cell activation against the target antigens of the vaccine, MUC-1 
and CEA as well as other potential cascade antigens, including but not limited to brachyury. 
4) To evaluate serum soluble factors and serum cytokine expression profiles at baseline and on 
treatment and determine correlates of clinical benefit. 
5) To evaluate the relationship between tumor mutation burden and clinical benefit. 
6) To evaluate the expansion of peripheral and, potentially, intratumoral T cell clones as correlates 
and identify correlation with clinical benefit. 
2.4. Exploratory Scientific Objectives (Both Arms) 
1) To assess, in patient tumor samples, the predictive value, and the changes in response to treatment 
of immune-inhibitory proteins and other cell signaling pathways as measured by reverse phase 
phosphoprotein pathway analysis of the laser capture microdissected tumor epithelium and tumor 
stroma/immune cell compartments. 
2) To develop ex vivo models of patient tumors derived from patient tumor samples. 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
45 
 
3. SUBJECT POPULATION  (See Appendix A for Eligibility Checklist) 
3.1. Subject population, Number of Subjects and Feasibility 
3.1.1. Subject Population 
Patients with metastatic pancreatic adenocarcinoma or metastatic colorectal carcinoma who are 
being treated with front line therapy and whose disease is stable or responding radiographically, per 
RECIST 1.1 
3.1.2. Number of Subjects 
Minimum: 28 Maximum: 52 
 
It is estimated that a total of 46 efficacy evaluable patients will be enrolled in the study (up to 52 
accounting for a drop-out rate of 10%).  Specifically, a minimum of 28 patients could be enrolled in 
the first Simon Minimax Stage of the two Phase II portions (14 in each cohort).  Each Phase II cohort 
will enroll a maximum of 23 evaluable patients, and allowing for a 10% dropout rate, up to 26 patients 
may be enrolled.  Thus, the absolute minimum number of patients for the trial is 28 and the absolute 
maximum number of patients for the trial is 52. 
3.1.3. Feasibility 
Across our centers, more than 400 new cases of pancreatic cancer and 800 cases of colorectal 
cancer are seen yearly, at least half of whom have metastatic disease.    Since at least 50% of patients 
with metastatic colon cancer and pancreatic cancer achieve stable disease on first line therapy, we 
anticipate that across our centers, at least 100 patients per year will be eligible for this trial.  
Nevertheless, given the barriers for recruiting any patient to a clinical trial, we conservatively estimate 
that recruitment will take 24 – 30 months.  With each patient followed for a minimum of 8 weeks, the 
anticipated time to complete follow-up of all patients will be 30 – 36 months. 
3.2. Inclusion Criteria 
Patients must meet all of the inclusion criteria listed below in order to participate in this study: 
1) Histologically proven metastatic pancreatic or colorectal adenocarcinoma with measurable disease, 
defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1 
criteria. 
2) Stable on, or responding to 1st line therapy for metastatic disease 
a. Radiographically (RECIST 1.1) confirmed stable or responding disease for at least 8, and not 
more than 16 weeks from the initiation of 1st line therapy for metastatic disease 
b. Due to the timing of enrollment, patients who have completed a maximum of 16 weeks of 1st line 
chemotherapy may be enrolled >16 weeks after initiation of 1st line therapy if disease 
stability/response (without additional intervening therapy) can be documented within 4 weeks prior 
to first dose of CV301 
3) Prior adjuvant chemotherapy is allowed, as long as a minimum of 3 months (for pancreatic cancer) 
and 6 months (for colorectal cancer) has passed between the completion of adjuvant therapy and 
the start of first line therapy 
4) Disease that is amenable to serial biopsies 
5) ECOG performance status 0-1 
6) Age >= 18 years 
7) Blood pressure <160/100 mmHg 


Version 2.4 01-Oct2019 
 
 
 
46 
 
8) Adequate hepatic, bone marrow, and renal function: 
a. Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3; 
Hemoglobin ≥ 9.0 g/dL 
b. Renal function: Serum creatinine ≤ 1.5 X upper normal limit of institution's normal range OR 
creatinine clearance ≥ 40 mL/min/1.73 m2 for subjects with creatinine levels above institutional 
normal.  Creatinine clearance should be determined by the Cockcroft-Gault formula (below) or by 
24-hour urine collection for determination of creatinine clearance: 
 
 
Males: 
 
 
Creatinine CL (mL/min) 
= Weight (kg) x (140 – Age)  
 
 
 
 
 
 
 
72 x serum creatinine (mg/dL) 
 
 
Females: 
 
 
Creatinine CL (mL/min) 
= Weight (kg) x (140 – Age) x 0.85 
 
 
 
 
 
 
 
72 x serum creatinine (mg/dL) 
c. Hepatic function: AST and ALT ≤ 2.5 X the upper normal limit of institution's normal range. Non-
fasting bilirubin ≤ 1.5 X the upper normal limit of institution's normal range. 
9) Partial Thromboplastin Time (PTT) must be ≤ 1.5 X upper normal limit of institution's normal range 
and INR (International Normalized Ratio) ≤ 1.5. Subjects on anticoagulant (such as coumadin) will 
be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by 
the investigator. Due to the drug-drug interaction between warfarin and capecitabine, alternate 
anticoagulation should be considered. 
10) Life expectancy > 12 weeks. 
11) Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days 
prior to initiation of treatment AND confirmed prior to initiation of treatment on Day 1.   
12) Alternatively, female subjects must be of non-reproductive potential (ie, post-menopausal by 
history: ≥60 years old and no menses for 1 year without an alternative medical cause; OR history 
of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy).   
13) Subject is capable of understanding and complying with parameters as outlined in the protocol and 
able to sign and date the informed consents, approved by the Institutional Review Board (IRB), prior 
to the initiation of any screening or study-specific procedures. 
3.3. Exclusion Criteria   
Any Patient who meets any of the exclusion criteria listed below at baseline will be excluded from 
study participation: 
1) Any prior immunotherapy or vaccine therapy 
2) History of active or prior documented autoimmune disease within the past 2 years including but not 
limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, auto-immune Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or 
glomerulonephritis, with the following caveats: 
o Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement 
hormone may be eligible. 
o Patients with Grave’s disease, vitiligo, autoimmune alopecia, or psoriasis not requiring 
systemic treatment (within the past 2 years) are eligible upon consultation with the Study 
Chairs 
o Patients with questionable diagnosis of autoimmune disease who have never been treated 
with immunosuppressive regimen and have no ongoing symptoms at the time of enrollment 
may be eligible after discussion with medical monitor and principal investigator 


Version 2.4 01-Oct2019 
 
 
 
47 
 
3) Treatment with systemic immunosuppressive medications (including but not limited to prednisone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and TNFα antagonists) within 28 days 
prior to Week 1, Day 1 
o Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after 
discussion with and approval by the Study Co-chairs. 
o The use of inhaled, intranasal, ophthalmic or topical corticosteroids is allowed 
o The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension 
is allowed. 
o Physiologic doses of systemic corticosteroids at doses which are not to exceed 10 mg/day 
of prednisone, or an equivalent corticosteroid 
o High dose steroid pre-treatment for CT contrast dye allergy is allowed, provided the dose(s) 
of steroids is(are) given at least 1 week prior to starting the study medications 
4) History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia 
(i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active 
pneumonitis on screening chest CT scan 
o History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
5) Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) 
6) Positive test for HIV infection 
7) Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) 
o Patients with past or resolved hepatitis B infection (defined as having a negative HBsAg test 
and a positive IgG antibody to hepatitis B core antigen [anti-HBc] OR negative HBV viral load 
by PCR) are eligible. 
8) Active hepatitis C 
o Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for 
HCV RNA. 
9) Active tuberculosis OR known history of previous clinical diagnosis of tuberculosis 
10) Severe infections within 4 weeks prior to Week 1, Day 1, including but not limited to hospitalization 
for complications of infection, bacteremia, or severe pneumonia 
11) Signs or symptoms of infection within 2 weeks prior to Week 1, Day 1 
12) Received oral or IV antibiotics within 2 weeks prior to Week 1, Day 1 
o Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or 
chronic obstructive pulmonary disease) are eligible. 
13) Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
14) Administration of a live, attenuated vaccine within 30 days before Week 1, Day 1 or anticipation that 
such a live attenuated vaccine will be required during the study 
o Influenza vaccination should be given during influenza season only. Patients must not 
receive live, attenuated influenza vaccine (e.g., FluMistTM) within 4 weeks prior to Week 1, 
Day 1 or at any time during the study. 
15) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized 
antibodies or fusion proteins 
16) Any anti-cancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 2 weeks 
prior to initiation of study treatment, with the following exceptions: 


Version 2.4 01-Oct2019 
 
 
 
48 
 
o Hormone-replacement therapy or oral contraceptives 
o Herbal therapy intended as anti-cancer therapy must be discontinued at least 1 week before 
Week 1, Day 1 
17) CNS metastases including a history of leptomeningeal carcinomatosis 
18) Subjects with uncontrolled seizures 
19) The subject has had another active malignancy within the past five years except for cervical cancer 
in situ, in situ carcinoma of the bladder or non-melanoma carcinoma of the skin. Questions regarding 
the inclusion of individual subjects should be directed to the Principal Investigator. 
20) Cardiovascular disease including unstable angina, therapy for life-threatening ventricular 
arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months 
21) Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms 
(ECGs) using Fridericia’s  Correction 
22) Life-threatening visceral disease or other severe concurrent disease 
23) Grade ≥2 proteinuria at screening (or known prior) 
24) Women who are pregnant or breastfeeding, or male or female patients of reproductive potential 
who are not employing two highly effective and acceptable forms of contraception throughout their 
participation in the study and for 90 days after last dose of study drug. 
25) Patients concurrently receiving any other investigational agents. 
26) History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
durvalumab or any excipient or any egg products 
27) Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
3.4. Prior and Concomitant Therapies 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at Screening up to the Final Visit must be recorded in source 
documents and the case report forms (CRFs). The reason for use, date(s) of administration (including 
start and end dates), and dosage information (including dose and frequency) must be recorded. Any 
change in concomitant therapy during the study period must be similarly recorded. Questions regarding 
prior or concomitant therapy should be directed to one of the investigators.  
3.4.1. Prior Anticancer Therapy 
For purposes of this protocol, anti-tumor treatment may be defined as, but is not limited to, anti-
cancer agents (cytotoxic chemotherapy, immunotherapy, or biologic therapy), radiotherapy, and 
investigational agents. An investigational agent is any drug or therapy not currently approved for 
use in humans. 
3.4.2. Prior Surgery 
Patients must have fully recovered from all effects of surgery.  Patients must have had at least two 
weeks after minor surgery and four weeks after major surgery before starting therapy.  Minor 
procedures requiring “Twilight” sedation such as endoscopies, tumor biopsies, or mediport placement 
may only require a 24 hour waiting period, but this must be discussed with an investigator. 
 
3.4.3. Supportive Care 
Subjects should receive best supportive care and treatment of symptoms during the study as 
appropriate, including transfusion of blood and blood products, oxygen therapy, nutritional support, 


Version 2.4 01-Oct2019 
 
 
 
49 
 
intravenous fluids, and treatment with appropriate medications (antibiotics, antiemetics, 
antidiarrheals, and analgesics, etc.).  Medications, including steroids, which are given for supportive 
care, such as appetite stimulation, may be given concurrently.  Management of immune-related 
complications, including the use of steroids, is detailed below in Section 5.10. 
 
3.4.4 Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except for 
those medications identified as “excluded” as listed in Section 3.4.5. 
 
3.4.5 Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapies 
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), immunotherapy, 
biologic or hormonal therapy for cancer treatment, other than any stated comparator or 
combination regimens. Concurrent use of hormones for noncancer-related conditions (e.g., 
insulin for diabetes and hormone replacement therapy) is acceptable.  NOTE: Local 
treatment of isolated lesions for palliative intent is acceptable (e.g., by local surgery or 
radiotherapy). 
3. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled, intranasal, ophthalmic and topical corticosteroids is permitted. A 
temporary period of steroids will be allowed for different indications, at the discretion of the 
principal investigator (e.g., chronic obstructive pulmonary disease, radiation, nausea, etc).    
4. Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to the first 
dose, during treatment with durvalumab and for 30 days post discontinuation of durvalumab.  
Inactivated vaccines, such as the injectable influenza vaccine, are permitted. 
 
    
Table 1. Prohibited and Rescue Medications 
3.5. Removal/replacement of Subjects from Therapy or Assessment 
The study requires that 46 efficacy evaluable subjects be enrolled.  An efficacy evaluable patient must 
meet all inclusion/exclusion criteria, and be evaluable for the primary endpoint of PFS8.5mos (colorectal 
cancer) or PFS4mos (pancreatic cancer)   
3.5.1. Screen Failures 
Patients will be identified and enrolled while still receiving first-line therapy.  All patients must continue 
to meet the inclusion and exclusion criteria up to and including the first day of treatment on the study 
Rescue/supportive medication/class of drug 
Usage 
Concomitant medications or treatments (e.g., acetaminophen or 
diphenhydramine) deemed necessary by the Investigator 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 
Best supportive care (including antibiotics, nutritional support, growth 
factor support, correction of metabolic disorders, optimal symptom 
control, and pain management [including palliative radiotherapy, etc.]) 
Should be used when necessary 
for all patients 


Version 2.4 01-Oct2019 
 
 
 
50 
 
medications. Reasons for patients who have enrolled, but become ineligible could include (but are 
not limited to): 
 
The patient is no longer eligible based on laboratory parameters 
 
The patient’s performance status has declined 
 
The patient no longer has measurable disease 
Patients who become ineligible during the course of first-line therapy, prior to initiation of study 
medications will be considered screen failures.  Screen failures must be replaced until a maximum of 
46 evaluable patients are enrolled or study termination, whichever occurs first. 
3.5.2. Evaluable Patients 
3.5.2.1 Evaluable for Toxicity 
Patients must complete 4 weeks of therapy – enough to have received at least one dose of CV301 
and durvalumab to be assessable for toxicity.  Patients who are taken off study prior to receiving 
the first dose of durvalumab will need to be replaced. 
 
3.5.2.2. Evaluable for Efficacy 
Of note, any patient who initiates study medications, and is taken off study prior to 8.5 months 
(colorectal cancer) or 4 months (pancreatic cancer) for disease progression or clinical 
progression, including death related to the underlying pancreatic or colorectal cancer (as 
determined by the treating oncologist) will be considered efficacy evaluable.  However, patients 
who have initiated study medications, and who withdraw from the study for any reason other than 
clinical or radiographic progression, or death believed related to their underlying pancreatic or 
colorectal cancer will not be considered evaluable for efficacy.  These patients will need to be 
replaced for the efficacy analysis.  Reasons for patients who have initiated study medications, but 
are no longer evaluable could include (but are not limited to): 
 
The patient cannot tolerate therapy despite dose modifications, and there is no evidence 
of clinical/radiographic disease progression at the time of stopping second-line therapy 
 
An unexpected and/or unrelated medical illness, such as a stroke or myocardial infarction 
that is considered unrelated to the underlying pancreatic or colorectal cancer 
 
An unexpected trauma or death that is considered unrelated to the underlying pancreatic 
or colorectal cancer 
3.6. Multi-institutional Trial Coordination 
See Appendix B for the patient registration form 
3.6.1. Personnel 
At each site, personnel dedicated to this protocol will be: 
- 
A study PI 
- 
A research coordinator and a data manager 
In addition, Georgetown University’s Multicenter Project Management Office will oversee the conduct 
of the trial Lombardi-Georgetown and additional sites.  Georgetown University’s Multicenter Project 
Management Office will be the main point of contact for the study chair, Dr. Pishvaian  and the other 
site PIs for any study related concerns, including data management and regulatory. 
3.6.2. Patient Enrollment 
Enrollment at the sites will be competitive.  If a patient is being screened for enrollment, the local 
research coordinator must send an email within 24 hours containing the patient’s screening number 
and initials, to the site PI, Dr. Pishvaian, and to Georgetown University’s Multicenter Project 
Management Office.  If a patient is successfully screened, the local research coordinator must send 
all supporting documentation to Georgetown University’s Quality Assurance Office (QAO) by secure 
email or fax to confirm eligibility.  Patients should not start therapy until Dr. Pishvaian and Georgetown 


Version 2.4 01-Oct2019 
 
 
 
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University’s QAO have reviewed the patient’s records and confirmed that the patient is indeed eligible 
for enrollment. 
3.6.3. Data collection and management 
Patient data will be entered into the on-line accessible database (the database will be built with case 
report forms (CRFs) at Georgetown upon trial approval).  This database is housed at Lombardi-
Georgetown, but is accessible anywhere there is internet access.  The data manager and research 
coordinator at each site will attend an on-line training session so that they may learn how to enroll 
data into the data base.  All screening data should be entered prior to initiating any study related 
activities, and all ongoing patient data should be entered within one week of each patient visit.   
3.6.4. Conference Calls 
A monthly conference call will be held between Lombardi-Georgetown and the other sites to review 
patient enrollment, toxicity, and response assessment. 
3.6.5. Trial Auditing 
Georgetown University’s Multicenter Project Management Office will provide annual trial auditing for 
this study.  Georgetown University’s Multicenter Project Management Office will arrange all primary 
source documents for the patients from all sites to be audited.  Auditing of the study will occur at 
Lombardi-Georgetown, but will be performed on a random sampling of the patients selected from any 
site. 
 
 
 


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52 
 
4. STUDY PROCEDURES 
4.1. Study Overview  
Basic Study Design 
This is a dual arm, open label phase II study to evaluate the safety and clinical activity of the combination 
of durvalumab with CV301 plus maintenance chemotherapy for patients with metastatic colorectal or 
pancreatic cancer whose disease is stable on, or responding to 1st line therapy for metastatic disease.  
Patients with metastatic colorectal or pancreatic adenocarcinoma who still have an adequate 
performance status and normal hepatic and renal function will be eligible. 
 
 
The trial will consist of two parallel Phase II trials – one for patients with metastatic colorectal cancer, and 
one for patients with metastatic pancreatic cancer (Figure 5). In the Phase II portion, patients will be seen 
every two weeks through eight weeks, and then routinely every 4 weeks thereafter for as long as the 
patient is on study.  Adverse events will be monitored throughout the trial (safety tests will be performed 
every 2 weeks for the first 8 weeks, and then every 4 weeks thereafter) and graded in severity according 
to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0.   
 
Restaging studies will be performed every 8 weeks (+/- 5 days) (typically CT scans), by the calendar.  
Patients whose tumors have not progressed at the time of restaging, and who continue to tolerate 
treatment will continue on study.   
 
The study is estimated to last 36 months.  Patient treatment will continue until disease progression, death, 
or until the physician or patient request removal from the study for any reason. 
 
Figure 3 (Figure 1 repeated): Trial Schema 
 
 
 
Response Assessment 


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The primary efficacy objective is to determine the PFS8.5mos in the colorectal cancer arm, and PFS4mos in 
the pancreatic cancer arm.  Disease response/progression will be assessed according to RECIST 1.1.  
However, RECIST 1.1 will be adapted to account for the potential of pseudoprogression, in which 
immune-mediated tumor infiltration may lead to an initial increase in the size of the tumors, and can lead 
to a clinical response after an initial increase in tumor burden or even the appearance of new lesions.  
Therefore, standard RECIST 1.1 criteria may not provide an accurate response assessment of 
immunotherapeutic agents such as durvalumab and CV301.   Therefore, RECIST 1.1 will be used with 
the following adaptations, as detailed in Section 6: 
 
If radiologic imaging shows initial PD, but patients are adequately tolerating therapy, patients may 
continue therapy until the next restaging while awaiting radiologic confirmation of progression.  The 
decision to continue therapy should be based on the subject’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Subjects may receive treatment while 
waiting for confirmation of PD if they are clinically stable as defined by the following criteria: 
•  Absence of signs and symptoms indicating disease progression 
•  No decline in ECOG performance status 
•  Absence of rapid progression of disease 
•  Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent 
alternative medical intervention 
 
When feasible, subjects should not be discontinued until progression is confirmed.  Subjects that are 
deemed clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease:  
• If repeat imaging shows a reduction in the tumor burden compared to the initial scan demonstrating 
PD, treatment may be continued.  If repeat imaging confirms progressive disease, subjects will be 
discontinued from study therapy.   
 
 
 
Study Product, Dose, Route, Regimen 
Please note that for all durvalumab and CV301 (and bevacizumab for the colorectal cancer patients), 
treatments and subject assessments may occur +/- 3 days to accommodate patient scheduling 
 
Patients will begin maintenance chemotherapy beginning Week 1.  This will be dosed as capecitabine 
1000mg orally twice a day given Monday – Friday every week. In addition, colorectal cancer patients will 
receive maintenance bevacizumab, dosed at 5mg/kg IV q2weeks 
 
The order in which the drugs will be administered is based on the fact that the durvalumab can be 
associated with infusion reactions – whereas the risk of infusion/administration reaction with 
bevacizumab and CV301 is extremely low.  The drugs should be administered: 
1) Capecitabine 1000mg PO BID weekly M-F will be ongoing oral administration and can be started 
at any time on the days of administration of the other agents 
2) Durvaluamab over approximately 60 minutes (±5 minutes) 
a. Note: The first dose of durvalumab is to be given over 90 minutes (±5 minutes) 
3) Bevacizumab 5mg/kg (Based on weight at screening unless 10% change) IV over 60 minutes (±5 
minutes) Q2weeks  
4) MVA-BN-CV301 (prime) - two priming doses of MVA-BN-CV301 given s.c. on Day 1 and Day 29.   
One dose of MVA-BN-CV301 consists of 4 injections of 4 X 108 Inf.U in 0.5mL (one in each arm, 
one in each leg). This results in a total administration of 1.6 x 109 Inf.U per dose. 
5) FPV-CV301 (boost) - One dose of FPV-CV301 consists of just one 0.5mL injection of at least 
1x109 Inf.U per 0.5 mL.  The vaccine will be injected subcutaneously into the thigh on Day 1 of 
Weeks 9, 13, 17, 21, 25, 37, and q24 weeks starting week 53.     
 
To intensify the opportunity for activation of tumor-infiltrating antigen-specific CD8 killer T cells 
(expressing high levels of IFN-gamma), whose anti-tumor activity would be enhanced by immune 
checkpoint blockade, we will employ a prime-boost treatment plan. Thus, patents first receive two priming 


Version 2.4 01-Oct2019 
 
 
 
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doses with MVA-BN-CV301 given s.c. on Day 1 and Day 29.   One dose of MVA-BN-CV301 consists of 
4 injections of 4 X 108 Inf.U in 0.5mL (one in each arm, one in each leg). This results in a total 
administration of 1.6 x 109 Inf.U per dose.  Then, starting week 9, patients will begin therapy with FPV-
CV301.  One dose of FPV-CV301 consists of just one 0.5mL injection of at least 1x109 Inf.U per 0.5 mL.  
The vaccine will be injected subcutaneously into the thigh on Day 1 of Weeks 9, 13, 17, and 21; and then 
weeks 25 and 37: and then starting week 53 q24 weeks continuously until progression.  
 
Week 3, Day 1, patients will also begin therapy with durvalumab, which will be subsequently given every 
two weeks until progression (or intolerance).  
 
Figure 4 (Figure 2 repeated): Durvalumab plus CV301 Treatment Schedule 
Durval  = Durvalumab 
 
 
Duration of administration 
Durvalumab and FPV-CV301 will continue until disease progression (or intolerance).  Maintenance 
chemotherapy (capecitabine (+ bevacizumab for CRC)) will also continue until disease progression (or 
intolerance).  However, in the unlikely event of a complete response, patients may stop the maintenance 
chemotherapy and continue the durvalumab and FPV-CV301 alone after 52 weeks (one year).  Patients 
who stop maintenance chemotherapy after 52 weeks, and whose disease then begins to progress/recur 
may be restarted on the maintenance chemotherapy until further disease progression.   
4.2. Patient Screening 
The screening window is 2 weeks prior to the first dose of CV301. Study activities are detailed in Table 
4, and a study activity checklist in Table 5. Assessments performed exclusively to determine eligibility 
for this study will be done only after obtaining informed consent. Assessments performed for clinical 
indications (not exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. For procedures performed at screening and 
repeated, the later procedure performed prior to dosing will serve as a baseline for clinical assessment.  
If any abnormality that would be an exclusion is identified at subject assessment at any time prior to 
initiating therapy on Day 1, the patient will not start treatment until the abnormality is resolved, and the 
patient again meets all inclusion/exclusion criteria.  The screening procedures include the following listed 
below. 
 
4.2.1. Informed Consent 
Signed informed consent will be obtained from the subject or the subject's legally acceptable 
representative before any study-specific procedures are undertaken.   
4.2.2. Medical History 
 
Complete medical and surgical history, including documentation of any clinically significant 
medical condition 
 
History of tobacco and alcohol use 
 
Presence and severity of any symptoms/conditions associated with colorectal or 
pancreatic cancer 
 
Detailed oncology history, including: 
o Date of primary cancer diagnosis 
o Pathology (histology or cytology) of primary tumor 
o Metastasis information (including the location) 


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o Surgical history (if any) 
o Anti-cancer and radiation treatments administered (including dates and type of 
modality) 
 
At each visit, the subject's medical history will be reviewed and any changes from baseline 
will be recorded in the case report form (CRF). On Week1, Day 1 any changes observed 
from the screening assessments, prior to dosing, will be recorded in the subject's medical 
history. All medications (prescription or over-the-counter, including vitamins and/or herbal 
supplements) will be recorded beginning with the Screening Visit and continuing up 
through the date of the off study visit. 
 
4.2.3. Demographics 
Age, gender, race and ethnicity will be recorded 
4.2.4. Review Subject Eligibility Criteria 
4.2.5. Review previous and concomitant medications 
4.2.6. Physical Exam Including Vital Signs, Height, and Weight 
A complete physical examination will be performed at the Screening Visit.  Body weight will be 
recorded during every physical exam. The subject will wear lightweight clothing and no shoes during 
weighing.  Height will be measured at the Screening Visit only; the subject will not wear shoes. 
4.2.7. Vital Sign Determinations 
Heart rate, blood pressure, respiratory rate, and body temperature will be obtained at the Screening 
Visit. If possible, blood pressure and heart rate measurements should not immediately follow 
scheduled blood collections. 
4.2.8. Hematology 
Hematology samples (CBC) will be collected and assessed using a certified laboratory.  The 
Investigator will review, initial and date all laboratory results. Any laboratory value outside the 
reference range stated in the inclusion criteria will preclude the patient from study participation. 
4.2.9. Serum Chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT, AST, BUN, 
creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate, magnesium), glucose, 
and total bilirubin. Creatinine clearance will be calculated as per section 3.2.  Amylase and lipase will 
be collected at screening, Week 1, Day 1 and every two weeks through week 9, and then every 4 
weeks thereafter.  TSH will be collected at screening, and every 8 weeks starting week 9.  Hepatitis 
and HIV serologies will be collected at screening only.   
4.2.10. Urinalysis 
4.2.11. Pregnancy Test and Pregnancy Prevention 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
Screening Visit within 14 days of Week 1, Day 1 and a urine pregnancy test will be done at the Week1, 
Day 1 visit prior to the first dose of study drug. Subjects considered not of childbearing potential must 
be documented as being surgically sterile or post-menopausal (for at least 1 year).  The test results 
must be reviewed and determined to be negative prior to dosing. If the urine pregnancy test is positive 
at Week1, Day 1, it should be confirmed by a serum pregnancy test. The test may be repeated at the 
discretion of the investigator at any time during the study.  Should a female study subject become 


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pregnant or suspect she is pregnant while participating in this study, she should inform the treating 
Investigator immediately. 
 
 
Females of childbearing potential who are sexually active with a nonsterilised male partner must use 
2 methods of effective contraception from screening, and must agree to continue using such 
precautions for 90 days after the final dose of durvalumab or CV301; cessation of birth control after 
this point should be discussed with a responsible physician.  While total abstinence is an acceptable 
method to prevent pregnancies, neither periodic abstinence (also considered the rhythm method), nor 
the withdrawal method are acceptable methods of birth control. 
 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause). 
 
Subjects must use 2 acceptable methods of effective contraception as described in Table 
4. 
 
Nonsterilised males who are sexually active with a female partner of childbearing potential 
must use 2 acceptable methods of effective contraception (see Table 4) from Day 1 and 
for 90 days after receipt of the final dose of investigational product. 
Table 2. Effective Methods of Contraception.  Two methods must be used.  
aThis is also considered a hormonal method. 
4.2.12. Tumor Assessment 
Only patients with metastatic pancreatic or colorectal cancer not eligible for resection will be 
considered for entry.  Subjects must have measurable disease, defined as at least 1 measurable 
lesion as defined by RECIST 1.1. Imaging for screening will be reviewed to prepare for tumor biopsies 
and to determine stable or responding disease (per RECIST 1.1) on 1st line therapy.   
 
4.2.13. Electrocardiogram 
Electrocardiograms (ECGs) obtained at screening, will be obtained in triplicate (with 2-5 minute lag 
time between each).  Twelve-lead ECGs will be obtained after the subject has been resting in a supine 
position for at least 5 minutes. QT interval corrected for heart rate should be calculated using 
Fridericia’s formula (QTcF). 
 
4.2.14 Performance Status 
Performance status will be evaluated prior to study entry according to the table below: 
 
 
 
 
 
 
 
 
 
 
Table 3: ECOG Performance Status 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone shot or injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system (e.g., Mirena®)a 
Combined pill 
Minipill 
Patch 
 
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade


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4.2.15 Adverse Event Assessment 
Baseline adverse events will be assessed. See Section 7 for Adverse Event monitoring and reporting.  
The Investigator will assess adverse events, laboratory data and vital signs throughout the study.  
Adverse events will be assessed by: 
Common Terminology Criteria for Adverse Events, Version 4.0, NCI, NIH, DHHS. June 14, 2010. 
Available at: CTCAE version 4.03 - 2010-06-14 
4.3. Patient Enrollment 
A minimum of 2 weeks must have passed before any prior chemotherapy or radiation therapy received 
during the course of first-line therapy before patients can begin study medications (i.e. at least 14 days 
prior to Week 1 of therapy).  The patient must meet all inclusion/exclusion criteria, including laboratory 
parameters, prior to study medication initiation.  Any patient who does not meet inclusion/exclusion 
criteria may be re-evaluated once any excluding factors are mitigated. But any patient who does not 
ultimately meet inclusion/exclusion criteria will be considered a screen failure, and will be replaced on 
the study.      
4.3.1. Patient Study Number Assignment and Sample Labelling 
Though out the study, the following labelling procedure will be followed. 
4.3.2. Patient Study Number Assignment 
Patients will be de-identified and labelled with a 5 character study label (AA-X-XX): 
o The first two characters will be the patient’s initials 
o The third character will be the site from which the patient was enrolled (single digit) 
 
1 = Georgetown 
 
2 = Mayo Clinic 
 
3 = MD Anderson 
 
4 = Emory University 
o The fourth and fifth characters will be the patient study number (e.g. 01, 02, 03, etc.) 
4.3.3. Sample Labelling (Appendix C) 
For all correlative samples that are stored at one of the study sites, patient labels will be de-identified 
and labelled with a 14 character study label (AA-X-XX-XX-X-MM/DD/YY): 
o The first two characters will be the patient’s initials 
o The third character will be the site from which the patient was enrolled (single digit) 
 
1 = Georgetown 
 
2 = Mayo Clinic 
 
3 = MD Anderson 
 
4 = Emory University 
o The fourth and fifth characters will be the patient study number (e.g. 01, 02, 03, etc.) 
o The sixth and seventh characters will be the correlative technique (two digit) 
 
01 = NIH Formalin 
 
02 = George Mason RPPA 
 
03 = NIH Frozen 
 
04 = TJU Organoids 
 
05 = Lombardi Zebrafish 
 06= Blood collection: Serum and PBMC 
 
Additional numbers can be added as needed for future research samples 
o The eighth character will be the timing of collection 
 
1 = Pre-treatment biopsy/sample 
 
2 = On treatment biopsy/sample 
 
3 = Serum collection 


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o The final characters will be the date in MM/DD/YY format 
 
 
Example:  AA-1-01–01-1-10/14/18 
 
 
 
Protocol: 2017-1189 
4.3.4. Tumor Biopsies and Blood Collection 
A rigorous tumor collection algorithm will be instituted for this protocol.   Biopsy sample prioritization, 
as well as shipping details and addresses are all summarized below, in greater detail in Section 9, 
and in Appendix C. 
 
Please note: Details on collection and shipping, particularly details on the acquisition of 
supplies and the personnel involved are subject to change.  Thus, details on collection and 
shipping in the Lab Manual are to be considered the most updated (note the Version number 
and dates).   
 
Of note, patients who are on chronic anticoagulation will be required to hold anticoagulation prior to 
the biopsies being performed.  Patients on warfarin must hold treatment for 5 days, but will be on low-
molecular weight heparin (LMWH), 1 mg/kg subcutaneously twice a day. The LMWH will continue 
until the last biopsy is complete.  Patients may then resume warfarin the day after the last biopsy.  
Additionally, patients on LMWH will hold (i.e., not receive) the dose of LMWH the morning of the 
procedure, but will resume the LMWH the evening of the day of the biopsy. 
 
4.3.4.1. 
Tumor  Biopsy Tissue Utilization and Prioritization 
For the pre-treatment and week 6 biopsy, six individual cores will be obtained with an 18-20 
gauge needle.  The cores will be prepared as follows (and as depicted in Appendix C): 
 
 
The first two cores (Correlative sample and phosphoprotein sample) should be placed 
INDIVIDUALLY in a single standard formalin vials and submitted to surgical pathology for 
paraffin embedding.  The samples from these FFPE block should not be cut for an H&E 
analysis.  Rather, the block will be requested from surgical pathology, and sent in batches 
to Dr. Schlom at the NIH (First core) and to George Mason University to Dr. Petricoin’s lab 
(second core) for laser capture microdissection of tumor epithelium and stroma for 
Reverse Phase Protein Microarray (RPPA) analysis. 
 
 
The next two cores (Correlative samples) should be placed INDIVIDUALLY in a single 
cryovials and snap frozen in liquid nitrogen, and stored at -80oC.  These frozen samples 
will be shipped in batches on dry ice to Dr. Schlom at the NIH. 
 
 
The fifth core (organoid sample) will be collected for organoids will be collected in pre-
supplied Eppendorf tubes containing Advanced DMEM/F12 (5mL) with Glutamax 1%, 
Pen/Strep 1%, and HEPES Buffer 1%.  Media will be sent to the sites in batches of 10 
upon request from Dr. Brody’s lab.  Samples will be collected, and shipped overnight on 
WET ice to Dr. Brody’s lab. 
 
 
The sixth core will be placed in a pre-provided Eppendorf tubes with CRC media with y-
compound.  This will be shipped on WET ice to the Shared Resources core, c/o Dr. Byers, 
at the Lombardi Cancer Center.   
 
4.3.4.2. 
Serial Blood Collection 
On the first treatment day (Week 1, CV301 alone), and on weeks 9, 17, and 49, and at the off 
study visit 6 green top (Na heparin, 10 mL) tubes and 2 red serum separator (8 mL) tubes will 
be obtained.  Shipping details are provided in Appendix C.  
 


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4.4. Detailed Patient Assessments 
Study activities are detailed in Table 4, and a study activity checklist in Table 5.  Please note that 
for patient assessments may occur +/- 3 days to accommodate patient scheduling 
4.4.1. Subject Assessments  
Patients will be seen on Week1, Day 1, then every two weeks through eight weeks, and then routinely 
every 4 weeks thereafter for as long as the patient is on study, and at the Final Visit.   
4.4.2. Physical Examinations 
A complete physical examination will be performed on Week1, Day 1, then every two weeks through 
eight weeks, and then routinely every 4 weeks thereafter for as long as the patient is on study, and 
at the Final Visit.  A complete physical examination will include: weight, vital signs, performance 
status, hematology samples, and a comprehensive metabolic panel.  Any significant physical 
examination findings after the administration of the first dose of the experimental therapy will be 
recorded as adverse events.  The subject will wear lightweight clothing and no shoes during weighing.   
4.4.3. Updated Medical History 
At each visit, the subject's medical history will be reviewed and any changes from baseline will be 
recorded in the CRF. On Week1, Day 1 any changes observed from the screening assessments, 
prior to dosing, will be recorded in the subject's medical history. All medications (prescription or over-
the-counter, including vitamins and/or herbal supplements) will be recorded beginning with the 
Screening Visit and continuing up through the date of the off study visit.   
4.4.4. Vital Signs 
Vital sign determinations of heart rate, blood pressure, respiratory rate, and body temperature will be 
obtained on Week1, Day 1, then every two weeks thereafter for as long as the patient is on study, 
and at the Final Visit.  If possible, blood pressure and heart rate measurements should not 
immediately follow scheduled blood collections.  On durvalumab treatment days, vital signs will be 
measured within an hour prior to start of durvalumab administration, at 30 minutes during the infusion 
(± 5 minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 minutes) and 60 minutes 
(± 5 minutes) post-infusion.  If the infusion takes longer than 60 minutes (such as with the first infusion, 
which lasts 90 minutes), then blood pressure and pulse measurements should follow the principles 
described here, or more frequently if clinically indicated.  For subsequent doses, the 1-hour 
observation period will not be required unless a subject experiences an infusion-related reaction. 
4.4.5. Tumor Markers 
Tumor markers such as a CA 19-9 and/or CEA should be checked every 4 weeks.  The actual 
marker(s) will be at the discretion of the treating physician – but at least one marker should be 
checked.   
4.4.6. Correlative Blood Samples  
Correlative blood samples will be obtained on the first treatment day (Week 1, CV301 alone), and on 
weeks 9, 17, and 49, and at the off study visit. 
4.4.7. Clinical Laboratory Tests 
All subjects will undergo the laboratory assessments outlined in Table 4. Hematology and chemistry 
samples (including magnesium) will be collected at the screening visit, at Week 1 and every 2 weeks 
thereafter.  Creatinine clearance will be calculated as per section 3.2.  PT/PTT/INR will be collected 
at during screening, and at the visit week 6 (prior to the second biopsy). Amylase and lipase will be 
collected at screening, Week 1, Day 1 and every two weeks through week 9, and then every 4 weeks 
thereafter.  TSH will be collected at screening, and every 8 weeks starting week 9.  Hepatitis and HIV 


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serologies will be collected at screening only.  Laboratory samples for this study will be assessed 
using the certified laboratory at the individual sites, and these data will be used for all data analysis.  
The Principal Investigator or sub-investigator will review, initial and date all laboratory results. Any 
laboratory value outside the reference range that is considered clinically significant by the investigator 
will be followed as appropriate. Clinically significant laboratory values will be recorded as adverse 
events if they meet the criteria as specified in Section 7. 
 
4.4.8 
Electrocardiograms 
Electrocardiograms (ECGs) will be obtained during screening, prior to starting durvalumab at the 
week 3 visit and the week 9 visit, and at the end of treatment, as well as at any other time point when 
clinically indicated.  ECGs recorded during the screening period will be obtained in triplicate (with 2-
5 minute lag time between each); ECGs recorded during the treatment phase will be single tracing.  
The same method of assessment should be used throughout the study. Twelve-lead ECGs will be 
obtained after the subject has been resting in a supine position for at least 5 minutes in each case. 
At the week 3 and week 9 visit, ECGs will be recorded within an hour prior to start of infusion of 
durvalumab and at least one time point 0 to 3 hours after the infusion.  QT interval corrected for heart 
rate should be calculated using Fridericia’s formula (QTcF). 
 
4.4.9 
Urinalysis 
A urinalysis should be performed at screening, and prior to treatment at the week 9 visit, and every 8 
weeks thereafter.   
 
4.4.10 
Imaging and Response Evaluation 
Patients will undergo a baseline tumor evaluation with imaging studies within four weeks of Week 1, 
Day 1(unless disallowed by patient’s insurance and/or the patient has had imaging within 4 weeks of 
starting therapy).  Imaging studies should include a diagnostic CT scan of the chest, abdomen, and 
pelvis (as well as any other known sites of disease (e.g. neck)) with PO and IV contrast.  Patients 
may undergo other modalities such as an MRI instead of a CT scan at the treating physician’s 
discretion if appropriate (such as patient allergy to CT contrast, extremity tumors, bone metastases 
requiring bone scans, etc.).  Response evaluation will occur at 8 weeks (+/- 5 days), and then at 16 
weeks (+/- 5 days), and every 8 weeks thereafter (+/- 5 days), and at the Final Visit (+/- 5 days), if not 
performed within the last four weeks.  Tumor response and/or disease progression will be assessed 
by the modality(ies) used prior to treatment.  If subjects respond to treatment and are able to have 
their disease resected, the patient’s response will be assessed prior to the surgery.  Patients will 
continue to remain on study as long as there is no evidence of progression of disease and the therapy 
is adequately tolerated. 
 
4.4.11 
Adverse Event Evaluation (See Section 5 for Full Details) 
The Principal Investigator or Sub-investigators will assess adverse events, laboratory data and vital 
signs throughout the study.  Adverse events will be assessed by NCI CTCAE Version 4.0. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf  
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on 
a routine basis throughout the study. The investigator will assess and record any adverse event in 
detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, time course, 
duration and outcome, relationship of the adverse event to study drug, and any action(s) taken. For 
serious adverse events not considered "probably related" to study drug, the investigator will provide 
an "Other" cause of the event. For adverse events to be considered intermittent, the events must be 
of similar nature and severity. Adverse events, whether in response to a query, observed by site 
personnel, or reported spontaneously by the subject will be recorded. All adverse events will be 
followed to a satisfactory conclusion. 
 
4.4.12 
Final Visit and Survival Follow-up 
When an investigator has determined that a subject should discontinue the study, a Final Visit will be 
conducted. At the Final Visit, patients will undergo a subject assessment (physical examination, vital 


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signs, performance status, chemistry, hematology, medication review, and adverse event evaluation).  
Additionally, information pertaining to survival and post treatment therapy will be collected 
approximately every 12 weeks (Months 3, 6, 9, 12, 15 and 18) beginning after the final visit, for a 
period up to 24 months.  Patients will be followed by phone or mail every 3 months after completion 
of (or early withdrawal from) study treatment for survival analysis until death or 12 months, whichever 
comes first.    
 
If a research subject cannot be located to document survival after the final visit, the subject may be 
considered “lost to follow-up.” All attempts to contact the subject during the two years must be 
documented for review by the DSMC. 
4.5. Removal of Subjects from Study 
Each subject has the right to withdraw from study treatment at any time. In addition, the investigator may 
discontinue a subject from the study treatment at any time for any reason if the investigator considers it 
necessary, including the occurrence of an adverse event or noncompliance with the protocol. Each 
subject will be withdrawn from the study if any of the following occur: 
 
1) The subject experiences either clinical or radiographic progressive disease as defined in Section 
6.  
2) The subject experiences toxicity that makes continuation in the protocol unsafe as defined in 
Section 5. 
3) Development of second malignancy (except for basal cell carcinoma or squamous cell carcinoma 
of the skin) that requires treatment, which would interfere with this study. 
4) The subject requires radiotherapy or alternate antineoplastic agents during the study period. 
5) The investigator believes it is in the best interest of the subject. 
6) Clinically significant deterioration of the subject's medical status as determined by the 
investigator. 
7) The subject requires alternative anti-cancer agents or non-palliative radiation therapy for primary 
or metastatic disease during the treatment portion of the study. 
8) The subject becomes pregnant or begins breastfeeding during the treatment portion of the study. 
9) The subject or subject's legally acceptable representative decides to withdraw consent for any 
reason.  
10) The subject is unable to comply with protocol requirements. 
11) Any other medical reason that the study investigator deems appropriate. 
4.5.1. Discontinuation of Individual Subjects 
When a subject discontinues from the study (without reaching a protocol-defined endpoint) is planned, 
the investigator will notify the principal investigator as soon as possible (provided, in each case, 
subject care and safety are not compromised).  When a subject discontinues the study, a final visit 
will be conducted (preferably prior to the initiation of another anticancer therapy). However, these 
procedures should not interfere with the initiation of any new treatments or therapeutic modalities that 
the investigator feels are necessary to treat the subject's condition. Following discontinuation of the 
study drug, the subject will be treated in accordance with the investigator's best clinical judgment.  At 
the final visit, the reason(s) for the discontinuation from the study will be recorded and a physical 
examination, body weight, vital signs measurement, laboratory analyses, performance status, tumor 
assessment, collection of unused study drug and an assessment of adverse events will be performed 
as soon as possible after discontinuation from the study.  All subjects will have one follow-up visit 
approximately 30 days after the final visit.  This follow-up visit does not need to be performed for 


Version 2.4 01-Oct2019 
 
 
 
62 
 
subjects who have had a final visit conducted ≥ 30 days after discontinuation of study drugs.  If a 
subject is discontinued from the study with an ongoing adverse event or an unresolved clinically 
significant laboratory result, the site will attempt to provide follow up until a satisfactory clinical 
resolution of the laboratory result or adverse event is achieved.  In the event that a positive result is 
obtained on a pregnancy test for a subject during the study, the administration of study drug to that 
subject must be discontinued immediately.   
4.5.2. Discontinuation of the Entire Study 
The investigators may terminate this study provided that written notice is submitted at a reasonable 
time in advance of the intended termination.  The following procedures for discontinuation will be 
followed:  
1) If the investigators have decided to prematurely discontinue the study, the investigators will 
promptly notify in writing the IRB of the decision and give detailed reasons for the 
discontinuation. 
2) The principal investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of protocol 
therapy, if applicable, by other appropriate regimens. 
 
 


Version 2.4 01-Oct2019 
 
 
 
63 
 
Table 4a: Study Activities to Week 24  
 
  
 
 
 
Screening 
(Day -14 to 
Day -1)
Week 
1
Week 
3
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
11
Week 
13
Week 
15
Week 
16
Week 
17
Week 
19
Week 
21
Week 
23
Week 
24
Off Study
Follow -upp
Informed consent
X
 
 
 
Demographics
X
Medical history
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds
X
X
X
X
 
X
 
X
 
X
 
 
X
 
X
 
 
X
-HCG
Xa
Xa
 
 
Vital signs
X
X
X
X
 
X
 
X
X
X
X
 
X
X
X
X
 
X
Height
X
 
 
Weight
X
X
X
X
 
X
 
X
X
X
X
 
X
X
X
X
 
X
History and Physical
X
X
X
X
 
X
 
X
 
X
 
 
X
 
X
 
 
X
Performance Status
X
X
X
X
 
X
 
X
 
X
 
 
X
 
X
 
 
X
Adverse event evaluation
X
X
X
X
 
X
 
X
 
X
 
 
X
 
X
 
 
X
Dispense Capecitabineb
X
 
X
 
 
X
 
X
 
 
X
 
X
 
 
Dispense Bevacizumabc               
(Colorectal Cancer Only)
X
X
X
 
X
X
X
X
X
 
X
X
X
X
 
Dispense MVA-BN-CV301
X
X
 
 
 
 
 
 
 
 
 
 
 
 
Dispense FPV-CV301
 
 
 
 
X
X
 
 
X
 
X
 
 
Dispense Durvalumabd
X
X
 
X
X
X
X
X
 
X
X
X
X
 
CBC w /diff
X
X
X
X
 
X
 
X
X
X
X
 
X
X
X
X
 
X
Serum chemistrye
X
X
X
X
 
X
 
X
X
X
X
 
X
X
X
X
 
X
Magnesium
X
X
X
X
 
X
X
X
X
X
 
X
X
X
X
 
X
Amylase and Lipase
X
X
X
X
 
X
X
 
X
 
 
X
 
X
 
 
X
TSH (Reflex Free T4 and Total T3 if 
TSH is abnormal)
X
X
X
 
X
Urinalysis
X
 
X
 
X
 
 
Hepatits and HIV Serologiesf
X
Tumor Markersg
 
X
X
 
X
X
 
X
 
X
Electrocardiogramh
X
X
 
 
 
X
 
 
 
 
 
 
 
X
Radiologic evaluation and Tumor 
Measurementsi
X
X
X
X
Xk
PT/PTTl
X
X
 
 
Tumor Biopsym
X
 
X
 
 
 
Research Blood Samplesp
 
X
 
 
 
X
 
 
 
X
 
 
 
 
X
Survival
 
 
 
 
 
 
 
 
 
 
Xr
Please note that for all durvalumab and CV301 (and bevacizumab for the colorectal cancer patients), treatments and subject assessments may occur +/- 3 days to accommodate patient scheduling
aFor w omen of childbearing potential, serum pregnancy test during screening; and urine pregnancy test on Week 1, Day 1
bCapecitabine BID M-F every w eek, commercial Supply, enough for four w eeks
cBevacizumab, commercial Supply; - Bevacizumab should be given IV over 60 minutes for the first tw o infusions, and then over 30 minutes thereafter
eSerum chemistries include: albumin, alkaline phos, total bili, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST, ALT, sodium
fHepatitis B surface antigen (reflex HBV viral load if sAg positive); Hepatitis C antibody (Reflex HCV RNA if antibody positive); HIV test
gTumor markers include CA 19-9, or CEA, as appropriate
iScreening scans should be w ithin 4 w eeks of starting treatment; Response scans must be performed every 8 w eeks (+/- 5 days) to assess response
lFor Biopsies
rFollow  up Assessments may be through office visits, or telephone follow -up and should be approximately every 12 w eeks
kUnless performed w ithin 4 w eeks of the off study date
pSix green top (Na heparin, 10 mL) tubes, 2 red serum separator (8 mL) tubes
mPre-treatment biopsy may occur any time from consent to Day -1; On study biopsy may occur +/- 1 w eek of w eek 6
dOn durvalumab treatment days, vital signs w ill be measured w ithin an hour prior to start of durvalumab administration, at 30 minutes during the infusion (± 5 minutes), at the end of infusion (+ 5 minutes), and 
at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post-infusion
hTriplicate Electrocardiograms w ill be performed at Screening.  ECGS obtained during w eek 3, w eek 9, and EOT w ill be single tracing only to assess QTcF.  ECGs obtained during treatment w ith durvalumab 
(Weeks 3 and 9) w ill be obtained w ithin an hour prior to start of infusion of durvalumab and at least one time point 0 to 3 hours after the infusion. 


Version 2.4 01-Oct2019 
 
 
 
64 
 
Table 4b: Study Activities Week 25-51 
 
  
 
 
 
Week 
25
Week 
27
Week 
29
Week 
31
Week 
32
Week 
33
Week 
35
Week 
37
Week 
39
Week 
40
Week 
41
Week 
43
Week 
45
Week 
47
Week 
48
Week 
49
Week 
51
Off Study
Follow -upp
Concurrent meds
X
 
X
 
 
X
 
X
 
 
X
 
X
 
 
X
 
X
Vital signs
X
X
X
X
 
X
X
X
X
 
X
X
X
X
 
X
X
X
Weight
X
X
X
X
 
X
X
X
X
 
X
X
X
X
 
X
X
X
History and Physical
X
 
X
 
 
X
 
X
 
 
X
 
X
 
 
X
 
X
Performance Status
X
 
X
 
 
X
 
X
 
 
X
 
X
 
 
X
 
X
Adverse event evaluation
X
 
X
 
 
X
 
X
 
 
X
 
X
 
 
X
 
X
Dispense Capecitabineb
X
 
X
 
 
X
 
X
 
 
X
 
X
 
 
X
 
Dispense Bevacizumabc             
(Colorectal Cancer Only)
X
X
X
X
 
X
X
X
X
 
X
X
X
X
 
X
X
Dispense FPV-CV301
X
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
Dispense Durvalumabd
X
X
X
X
 
X
X
X
X
 
X
X
X
X
 
X
X
CBC w /diff
X
X
X
X
 
X
X
X
X
 
X
X
X
X
 
X
X
X
Serum chemistrye
X
X
X
X
 
X
X
X
X
 
X
X
X
X
 
X
X
X
Magnesium
X
X
X
X
 
X
X
X
X
 
X
X
X
X
 
X
X
X
Amylase and Lipase
X
 
X
 
 
X
 
X
 
 
X
 
X
 
 
X
 
X
TSH (Reflex Free T4 and Total T3 
if TSH is abnormal)
X
X
 
X
X
 
X
Urinalysis
X
X
 
 
X
X
 
Tumor Markersf
X
 
X
X
 
X
 
X
 
X
X
 
X
Electrocardiogramg
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
Radiologic evaluation and Tumor 
Measurementsh
X
X
X
Xi
Research Blood Samplesm
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
X
Survival
 
 
 
 
 
 
 
Xp
Please note that for all durvalumab and CV301 (and bevacizumab for the colorectal cancer patients), treatments and subject assessments may occur +/- 3 days to accommodate patient scheduling
bCapecitabine BID M-F every w eek, commercial Supply, enough for four w eeks
cBevacizumab, commercial Supply; - Bevacizumab should be given IV over 60 minutes for the first tw o infusions, and then over 30 minutes thereafter
eSerum chemistries include: albumin, alkaline phos, total bili, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST, ALT, sodium
fTumor markers include CA 19-9, or CEA, as appropriate
gECGS obtained at the EOT w ill be single tracing only to assess QTcF.
hResponse scans must be performed every 8 w eeks (+/- 5 days) to assess response
iUnless performed w ithin 4 w eeks of the off study date
mSix green top (Na heparin, 10 mL) tubes, 2 red serum separator (8 mL) tubes
pFollow  up Assessments may be through office visits, or telephone follow -up and should be approximately every 12 w eeks
dOn durvalumab treatment days, vital signs w ill be measured w ithin an hour prior to start of durvalumab administration, at 30 minutes during the infusion (± 5 minutes), at the end of infusion (+ 5 minutes), and 
at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post-infusion


Version 2.4 01-Oct2019 
 
 
 
65 
 
Table 4c: Study Activities Week 53 on... 
 
 
Week 53
Every 2 w eeks,     
Week 55 until 
progression
Every 4 w eeks,   
Week 57 until 
progression
Every 8 w eeks,      
Week 56 until 
progression
Every 8 w eeks,      
Week 57 until 
progression
Every 24 w eeks,       
Week 53 until 
progression
Off Study
Follow -upp
Concurrent meds
X
 
X
X
Vital signs
X
X
X
X
Weight
X
X
X
X
History and Physical
X
 
X
X
Performance Status
X
 
X
X
Adverse event evaluation
X
 
X
X
Dispense Capecitabineb
X
 
X
Dispense Bevacizumabc             
(Colorectal Cancer Only)
X
X
X
Dispense FPV-CV301
X
 
 
X
Dispense Durvalumabd
X
X
X
CBC w /diff
X
X
X
X
Serum chemistrye
X
X
X
X
Magnesium
X
X
X
X
Amylase and Lipase
X
 
X
X
TSH (Reflex Free T4 and Total T3 
if TSH is abnormal)
 
X
 
X
Urinalysis
 
X
 
Tumor Markersf
X
X
X
Electrocardiogramg
X
Radiologic evaluation and Tumor 
Measurementsh
 
X
 
 
Xi
Research Blood Samplesm
 
 
 
 
 
X
Survival
 
 
 
 
 
 
Xp
Please note that for all durvalumab and CV301 (and bevacizumab for the colorectal cancer patients), treatments and subject assessments may occur +/- 3 days to accommodate patient scheduling
bCapecitabine BID M-F every w eek, commercial Supply, enough for four w eeks
cBevacizumab, commercial Supply; - Bevacizumab should be given IV over 60 minutes for the first tw o infusions, and then over 30 minutes thereafter
eSerum chemistries include: albumin, alkaline phos, total bili, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST, ALT, sodium
fTumor markers include CA 19-9, or CEA, as appropriate
gECGS obtained at the EOT w ill be single tracing only to assess QTcF.
hResponse scans must be performed every 8 w eeks (+/- 5 days) to assess response
iUnless performed w ithin 4 w eeks of the off study date
mSix green top (Na heparin, 10 mL) tubes, 2 red serum separator (8 mL) tubes
pFollow  up Assessments may be through office visits, or telephone follow -up and should be approximately every 12 w eeks
dOn durvalumab treatment days, vital signs w ill be measured w ithin an hour prior to start of durvalumab administration, at 30 minutes during the infusion (± 5 minutes), at the end of infusion (+ 5 minutes), 
and at 30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) post-infusion


Version 2.4 01-Oct2019 
 
 
 
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Table 5: Study Activities Checklist (With Specific Details Through Week 16) 
 
Screening (Within 2 weeks of Cycle 1, Day 1) 
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Eligibility Criteria 
 
 
 
 
 
 
 
 
_______ 
Informed Consent  
 
 
 
 
 
 
 
_______ 
Pregnancy Test (if appropriate)  
 
 
 
 
_______ 
Radiology Evaluation and Tumor Measurements 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Height and Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
TSH (Reflex Free T4 and Total T3 if TSH abnormal)_______ 
Urinalysis  
 
 
 
 
 
 
 
 
 
_______ 
Hepatits and HIV Serologies 
 
 
 
 
 
_______ 
PT/INR, PTT  
 
 
 
 
 
 
 
 
_______ 
Electrocardiogram (Triplicate)  
 
 
 
 
_______ 
Tumor Biopsy (ies) (From consent to Day -1) 
 
_______ 
 
Week 1  
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Pregnancy Test (if appropriate)  
 
 
 
 
_______ 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
CA 19-9 and/or CEA 
 
 
 
 
 
 
 
_______ 
Research Serum Samples  
 
 
 
 
 
_______ 
MVA-BN-CV301, (Bevacizumab) 
 
 
 
 
_______ 
Capecitabine  
 
 
 
 
 
 
 
 
______ 
 
Week 3  
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
Electrocardiogram   
 
 
 
 
 
 
 
_______ 
Durvalumab, (Bevacizumab) 
 
 
 
 
 
_______ 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
67 
 
Week 5 
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
CA 19-9 and/or CEA 
 
 
 
 
 
 
 
_______ 
Durvalumab, MVA-BN-CV301, (Bevacizumab)  
_______ 
Capecitabine  
 
 
 
 
 
 
 
 
_______ 
 
Week 6 
PT/INR, PTT  
 
 
 
 
 
 
 
 
_______ 
Tumor Biopsy (ies)  
 
 
 
 
 
 
 
_______ 
 
Week 7  
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
Electrocardiogram   
 
 
 
 
 
 
 
_______ 
Durvalumab, (Bevacizumab) 
 
 
 
 
 
_______ 
 
Every 8 Weeks, Week 8 Until Progression (Week 8) 
Radiology Evaluation and Tumor Measurements 
_______ 
 
Week 9  
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
TSH (Reflex Free T4 and Total T3 if TSH abnormal)_______ 
Urinalysis  
 
 
 
 
 
 
 
 
 
_______ 
CA 19-9 and/or CEA 
 
 
 
 
 
 
 
_______ 
Electrocardiogram   
 
 
 
 
 
 
 
_______ 
Research Serum Samples  
 
 
 
 
 
_______ 
Durvalumab, FPV-CV301, (Bevacizumab)  
 
_______ 
Capecitabine  
 
 
 
 
 
 
 
 
_______ 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
68 
 
 
Every 2 weeks, Week 11 Until Progression (Week 11) 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Durvalumab, (Bevacizumab) 
 
 
 
 
 
_______ 
 
Every 4 Weeks, Week 13 Until Progression (Week 13) 
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
CA 19-9 and/or CEA 
 
 
 
 
 
 
 
_______ 
Capecitabine  
 
 
 
 
 
 
 
 
_______ 
 
Every 2 weeks, Week 11 Until Progression (Week 13) 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Durvalumab, (Bevacizumab) 
 
 
 
 
 
_______ 
 
Every 2 weeks, Week 11 Until Progression (Week 15) 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Durvalumab, (Bevacizumab) 
 
 
 
 
 
_______ 
 
Every 8 Weeks, Week 8 Until Progression (Week 16) 
Radiology Evaluation and Tumor Measurements 
_______ 
 
Every 4 Weeks, Week 13 Until Progression (Week 17 Onward) 
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
CA 19-9 and/or CEA 
 
 
 
 
 
 
 
_______ 
Capecitabine  
 
 
 
 
 
 
 
 
_______ 
 
Every 2 weeks, Week 11 Until Progression (Week 17 Onward) 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Durvalumab, (Bevacizumab) 
 
 
 
 
 
_______ 
 
Every 8 Weeks, Week 17 Until Progression 
Urinalysis  
 
 
 
 
 
 
 
 
 
_______ 
TSH (Reflex Free T4 and Total T3 if TSH abnormal)_______ 
Research Serum Samples  
 
 
 
 
 
_______ 


Version 2.4 01-Oct2019 
 
 
 
69 
 
 
Week 17  
FPV-CV301 
 
 
 
 
 
 
 
 
 
_______ 
Research Serum Samples  
 
 
 
 
 
_______ 
 
Week 21  
FPV-CV301 
 
 
 
 
 
 
 
 
 
_______ 
 
Weeks 25 and 37  
FPV-CV301 
 
 
 
 
 
 
 
 
 
_______ 
 
Every 24 weeks, Week 53 until progression 
FPV-CV301 
 
 
 
 
 
 
 
 
 
_______ 
 
Week 49  
Research Serum Samples  
 
 
 
 
 
_______ 
 
Off Study 
Subject Assessment 
 
 
 
 
 
 
 
_______ 
Weight 
 
 
 
 
 
 
 
 
 
 
_______ 
Vital Signs  
 
 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
 
_______ 
Adverse Event Evaluation  
 
 
 
 
 
_______ 
History and Physical 
 
 
 
 
 
 
 
_______ 
Performance Status 
 
 
 
 
 
 
 
_______ 
Adverse Events Evaluation  
 
 
 
 
 
_______ 
CBC with Differential 
 
 
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
 
_______ 
Magnesium 
 
 
 
 
 
 
 
 
 
_______ 
Amylase and Lipase 
 
 
 
 
 
 
 
_______ 
TSH (Reflex Free T4 and Total T3 if TSH abnormal)_______ 
Research Serum Samples  
 
 
 
 
 
_______ 
CA 19-9 and/or CEA 
 
 
 
 
 
 
 
_______ 
Radiology Evaluation and Tumor Measurements 
_______ 
Electrocardiogram   
 
 
 
 
 
 
 
_______ 
 
Follow-up Assessments 
  Survival, post-trial therapy  
 
 
 
 
 
_______ 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
70 
 
5. SAFETY VARIABLES AND TOXICITY ASSESSMENT 
The Principal Investigator or Sub-investigators will assess adverse events, laboratory data and vital 
signs throughout the study.  Adverse events will be assessed by NCI CTCAE Version 4.0. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf  
5.1. Adverse Events Assessment 
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study. The investigator will assess and record any adverse event in detail 
including the date of onset, event diagnosis (if known) or sign/symptom, severity, time course, duration 
and outcome, relationship of the adverse event to study drug, and any action(s) taken. For serious 
adverse events not considered "probably related" to study drug, the investigator will provide an "Other" 
cause of the event. For adverse events to be considered intermittent, the events must be of similar nature 
and severity. Adverse events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded. All adverse events will be followed to a satisfactory 
conclusion. 
 
The following will be detailed further below, but these guidelines are meant as an important summary to 
adverse event definition, and reporting rules for this protocol: 
- 
Adverse events of special interest: An adverse event of special interest (AESI) for durvalumab 
and for the combination of agents in this study include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone replacement 
therapy.  
 
Not all AESIs are Serious Adverse Events (SAEs) 
 
All AESIs should be reported to Astra Zeneca and Bavarian Nordic within 24 hours 
 
- 
Serious Adverse Events: A serious adverse event (SAE) is any adverse event which could 
result/has resulted in a subject’s death, hospitalization/prolongation of hospitalization, significant 
disability/incapacity, the need for urgent medical or surgical intervention, or birth 
defects/spontaneous abortion.   
 
Not all SAEs are AESIs 
 
Only “reportable” serious adverse events will be reported.  “Reportable” is defined as any 
SAE that is unexpected (i.e. not among the known adverse events associated with the 
therapies used or with the study procedures performed) or is possibly, probably, or 
definitely related to the therapy.  Each site is required to follow their local policies for 
reporting SAEs to their local IRB.   
 
All SAEs must be reported to Astra Zeneca 
 
Only unexpected SAEs that are possibly, probably, or definitely related to the therapy 
(any part of the combination) should be reported to the Georgetown DSMC, and to the 
FDA 
5.2. Study Monitoring 
Data safety monitoring committee (DSMC) 
The Georgetown Lombardi Comprehensive Cancer Center (LCCC) will be responsible for the data 
and safety monitoring of this multi-site trial.  As this study is an investigator initiated Phase I/II study 
non-FDA approved therapies, it is considered a high risk study which requires real-time monitoring 
by the PI and study team and quarterly reviews by the LCCC Data and Safety Monitoring Committee 
(DSMC). 
 
The Study Chairs and Associate Investigators will review the data including safety monitoring at their 
monthly teleconferences of participating sites.   
 


Version 2.4 01-Oct2019 
 
 
 
71 
 
All “reportable” (defined above) Severe Adverse Events (SAEs) are required to be reported to the 
local and to the Georgetown IRB, as detailed above.  Based on SAEs, the IRB retains the authority 
to suspend further accrual pending more detailed reporting and/or modifications to further reduce risk 
and maximize the safety of participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety 
Monitoring Committee every 3 months from the time the first patient is enrolled on the study. Results 
of the DSMC meetings will be forwarded to the IRB with recommendations regarding need for study 
closure. 
 
DSMC recommendations should be based not only on results for the trial being monitored as well as 
on data available to the DSMC from other studies.  It is the responsibility of the Study Chair to ensure 
that the DSMC is kept apprised of non-confidential results from related studies that become available.  
It is the responsibility of the DSMC to determine the extent to which this information is relevant to its 
decisions related to the specific trial being monitored. 
 
A written copy of the DSMC recommendations will be given to the trial Study Chair and the IRB.  If 
the DSMC recommends a study change for patient safety or efficacy reasons the Study Chair must 
act to implement the change as expeditiously as possible.  In the unlikely event that the Study Chair 
does not concur with the DSMC recommendations, then the LCCC Associate Director of Clinical 
Research must be informed of the reason for the disagreement.  The Study Chair, DSMC Chair, and 
the LCCC AD for Clinical Research will be responsible for reaching a mutually acceptable decision 
about the study and providing details of that decision to the IRB.  Confidentiality must be preserved 
during these discussions.  However, in some cases, relevant data may be shared with other selected 
trial investigators and staff to seek advice to assist in reaching a mutually acceptable decision. 
 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy the 
DSMC will provide an adequate rationale for its decision. If the DSMC recommends that the trial be 
closed for any reason, the recommendation will be reviewed by the Associate Director for Clinical 
Research at G-LCCC.  Authority to close a trial for safety reasons lies with the IRB, with the above 
described input from DSMC and the AD for Clinical Research.   
 
Of note, the DSMC will also review the safety data of the patients enrolled outside of Georgetown 
University.  The Multicenter Project Management Office will be tasked with the job of collecting all 
primary source documentation for patients enrolled outside of Georgetown University.  In addition, 
the data managers at each site will be entering data into the Georgetown database, so that all data 
will be available for the DSMC at Georgetown to review.  Faxed records should be sent to 202-687-
3821 with an email to the Multicenter Project Managers and Dr. Weinberg to confirm receipt of those 
records. 
5.3.  Adverse Events and Toxicity Definitions 
5.3.1. Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not the event is 
considered causally related to the use of the product.  Such an event can result from use of the drug 
as stipulated in the protocol or labeling, as well as from accidental or intentional overdose, drug 
abuse, or drug withdrawal. Any worsening of a pre-existing condition or illness is considered an 
adverse event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic medical 
intervention, and/or if the investigator considers them to be adverse events.  The term AE is used to 
include both serious and non-serious AEs. 


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Adverse events may be treatment emergent (i.e., occurring after initial receipt of the investigational 
product) or non-treatment emergent. A non-treatment emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product.  
 
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse 
event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre planned prior to study entry.  However, if the pre-existing condition 
deteriorates unexpectedly during the study (e.g., surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done will be considered 
an adverse event. 
5.3.2. Serious Adverse Events 
1) Death of Subject an event that results in the death of a subject. 
2) Life-Threatening an event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken. This does not include an event 
that would have been fatal if it had occurred in a more severe form. 
3) Hospitalization or 
4) Prolongation of Hospitalization an event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay. This does not include an emergency 
room visit or admission to an outpatient facility. 
5) Congenital Anomaly an anomaly detected at or after birth, or any anomaly that results in 
fetal loss.  
6) Persistent or Significant Disability/Incapacity an event that results in a condition that 
substantially interferes with the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle). 
7) Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious 
Outcome An important medical event that may not be immediately life-threatening or result 
in death or hospitalization, but based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any of the outcomes listed above (i.e., 
death of subject, life-threatening, hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity). Examples of such 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. 
8) Spontaneous Abortion Miscarriage experienced by study subject.  
9) Elective Abortion Elective abortion performed on study subject. 
5.3.3. Adverse Event Severity 
The study investigator will rate the severity of each adverse event according to the NCI CTCAE 
Version 4.0.  For adverse events not captured by the NCI CTCAE Version 4.0, the following should 
be used: 
1) Grade 1 (Mild) The adverse event is transient and easily tolerated by the subject. 
2) Grade 2 (Moderate) The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.  


Version 2.4 01-Oct2019 
 
 
 
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3) Grade 3/4 (Severe or Life Threatening) The adverse event causes considerable interference 
with the subject's usual activities and may be incapacitating or life-threatening. 
4) Grade 5 (Severe, resulting in Death) The adverse event resulted in death of the subject. 
5.3.4. Relationship to Study Drugs 
The investigator will use the following definitions to assess the relationship of the adverse event to 
the use of study drug(s). 
1) Definitely Related An adverse event has a clear temporal relationship to study drug(s) and/or 
recurs on re-challenge and an Other cause of event is extremely unlikely. 
2) Probably Related An adverse event has a strong temporal relationship to study drug(s) or 
recurs on re-challenge and an Other cause of event is unlikely or significantly less likely. 
3) Possibly Related An adverse event has a strong temporal relationship to the study drug(s) 
and an Other cause of event is equally or less likely compared to the potential relationship to 
study drug.  
4) Probably Not Related An adverse event has little or no temporal relationship to the study 
drug(s) and/or a more likely Other cause of event exists.   
5) Not Related An adverse event is due to an underlying or concurrent illness or effect of another 
drug(s) and is not related to the study drug (e.g., has no temporal relationship to study drug 
or has a much more likely Other cause of event). 
 
If an investigator's opinion of possibly, probably not, or not related to study drug(s) is given, an 
Other cause of event must be provided by the investigator for the serious adverse event.  
 
Special consideration must be taken into consideration as to which study drug(s) the adverse 
event is linked to.  If this is not known, or cannot be stated definitively, then the investigator should 
not the relationship to “study regimen” – or similar language that links the AE to any/all of the 
therapies 
 
It is important to note: 
- 
Not all SAEs are AESIs 
- 
Only “reportable” serious adverse events will be reported.  “Reportable” is defined as any 
SAE that is unexpected (i.e. not among the known adverse events associated with the 
therapies used or with the study procedures performed) or is possibly, probably, or 
definitely related to the therapy.  Each site is required to follow their local policies for 
reporting SAEs to their local IRB.   
- 
All SAEs must be reported to Astra Zeneca and to Bavarian Nordic 
- 
Only unexpected SAEs that are possibly, probably, or definitely related to the therapy (any 
part of the combination) should be reported to the Georgetown DSMC, and to the FDA 
5.3.5. Non-Serious Adverse Events of Special Interest (Immediately Reportable) 
5.3.5.1 Definition of Adverse Events of Special Interest (AESI) 
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 and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious.  The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
 
It is important to note: 
- 
Not all AESIs are Serious Adverse Events (SAEs) 
- 
All AESIs should be reported to Astra Zeneca and to Bavarian Nordic within 24 hours 
 


Version 2.4 01-Oct2019 
 
 
 
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5.3.5.2 Reportable AESIs 
AESIs for durvalumab and for the combination of agents in this study include but are not limited to 
events with a potential inflammatory or immune-mediated mechanism and which may require more 
frequent monitoring and/or interventions such as steroids, immunosuppressants and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with durvalumab 
monotherapy and combination therapy. Many of these AESIs are being monitored for the potential 
as immune-related adverse events.   
 
An immune-related adverse event (irAE) is defined as an adverse event that is associated with 
drug exposure and is consistent with an immune-mediated mechanism of action and where there 
is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an irAE diagnosis. Appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE.  
 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Chair or Co-Chair. 
 
5.3.5.3 Specific AESIs 
Adverse events of special interest for this study include the following:  
 
In general, conditions (regardless of Grade) suggestive of an autoimmune disorder, including 
but not limited to hepatitis, pneumonitis, colitis, endocrinopathies, pancreatitis (clinical OR 
asymptomatic increased serum lipase or increased serum amylase), thyroiditis, rheumatoid 
arthritis, Type I diabetes, vasculitis, neuritis, systemic lupus erythematosus, Sjögren’s 
syndrome, and multiple sclerosis.  
o For patients with Grade 1 laboratory abnormalities at baseline that were NOT 
exclusionary, an AESI would be defined as any INCREASE in the Grade of lab 
abnormality 
 
E.g. – for a patient with Grade 1 AST at study entry (not exclusionary), an 
AESI would be defined if the AST increased to Grade 2 
 
Grade ≥ 2 events suggestive of hypersensitivity, cytokine release, systemic inflammatory 
response, or infusion reaction syndromes, including but not limited to influenza-like illness, 
fever, chills, rash, urticaria, dyspnea, wheezing, angioedema, tachycardia, and hypotension 
occurring within 24 hours of the end of the infusion.  
 
Grade ≥ 2 events suggestive of cytokine release syndrome (occurring ≥ 24 hours after the 
end of the infusion), including but not limited to influenza-like illness, nausea, headache, 
fevers, chills, tachycardia, hypotension, and shortness of breath.  
 
Grade ≥ 3 acute infection (bacterial, viral, zoonotic, or fungal)  
 
Grade ≥ 2 rash, vitiligo, or pruritus (concern for dermatitis)  
 
Grade ≥ 2 diarrhea (concern for colitis) 
 
Grade ≥ 2 hypoxia or dyspnea (concern for pneumonitis) 
 
Grade ≥ 2 pleural effusion  
 
Grade ≥ 2 pericardial effusion  
 
Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 
 
Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism) 
 
Nephritis 


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75 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator Brochure [2]. 
 
5.3.5.4 Criteria for Hy’s Law (FDA Guidance 2009) 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3 fold or greater 
elevations above the ULN of ALT or AST than the (non hepatotoxic) control drug or placebo  
 
Among trial subjects showing such aminotransferase elevations, often with aminotransferases 
much greater than 3 x ULN, one or more also show elevation of serum total bilirubin to >2 x ULN, 
without initial findings of cholestasis (elevated serum alkaline phosphatase)  
 
No other reason can be found to explain the combination of increased aminotransferases and total 
bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another drug 
capable of causing the observed injury. 
5.4. Recording of Adverse Events and Serious Adverse Events 
Adverse events will be recorded in the source documentations (such as the electronic medical record 
system) and/or patient study chart using a recognized medical term or diagnosis that accurately reflects 
the event. Adverse events will be assessed by the investigator for severity, relationship to the 
investigational product, possible etiologies, and whether the event meets the definition of a reportable 
finding.  
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
Description of AE 
• 
The date when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
For an AE that is an AESI or SAE, a specific notation will be made 
• 
Separate Investigator causality ratings against durvalumab (yes or no) and/or CV301, and/or 
capecitabine, and/or bevacizumab (for colorectal cancer patients) OR to a study procedure 
• 
Action taken with regards to any/all of the study agents (listed above) 
• 
Outcome 
 
In addition, the following variables will be collected for AESIs and SAEs, as applicable: 
• 
Date the AE met criteria for an AESIs or SAEs 
• 
Date Investigator became aware of the AESIs or SAEs 
• 
Reason the AE qualified as an AESIs or SAEs 
• 
Date of hospitalization (if applicable) 
• 
Date of discharge (if applicable) 
• 
Probable cause of death (if applicable) 
• 
Date of death (if applicable) 
• 
Autopsy performed (if applicable) 
5.5. Adverse Event Collection Period 
All adverse events are reported from the period immediately following the time that written informed 
consent is obtained through 90 days after the last dose of durvalumab, CV301, capecitabine, or 
bevacizumab – whichever is given last as part of the clinical trial (patients who continue capecitabine or 
bevacizumab as part of standard of care, the reporting period is ONLY 90 days after the last dose given 
on study) or until the initiation of alternative anticancer therapy.   
 
OF NOTE: For the time between when consent is obtained, and the first dose of therapy is given, AESIs 
and SAEs are only reported if the event is related to a study procedure. 
 


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During the course of the study all AEs, AESIs, and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events continue 
after discontinuation/study completion. 
 
If a subject discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related AESIs or SAEs must be captured until 
the patient is considered to have confirmed PD and will have no further tumor assessments. 
 
The investigator is responsible for following all AESIs or SAEs until resolution, until the subject returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain chronic, 
even if this extends beyond study participation. 
 
In addition, all AESIs or SAEs related to protocol requirements will be collected from the time the subject 
signed the study-specific informed consent.  This could include, for example, AESIs or SAEs associated 
with study-required biopsies prior to initiating study medications. However, AESIs and SAEs that are 
unrelated to any study events (for example a hospitalization related to the underlying disease that occurs 
prior to initiating study medications) do not need to be reported.  Any questions or uncertainties should 
be directed to the Study Chairs. 
5.6. Adverse Event Reporting 
All AESIs will be reported to Astra Zeneca and to Bavarian Nordic within 24 hours. 
 
Only “reportable” SAEs will be reported.  “Reportable” is defined as any SAE that is unexpected (i.e. not 
among the known adverse events associated with the therapies used or with the study procedures 
performed) or is possibly, probably, or definitely related to the therapy.  Each site is required to follow 
their local policies for reporting SAEs to their local IRB.   
 
All “reportable” SAEs must be reported within 24 hours to Astra Zeneca and to Bavarian Nordic. 
 
Only unexpected SAEs that are possibly, probably, or definitely related to the therapy (any part of the 
combination) should be reported to the Georgetown DSMC, and to the FDA 
 
For patients enrolled outside of Georgetown University, all supporting documentation for SAEs that need 
to be reported to the Georgetown IRB will be sent (faxed or HIPPA compliant email) to the Multicenter 
Project Management Office and to the Study Chair, Dr. Pishvaian within 24 hours.  Faxed records should 
be sent to 202-687-3821, with an email to the Multicenter Project Managers, Dr. Weinberg 
(benjamin.a.weinberg@gunet.georgetown.edu), and Dr. Pishvaian (pishvaim@georgetown.edu) to 
confirm receipt of those records. 
 
The adverse event (AESI or SAE) report should comprise a full written summary, detailing relevant 
aspects of the adverse events in question.  Where applicable, information from relevant hospital case 
records and autopsy reports should be included.    
 
For AEs that require reporting to the FDA (Unexpected SAEs related to therapy only) or Astra Zeneca / 
Bavarian Nordic (AESIs or SAEs), reporting will occur via a MedWatch/AdEERs form, in accordance 
with the reporting obligations of 21 CFR 312.32. For AEs that must be reported to AstraZeneca and 
Bavarian Nordic., a copy of the MedWatch/AdEERs report must be faxed or emailed to AstraZeneca 
and Bavarian Nordic at the time the event is reported to the FDA.  It is the responsibility of the sponsor 
(Georgetown) to compile all necessary information and ensure that the FDA receives a report according 
to the FDA reporting requirement timelines and to ensure that these reports are also submitted to 
AstraZeneca and Bavarian Nordic at the same time. 
 
 
A cover page should accompany the MedWatch/AdEERs form indicating the following: 


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77 
 
 
“Notification from an Investigator Sponsored Study” 
 
The investigator IND number assigned by the FDA 
 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ISS reference number (ESR-14-10067) 
 
The investigator must note if the AE is an AESI, SAE, or unexpected SAE related to therapy 
 
The investigator must also indicate, either in the adverse event report or the cover page, the 
causality of events in relation to all study medications and if the adverse event is related to 
disease progression, as determined by the investigator. 
 
Send the AE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox:    AEMailboxClinicalTrialTCS@astrazeneca.com 
 
Send the AE report and accompanying cover page by way of email to Bavarian Nordic’s 
designated mailbox:    drug.safety@bavarian-nordic.com 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be provided 
to the IRB, AstraZeneca, Bavarian Nordic and the FDA, as detailed above. 
5.7. Pregnancy 
In the event of a positive pregnancy test result, study drugs will be immediately discontinued. The 
investigator must report the positive pregnancy test within 1 working day of the site becoming aware of 
the pregnancy to the local and the Georgetown IRB.  Patients should also notify the investigator if it is 
determined after completion of the study that they become pregnant either during the treatment phase of 
the study or within five days after the treatment period.  Information regarding a pregnancy occurrence 
in a study subject and the outcome of the pregnancy will be collected, and the status of the mother and 
child should be reported to the local and the Georgetown IRB after delivery.  Male subjects should also 
notify the investigators if the subject's partner should become pregnant during the study, this should also 
be reported within 1 working day of site awareness. 
5.7.1. 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 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 AstraZeneca 
representative will work with the Investigator to ensure that all relevant information is provided to the 
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.   
5.7.2. Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 90 days 
after the last dose of durvalumab or CV301.  Pregnancy of the patient’s partner is not considered to 
be an AE.  However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose 
until 90 days after the last dose should, if possible, be followed up and documented.  Where a report 
of pregnancy is received, prior to obtaining information about the pregnancy, the Investigator must 


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obtain the consent of the patient’s partner.  Therefore, the local study team should adopt the generic 
ICF template in line with local procedures and submit it to the relevant Ethics Committees 
(ECs)/Institutional Review Boards (IRBs) prior to use.   
5.8. Overdose 
An overdose is defined as a subject receiving a dose of study medication in excess of that specified in 
the protocol. 
 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is required to 
be reported within 24 hours of knowledge of the event to the sponsor (Georgetown) and 
AstraZeneca/MedImmune Patient Safety or designee using the designated Safety e-mailbox 
(AEMailboxClinicalTrialTCS@astrazeneca.com). If the overdose results in an AE, the AE must also be 
recorded as an AE.  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. There is currently no specific treatment in the event of an overdose of 
durvalumab. The investigator will use clinical judgment to treat any overdose. 
 
5.9. Cardiac Events Management  
Based on the total clinical experience with poxvirus vectors for anticancer vaccines, including CV301’s 
predecessor product PANVAC, a causal relationship of cardio-toxicity following treatment with CV301 
and/or PANVAC is unlikely. Nonetheless, a proactive approach in pharmacovigilance will be applied 
prospectively, requesting from the investigators a deeper characterization of every case with a cardiac 
AE with the working hypothesis that myocarditis/pericarditis may be the underlying cause. As deemed 
necessary by the investigator, ECG and/or troponin testing may be performed in the presence of any 
cardiac symptoms, in order to exclude the diagnosis of myo-/pericarditis. The reporting of cardiac events 
follows the standard processes as outlined in the sections above. 
5.10. Hepatic Function Abnormality 
Hepatic function abnormality (defined as a worsening over baseline in total bilirubin, AST, or ALT) in a 
study subject, with or without associated clinical manifestations, and of any grade is required to be 
reported as an AESI within 24 hours of knowledge of the event to AstraZeneca/MedImmune Patient 
Safety using the designated Safety e-mailbox (AEMailboxClinicalTrialTCS@astrazeneca.com). 
 
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 subject will be based on the 
clinical judgment of the investigator. 
 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study subject 
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 sponsor and AstraZeneca/MedImmune.  
5.11. Protocol Deviations 
The investigator should not implement any deviation from the protocol without prior review and 
agreement by the Study Chair and in accordance with the Georgetown IRB and local regulations, except 
when necessary to eliminate an immediate hazard to study subjects.  
5.12. Toxicity Management (See Appendix E) 
Importantly, the dose of capecitabine parallels the dose used in the “maintenance” setting for pancreatic 
cancer[3].  However, for colorectal cancer, the dose of capecitabine in the CAIRO 3 trial was higher – 


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625mg/m2 continuously daily [4]. In our experience, that dose given chronically can lead to significant 
toxicities and is not ideally suited for the “maintenance” setting. 
 
Dose modifications or adjustments for capecitabine and bevacizumab are detailed below.  There will be 
no dose modifications or adjustments for durvalumab.  Patients who experience significant toxicities 
requiring holding durvalumab will be allowed symptomatic care, followed by a re-challenge of 
durvalumab, as detailed below. There will be no dose modifications of the CV301 doses.  
5.12.1. Management of Toxicities Related to Capecitabine 
Capecitabine dosing will be 1000mg orally twice a day, Monday – Friday weekly.  Common toxicities 
associated with capecitabine include nausea, vomiting, myelosuppression, stomatitis, and hand-foot 
syndrome, though at these maintenance doses, those AEs are less common. For patients who 
experience AEs that are clearly attributable in the investigators opinion to capecitabine, the following 
dose adjustments can be made.   
 
If capecitabine doses need to be held for toxicity related to capecitabine, all other study medications 
may continue. 
 
Table 6: Capecitabine Dose Adjustments 
5.12.2. Management of Toxicities Related to Bevacizumab 
Bevacizumab dosing will be 5mg/kg IV q2weeks.  Toxicities attributable strictly to bevacizumab are 
uncommon, 
but 
known 
toxicities 
include 
proteinuria, 
bowel 
perforation, 
and 
arterial 
Adverse Event
First Occurrence
Second Occurrence
Third Occurrence
• Grade ≥ 4 neutropenia (absolute 
neutrophil count [ANC] < 500/uL) 
lasting ≥ 7 days 
• Grade ≥ 3 febrile neutropenia 
• Grade ≥ 4 anemia 
• Grade ≥ 4 thrombocytopenia, or Grade 
3 thrombocytopenia associated with 
clinically significant bleeding 
1. Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL, Platelets 
≥75000/mL, and HgB ≥8g/dL                                    
AND                                                                             
2. Decrease Capecitabine to 1000mg QAM, and 
500mg QPM
1. Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL, Platelets 
≥75000/mL, and HgB ≥8g/dL                                     
AND                                                                              
2. Decrease Capecitabine to 500mg QAM, and 
500mg QPM
Discontinue Capecitabine
ANC≥500/ml but <1000/mL                      
OR                                                                   
Platelets ≥75000/ml but <100000/mL 
1. Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL, Platelets 
≥75000/mL, and HgB ≥8g/dL                                    
AND                                                                             
2. Decrease Capecitabine to 1000mg QAM, and 
500mg QPM
1. Hold all therapy and check CBC weekly until 
recovery to: ANC ≥1000/mL, Platelets 
≥75000/mL, and HgB ≥8g/dL                                     
AND                                                                              
2. Decrease Capecitabine to 1000mg QAM, and 
500mg QPM
Discontinue Capecitabine
ANC ≥1000/ml but <1500/mL                      
OR                                                                   
Platelets ≥75000/ml but <100000/mL 
1. Continue therapy                                                    
AND                                                                             
2. Decrease Capecitabine to 1000mg QAM, and 
500mg QPM
1. Continue therapy                                                    
AND                                                                              
2. Decrease Capecitabine to 1000mg QAM, and 
500mg QPM
Discontinue Capecitabine
Nausea/Vomiting CTC ≥ Grade 3 despite 
optimal anti-emetic therapy 
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline)                        
AND                                                                             
2. Decrease Capecitabine to 1000mg QAM, and 
500mg QPM
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline)                        
AND                                                                              
2. Decrease Capecitabine to 500mg QAM, and 
500mg QPM
Discontinue Capecitabine
Diarrhea CTC ≥ Grade 3, despite optimal 
antidiarrheal therapy   OR   Fatigue CTC 
≥ Grade 3   OR   Mucositis CTC ≥ Grade 
3   OR   Other Toxicity Not Defined 
Herein CTC ≥ Grade 3 despite optimal 
supportive care
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline)                        
AND                                                                             
2. Decrease Capecitabine to 1000mg QAM, and 
500mg QPM
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline)                        
AND                                                                              
2. Decrease Capecitabine to 500mg QAM, and 
500mg QPM
Discontinue Capecitabine
Capecitabine-Specific Toxicity
Hand-Foot syndrome CTC ≥ Grade 3
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline)                        
AND                                                                             
2. Decrease Capecitabine to 1000mg QAM, and 
500mg QPM
1. Hold all therapy until recovery to Grade 1 (or 
Grade 2 level, if present at baseline)                        
AND                                                                              
2. Decrease Capecitabine to 500mg QAM, and 
500mg QPM
Discontinue Capecitabine
Hematologic Toxicity 
Non-Hematologic Toxicity


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thromboembolism.  Bevacizumab can also enhance thrombocytopenia.  There will be no dose 
adjustments for bevacizumab. Bevacizumab will be HELD for the following: 
 Grade 2 or 3 proteinuria 
 Grade ≥ 3 hypertension 
The bevacizumab may be resumed if these AEs resolve to Grade ≤1, with medical intervention as 
necessary. 
 
Patients who experience the following AEs that are clearly attributable in the investigators opinion to 
bevacizumab, the bevacizumab will simply be discontinued altogether: 
 Any Grade of bowel perforation   
 Grade 4 proteinuria 
 Any arterial thromboembolism 
5.12.3. General Management of Immune-Related Toxicities (Additional Details Provided in 
Appendix E, Below) 
5.12.3.1. Infusion-Related Reactions  
Because durvalumab is a monoclonal antibody and targets the tumor cell-immune cell 
interaction, infusion-related reactions associated with hypersensitivity reactions, target-
mediated cytokine release, and/or emergent anti-therapeutic antibodies may occur.  
 
To minimize the risk and sequelae of infusion-related reactions, the initial dose of durvalumab 
will be administered over 90 minutes followed by a 90-minute observation period and 
subsequent infusion times will be shortened to 60 minutes only if the initial dose administration 
is well tolerated.  
5.12.3.2. Cytokine Release Syndrome  
Cytokine release as a result of T-cell activation is a theoretical response to durvalumab. Mild 
flu-like symptoms such as fever, headache, and myalgias may occur following infusion (hours 
to days). In contrast, severe, exaggerated cytokine release is not anticipated in response to 
durvalumab.  
 
Mild to moderate presentations of CRS may be treated symptomatically with analgesics, anti-
pyretics, antihistamines and IV fluids as indicated. Severe or life-threatening presentations of 
CRS, such as hypotension not responsive to initial IV fluid bolus, tachycardia, dyspnea or 
chest discomfort should be treated aggressively with supportive and resuscitative measures 
as indicated, including the use of high dose corticosteroids, IV fluids, and other supportive 
measures. 
5.12.3.3. Gastrointestinal Toxicity  
Gastrointestinal 
toxicity, 
including 
autoimmune 
colitis, 
has 
been 
observed 
with 
immunomodulatory agents targeting the PD-L1/PD-1 pathways. Gastrointestinal toxicity is a 
potential risk for durvalumab, and the risk of gastrointestinal toxicity with the combination of 
durvalumab and CV301 is unknown. Patients with known history of active inflammatory bowel 
diseases, including those with small or large intestine inflammation, such as Crohn’s disease 
or ulcerative colitis, will be excluded from the study.  
Diarrhea (defined as either first watery stool or an increase in frequency of 50% above 
baseline with urgency or nocturnal bowel movement or bloody stool) should be further 


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evaluated, and infectious or alternate etiologies should be ruled out. Patients should be 
advised to inform the investigator if any diarrhea occurs, even if it is mild.  
If the event is of significant duration or magnitude or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased CRP or platelet count or bandemia), it 
is recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with 
three to five specimens for standard paraffin block be performed. All patients with confirmed 
colitis should also have an ophthalmic examination, including a slit lamp examination, to rule 
out uveitis.  
Study treatment should be interrupted for patients who develop Grade ≥ 2 diarrhea and the 
use of corticosteroids should be considered. In addition, if the patient is being managed with 
corticosteroids, treatment should not be restarted until the steroids have been tapered off (i.e., 
to a prednisone dose ≤10 mg/day or equivalent). Patients with colitis should also discontinue 
any non-steroidal anti-inflammatory medications or any other medications known to 
exacerbate colitis symptoms.  
Patients who resume treatment should be monitored closely for signs of renewed diarrhea.  
5.12.3.4. Hepatotoxicity 
Hepatotoxicity has been observed with immunomodulatory agents targeting the PD-L1/PD-1 
pathways. Hepatitis is a potential risk of durvalumab. The risk of hepatotoxicity with the 
combination of durvalumab and CV301 is unknown.  
Eligible patients must have adequate liver function, as manifested by measurements of total 
bilirubin and hepatic transaminase, and liver function will be monitored throughout study 
treatment. Patients with documented liver metastases are eligible for enrollment but must 
have AST and ALT values ≤ 2.5X ULN at screening. Patients with known liver disease that 
could increase susceptibility to or exacerbate the impact of any potential hepatotoxicity of 
study treatment, including those with active hepatitis B or active HCV infection will be excluded 
from the study.  
While on this study, patients presenting with right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should have LFTs performed within 24 hours of presentation 
and reviewed before administration of the next dose of study drug.  
If increased LFTs are observed, neoplastic, concurrent medications, viral hepatitis, and toxic 
etiologies should be considered and addressed, as appropriate. Imaging of the liver, gall 
bladder, and bile duct should be performed to rule out neoplastic or other causes for the 
increased LFTs. Liver biopsy should be considered and anti-nuclear antibody, perinuclear 
anti-neutrophil cytoplasmic antibody, anti-LKM, and anti-smooth muscle antibody tests should 
be performed if an autoimmune etiology is considered.  
Patients with LFT abnormalities should be managed according to the following guidelines 
(Table 10). For patients with elevated LFTs at baseline due to documented liver metastases, 
further elevation of LFTs may not require dose interruptions if there are no progressive 
changes in the ALT and/or AST (i.e., less than a doubling) and if there are no progressive 
elevations in total bilirubin or PT/INR.   
 
 


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Table 7: Management of Hepatotoxicity 
 
5.12.3.5. Dermatologic Toxicity 
Dermatologic toxicity has been observed with immunomodulatory agents targeting the PD-
L1/PD-1 pathways, and is a potential risk of durvalumab. The risk of dermatologic toxicity with 
the combination of durvalumab and CV301 is unknown.  
Patients with a rash can be treated with antihistamines and topical steroids.  If the rash is 
≥Grade 2, then a dermatologist should be consulted.  If the rash is ≥ Grade 3, the durvalumab 
and CV301 should be held, and oral prednisone (e.g. 10mg/day or equivalent) can be 
administered.  The durvalumab and CV301 may be restarted if the rash resolves to ≤ Grade 
1 and systemic steroid dose is prednisone ≤ 10 mg/day or equivalent.  The durvalumab and 
AST/ALT > ULN to 3X ULN with total 
bilirubin ≤ 2X ULN
OR
AST/ALT rises  > 3–fold baseline
Continue durvalumab and FPV-CV301                                                                 
Monitor LFTs weekly           
AST/ALT >3X ULN to <5X ULN with 
total bilirubin ≤ 2X ULN
HOLD durvalumab and FPV-CV301                                                                     
Monitor LFTs weekly                                                                                          
Restart durvalumab and FPV-CV301 if AST/ALT ≤3X ULN with total bilirubin ≤2X 
ULN       
AST/ALT >5X ULN with total bilirubin ≤ 
2X ULN
HOLD durvalumab and FPV-CV301                                                                     
Consider administering high dose IV steroids (e.g., methylprednisolone) for 24-48 
hours followed by prednisone 1-2 mg/kg/day (or equivalent) with taper over 1 
month; consider liver biopsy prior to initiation of steroids                                        
If LFTs do not decrease within 48 hours after initiation of systemic steroids, 
consider addition of an alternative immunosuppressive agent (e.g., mycophenolate 
or TNFa antagonist) to the corticosteroid regimen
Monitor LFTs every 48-72 hours until decreasing, and then follow weekly                
Restart durvalumab and FPV-CV301 if AST/ALT ≤3X ULN with total bilirubin ≤2X 
ULN                                                                                                                  
Permanently discontinue the durvalumab and FPV-CV301 for life threatening 
immune related hepatic events
AST/ALT > ULN with total bilirubin > 
2X ULN
HOLD durvalumab and FPV-CV301                                                                     
Consider administering high dose IV steroids (e.g., methylprednisolone) for 24-48 
hours followed by prednisone 1-2 mg/kg/day (or equivalent) with taper over 1 
month; consider liver biopsy prior to initiation of steroids                                        
If LFTs do not decrease within 48 hours after initiation of systemic steroids, 
consider addition of an alternative immunosuppressive agent (e.g., mycophenolate 
or TNFa antagonist) to the corticosteroid regimen
Monitor LFTs every 48-72 hours until decreasing, and then follow weekly                
Restart durvalumab and FPV-CV301 if AST/ALT ≤3X ULN with total bilirubin ≤2X 
ULN                                                                                                                  
Permanently discontinue the durvalumab and FPV-CV301 for life threatening 
immune related hepatic events


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CV301 should be permanently discontinued for life threatening immune-related dermatologic 
toxicity.  
5.12.3.6. Endocrine Toxicity 
Endocrine toxicity has been observed with immunomodulatory agents targeting the PD-
L1/PD-1 pathways, and is a potential risk of durvalumab. The risk of endocrine toxicity with 
the combination of durvalumab and CV301 is unknown.  
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental status 
changes, or constipation should be investigated for the presence of thyroid, pituitary, or 
adrenal endocrinopathies. An endocrinologist should be consulted if an endocrinopathy is 
suspected. 
TSH and free T4 levels should be obtained to determine whether thyroid abnormalities are 
present. TSH, prolactin, and a morning cortisol level will help to differentiate primary adrenal 
insufficiency from primary pituitary insufficiency. 
Patients who are found to have asymptomatic elevations in the TSH may continue the 
durvalumab and CV301, and be started on thyroid hormone replacement therapy.  If the 
hypothyroidism is symptomatic, the durvalumab and CV301 should be held, and thyroid 
hormone replacement therapy started until the TSH is normal, in which case the durvalumab 
and CV301 may be restarted.   
5.12.3.7. Ocular Toxicity 
Ocular toxicity has been observed with immunomodulatory agents targeting the PD-L1/PD-1 
pathways, and is a potential risk of durvalumab. The risk of ocular toxicity with the combination 
of durvalumab and CV301 is unknown.  
An ophthalmologist should evaluate ocular complaints with an examination of the conjunctiva, 
anterior and posterior chambers, and retina; visual field testing and an electroretinogram 
should also be performed. Uveitis or episcleritis may be treated with topical corticosteroid eye 
drops. Patients in the study are encouraged to maintain eye hydration, generally through the 
use of moisturizing eye drops.  In the event of symptomatic autoimmune uveitis, iritis, or 
episcleritis, the durvalumab and CV301 should be held until resolution of the autoimmune 
reaction (with topical steroids if necessary), in which case the durvalumab and CV301 may 
be restarted.  The durvalumab and CV301 should be permanently discontinued if topical 
therapy is insufficient for controlling the autoimmune opthamologic toxicities.  
5.12.3.8. Pulmonary Toxicity 
Pulmonary toxicity has been observed with immunomodulatory agents targeting the PD-
L1/PD-1 pathways, and is a potential risk of durvalumab. The risk of pulmonary toxicity with 
the combination of durvalumab and CV301 is unknown.  
Patients with known history of idiopathic pulmonary fibrosis, pneumonitis (including drug 
induced), organizing pneumonia, or evidence of active pneumonitis on screening chest CT 
scan will be excluded from the study.  
Patients will be assessed for pulmonary signs and symptoms such as dyspnea, cough, 
fatigue, and hypoxia throughout the study. Patients will also have CT scans of the chest at 
every tumor assessment and any new pulmonary infiltrates should be assessed. Workup of 
pulmonary adverse events may include, as appropriate:  
 
Measurement of oxygen saturation (i.e., arterial blood gas)  
 
High-resolution CT of the chest  
 
Bronchoscopy with bronchoalveolar lavage and biopsy  


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 
Pulmonary function testing (with diffusion capacity of lung carbon monoxide)  
 
Alternative causes of pulmonary adverse events (e.g., lymphangitic carcinomatosis, infection, 
heart failure, or chronic obstructive pulmonary disease) should be explored in parallel. 
Treatment should be dictated by clinical severity and may include administration of steroids 
and oxygen. Consultation with a pulmonologist is appropriate for a suspected lung immune-
related adverse events, and a biopsy should be strongly considered prior to the administration 
of steroids. 
Study treatment should be interrupted for patients who develop Grade ≥ 2 dyspnea or hypoxia, 
and a pulmonologist should be consulted before consideration of systemic steroids.  In 
addition, if the patient is being managed with corticosteroids, treatment should not be restarted 
until the steroids have been tapered off (i.e., to a prednisone dose ≤10 mg/day or equivalent). 
The durvalumab and CV301 should be permanently discontinued in the event of life-
threatening pulmonary toxicity. 
 
 
 
 
Table 8: Management of Pulmonary Toxicity 
 
 
 
Grade 1  (Asymptomatic, clinical or 
diagnostic, e.g. radiographic 
observations only, intervention not 
indicated)
Continue durvalumab and FPV-CV301                                                             
- Monitor and closely follow up in 2-4 days for clinical symptoms, pulse oximetry (resting and exertion) and laboratory work-
up and then as clinically indicated
- Consider pulmonary and  infectious disease consult
Grade 2  (Symptomatic, medical 
intervention indicated, limiting 
instrumental ADL) 
HOLD durvalumab and FPV-CV301 until grade 2 resolution to ≤ Grade 1
• If  toxicity worsens then treat as Grade 3 or Grade 4 
• If toxicity improves to baseline then the decision to reinitiate study drug/regimen at next scheduled treatment date will be 
based upon treating physician’s clinical judgment.                                                                                                              
- Monitor symptoms daily and consider hospitalization
- Promptly start systemic steroids (e.g., prednisone 1-2mg/kg/day or IV equivalent)
- Reimaging as clinically indicated
- If no improvement within 3-5 days, additional workup should be considered and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started 
- If still no improvement within 3-5 days despite IV methylprednisone at 2-4m4mg/kg/day, promptly start immunosuppressive 
therapy (infliximab at 5mg/kg every 2 weeks). Caution: Important to rule out sepsis and refer to infliximab label for general 
guidance before using infliximab 
- Once improving, gradually taper steroids over ≥4 weeks  and consider prophylactic antibiotics, antifungal or anti PCP 
treatment (refer to current  NCCN guidelines for treatment of  cancer-related infections (Category 2B recommendation)   
- Consider pulmonary and infectious disease consult
- Consider as necessary  discussing with study physician
Grade 3 or 4 
(Grade 3: Severe symptoms; limiting 
self-care ADL; oxygen indicated)          
(Grade 4: life threatening respiratory 
compromise, urgent intervention 
indicated [e.g. tracheostomy or 
intubation]) 
PERMANENTLY DISCONTINUE DURVALUMAB AND FPV-CV301                                                                                     
- Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or equivalent 
- Obtain pulmonary and infectious disease  consult
- Hospitalize the patient
- Supportive Care (oxygen, etc.)
- If no improvement within 3-5 days, additional workup should be considered and prompt treatment with additional 
immunosuppressive therapy infliximab at 5mg/kg every 2 weeks dose) started. Caution: rule out sepsis and refer to infliximab 
label for general guidance before using infliximab 
- Once improving, gradually taper steroids over ≥4 weeks  and consider prophylactic antibiotics, antifungals and in particular,  
anti PCP treatment (please refer to current  NCCN guidelines for treatment of  cancer-related infections


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6. MEASUREMENT OF EFFECT 
6.1. Assessment Parameters 
Response and progression will be evaluated in this study using RECIST 1.1 Criteria, as well as modified 
RECIST (both detailed below).  Response assessment data, disease control rate, PFS, and OS will be 
summarized for all patients with measurable disease by dose level or tumor type, when appropriate.  
Objective response is defined as a CR or PR, as determined by investigator assessment and confirmed 
by repeat assessment ≥ 4 weeks after initial documentation.  Patients with missing baseline or no 
additional response assessments will be classified as non-responders.  Among patients with an objective 
response, duration of objective response will be defined as the time from the initial complete or partial 
response to the time of disease progression or death, whichever occurs first. For patients who do not 
die or experience disease progression before the end of the study or who are lost to follow-up, duration 
of objective response will be censored at the day of the last tumor assessment.  PFS is defined as the 
time from the first day of study treatment (Week 1, Day 1) until documented disease progression or 
death, whichever occurs first. For patients who do not have documented progressive disease or death 
before the end of the study or who are lost to follow-up, PFS will be censored at the day of the last tumor 
assessment. OS is defined as the time from the first dose of study treatment to the time of death from 
any cause. For patients who do not die before the end of the study or who are lost to follow-up, OS will 
be censored at the date of last contact. 
6.1.1. Definitions 
Evaluable for toxicity:  Patients must have received at least one dose of CV301 and durvalumab to 
be assessable for toxicity.  Patients who are taken off study prior to receiving the first dose of 
durvalumab will need to be replaced. 
 
Evaluable for objective response:  Any patient who initiates study medications, and is taken off study 
prior to 8.5 months (colorectal cancer) or 4 months (pancreatic cancer) for disease progression or 
clinical progression, including death related to the underlying pancreatic or colorectal cancer (as 
determined by the treating oncologist) will be considered efficacy evaluable.  However, patients who 
have initiated study medications, and who withdraw from the study for any reason other than clinical 
or radiographic progression, or death believed related to their underlying pancreatic or colorectal 
cancer will not be considered evaluable for efficacy.  These patients will need to be replaced for the 
efficacy analysis.  Reasons for patients who have initiated study medications, but are no longer 
evaluable could include (but are not limited to): 
 
The patient cannot tolerate therapy despite dose modifications, and there is no evidence 
of clinical/radiographic disease progression at the time of stopping therapy 
 
An unexpected and/or unrelated medical illness, such as a stroke or myocardial infarction 
that is considered unrelated to the underlying pancreatic or colorectal cancer 
 
An unexpected trauma or death that is considered unrelated to the underlying pancreatic 
or colorectal cancer 
Patients will have their response classified according to the definitions stated below.  (Note:  Patients 
who exhibit objective disease progression prior to the end of week 8 will also be considered 
evaluable.) 
6.2. Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
6.2.1. Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques 
(CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 


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Note:  Previously irradiated lesions are non-measurable except in cases of documented progression 
of the lesion since the completion of radiation therapy. 
 
Malignant Lymph Nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan; or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, abdominal masses (not followed by CT or MRI), peritoneal 
carcinomatosis, and cystic lesions are all non-measurable. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be calculated 
and reported as the baseline sum LD.  The baseline sum LD will be used as reference by which to 
characterize the objective tumor response. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up. 
6.2.2. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred 
to evaluation by clinical examination when both methods have been used to assess the antitumor 
effect of a treatment. 
6.2.3. Response Criteria 
6.2.3.1. 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions, determined by two separate observations 
conducted not less than 4 weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD.  There can be no appearance of new lesions.  
Partial responses may be claimed if these criteria are met at a subsequent time point 
≥ 4 weeks later. 
 
 
 


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Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started, or the appearance of one or 
more new lesions. 
 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started. 
6.2.3.2. 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions 
6.2.3.3. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, 
some comments on detection of new lesions are important. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new 
lesion should be unequivocal, that is, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something 
other than tumor (for example, some “new” bone lesions may be simply healing or flare 
of preexisting lesions). This is particularly important when the patient’s baseline 
lesions show PR or CR. For example, necrosis of a liver lesion may be reported on a 
CT scan report as a “new” cystic lesion, which it is not.  
 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  
 
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan. 
6.2.4. RECIST 1.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
 
 
 
 
 
 
 


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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Response for this Category 
Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”.  Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
 
Table 9:  Response Evaluation.  Note: If subjects respond to treatment and are able to have their 
disease resected, the patient’s response will be assessed prior to the surgery. 
6.3. Modified Response Evaluation Criteria in Solid Tumors (RECIST) 
Conventional response criteria may not be adequate to characterize the anti-tumor activity of 
immunotherapeutic agents, which can produce delayed responses that may be preceded by initial 
apparent radiographic progression, including the appearance of new lesions. Therefore, modified 
response criteria have been developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment. Modified Response Evaluation 
Criteria in Solid Tumors (RECIST) is derived from RECIST, Version 1.1 (v1.1) conventions and immune-
related response criteria (irRC). When not otherwise specified, RECIST v1.1 conventions will apply. 
 
 
 
 
Table 10:  Differences Between RECIST 1.1 and Modified RECIST 
6.3.1. Impact of Non-target Lesion Response on Modified RECIST 
The assessment of non-target lesions will be captured at each timepoint using standard RECIST 1.1 
definitions of CR, non-CR/non-PD, and PD. However, in determining the overall modified RECIST 
tumor response, non-target lesions contribute only to the assessment of a complete response. Non-
target lesions are not considered in the overall definition of PR, SC, or PD per modified RECIST. 
RECIST 1.1 
Modified RECIST
New lesions after baseline
Define progression
New measurable lesions are added into 
the total tumor burden and followed.
Non-target lesions
May contribute to the designation of 
overall progression
Contribute only in the assessment of a 
complete response
Radiographic progression
First instance of ≥ 20% increase in the 
sum of diameters or unequivocal 
progression in non-target disease
Determined only on the basis of 
measurable disease; may be confirmed 
by a consecutive assessment ≥4 
weeks from the date first documented 


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6.3.2. Impact of New Lesions on Modified RECIST 
New lesions alone do not qualify as progressive disease. However, their contribution to total tumor 
burden is included in the sum of the diameters, which is used to determine the overall modified 
RECIST tumor response. 
6.4. Definition of Disease Progression 
Disease response/progression will be assessed according to RECIST 1.1, as detailed above.  However, 
RECIST 1.1 will be adapted to account for the potential of pseudoprogression, in which immune-mediated 
tumor infiltration may lead to an initial increase in the size of the tumors, and can lead to a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions.  Therefore, 
standard RECIST 1.1 criteria may not provide an accurate response assessment of immunotherapeutic 
agents such as durvalumab and CV301.   Therefore, for defining disease progression, RECIST 1.1 will 
be used with the following adaptations that take into account Modified RECIST, as detailed above: 
 
If radiologic imaging shows initial PD, as defined by RECIST 1.1, but patients are adequately tolerating 
therapy, patients may continue therapy until the next restaging while awaiting radiologic confirmation of 
progression.  The decision to continue therapy should be based on the subject’s overall clinical condition, 
including performance status, clinical symptoms, and laboratory data.  Subjects may receive treatment 
while waiting for confirmation of PD if they are clinically stable as defined by the following criteria: 
 
Absence of signs and symptoms indicating disease progression 
 
No decline in ECOG performance status 
 
Absence of rapid progression of disease 
 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent 
alternative medical intervention 
 
When feasible, subjects should not be discontinued until progression is confirmed.  Subjects that are 
deemed clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease: 
If repeat imaging shows a reduction in the tumor burden compared to the initial scan demonstrating PD, 
treatment may be continued.  If repeat imaging confirms progressive disease, subjects will be 
discontinued from study therapy.   
 
 


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7. STATISTICAL CONSIDERATIONS 
7.1. Study Design 
This is a dual arm, open label phase II study to evaluate the safety and clinical activity of the combination 
of durvalumab with CV301 for patients with metastatic colorectal or pancreatic cancer whose disease is 
stable on, or responding to 1st line therapy for metastatic disease.  Patients with metastatic colorectal or 
pancreatic adenocarcinoma who still have an adequate performance status and normal hepatic and 
renal function will be eligible. 
 
The trial will consist of two parallel Phase II trials – one for patients with metastatic colorectal cancer, 
and one for patients with metastatic pancreatic cancer (Figure 5). Patients will be seen every two weeks 
through eight weeks, and then routinely every 4 weeks thereafter for as long as the patient is on study.  
Adverse events will be monitored throughout the trial (safety tests will be performed every 2 weeks for 
the first 8 weeks, and then every 4 weeks thereafter) and graded in severity according to the guidelines 
outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.   
 
Restaging studies will be performed every 8 weeks (typically CT scans), by the calendar.  Patients 
whose tumors have not progressed at the time of restaging, and who continue to tolerate treatment will 
continue on study.   
 
The study is estimated to last 36 months.  Patient treatment will continue until disease progression, 
death, or until the physician or patient request removal from the study for any reason. 
7.2. Sample Size Considerations 
The trial will use a two-stage Simon Minimax Phase II design[6] in each arm.  All patients meeting the 
eligibility criteria who have signed a consent form, begun treatment, and are not lost to follow-up or who 
are not taken off study for reasons other than progression or death before 4 months for pancreatic cancer 
arm or 8.5 months for colorectal cancer arm will be considered evaluable for the 4-month PFS rate for 
pancreatic cancer arm or for the 8.5 month PFS rate for colorectal cancer arm.  We will assume a one-
sided alpha level of 0.05 and a power of 80% to test the null hypothesis of PFS rate is at most 50% vs. 
the alternative hypothesis of PFS rate at least 75% for each arm. In the first stage, 14 patients will be 
needed. If 7 or fewer of the 14 patients are alive and progression-free at 4 months, we will conclude that 
this treatment is insufficiently active in this population and terminate the study. If 8 or more of these 14 
patients are alive and progression-free at 4 months, we will continue the study to the second stage and 
accrue a total of 23 evaluable patients. If 15 or fewer of these 23 patients are alive and progression-free 
at 4 months, we will conclude that this treatment is insufficiently active in this population.  If 16 or more 
of these 23 patients are alive and progression-free at 4 months, this will be considered adequate 
evidence of efficacy of this treatment and may be recommended for further testing in subsequent 
studies.   Assuming a drop-out rate of 10%, a total of 26 patients for each arm will be accrued in the 
Phase II portion. 
7.3. Efficacy Endpoints 
7.3.1. Primary Endpoint 
The primary endpoints are the proportion of patients who are progression free at 4 month (PFS4mos) 
in the pancreatic cancer arm, and the 8.5 months PFS rate in the colorectal cancer arm. PFS is 
defined as the time from consenting to first disease progression event or death from any cause. 
7.3.2. Secondary Endpoints 
 
Median overall survival (mOS). OS is defined as the time from consenting until death from 
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 
Objective Response Rate (ORR). ORR is defined as the proportion of patients whose best 
overall response recorded during treatment is either CR or PR according to the RECIST 
version 1.1. 
o The duration of response will also be captured as the time from which a response was 
first identified, until progression of disease (or death due to any cause). 
 
Disease control rate (DCR). DCR is defined as the proportion of patients with a documented 
CR, PR, or SD at 4 months according to the RECIST version 1.1. 
 
Median progression-free survival (mPFS). PFS is defined as the time from consenting to 
determination of tumor progression by RECIST version 1.1 or death due to any cause, 
whichever occurs first. 
 
Change in tumor marker (CA 19-9 or CEA) Levels. Will be calculated as absolute change and 
percentage change from baseline at each assessment using RECIST 1.1 tumor response. 
7.3.3. Exploratory Endpoints 
 
Characteristics of the correlative markers in biopsy and peripheral blood samples 
7.4. Analysis Populations 
The safety population will consist of all subjects who receive at least 1 dose of durvalumab plus CV301 
in combination with maintenance capecitabine and bevacizumab (bevacizumab for the colon cancer 
patients).  
 
The full analysis population will be used primarily for the analysis of efficacy-related data and will include 
all subjects who receive at least one dose of durvalumab plus CV301 in combination with maintenance 
capecitabine and bevacizumab (bevacizumab for the colon cancer patients only). 
7.5. Analysis Plan 
 
7.5.1 Demographics Characteristics 
Descriptive summaries of demographic characteristics for all enrolled patients will be tabulated. Subjects 
will be tabulated by cancer type and overall. 
 
7.5.2 Safety Analysis 
Safety will be assessed by clinical review of all relevant parameters including adverse events, serious 
adverse events, laboratory values, vital signs and ECG values. Summary tables and listings will be 
provided for all reported treatment adverse event by grade,    
 
7.5.3 Efficacy Analysis 
We assume that the survival times (PFS and OS) follow exponential distributions.  
7.5.4 Analysis for the Primary Endpoint 
The Kaplan-Meier method will be used to estimate the PFS at 4 months for the pancreatic cancer arm, 
and the PFS at 8.5 month for the colorectal cancer arm, and the survival curves will be generated. The 
PFS rates and their corresponding 95% confidence intervals (CIs) will be presented. The hazard ratio of 
the PFS and its 95% CI will be presented using Cox regression model.  
7.5.5 Analysis for the Secondary Endpoints 
OS and PFS will be evaluated using Kaplan-Meier methods. The median OS and PFS and their 95% 
CIs will be reported and survival curves will be generated based on Kaplan-Meier estimates.  
 


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The percentage of subjects with OR and DC will be calculated for each treatment arm with their two-
sided 95% CI.  
7.5.6 Analysis for the Exploratory Endpoints 
The characteristics (high/low; present/absent; specific scoring) of the correlative markers from patient 
tumor samples and serum will be summarized descriptively by patient, and will take into account the 
visit/biopsy number. Changes in these characteristics between the pre-treatment collections, and the 
collections during treatment will be summarized using descriptive statistics.  
 
 


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8. Drug Information, Including Storage and Dispensation 
Capecitabine (and bevacizumab for colorectal cancer patients) must be obtained from commercial sources 
(i.e. they are not provided by the study). 
 
CV301 and durvalumab will be shipped to each individual site once a patient is enrolled.  Of note, CV301 will 
be distributed via our drug depot in Durham, NC.  Shipment to and vaccine storage at sites needs to be at -
20°C 
 
The order in which the drugs will be administered is based on the fact that the durvalumab can be associated 
with infusion reactions – whereas the risk of infusion/administration reaction with bevacizumab and CV301 
is extremely low.  The drugs should be administered: 
1) Capecitabine 1000mg PO BID weekly M-F will be ongoing oral administration and can be started 
at any time on the days of administration of the other agents 
2) Durvaluamab 
3) Bevacizumab 5mg/kg (Based on weight at screening unless 10% change) IV Q2weeks  
- 
Bevacizumab should be given IV over 60 minutes for the first two infusions, and then over 30 
minutes thereafter 
4) MVA-BN-CV301 (prime) - two priming doses of MVA-BN-CV301 which is given s.c. on Day 1 and 
Day 29. One dose of MVA-BN-CV301 consists of 4 injections of 4 X 108 Inf.U in 0.5mL (one in 
each arm, one in each leg). This results in a total administration of 1.6 x 109 Inf.U per dose.   
5) FPV-CV301 (boost) - One dose of FPV-CV301 consists of just one 0.5mL injection of at least 
1x109 Inf.U per 0.5 mL.  The vaccine will be injected subcutaneously into the thigh on Day 1 of 
Weeks 9, 13, 17, 21, 25, 37, and q24 weeks starting week 53.     
8.1. Durvalumab 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply durvalumab to the 
investigator as a 500-mg vial solution for infusion after dilution. 
 
8.1.1. Durvalumab Formulation, Packaging, and Storage 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after dilution. The 
solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0. The nominal fill volume is 
10 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Durvalumab must be used within the individually assigned expiry date on the label. 
8.1.2. Study Drug Preparation 
For patients weighing ≥ 30 kg, a fixed dose of 750 mg Q2W durvalumab (equivalent to 10 mg/kg 
Q2W) (based on an average body WT of 75 kg) should be prepared. For subjects <30 kg body 
weight, dose is determined using body mass.  For subjects <30 kg body weight, please contact the 
Study Chair or Co-chair 
8.1.3. Preparation of Durvalumab Doses for Administration with an IV Bag 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s designated 
IP manager using aseptic technique.  Total time from needle puncture of the durvalumab vial to the 
start of administration should not exceed:  
 
 
24 hours at 2°C to 8°C (36°F to 46°F) 
 
 
4 hours at room temperature 
 


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If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration. 
 
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. Dose of 750mg durvalumab for patients >30 kg will be administered using an IV bag 
containing 0.9% (w/v) saline with a final durvalumab concentration ranging from 1 to 20 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter.  
 
Remove a volume of IV solution from the IV bag equal to the calculated volume of durvalumab to be 
added to the IV bag prior to addition of durvalumab.  Next, the volume of durvalumab (ie, 15.0 mL for 
750 mg or 30.0 mL for 1500 mg of durvalumab) is added to the IV bag such that final concentration 
is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL).  Mix the bag by gently inverting to ensure 
homogeneity of the dose in the bag. 
 
Patient weight at baseline should be used for dosing calculations in patients ≤30 kg unless there is a 
≥10% change in weight.  Dosing day weight can be used for dosing calculations instead of baseline 
weight per institutional standard. 
 
Durvalumab will be administered at room temperature (approximately 25°C) by controlled infusion via 
an infusion pump into a peripheral or central vein. Following preparation of durvalumab, the entire 
contents of the IV bag should be administered as an IV infusion over approximately 60 minutes (±5 
minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 minutes is considered a deviation. 
 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) 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 and document if the line was 
not flushed. 
 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature.  The table below summarizes time allowances 
and temperatures. 
8.1.4. Monitoring of Dose Administration 
Subjects will be monitored before, during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessment. Subjects are monitored (pulse rate, blood pressure) 
every 30 minutes during the infusion period (including times where infusion rate is slowed or 
temporarily stopped). 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be decreased 
by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial 
rate until completion of the infusion.  For subjects with a ≤Grade 2 infusion-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. 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 4 hours at room temperature, with maximum total time at room temperature not 
exceeding 4 hours (otherwise requires new infusion preparation). 
 
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 


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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 subjects 
to an intensive care unit if necessary. 
 
8.2. CV301 
Please refer to the accompanying drug handbooks for CV301 preparation. 
 
8.2.1. MVA-BN-CV301  
MVA-mBN336B (common name MVA-BN-CV301 vaccine), is a liquid-frozen, highly 
attenuated, live recombinant virus based on the viral vector MVA-BN. It is administered as 
s.c. application. The packages and vials will be labeled according to the respective Product 
Specifications. 
One MVA-BN-CV301 vaccine vial has a nominal titer of 4 x 108 Inf. U in 0.5 mL of the drug 
product. The specific dose will be determined upon release testing of the drug product and 
the actual titer upon vaccination will be reported based on results from ongoing stability 
studies. 
One dose of MVA-BN-CV301 consists of 4 injections of 4 X 108 Infectious Units (Inf.U) in 
0.5mL (one in each arm, one in each leg). This results in a total administration of 1.6 x 109 
Inf.U per dose.   
For further details on MVA-BN-CV301 vaccine see current version of the CV301 Investigator’s 
Brochure. 
8.2.2. FPV-CV301 
 
FPV-mBN373B (common name FPV-CV301 vaccine), is a liquid-frozen, highly attenuated, 
live recombinant virus. It is administered as s.c. application. The packages and vials will be 
labeled according to the respective Product Specifications. 
 
One vaccine dose has a minimum virus titer of 1 x 109 Inf.U FPV-CV301 vaccine in 0.5 mL of 
the drug product. The specific dose will be determined upon release testing of the drug product 
and the actual titer upon vaccination will be reported based on results from the ongoing 
stability studies. 
 
One dose of FPV-CV301 consists of just one 0.5mL injection of at least 1x109 Inf.U per 0.5 
mL.  The vaccine will be injected subcutaneously into the thigh at each dosing timepoint. 
 
For further details on FPV-CV301 vaccine see current version of the CV301 Investigator’s 
Brochure. 
8.2.3. Patient Care Implications 
Patients should be monitored for 30 minutes after each dose for signs/symptoms of allergic 
reaction or anaphylaxis. Patients should monitor and report degree and duration of injection site 
reaction and flu-like symptoms. 
 
 
 


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9. Correlative Scientific Studies 
 
Please note: Details on collection and shipping, particularly details on the acquisition of supplies 
and the personnel involved are subject to change.  Thus, details on collection and shipping in 
the Lab Manual are to be considered the most updated (note the Version number and dates).   
 
Serial tumor biopsies will be taken before treatment and after 6 weeks.  The levels of immune-inhibitory 
proteins, including PD-1, PD-L1 (B7H1), B7H3, B7H4, IDO, and arginase will be measured in tumor 
tissue and their predictive value assessed.  The characteristics of the infiltrating T-cells in tumor samples 
will also be analyzed.  In addition, RPMA will be used for phopshoprotein analysis, and tumor samples 
will be grown ex vivo for additional scientific analyses. 
 
This trial will be conducted in conjunction with Dr. Jeffrey Schlom, Chief of the Laboratory of Tumor 
Immunology and Biology; Dr. James Gulley, Chief of the Genitourinary Malignancies Branch (Head, 
Immunotherapy Section) in the Center for Cancer Research, NCI, NIH; Dr. Emmanuel (Chip) Petricoin, 
III with his team at George Mason University; Dr. Jonathan Brody at Thomas Jefferson University; and 
Dr. Stephen Byers at Georgetown University. 
9.1. Tissue Prioritization 
Additional details are provided in Appendix C. 
 
9.1.1. Biopsy Tissue Utilization and Prioritization 
For the pre-treatment and 6 week biopsy, 6 individual cores will be obtained with an 18-20 gauge 
needle.  The cores will be prepared as follows (and as depicted in Appendix C): 
 
 
The first two cores (Correlative sample and phosphoprotein sample) should be placed 
INDIVIDUALLY in a single standard formalin vials and submitted to the Histopathology 
and Tissue Shared Resource (HTSR) to be processed into paraffin blocks.  The samples 
from these FFPE block should not be cut for an H&E analysis.  Rather, the block will be 
sent in batches to Dr. Schlom at the NIH (First core) and to George Mason University to 
Dr. Petricoin’s lab (second core) for laser capture microdissection of tumor epithelium and 
stroma for Reverse Phase Protein Microarray (RPPA) analysis. 
 
 
The next two cores (Correlative samples) should be placed INDIVIDUALLY in a single 
cryovials and snap frozen in liquid nitrogen, and stored at -80oC.  These frozen samples 
will be shipped in batches on dry ice to Dr. Schlom at the NIH. 
 
 
The fifth core (organoid sample) will be collected for organoids will be collected in pre-
supplied Eppendorf tubes containing Advanced DMEM/F12 (5mL) with Glutamax 1%, 
Pen/Strep 1%, and HEPES Buffer 1%.  Media will be sent to the sites in batches of 10 
upon request from Dr. Brody’s lab.  Samples will be collected, and shipped overnight on 
WET ice to Dr. Brody’s lab. 
 
 
The sixth core will be placed in a pre-provided Eppendorf tubes with CRC media with y-
compound.  This will be shipped on WET ice to the Shared Resources core, c/o Dr. 
Glasgow, at the Lombardi Cancer Center.   
9.1.2. Serial Blood Collection 
On week 1, Day 1, Weeks 9, 17, 49 and at the off study visit, 6 green top (Na heparin, 10 mL) tubes 
and 2 red serum separator (8 mL) tubes will be obtained.  Shipping details are provided in Appendix 
C.  
 


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9.1.3. Test Prioritization 
There are several correlative markers that will be tested.  We do not anticipate that there will be 
limitations in the samples from blood collection for the flow cytometry analyses or for the assessment 
of serum soluble factors and cytokine expression profiles.  The core biopsy sample collection 
prioritization is detailed above.  In the event that, from the first two cores to be sent to Dr. Schlom’s 
lab, there is insufficient biopsy tissue sample for testing, the following tests prioritization order will be 
followed (Highest priority is listed first): 
1) PD-1 
2) PD-L1 (Ventana assay with SP263 antibody) 
3) B7H3 
4) B7H4 
5) CD8 
6) CD4 
7) FOXPC 
8) IDO 
9) Arginase 
10) Characteristics of the infiltrating T-cells in tumor samples. 
9.2. Immune Correlates – Methodology 
9.2.1. Peripheral blood Antigen Specific T cell Immune Response 
Analysis of antigen-specific responses will be assessed by intracellular cytokine staining (ICS) 
following a period of in vitro stimulation with overlapping 15-mer peptide pools encoding the tumor-
associated antigens (TAAs) CEA, MUC-1, and brachyury. The TAA peptide pools have been 
designed to contain agonist epitopes that have been previously identified; [7-9] peptide pools 
encoding for HLA and CEFT (a mixture of CMV, EBV, Flu, and Tetanus toxin) will serve as negative 
and positive controls, respectively. Peptide mixes will be purchased from JPT (Berlin, Germany), 
reconstituted in DMSO, and utilized immediately. Cryopreserved PBMC from patients before therapy 
and at specified time points will be thawed and rested overnight at 37oC, 5% CO2 in complete media 
(IMDM supplemented with 10% Human AB, 2mM glutamine, 100 units/ml penicillin, and 100 μg/ml 
streptomycin). The next day (Day 0), PBMC will be seeded in 12 well plates (2.5 x106 in 1 mL), and 
stimulated with peptide mixes (0.1μg/mL per peptide); cultures will be supplemented on days 3 and 
5 with cytokines (IL7 and IL15, 10 ng/mL, PeproTech, Rocky Hill, NJ) and fresh media, and on day 7 
will be rested (with removal of cytokines and peptide). On day 11, 1x106 cells will be restimulated for 
24 hours in 96 well plates with peptide mixes in the presence of anti-CD107a-APC (clone H4A3, BD 
Biosciences); brefeldin A (1μl/mL) and monensin (0.7μl/mL) (BD Biosciences) will be added to 
cultures 2 hours after the start of the restimulation and incubated for the final 22 hours. PBMC will 
then be stained with anti-CD4-PerCP-Cy5.5 (clone OKT4, Biolegend), anti-CD8-AF700 (clone OKT8, 
Ebioscience), and anti-TNF-PE (clone MAb11), anti-IFNg-PE-Cy7 (clone 4SB3), and anti-IL-2-BV521 
(clone 5344.111) (BD Biosciences).  
 
For all flow cytometry experiments, at least 3x105 events in the live gate will be acquired with a BD 
LSR-II flow cytometer equipped with a UV, violet, blue, and red laser. FCS files will be imported and 
analyzed with FlowJo V.9.7 for Macintosh (TreeStar, Ashland, OR). Fluorescence minus one (FMO) 
controls will be used for gating, and non-viable cells will be excluded. For ICS experiments, the 
absolute number of CD4+ or CD8+ lymphocytes producing cytokine or positive for CD107a will be 
calculated per 1x106 cells plated at the start of the in vitro stimulation (IVS) [10]. The background 
signal (obtained with the HLA peptide pool), and values obtained prior to therapy will be subtracted 
from those obtained post-therapy. Values >250 will be scored as positive for TAA-specific immune 
response following therapy. 
 


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9.2.2. Peripheral Blood Mononuclear Cell Subset Analysis 
Multicolor flow cytometry will be performed on frozen peripheral blood mononuclear cells (PBMC) as 
previously described [11]. Staining will be performed using 5 panels (Appendix D, table 1) to identify 
markers involved in PD-1 signaling (Appendix D, table 2, panel 1), CD4+ T cells, CD8+ T cells, and 
B cells (Appendix D, table 2, panel 2), Tregs (Appendix D, table 2, panel 3), NKs, NK-T, cDCs, and 
pDCs (Appendix D, table 2, panel 4), and MDSCs (Appendix D, table 2, panel 5). These panels will 
identify a total of 123 peripheral immune cell subsets (Appendix D, Table 3), which include 9 parental 
immune cell types and 114 subsets relating to maturation and function within the parental types. 
Optimal amounts of antibodies for staining were determined by previous titration experiments. Briefly, 
1 million PBMCs per test will be incubated for 15 minutes at 4°C with 2 µL of human TruStain FcX 
(Biolegend, San Diego, CA) and Live Dead Fixable Stain Blue (Invitrogen, Waltham, MA). Surface 
antibodies will be added for 30 minutes at 4°C. Cells will then be washed, permeabilized (eBioscience, 
San Diego, CA), and stained with intracellular antibodies for 30 minutes at room temperature. 
Samples will be acquired on an LSRII flow cytometer (BD Biosciences, San Jose, CA) equipped with 
a UV, violet, blue, and red laser, and analyzed using FlowJo V9.7 for Macintosh (Treestar, Ashland, 
OR). The gating strategy will identify 123 peripheral immune cell subsets, with non-viable cells 
excluded, and negative gates set based on fluorescence minus one controls. All values will be 
reported as % of PBMCs in order to help eliminate the bias that could occur in the smaller populations 
with fluctuations in leukocyte subpopulations [12]. 
9.2.3. Serum Cytokine and Soluble Factor Analysis 
Serum cytokines and soluble factors related to immune regulation will be analyzed using standard 
ELISA kits for soluble factors, as previously described [13] and cytokines (available via the Inglefield 
Laboratory, NCI, Frederick using the MesoScale platform (Rockville, MD), V-plex kit).  
9.2.4. T Cell Clonal Expansion Assay 
cDNA from PBMC will be amplified using locus specific primers for TCR-β.  Previously described 
methods will be used to map the V region and identify the J region [14] and identify clonal sequences 
of interest. Analytics tools will be used to sort and identify clonal populations of interest in the post- 
versus pre-treatment samples.  Correlation of expansion of a clonal TCR population post treatment 
will be correlated with clinical outcomes. 
9.2.5. Tumor Immunohistochemistry Analysis 
We will employ digital immunohistochemistry using MAbs anti-PD-1, anti-PD-L1  (Ventana assay with 
SP263 antibody), anti-B7H3, and anti-B7H4 along with isotype control MAbs to examine the extent 
of immune infiltrate in any biopsies collected before treatment and prior to the 2nd dosing of CV301 
with durvalumab [86]. We will also employ anti-CD8, anti-CD4, and anti-FOXPC MAbs. 
9.2.6. Measurements of Serum Indoleamine 2,3-dioxygenase (IDO) 
Tryptophan is catabolized by IDO to N-formylkynurenine which is rapidly converted to kynurenine. 
Measurement of serum levels of kynurenine and tryptophan can provide evidence of functional IDO 
activity. Because kynurenine can be further metabolized to downstream products, this assay is not 
entirely quantitative, but the ratio of tryptophan/kynurenine can provide a relative indication of IDO 
functional activity. Serum samples from patient taken before treatment and prior to the 2nd dosing of 
CV301 with durvalumab will be analyzed for kynurenine and tryptophan levels by HPLC. HPLC will 
be performed according to the method described by Yong, et al [15]. 
9.2.7. Immunohistochemistry for Detection of IDO in Tissue Samples 
Immunohistochemical staining will be performed on 10% formalin fixed, paraffin-embedded tissue 
sections (4 μm). After deparaffinization and rehydration, the sections will be treated with 0.3% 
hydrogen peroxide and incubated with 10% bovine serum albumin to block nonspecific staining. The 
sections will be incubated for 15 minutes at 37°C with proteinase for antigen-retrieval. The sections 


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will be incubated at room temperature with anti-IDO monoclonal antibody. The sections will then be 
rinsed and incubated with the biotinylated second antibody. After washing, the sections will be 
incubated with horseradish peroxidase-conjugated streptavidin, and finally treated with 3,3’ 
diaminobenzidine tetrahydrochloride. The slides will counter stain with Meyer’s Hematoxylin [16]. 
 
Double immunohistochemical analysis for the detection of CD3+ T-cells in the IDO-stained tissue 
sections will also be performed using mouse anti-CD3 monoclonal antibodies.  
 
Analyses will be done on biopsies taken before treatment and after 6 weeks on therapy with CV301 
with durvalumab. 
9.2.8. Measurements of Serum Arginase-1 
Arginase is a hydrolase mostly found in liver. It catalyzes the amino acid L-arginine to ornithine and 
urea. There are two isoforms of arginases, cytoplasmic arginase I and mitochondrial arginase II. 
Myeloid-derived suppressor cells (MDSC) expressing arginase I deplete L-arginine and profoundly 
inhibit T-cell functions. Increased levels of MDSC on cancer patients correlated with low L-arginase 
and high ornithine levels in plasma and T-cell dysfunction. 
 
Serum level of arginase I will be determined by two assays. (a) ELISA kit (BioVendor) using 
monoclonal antibody to arginase [17] and (b) The function of arginase will be determined by 
measuring the serum levels of L-arginase and L-ornithine by HPLC [18].  These analyses will be done 
on samples taken before treatment and after 8 weeks on therapy with CV301 with durvalumab. 
9.2.9. Immunohistochemistry for Detection of Arginase-1 in Tissue Samples 
Four μm thick sections of the formalin-fixed paraffin-embedded tissue will be stained with polyclonal 
antibody against arginase I. Double immunohistochemical analysis for the detection of MDSC 
(CD11b+/CD14- and CD11b+/CD14+) MDSC in the arginase stained tissue sections will also be 
performed [19]. 
9.2.10. Reverse Phase Protein Microarray (RPPA) 
The Reverse Phase Protein Microarray (RPPA) technology has been developed to address the 
analytical challenges of the sandwich and forward phase protein arrays (e.g. mismatch of sandwich 
antibody affinity, imprecision within and between analytes, and poor sensitivity).  The platform has 
been designed to enable non-subjective, quantitative, multiplexed analysis of specific forms of cellular 
proteins (e.g. phosphorylated, unphosphorylated, and cleaved) from a limited amount of starting 
sample, such as with a fine needle aspirate or laser capture microdissected (LCM) cellular material 
to procure pure populations of the target cells of interest. Particularly suited for clinical tissue samples, 
RPPA uses a single antibody directed against the epitope of interest When coupled to LCM, the 
RPPA technology can be used to quantifiably measure multiplexed protein phosphorylation changes 
and total proteins in selected cellular niche (e.g. epithelium and stroma/immune infiltrates). 
 
A key attribute of the RPPA is the ability to quantitatively measure hundreds of signaling proteins 
concomitantly from only a few thousand cells, thus providing a critical means of broad-scale cell 
signaling analysis directly from tissue samples, cell culture models, and animal tissues from pre-
clinical studies. The RPPA technology, invented in the lab of Drs. Liotta and Petricoin at George 
Mason University and now optimized for routine clinical sample analysis [20-27], is currently being 
employed within the CAP/CLIA complaint proteomics laboratory within the Center for Applied 
Proteomics and Molecular Medicine at George Mason University. No other technology can measure 
the activity of as many signaling proteins at once from such small amounts of input material. 
 
A selection of peer-reviewed publications contains extensive detailed description of the basic core 
components RPPA methodology [20-27]. The RPPA format immobilizes an individual test sample in 
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Each array is incubated with a single primary antibody and a single analyte end point is measured.  
Since RPPAs maintain the concentration of the input sample, the sensitivity is greater as compared 
with a forward phase, (e.g. antibody array) probed with the same small number of input cells. 
 
With the RPPA technology, serial dilutions are printed of each sample, control or standard, to maintain 
sample concentration.  Each spot contains a bait zone measuring only a few hundred microns in 
diameter.  The detection probe can be tagged and signal amplified independently from the 
immobilized analyte protein.  Coupling the detection antibody with highly sensitive amplification 
systems can yield detection sensitivities to fewer than 1,000 to 5,000 molecules per spot with good 
linearity (correlation coefficient or R2 = 0.990-0.999) and inter-experiment precision (R2= 0.973).  
Between run and within run analytical precision is between a 3-13% CV (coefficient of variation). 
 
The RPPA technology has been developed and optimized for performance as a fluorescent-based 
calibrated assay, generally identical in design and analysis to standard ELISA or standard clinical 
immunoassays. As a calibrated assay, each assay consists of: 
 
a. Experimental patient samples printed in triplicate two-spot dilutions (neat and 1:4) 
b. High, medium, and low controls printed in triplicate two-spot dilutions (neat and 1:4) 
c. A calibrator, consisting of a 6-10-point curve whereby the analyte of interest is decreasing 
in concentration in the background of a constant protein concentration that spans the 
dynamic range of the analyte in the actual clinical specimen 
 
The analyte concentration is thereby determined by extrapolation to a non-parametrically determined 
curve fit of the calibration curve and reported in relative fluorescent units (Figure 5, below) 
 
Figure 5. Illustrated schematic of a typical RPPA slide configuration 
9.2.10.1. Sample Preparation for Microarray 
In order to prepare the sample for arraying, proteins are extracted from the LCM polymer cap 
as a whole cell lysate using a heated sodium dodecyl sulfate-based lysing solution which 
produces a denatured lysate suspended in the sample/extraction buffer.  The optimal 
extraction buffer for extracting proteins from tissue cells that have been procured by LCM, 
with the purpose of performing reverse phase protein arrays, consists of a detergent, 
denaturing agent and buffer.  This buffer is an efficient denaturing extraction buffer for the 


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extraction and solubilization of cellular proteins from fixed and frozen tissue. An array layout 
grid is used to determine exact placement of sample and control cell lysates on the printed 
microarray. Cell lysate solutions for each sample, of a known volume and concentration are 
loaded into 384 well microtiter plates.  Microtiter plates are specifically labeled and loaded into 
the well plate hotel in the correct order.  The RPPA uses slides coated with nitrocellulose.  
This type of slide is chosen for its high binding capacity, high surface area, minimum effect on 
protein structure, and intrinsically low background signal.  For the printing run, up to 100 slides, 
(10 slides/platen and 10 platens within the Substrate Hotel), can be loaded into the Aushon 
2470 Arrayer at a time. 
9.2.10.2. Array Preparation 
The Aushon 2470 Arrayer has a general software program to manage the printing process.  
The program enables customization of array printing, with parameters such as top and left 
offset of printing, depositions/feature, slide lot number, number of replicates, dwell time for 
pins, total number of immersions, maximum number of extractions and wash sequences. 
9.2.10.3. Calibration of Values 
Each array contains a printed calibrator(s), a series of cell lystates derived from cells treated 
with a variety of mitogens such that broad pathway activation has been achieved. The 
calibrator(s) will consist of 6 – 10 dilutions of whole cell lysates from stimulated and 
unstimulated cells (eg. HeLa cells treated and untreated with pervandate for 30 minutes; jurkat 
cells treated and untreated with calyculin for 30 minutes; A431 cells treated and untreated 
with EGF for 30 minutes) pre-mixed in various ratios such that the total protein in any spot 
does not change, but the phospho-analyte changes in a predictable and defined 
concentration.   Another type of calibrator can be prepared by spiking-in known amounts of 
recombinant protein or peptides that correspond to the target analyte and react specifically 
with antibodies directed to the target protein into a lystate that does not contain the target 
analyte. We print the EXACT SAME CALIBRATOR ON EVERY SINGLE SLIDE. The defining 
characteristic of this calibrator is that protein concentration does not vary but staining intensity 
does. Much like a clinical assay run in a diagnostic laboratory, each experimental value is 
extrapolated to a non-parametric curve fit of the calibrator within he region that span the 
dynamic range of the population such that results can be compared over time and across 
arrays. The calibrator is defined either in absolute amounts (if the analyte concentration is 
known), or in relative units (RUs) if the absolute amount of the analyte within the calibrator is 
not known. Most applications will use RU calibration units.  
9.2.10.4. Data Normalization 
Each protein analyte value is normalized to the total amount of protein printed on that spot by 
first incubated the slide with a florescent stain (Sypro Ruby Blot Stain, Molecular Probes, 
Eugene OR) that binds to proteins without bias and does not interfere with subsequent 
antibody binding. The protein loading value is also obtained by a calibrated assay technique. 
ON EVERY SLIDE WE PRINT A PROTIEN CALIBRATION CURVE OF THE EXACT SAME 
SAMPLE ON EVERY SINGLE SLIDE. This total protein calibrator consists of a protein lysate, 
which upon dilution, spans the linear dynamic range of protein concentration. Each sample 
value is then extrapolated to the calibrator. Consequently, while the total amount of protein 
may vary in any given sample compared to each other- thus affecting phopsho-protein 
measurements for each sample, this variance is greatly minimized by such a normalization 
procedure. 
9.2.10.5. Blocking Procedure 
Once arrays have been printed and stained for total protein, slides undergo a blocking 
procedure.  Casein based solutions provide a uniform protein solution capable of binding to 
non antigenic sites on nylon, PVDF and nitrocellulose membranes.  Casein blocks these sites, 


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inhibiting binding of antibody.  This results in reduced background staining for reverse phase 
protein arrays.  
9.2.10.6. Staining and Image Acquisition 
Arrays are probed using an antibody specific for the phospho-protein, or any protein analyte. 
Our current repertoire consists of over 350 phopshoproteins that have been extensively pre-
validated for specificity using Western blotting and peptide competition.  A Dako Cytomation 
Autostainer (FDA approved for the HercepTest) is used to perform the staining procedure.  
This includes the processes of incubation with primary antibody, specific for the analyte of 
interest as well as incubation with secondary antibody.  A signal is generated using a near-IR 
fluorescent dye (LICOR Biosciences) that is coupled to the secondary antibody. The current 
iteration of the RPPA uses a fluorometric image capture processing system (e.g. NovaRay, 
Alpha Innotech) for image acquisition.  The system measures the sample’s fluorescence 
intensity value, subtracts the background, normalizes the result to the total protein, and 
extrapolates the value to the non-parametrically fit calibration curve to generate a final 
intensity value. The median of the triplicate values is reported. 
9.2.10.7. Correlation of Calibrated Values with Clinical Outcomes 
Final calibrated values of patient samples are then correlated with outcomes results 
(discontinuous variables (alive v dead, long v short survival), or continuous variables (overall 
survival, disease free survival, time to progression, etc). These values are usually reported in 
days, weeks or months. Statistical analysis is used for the correlative findings. Parametric 
(e.g, Student t-test) or non-parametric (e.g. Wilcoxon Rank Sum) of mean comparison is used, 
Kaplan Meir and ROC curves are used to uncover relationships between continuous clinical 
variables and continuous calibrated values. Optimally, any optimal cutpoint found by such 
analysis should be tested in independent study sets using ROC and or KM type analysis.  
9.2.11. Ex Vivo Models 
9.2.11.1. Organoids 
Organoid models will be generated at Thomas Jefferson University using the method 
previously described by Huch et al. and Boj et al[87, 88]. Our gastroenterologists, via 
endoscopic ultrasound, will obtain de-identified core biopsy samples of metastatic pancreas 
tumor. Tumor tissue will be minced and digested with collagenase II in culture media at 37°C 
for 16 hours. Culture media will be composed of AdDMEM, F12 supplemented with HEPES, 
Glutamax, penicillin/streptomycin, B27, Primocin, N-acetyl-L-cysteine, RSPO1-conditioned 
medium, Noggin, EGF, Gastrin, FGF, Nicotinamide, and A83-01. The tissue will be further 
digested with TrypLE at 37°C for 15 min. It will then be embedded in GFR Matrigel and 
cultured in culture media versus various treatment conditions. Organoids will be grown in 
Matrigel for up to one week and then subject to genomic and proteomic evaluation to assess 
response to treatment.  
9.2.11.1.1. Detailed Methodology 
Organoid models will be generated at Thomas Jefferson University using the method 
previously described by Boj et al and Huch et al. [87, 88] One core of tumor tissue will 
be minced and digested with collagenase II in culture media at 37°C for 16 hours. 
Culture media will be composed of AdDMEM, F12 supplemented with HEPES, 
Glutamax, penicillin/streptomycin, B27, Primocin, N-acetyl-L-cysteine, RSPO1-
conditioned medium, Noggin, EGF, Gastrin, FGF, Nicotinamide, and A83-01. The 
tissue will be further digested with TrypLE at 37°C for 15 min. It will then be embedded 
in GFR Matrigel and cultured in culture media versus various treatment conditions. 


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Organoids will be grown in Matrigel for up to one week and then subject to genomic 
and proteomic evaluation to assess response to treatment. 
9.2.11.1.2. Shipping Details 
Biopsy samples collected for organoids will be collected in pre-supplied Eppendorf 
tubes containing CRC media and y-compound, and shipped overnight on ice to: 
Dr. Jonathan Brody and Joe Cozzitorto  
Curtis 618 
1015 Walnut Street 
Philadelphia, PA 19106 
9.2.11.2. Zebrafish Ex-vivo Avatars 
9.2.11.2.1. Introduction 
Testing of therapeutic agents in patient-derived primary (or metastatic) tumor 
xenografts (PDX) in nude mice is generally considered the most reliable and 
convincing demonstration of drug efficacy in pre-clinical models. Advantages include 
the high efficiency of tumor take and the remarkable genotypic and phenotypic 
resemblance to the tumor from which the xenograft was derived. However, 
disadvantages, which include the necessity for large amounts of tissue, expense and 
the length of time required to carry out the analyses prohibit PDX in mice as a viable 
method for large-scale drug testing in a personalized medicine setting. Data from 
Georgetown and other institutions have shown that zebrafish embryos and even adult 
immuno-compromised zebrafish are excellent hosts for xenografts derived from 
cultured human tumor cells and are also well suited for drug screening. Our preliminary 
studies used fresh and cryopreserved pancreatic tumor tissue isolated from seven 
patients to show that it is possible to simultaneously prepare tumor tissue for zebrafish 
xenografts (Zevatars), conditional immortalization as well as for collection of 
pancreatic stellate cells (PSCs) (Table 11). Creation of CRCs and Zevatars was 
successful in every case and PSCs have been isolated from the earlier collections-we 
are awaiting results for those patients collected more recently as PSCs take longer to 
establish. The PSCs we have characterized express cadherin-11, a marker for 
activated PSCs. In this protocol, we will use the zebrafish embryo as a host for 
xenografts of cryopreserved fragments of tumor tissue obtained directly from patient 
biopsies. Preliminary work shows that hundreds, and potentially thousands of embryos 
bearing living xenografts can be prepared from a single cryopreserved patient 
specimen in a few hours. As a likely, though not yet defined aim of this protocol, the 
large number of replicates should allow for testing of many drugs in a PDX setting in 
a few days. 
 
 


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ID 
Date 
CRC Fresh CRC Cryo 
Zevatar fresh (n) 
Zevatar Cryo (n) 
PSC 
1A1340 2/27/15 Established No, all went 
for Zevatars 
Yes (9) other pieces 
too large 
Yes (80) 
Yes 
1A1386 5/8/15 
In culture 
Yes 
Yes (41) 
TBD 
No 
1A1390 5/15/15 Established Yes 
Yes (41) 
TBD 
Yes but 
contaminated 
1A1395 5/21/15 In culture 
Yes 
Yes (74) 
TBD 
Unknown 
1A1399 5/22/15 Established Yes 
Yes (76) 
TBD 
Yes 
1A1400 5/26/15 In culture 
Yes 
Yes (26) 
TBD 
Unknown 
1A1408 6/4/15 
In culture 
Yes 
ND 
TBD 
Yes 
 
Table 11. Outcome from 7/10 PDAC specimens collected by Indivumed-Georgetown (February-
June 2015). Three additional specimens have been approved for collection by our Biospecimen Use 
Committee but have yet to be processed. Some CRCs have grown sufficiently that we have 
cryopreserved a large number of cells (established). Others are still being expanded in culture. Up to 80 
Zevatars were prepared but with assistance it is quite likely that several hundred replicates can be 
obtained from a single patient specimen. ND-not done: TBD to be determined 
9.2.11.2.2. Detailed Methodology 
Importantly, the zebrafish xenograft studies only need a small amount of tissue.  The 
patient tissue will be processed as soon as it arrives in the core lab and minced into 
1-3 mm cubes. To perform patient derived zevatar experiments, zebrafish embryos 
will injected with small tissue fragments 48 hours post fertilization of the zebrafish.  The 
tissue will be further fragmented with forceps or digested briefly with collagenase to 
partially dissociate the cellular components. For visualization of the implanted 
samples, the cells will be labeled with CM-diI CellTracker fluorescent probes from 
Invitrogen and implanted into zebrafish embryos. Sample implantation and metastases 
will be monitored by fluorescence microscopy. Imaging will occur within 12 hours 
following implantation in order to capture initial conditions. At this time, embryos that 
are not successfully implanted will be removed from the study. The embryos will be 
imaged again at 2 days post-implantation. Imaging will be performed on an Olympus 
IX-71 inverted microscope with a color CCD camera. The images will be processed 
using Image J. 
 
Following tumor implantation, the embryos will be arrayed into 96-well plates where 
each embryo containing an implant will be imaged. We will capture a bright-field or 
phase image as well as green fluorescent and red fluorescent images. The red 
fluorescent image will show the labeled tumor implant. The green fluorescent image 
shows the vasculature since we will use kdrl:GFP transgenic embryos. This enables 
more accurate localization of the implant and any movement of tumor cells within the 
embryo. Finally, the bright-field/phase image ensures we have captured the correct 
focal plane and enhances our ability to evaluate the health and orientation of the 
embryos. 
 
The viability of the tumor cells following preparation and labeling as well as post 
implantation will be determined by fixing and embedding tumor fragments and 
embryos for histopathology and immunohistochemical analysis. The embryos will be 
fixed in 4% paraformaldehyde overnight, washed, dehydrated to 70% ethanol, and 
then taken to HTSR for embedding and sectioning. At this point they can be treated 
like any other histopathology specimen. Success rates for implanted versus injected 
cells will be evaluated in terms of cellular behaviors and the viability of the implanted 
or injected cells. Further, we will identify the cell types in the implanted tumors, as well 
as those that survive, grow and migrate within the embryo. Unlike mouse xenografts 
or cultured cells, zebrafish xenograft assays directly measure the behavior of the 


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implanted cells in real time. In the case of tumor xenografts, multiple cell types along 
with stroma are present, including components of the immune system. Thus, it is 
important have an understanding of what cells are being implanted and which cells 
are surviving, growing, migrating and metastasizing in this assay. 
9.2.11.2.3. Sample Collection and Shipping Details 
The zebrafish xenograft studies only need a small amount of tissue. Therefore, a single 
biopsy core will placed in a cryovial containing CRC medium.  Unused vials will be 
shipped to a site on ice when a patient is enrolled in the protocol, prior to the biopsy.  
The patient samples in the cryovial will be placed on WET ice and shipped out 
immediately by overnight express to: 
 
 
Dr. Glasgow's lab 
 
 
Suite 343, Building D 
 
 
Georgetown University Medical Center 
 
 
Washington D.C. 20057 
 
 


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10. 
ETHICAL CONSIDERATIONS AND STUDY MANAGMENT 
This study will be conducted in compliance with the protocol, GCP, HIPAA and all applicable regulatory 
requirements: 
 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting trials that involve human patients. Compliance with this standard 
provides public assurance that the rights, safety, and wellbeing of trial patients are protected; consistent with 
the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. 
For detailed information on Investigator’s and Sponsor’s obligation see www.fda.gov/oc/gcp/ and 
www.ich.org/ 
10.1. Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by 
their local institution.  All investigators will follow the conflict of interest policy of their local institution. 
10.2. Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations.  The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study 
and will be given the opportunity to review the consent form. Each consent form must include all the 
relevant elements currently required by the FDA Regulations and local or state regulations. Once this 
essential information has been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
10.3. Required Documentation 
Before the study can be initiated at any site, the following documentation must be provided to the 
Research Office: 
 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
CVs and medical licensure for the principal investigator and any associate investigators who will 
be involved in the study 
 
A copy of the IRB-approved consent form 
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Executed clinical research contract 
10.4. Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 


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Government agency regulations and directives require that all study documentation pertaining to the 
conduct of a clinical trial must be retained by the study investigator.  In the case of a study with a drug 
seeking regulatory approval and marketing, these documents shall be retained for at least two years 
after the last approval of marketing application in an International Conference on Harmonization (ICH) 
region.  In all other cases, study documents should be kept on file until three years after the completion 
and final study report of this investigational study. 
10.5. Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  The Principal Investigator 
is responsible for personally overseeing the treatment of all study patients.  The Principal Investigator 
must assure that all study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be reviewed 
by the Principal Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 


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prostate cancer patients: immune correlates. Cancer immunology, immunotherapy : CII, 2014. 63(4): p. 
407-418. 
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(bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC). ASCO Meeting 
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Hannani, D., et al., Prerequisites for the antitumor vaccine-like effect of chemotherapy and 
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2010. 140(6): p. 798-804. 
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Liu, C., et al., BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity 
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Zhang, S., et al., Fixed dosing versus body size-based dosing of therapeutic peptides and proteins in 
adults. J Clin Pharmacol, 2012. 52(1): p. 18-28. 
83. 
Wang, D.D., et al., Fixed dosing versus body size-based dosing of monoclonal antibodies in adult 
clinical trials. J Clin Pharmacol, 2009. 49(9): p. 1012-24. 
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pharmacokinetic analysis. Pharm Res, 2006. 23(6): p. 1275-84. 
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Farsaci, B., et al., Identification by digital immunohistochemistry of intratumoral changes of immune 
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12. APPENDICES 
APPENDIX A: STUDY ELIGIBILITY CHECKLIST 
A Phase II Trial of the PD-L1 Inhibitor, Durvalumab plus CV301 as Maintenance Therapy for 
Patients with Metastatic Colorectal or Pancreatic Adenocarcinoma 
Patient Initials: _________  Study ID: _________ 
Instructions: This form and all supporting documentation should be completed by the research staff and faxed to the Lombardi QAO 
at 202-687-9361 or scanned/emailed to lcccqao@georgetown.edu. 
□Georgetown University Medical Center 
 
   
□Emory University   
 
 
□Mayo Clinic 
 
□ MD Anderson 
□ Other: _________________________________________ 
 
KEY INCLUSION CRITERIA (ALL ITEMS MUST BE CHECKED YES) 
YES | NO 
 
□ | □ 
Histologically proven pancreatic adenocarcinoma or colorectal with radiographically measurable disease 
 
□ | □ 
Actively on first line therapy for metastatic pancreatic or colorectal adenocarcinoma 
A. 
Stable on, or responding to 1st line therapy for metastatic disease: 
B. 
Stable or responding disease at least 8 and not more than 16 weeks after initiating 1st line therapy for metastatic 
disease. Due to the timing of enrollment, patients who have completed a maximum of 16 weeks of 1st line 
chemotherapy may be enrolled >16 weeks after initiation of 1st line therapy if disease stability/response (without 
additional intervening therapy) can be documented within 4 weeks prior to first dose of CV301 
C. 
Prior adjuvant chemotherapy is allowed, as long as a minimum of 3 months (for pancreatic cancer) and 6 months (for 
colorectal cancer) has passed between the completion of adjuvant therapy and the start of first line therapy 
□ | □ 
Biopsy accessible tumor deposits (as can best be determined by imaging) – A patient’s biopsied lesion must be at least 1cm in 
diameter (in at least one dimension) 
□ | □ 
Age ≥ 18 years 
□ | □ 
□ | □ 
ECOG performance status 0 or 1 (see Table 12 below) 
 
Blood Pressure <160/100 mmHg 
□ | □ 
Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment AND 
confirmed prior to initiation of treatment on Day 1, and/or postmenopausal women must be amenorrheic for at least 12 months to 
be considered of non-childbearing potential. 
□ | □ 
Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the 
informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific 
procedures 
□ | □ 
 
□ | □ 
Patients must have fully recovered from all effects of surgery.  Patients must have had at least two weeks after minor surgery and 
four weeks after major surgery before starting therapy.  Minor procedures requiring “Twilight” sedation such as endoscopies, tumor 
biopsies, or mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator. 
 
Life expectancy > 12 weeks 
 
CRITICAL LAB VALUES (ALL MUST BE CHECKED YES) 
YES | NO 
 
□ | □ 
Absolute neutrophil count (ANC) ≥ 1,500/mm3 
□ | □ 
Platelets ≥ 100,000/mm3 
□ | □ 
Hemoglobin ≥ 9.0 g/dL 
□ | □ 
Serum creatinine ≤ 1.5 X the upper limit of normal of the institution’s normal range OR creatinine clearance ≥ 40 mL/min/1.73 m2 
for subjects with creatinine level above the upper limit of normal 
□ | □ 
AST, ALT, and alkaline phosphatase ≤ 2.5 X the upper limit of normal of the institution’s normal range. For patients with known 
hepatic metastases, AST and ALT ≤ 5 X the upper normal limit of institution's normal range  
□ | □ 
Bilirubin ≤ 1.5 X the upper limit of normal of the institution’s normal range 
□ | □ 
Prothrombin Time and Partial Thromboplastin Time (PTT) ≤ 1.5 X the upper limit of the institution’s normal range 
□ | □ 
INR (International Normalized Ratio) < 1.5, subjects on anticoagulation will be permitted as long as the INR is in an acceptable 
therapeutic range as determined by the investigator 
 
 
 


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CRITICAL EXCLUSION CRITERIA (ELIGIBLE PATIENTS MUST ALL BE CHECKED NO)  
□ | □ 
Prior vaccine or immunotherapy OR prior solid organ transplant 
□ | □ 
History of autoimmune disease or prior bone marrow transplant OR treatment with immunosuppressive medications 
□ | □ 
History of pulmonary fibrosis OR inflammatory bowel disease 
□ | □ 
Positive test for HIV; or active hepatitis B or C, or tuberculosis 
□ | □ 
Recent severe infections, or actively on antibiotics 
□ | □ 
Live, attenuated vaccine within 4 weeks 
□ | □ 
Allergic/hypersensitivity reaction to antibodies 
□ | □ 
Anti-cancer therapy within 2 weeks 
□ | □ 
The subject has had another active malignancy within the past five years except for cervical cancer in situ, in situ carcinoma of the bladder 
or non-melanoma carcinoma of the skin. Questions regarding the inclusion of individual subjects should be directed to the Study Chair 
□ | □ 
CNS Metastases (if yes, see details in inclusion/exclusion) 
□ | □ 
QTc ≥470ms on EKG 
□ | □ 
Grade ≥2 proteinuria 
□ | □ 
Patient is receiving any other investigational agents 
□ | □ 
Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, 
stroke, or congestive heart failure within the last 6 months 
□ | □ 
Life-threatening visceral disease or other severe concurrent disease 
□ | □ 
Woman who is pregnant or breast feeding 
□ | □ 
□ | □ 
 
Subjects with uncontrolled seizures 
 
History of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab or any excipient or any 
egg products 
□ | □ 
 
□ | □ 
 
Anticipated survival under 2months 
 
Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements 
 
 
 
 
 
Table 12: ECOG Performance Status Scale (Repeated) 
 
 
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade


Version 2.4 01-Oct2019 
 
 
 
115 
 
 
APPENDIX B: PATIENT REGISTRATION FORM 
A Phase II Trial of the PD-L1 Inhibitor, Durvalumab plus CV301 as Maintenance Therapy for Patients with Metastatic 
Colorectal or Pancreatic Adenocarcinoma 
 
Patient Initials: _________  Study ID (IRB#): _________ 
 
Instructions: This form and all supporting documentation should be completed by the research staff and faxed to the Lombardi QAO 
at 202-687-9361 or scanned/emailed to lcccqao@georgetown.edu. 
 
Enrolling site: 
□ Georgetown University Medical Center 
 
   
□ Emory University   
 
 
□ Mayo Clinic 
 
 
□ MD Anderson  
□ Other:_________________________________________ 
  
1. Site PI: _________________________________________  
2. Enrolling MD: ____________________________________  
3. Date Informed Consent signed: ___/___/______  
4. Date HIPAA authorization signed: ___/___/_____  
5. Proposed Start date for Treatment: ___/____/______  
6. Treatment Location: ___________________________________  
7. Date of last chemotherapy: ___/____/_____  
8. Prior antineoplastic therapy- ie. Cytotoxic, Cytokine base immunotherapy, immunoregulatory antibody therapy, radiation 
(Date/Type): 
____________________________________________________________________________________________________________
____________________________________________________________________________________________________________
_____________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
  
9. Please fax documentation supporting eligibility per protocol (Check those included):  
 
□ 
Pathology Report 
□ 
Physicians Note validating: 
 
 
▪Previous treatments 
□ 
CT showing RECIST 1.1 criteria 
□ 
Laboratory Results 
□ 
Past Medical History 
 
ON-STUDY CARD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOR QAO USE ONLY: 
Subject Study ID: _________________________________ 
Comments: 
 
STUDY NUMBER:_________________ 
DOB: ____/_____/______ 
Zip Code: __________________ 
Race: 
□ African American 
 
□ Asian 
 
□ Caucasian 
 
□ Hispanic 
 
□ Native American 
 
□ Pacific Islander 
 
□ Other 
 
□ Unknown 
 
Gender:   □ Male  □ Female   □ Unknown 
Treating Physician: __________________ 
RN: _______________________________ 
Ethnicity: □ Hispanic or Latino 
 
□ Not Hispanic or Latino 
             
□ Unknown 
Consent Approval Date:   ___/____/________ 
Screen Failure:      □ Yes    □ No 
Baseline Start Date:  ____/____/________ 
On Study Date:   ____/____/________ 
 
Protocol Waiver:   □ Yes    □ No 
 
Reason: _______________________ 
Registration Site:  _______________ 
First Scheduled Date: ____/____/________ 
Primary Site:________________________ 


Version 2.4 01-Oct2019 
 
 
 
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APPENDIX C SAMPLE COLLECTION AND SHIPPING INFORMATION 
Tissue Prioritization Schema 
 
 
 
Instructions for Collection and Shipping of Research Samples 
Please note: for all shipping, a Georgetown FedEx Account Number will be supplied 
 
1) Labeling of Blood Samples 
Research specimens will be de-identified and labeled with a 14 character study label (AA-X-
XX-XX-X-MM/DD/YY): 
o The first two characters will be the patient’s initials 
o The third character will be the site number from which the patient was enrolled (single digit) 
 
1 = Georgetown 
 
2 = Mayo Clinic 
 
3 = Emory University 
o The fourth and fifth characters will be the patient study number (e.g. 01, 02, 03, etc.) 
o The sixth and seventh characters will be the correlative technique (two digit) 
 
01 = NIH Formalin 
 
02 = George Mason RPPA 
 
03 = NIH Frozen 
 
04 = TJU Organoids 
 
05 = Lombardi Zebrafish 
 06= Blood collection: Serum and PBMC 
 
Additional numbers can be added as needed for future research samples 
o The eighth character will be the timing of collection 
 
1 = Pre-treatment biopsy/sample 


Version 2.4 01-Oct2019 
 
 
 
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 
2 = On treatment biopsy/sample 
 
3 = Serum collection 
o The final characters will be the date in MM/DD/YY format 
 
 
Example:  AA-1-01–01-1-10/14/18 
 
 
 
Protocol: 2017-1189 
 
2) Tumor Biopsy Samples 
 
a) Supplies 
For the trial, the individual sites will supply the following:  
- 
Wet and dry ice (typically available on site) 
- 
Green top (Na heparin, 10 mL) tubes  
- 
Red serum separator (8 mL) tubes  
 
Additionally, the site will order the following supplies directly from VWR: 
 
 
Finally, the following materials will need to be sent to the participating sites upon request and stored.  
The first batch will be shipped upon request once a patient has been consented. 
 
i) Organoid Media 
- 
Biopsy samples collected for organoids will be collected in pre-supplied Eppendorf tubes 
containing Advanced DMEM/F12 (5mL) with Glutamax 1%, Pen/Strep 1%, and HEPES Buffer 
1%.  Media will be sent to the sites in batches of 5 upon request from Dr. Brody’s lab.   
- 
To be sent to the sites in batches of 5 
- 
Sent to the sites upon request from Dr. Brody’s lab 
- 
Please contact Dr. Brody for a shipment - jonathan.brody@jefferson.edu 
- 
Store at 4oC  
- 
Each batch expires after 1 month 
 
ii) Zebrafish (CRC) Media 
- 
Biopsy samples will placed in a cryovial containing CRC medium + y-compound 
- 
Vials will be shipped to the sites in batches of 5, upon request from Dr. Glasgow’s Lab 
- 
Please contact Shaila Mudambi for a shipment - sm3468@georgetown.edu  
- 
Store at 4oC  
- 
Each batch expires after 1 month 
 
b) Collection Details (Tumor samples) 
i) 
Formalin samples (First two cores) 
- 
The first two cores (Correlative sample and phosphoprotein sample) should be placed 
INDIVIDUALLY in a single standard formalin vials and submitted to histopathology for paraffin 
embedding 
- 
The samples do NOT require surgical pathology assessment.   
- 
The samples from these FFPE blocks should not be cut for an H&E analysis.   
Item
Details
Catalog #
Price
EHS Combo Shipping System
Case of 2
10029-406
$53.34 
Cat B Ambient 95kPa Bag, 6-Tube
Case of 16
10029-264
$66.20 
Corning Cryovial tube Round-Bottom (2mL) , Self-Standing
Case of 500
66021-974
$372.39 
Prefilled 10% Neutral Buffered Formalin
Case of 48 (40ml) 16004-115
$74.70 
Disposable forceps 121 mm (43/4")
Pack of 100
12576-934
$200.42 


Version 2.4 01-Oct2019 
 
 
 
118 
 
ii) 
Frozen Samples (Third and fourth core) 
- 
The next two cores should be placed INDIVIDUALLY in a single cryovials and snap frozen in 
liquid nitrogen, and stored at -80oC.   
iii) 
Organoid Samples (Fifth core) 
-  The fifth core (organoid sample) will be collected in pre-supplied Eppendorf tubes containing 
Advanced DMEM/F12 (5mL) with Glutamax 1%, Pen/Strep 1%, and HEPES Buffer 1%.   
iv) 
Zebrafish Samples (Sixth core) 
- 
The sixth core will be placed in a pre-provided Eppendorf tubes with CRC media with y-
compound.   
 
c) Shipping Details (Tumor samples) 
i) Formalin samples (First core) 
- 
FFPEs of the first cores (Correlative sample) can be sent in protective wrapping in batches 
to: 
Leidos 
Biomedical Research 
Attn: Bill Kopp/Theresa Burks 
1050 Boyles Street 
Bldg. 469/Room 121 
Frederick, MD 21702 
Phone 301-846-5125, or 301-846-1707 
- 
Please notify the Frederick laboratory when specimens are being shipped. Please email 
Frederick prior to shipping to notify the lab. 
- 
Emails should be sent to the following individuals: 
Bill Kopp, koppw@mail.nih.gov 
Theresa Burks, burkst@mail.nih.gov 
Caroline Jochems, jochemscm@mail.nih.gov 
Michael Pishvaian, pishvaim@georgetown.edu 
- 
Additionally, NO specimens should be shipped on Fridays or the day before a Federal holiday.   
 
ii)  Formalin samples (Second core) 
- 
FFPEs of the second cores (Phosphoprotein sample) can be sent in protective wrapping in 
batches to: 
 
 
 
 
 
 
Emanuel F Petricoin, PhD 
  
 
 
 
University Professor 
  
 
 
 
Co-Director Center for Applied Proteomics and Molecular Medicine 
  
 
 
 
School of Systems Biology 
  
 
 
 
George Mason University  
  
 
 
 
10920 George Mason Circle 
  
 
 
 
Room 2006 Institute of Advanced Biomedical Research 
  
 
 
 
Manassas, VA 20110 
- 
Please notify Dr. Petricoin’s laboratory when specimens are being shipped. Please email Dr. 
Petricoin prior to shipping to notify the lab. 
- 
Emails should be sent to the following individuals: 
  
 
Chip Petricoin epetrico@gmu.edu 
- 
Additionally, NO specimens should be shipped on Fridays or the day before a Federal holiday.   
 
iii) Frozen cores can be sent by overnight shipping ON DRY ICE in batches to: 
- 
Please notify the Frederick laboratory when specimens are being shipped. Please email 
Frederick prior to shipping to notify the lab. 
- 
Emails should be sent to the following individuals: 
 
 
 
 
Bill Kopp, koppw@mail.nih.gov 
 
 
 
 
Theresa Burks, burkst@mail.nih.gov 


Version 2.4 01-Oct2019 
 
 
 
119 
 
 
 
 
 
Caroline Jochems, jochemscm@mail.nih.gov 
 
 
 
 
Michael Pishvaian, pishvaim@georgetown.edu 
- 
Additionally, NO specimens should be shipped on Fridays or the day before a Federal holiday.   
 
 
iv) Organoid Samples can be sent on WET ICE immediately to: 
Dr. Jonathan Brody and Joe Cozzitorto  
Immediate attention 
Curtis 618 
1015 Walnut Street 
Philadelphia, PA 19106 
- 
Please notify Dr. Brody when specimens are being shipped. Please email Dr. Brody prior to 
shipping to notify the lab. 
- 
Emails should be sent to the following individuals: 
  
 
Jonathan Brody jonathan.brody@jefferson.edu 
  
 
Henry Thomsett henry.thomsett@jefferson.edu 
  
 
Monique Maubert monique.maubert@jefferson.edu  
- 
Additionally, NO specimens should be shipped on Fridays or the day before a Federal holiday.   
 
v) Zebrafish Samples can be sent on WET ICE immediately to: 
Dr. Glasgow's lab 
Suite 343, Building D 
Georgetown University Medical Center 
Washington D.C. 20057 
- 
Please notify Dr. Glasgow when specimens are being shipped. Please email Dr. Glasgow 
prior to shipping to notify the lab. 
- 
Emails should be sent to the following individuals: 
  
 
Eric Glasgow eg239@georgetown.edu 
  
 
Shaila Mudambi sm3468@georgetown.edu 
  
 
Steve Byers byerss@georgetown.edu 
  
 
Michael Pishvaian pishvaim@georgetown.edu 
- 
Additionally, NO specimens should be shipped on Fridays or the day before a Federal holiday.   
 
d) Blood Samples 
i. 
Collection: 
- 
6 green top (Na heparin, 10 mL) tubes  
- 
2 red serum separator (8 mL) tubes  
ii. Timing - Blood is collected at the following timepoints:  
- 
On the first treatment day (Week 1, CV301 alone) 
-  Week 9 
-  Week 17 
-  Week 49 
-  At the off study visit 
 
 
 
 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
120 
 
iii. Shipping: 
- 
Blood samples are to be sent on the day of draw by overnight shipping (ambient 
temperature) to: 
Leidos 
Biomedical Research 
Attn: Bill Kopp/Theresa Burks 
1050 Boyles Street 
Bldg. 469/Room 121 
Frederick, MD 21702 
Phone 301-846-5125, or 301-846-1707 
- 
Please notify the Frederick laboratory when specimens are being shipped. Please email 
Frederick prior to shipping to notify the lab. 
- 
Emails should be sent to the following individuals: 
 
 
 
 
Bill Kopp, koppw@mail.nih.gov 
 
 
 
 
Theresa Burks, burkst@mail.nih.gov 
 
 
 
 
Caroline Jochems, jochemscm@mail.nih.gov 
 
 
 
 
Michael Pishvaian, pishvaim@georgetown.edu 
- 
Additionally, NO specimens should be shipped on Fridays or the day before a Federal holiday.   
 
 
 
 


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APPENDIX D FLOW CYTOMETRY ASSAYS 
Table 13. Flow Cytometry Markers.  Flow cytometry analysis of parental immune cell types in PBMCs using 
30 unique markers to identify 123 subsets  
 
 
 
 
 
 
 
 
 
 


Version 2.4 01-Oct2019 
 
 
 
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Table 14. Antibodies used for 5 panel stain to identify 123 peripheral immune cell subsets. Panel 1: PD-
1 signaling; Panel 2: CD4+ T cells, CD8+ T cells, B cells; Panel 3: Tregs; Panel 4: NK, NK-T, cDC, pDC; Panel 
5: MDSC. Intracellular antibodies are underlined, and clones and company are listed under each antibody. 
 
  
 
 
 


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Table 15. Complete list of 123 peripheral immune cell subsets analyzed by flow cytometry. Nine 
standard subsets were identified as well as 114 subsets relating to maturation and function within the standard 
subsets. 
 
 
 
 


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Appendix E. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions for Durvalumab 
 
Immune-Mediated Reactions 
 
Dose Modifications 
Toxicity Management 
Immune-
related 
Adverse 
Events 
(Overall 
Manage-
ment For 
toxicities 
not noted 
below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration modifications of study 
drug/study regimen will be made to manage 
potential immune-related AEs based on severity of 
treatment-emergent toxicities graded per NCI 
CTCAE v4.03. 
 
In addition to the criteria for permanent 
discontinuation of study drug/regimen based on 
CTC grade/severity (table below) , permanently 
discontinue study drug/study regimen for  the 
following conditions:  
 
Inability to reduce corticosteroid to a dose of 
≤10 mg of prednisone per day (or 
equivalent) within 12 weeks after last dose 
of study drug/regimen 
 
Recurrence of a previously experienced 
Grade 3 treatment-related AE following 
resumption of dosing. 
It is recommended that management of irAEs follow 
the guidelines presented in this table 
- 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
concomitant medications, infections, etc.) 
- 
In the absence of a clear alternative etiology, all 
events should be considered potentially immune 
related. 
- 
Symptomatic and topical therapy should be 
considered for low-grade (Grade 1 or 2, unless 
otherwise specified) events  
- 
For persistent  (greater than 3 to 5 days) low-grade 
(Grade 2)  or severe (Grade ≥3) events  promptly 
start prednisone PO 1-2mg/kg/day or IV equivalent  
- 
If symptoms recur or worsen during corticosteroid 
tapering 28 days of taper), increase the 
corticosteroid dose (prednisone dose  [e.g. up to 2-
4mg/kg/day or IV equivalent])   until stabilization or 
improvement of symptoms, then resume 
corticosteroid tapering at a slower rate (> 28 days 
of taper) 
- 
More potent immunosuppressives such as TNF 
inhibitors (e.g. infliximab) – (also refer to the 
individual sections of the immune related adverse 
event for specific type of immunosuppressive) 
should be considered for events not responding to 
systemic steroids.   
- 
Discontinuation of study drug is not mandated for 
Grade 3 / Grade 4 inflammatory reactions 
attributed to local tumour response (e.g. 
inflammatory reaction at sites of metastatic 
disease, lymph nodes etc.). Continuation of study 
drug in this situation should be based upon a 
benefit/risk analysis for that patient  
 
 
 
 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1 
• 
If toxicity worsens then treat as Grade 
3 or Grade 4 
• 
Study drug/study treatment can be 
resumed once event stabilizes to 
Grade ≤1  after completion of steroid 
taper 
• 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement can be retreated 
with study drug/study regimen on the 
following conditions: 1) the event 
stabilizes and is controlled , 2) the 
patient is clinically stable as per 
Investigator or treating physician’s 
clinical judgement, and 3) doses of 
prednisone are at less than or equal 
to 10mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, may 
permanently discontinue study 
drug/study regimen. Please refer to 
guidelines below 
Grade 4 
Permanently discontinue study 
drug/study regimen  
Note:  For Grade 3 and above asymptomatic amylase 
or lipase levels hold study drug/regimen and if 
complete work up shows no evidence of pancreatitis, 
may continue or resume study drug/regimen 
 


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 Appendix E. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Pneumo-
nitis/ILD 
Grade of 
Pneumonitis 
(CTCAE 
version 4.03)  
General Guidance 
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 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), laboratory 
work-up and high-resolution CT scan.  
Grade 1  
(Asymptomati
c, clinical or 
diagnostic 
observations 
only, 
intervention 
not indicated) 
No dose modification 
required. However, 
consider holding study 
drug/study regimen 
dosing as clinically 
appropriate and during 
diagnostic work-up for 
other etiologies 
For Grade 1 (Radiographic Changes Only) 
-   Monitor and closely follow up in 2-4 days for clinical 
symptoms, pulse oximetry (resting and exertion) and 
laboratory work-up and then as clinically indicated 
-   Consider pulmonary and  infectious disease consult 
Grade 2  
(Symptomatic, 
medical 
intervention 
indicated, 
limiting 
instrumental 
ADL)  
Hold study drug/study 
regimen dose until grade 
2 resolution to ≤ Grade 1 
• 
If  toxicity worsens 
then treat as Grade 3 
or Grade 4  
• 
If toxicity improves to    
≤ Grade 1 baseline 
then the decision to 
reinitiate study 
drug/regimen at next 
scheduled treatment 
date will be based 
upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper   
For Grade 2 (Mild to Moderate New Symptoms) 
- 
Monitor symptoms daily and consider hospitalization 
- 
Promptly start systemic steroids (e.g., prednisone 1-
2mg/kg/day PO or IV equivalent) 
- 
Reimaging as clinically indicated 
- 
If no improvement within 3-5 days, additional workup should 
be considered and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started  
- 
If still no improvement within 3-5 days despite IV 
methylprednisone at 2-4/g/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors (e.g. 
infliximab at 5mg/kg every 2 weeks). Caution: Important to 
rule out sepsis and refer to infliximab label for general 
guidance before using infliximab  
- 
Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungal or anti PCP 
treatment (refer to current  NCCN guidelines for treatment 
of  cancer-related infections (Category 2B 
recommendation)iii1 
- 
Consider pulmonary and infectious disease consult 
- 
Consider as necessary  discussing with study physician 
                                                 
1 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking 
Antibody Side Effects”  


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 Appendix E. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4  
(Grade 3: 
Severe 
symptoms; 
limiting self-
care ADL; 
oxygen 
indicated;  
 
Grade 4: life 
threatening 
respiratory 
compromise, 
urgent 
intervention 
indicated [e.g. 
tracheostomy 
or intubation])  
Permanently discontinue 
study drug/study regimen 
 
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life threatening  
- 
Promptly initiate empiric IV methylprednisolone 1 to 4 
mg/kg/day or equivalent  
- 
Obtain pulmonary and infectious disease  consult 
- 
Hospitalize the patient 
- 
Supportive Care (oxygen, etc.) 
- 
If no improvement within 3-5 days, additional workup should 
be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors (e.g. 
infliximab at 5mg/kg every 2 weeks dose) started. Caution: 
rule out sepsis and refer to infliximab label for general 
guidance before using infliximab  
- 
Once improving, gradually taper steroids over ≥28 days  
and consider prophylactic antibiotics, antifungals and in 
particular,  anti PCP treatment (please refer to current  
NCCN guidelines for treatment of  cancer-related infections 
(Category 2B recommendation)iii 
Diarrhea/ 
Entero-
colitis 
Grade of 
Diarrhea 
(CTCAE 
version 4.03) 
General Guidance 
- 
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) 
- 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, infections including testing for clostridium 
difficile toxin,  etc.) 
- 
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 
- 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis 
Grade 1 
diarrhea  
(stool 
frequency of 
<4 over 
baseline per 
day)  
No dose modification 
For Grade 1 diarrhea :  
-      Close monitoring for worsening symptoms 
-      Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use of 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
diarrhea (stool 
frequency of 
4-6 over 
baseline per 
day)  
Hold study drug/study 
regimen until resolution to 
≤ Grade 1 
• 
If  toxicity worsens 
then treat as Grade 
3/Grade 4 
• 
If toxicity improves to  
≤ Grade 1, then study  
drug/study regimen 
can be resumed after 
completion of steroid 
taper  
For Grade 2 diarrhea:  
- 
Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide  
- 
Promptly start  prednisone 1 to 2  mg/kg/day PO or IV 
equivalent  
- 
If event is not responsive within 3-5 days or worsens 
despite prednisone at 1-2 mg/kg/day PO or IV equivalent, 
GI consult should be obtained for consideration of further 
workup such as imaging and/or colonoscopy to confirm 
colitis and rule out perforation,   and prompt treatment with 
IV methylprednisolone 2-4mg/kg/day started.  


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Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
- 
If still no improvement within 3-5 days despite 2-4mg/kg IV 
methylprednisolone, promptly start  immunosuppressives 
such as  (infliximab at 5mg/kg once every 2 weeks2). . 
Caution: Important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab   
- 
Consult study physician if no resolution to ≤ Grade 1 in 3-4 
days 
- 
Once improving, gradually taper steroids over ≥28 days  
and consider prophylactic antibiotics, antifungals and anti 
PCP treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
Grade 3 or 4 
diarrhea  
 
(Grade 3: 
stool 
frequency of 
≥7 over 
baseline per 
day;  
 
Grade 4: life 
threatening 
conse-
quences) 
Permanently discontinue 
study drug/study regimen 
For Grade 3 or 4 diarrhea: 
- 
Promptly initiate empiric IV methylprednisolone 2 to 4 
mg/kg/day or equivalent  
- 
Monitor stool frequency and volume and maintain hydration   
- 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate 
- 
If still no improvement within 3-5 days of IV 
methylprednisolone  2 to 4mg/kg/day or equivalent, 
promptly start further immunosuppressives (e.g. infliximab 
at 5mg/kg once every 2 weeks).   
- 
Caution: Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before using 
infliximab.  
- 
Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
Hepatitis 
(Elevated 
LFTs) 
Infliximab 
should not 
be used for 
manageme
nt of 
Immune 
Related 
Hepatitis 
Grade of Liver 
Function Test 
Elevation 
(CTCAE 
version 4.03) 
Any Grade 
  
- 
Monitor and evaluate liver function test: AST, ALT, ALP and 
total bilirubin  
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications)  
Grade 1  
(AST or ALT > 
ULN to 3 
times ULN 
and/or TB > 
ULN to 1.5 
times ULN) 
No dose modification 
If  it worsens, treat as 
Grade 2 event 
For Grade 1 AST or ALT and/or TB elevation        
  -     Continue LFT monitoring per protocol   
                                                 
2 ASCO Educational Book 2015 Michael Postow MD “Managing Immune Checkpoint Blocking 
Antibody Side Effects   


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Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 2  
(AST or ALT > 
3 to 5 times 
ULN and/or 
TB >1.5-3.0 
times ULN) 
Hold Study drug/study 
regimen dose until grade 
2 resolution to ≤ Grade 1 
If  toxicity worsens then 
treat as Grade 3 or Grade 
4 
• If toxicity improves to  
≤ Grade 1 or baseline, 
resume  study drug/study 
regimen after completion 
of steroid taper 
For Grade 2 AST or ALT and or TB elevation :  
- 
Regular and frequent checking of LFTs (e.g. every 1-2 
days) until elevations of these are improving or resolved.   
- 
If no resolution to ≤ Grade 1 in 1-2 days, discuss with study 
physician. 
- 
If event is persistent (> 3-5 days) or worsens, promptly start 
prednisone 1-2mg/kg/day PO or IV equivalent.  
- 
If still no improvement within 3-5 days despite 1-2mg/kg/day 
of prednisone PO or IV equivalent, consider additional 
workup and prompt treatment with IV methylprednisolone 2-
4mg/kg/day started. 
- 
If still no improvement within 3-5 days despite 2-4mg/kg/day 
of IV methylprednisolone, promptly start 
immunosuppressives (mycophenolate mofetil). Discuss with 
study physician if mycophenolate mofetil is not available.  
Infliximab should NOT be used. 
- 
Once improving, gradually taper steroids over ≥28 days  
and consider prophylactic antibiotics, antifungals and anti 
PCP treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
Grade 3 
(AST or ALT 
>5-20 times 
ULN and/or 
TB > 3.0-10 
times ULN 
For elevations in 
transaminases ≤ 8 × ULN, 
or elevations in bilirubin ≤ 
5 × ULN  
• 
Hold study drug/study 
regimen dose until 
resolution to ≤ Grade 
1 or baseline   
• 
Resume study 
drug/study regimen 
administration at the 
next scheduled dose 
if elevations 
downgrade ≤ Grade 1 
or baseline within 14 
days and after 
completion of steroid 
taper 
Permanently discontinue 
study drug/study regimen 
if the elevations do not 
downgrade to ≤ Grade 1 
or baseline within 14 days  
 
For elevations in 
transaminases > 8 × ULN 
or elevations in bilirubin > 
5 × ULN, discontinue 
study drug/study regimen  
 
Permanently discontinue 
study drug/study regimen 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
- 
Promptly initiate empiric IV methylprednisolone at 1 to 4 
mg/kg/day or equivalent  
- 
If still no improvement within 3-5 days despite 1 to 4 
mg/kg/day methylprednisolone IV or equivalent , promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil)  Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
- 
Hepatology consult, abdominal workup, and imaging as 
appropriate. 
- 
Once improving, gradually taper steroids over ≥28 days  
and consider prophylactic antibiotics, antifungals and anti 
PCP treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 


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Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
for any case meeting Hy’s 
law criteria (ALT > 3x 
ULN + bilirubin > 2x ULN 
without initial findings of 
cholestasis (i.e. elevated 
alkaline P04) and  in the 
absence of any 
alternative cause 
Grade 4  
(AST or ALT > 
20 times ULN 
and/or TB > 
10 times ULN)  
Permanently discontinue 
study drug/study regimen  
Nephritis or 
Renal 
Dysfunction 
(Elevated 
Serum 
Creatinine)  
Grade of 
Elevated 
Serum 
Creatinine 
(CTCAE 
version 4.03) 
 
Any Grade  
General Guidance 
 
 
 
- 
Consult with Nephrologist 
- 
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.) 
- 
Steroids should be considered in the absence of clear 
alternative etiology even for low grade events (Grade 2) , in 
order to prevent potential progression to higher grade event 
Grade 1 
[Serum 
Creatinine > 1-
1.5X baseline;  
> ULN to 1.5X 
ULN]  
No dose modification 
For Grade 1 elevated creatinine:  
-      Monitor serum creatinine weekly and any accompanying 
symptom 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If it worsens, depending on the severity , treat as Grade 
2 or Grade 3 or 4  
-      Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc. 
Grade 2 
[Serum 
Creatinine>1.5
-3.0X 
baseline; 
>1.5X-
3.0XULN] 
Hold study drug/study 
regimen until resolution to 
≤ Grade 1 or baseline 
• 
If  toxicity worsens 
then treat as Grade 3 
or Grade 4 
• 
If toxicity improves to 
≤ Grade 1 or baseline 
then resume study 
drug/study regimen 
after completion of 
steroid taper 
For Grade 2 elevated creatinine:  
- 
Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc.  
- 
Carefully monitor serum creatinine  every 2-3 days and as 
clinically warranted 
- 
Consult Nephrologist and consider renal biopsy if clinically 
indicated 
- 
If event is persistent (> 3-5 days) or worsens,  promptly start  
prednisone 1 to 2 mg/kg/day PO or IV equivalent  
- 
If event is not responsive within 3-5 days or worsens 
despite prednisone at 1-2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt 
treatment with IV methylprednisolone at 2-4mg/kg/day 
started.  


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Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
- 
Once improving gradually taper steroids over ≥28 days and   
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).  
- 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4  
(Grade 3:  
Serum 
Creatinine > 
3.0 X 
baseline; >3.0-
6.0 X ULN 
 
Grade 4: 
Serum 
Creatinine > 
6.0 X ULN)  
Permanently discontinue 
study drug/study regimen 
- 
Carefully monitor serum creatinine  on  daily basis 
- 
Consult Nephrologist and consider renal biopsy if clinically 
indicated 
- 
Promptly  start  prednisone 1 to 2  mg/kg/day PO or IV 
equivalent  
- 
If event is not responsive within 3-5 days or worsens 
despite prednisone at 1-2 mg/kg/day PO or IV equivalent, 
additional workup should be considered and prompt 
treatment with IV methylprednisolone 2-4mg/kg/day started.  
- 
Once improving,  gradually taper steroids over ≥28 days  
and consider prophylactic antibiotics, antifungals and anti 
PCP treatment (please refer to current  NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]  
Rash 
(excluding 
Bullous skin 
formations) 
Grade of Skin 
Rash  
(Please refer 
to NCICTCAE 
version 4.03 
for definition of 
severity/grade 
depending on  
type of skin 
rash)  
General Guidance 
Monitor for signs and symptoms of dermatitis (rash and pruritus)  
**IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED** 
Grade 1  
No dose modification 
For Grade 1: 
- 
Consider symptomatic treatment including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream) 
 
Grade 2 
For persistent (> 1- 2 
weeks) Grade 2 events, 
hold scheduled study 
drug/study regimen until 
resolution to ≤ Grade 1 or 
baseline  
• 
If  toxicity worsens 
then treat as Grade 3  
• 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume 
drug/study regimen 
after completion of 
steroid taper  
 
For Grade 2 : 
- 
Obtain dermatology consult  
- 
Consider symptomatic treatment including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream) 
- 
Consider moderate-strength topical steroid  
- 
If no improvement of rash/skin lesions occurs within 3-5 
days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, discuss with study 
physician and promptly start systemic steroids prednisone  
1-2 mg/kg/day PO or IV equivalent   
- 
Consider skin biopsy if persistent for >1-2 weeks or recurs 


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Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 
Hold study drug/study 
regimen until resolution to 
≤ Grade 1 or baseline 
If temporarily holding the 
study drug/study regimen 
does not provide 
improvement of the 
Grade 3 skin rash  to ≤ 
Grade 1 or baseline 
within 30 days, then 
permanently discontinue 
Study drug/study regimen  
For Grade 3 or 4: 
- 
Consult dermatology  
- 
 Promptly initiate empiric IV methylprednisolone 1 to 4 
mg/kg/day or equivalent  
- 
Consider hospitalization 
- 
Monitor extent of rash [Rule of Nines] 
- 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
- 
Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
- 
Discuss with Study Physician 
Grade 4 
Permanently discontinue 
study drug/study regimen  
Endocrin-
opathy (e.g., 
hyperthy-
roidism, 
hypothy-
roidism, 
hypopitui-
tarism, 
adrenal 
insuffi-
ciency, etc.) 
Any Grade  
(Depending on 
the type of 
endocrino-
pathy, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade/se-
verity)  
General Guidance 
- 
Consult Endocrinologist 
- 
Monitor patients for signs and symptoms of 
endocrinopathies.  Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, 
hypotension and weakness. 
- 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including 
brain metastases, infections, etc.) 
- 
Monitor and evaluate thyroid function tests: TSH, free T3 
and free T4 and other relevant endocrine labs depending on 
suspected endocrinopathy.  
- 
If a patient experiences an AE that is thought to be possibly 
of autoimmune nature (e.g., thyroiditis, pancreatitis, 
hypophysitis, diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing  
Grade 1 
(Depending on 
the type of 
endocrino-
pathy, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC grade 
1) 
No dose modification 
For Grade 1: (including those with asymptomatic TSH elevation) 
- 
Monitor patient with appropriate endocrine function tests 
- 
If TSH < 0.5X LLN, or TSH >2X ULN or consistently out of 
range in 2 subsequent measurements, include FT4 at 
subsequent visits as clinically indicated and consider 
endocrinology consult. 


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Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 2  
(Depending on 
the type of 
endocrino-
pathy, refer to 
NCI CTCAE 
version 4.03 
for defining 
the CTC 
grade/severity 
2) 
 
 
For Grade 2 
endocrinopathy other 
than hypothyroidism, hold 
study drug/study regimen 
dose until  subject is 
clinically stable 
• If  toxicity worsens 
then treat as Grade 3 
or Grade 4  
Study drug/study regimen 
can be resumed once 
event stabilizes after 
completion of steroid 
taper 
 
Patients with 
endocrinopathies who 
may require prolonged or 
continued steroid 
replacement can be 
retreated with study 
drug/study regimen on 
the following conditions: 
1) the event stabilizes 
and is controlled ,2) the 
patient is clinically stable 
as per Investigator or 
treating physician’s 
clinical judgement, and 3) 
doses of prednisone are 
at less than or equal to 
10mg/day or equivalent. 
For Grade 2: (including those with symptomatic endocrinopathy) 
- 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids 
- 
Initiate hormone replacement as needed for management 
- 
Evaluate endocrine function, and as clinically indicated,  
consider pituitary scan 
- 
For patients with abnormal endocrine work up, except for 
those  with isolated hypothyroidism,  consider short-term, 
corticosteroids (e.g., 1-2mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation of treatment with 
relevant hormone replacement (e.g. Levothyroxine, 
hydrocortisone, or sex hormones). -  
- 
Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of  cancer-related infections [Category 2B 
recommendation]) 
- 
For patients with normal endocrine work up (lab or MRI 
scans), repeat labs/MRI as clinically indicated. 
Grade 3 or 4 
(Depending on 
the type of 
endocrinopath
y, refer to NCI 
CTCAE 
version 4.03 
for defining 
the CTC 
grade/severity 
3 or 4)  
For Grade 3 or 4 
endocrinopathy other 
than hypothyroidism, hold 
study drug/study regimen 
dose until endocrinopathy 
symptom(s) are controlled 
 
Study drug/study regimen 
can be resumed once 
event stabilizes and after 
completion of steroid 
taper 
For Grade 3 or 4: 
- 
Consult endocrinologist 
- 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent 
- 
Administer hormone replacement therapy as necessary. 
- 
For adrenal crisis, severe dehydration, hypotension, or 
shock: immediately initiate intravenous corticosteroids with 
mineralocorticoid activity 
- 
Once improving, gradually taper immunosuppressive 
steroids over ≥28 days and consider prophylactic 
antibiotics, antifungals and anti PCP treatment (please refer 
to current NCCN guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
- 
Discuss with study physician 
 
 
 
 


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 Appendix E. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Immune 
mediated  
Neurotox-
icity (to 
include but 
not limited 
to limbic 
encepha-
litis, 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-
Barre)   
 
Grade of 
Neurotoxicity  
Depending on 
the type of 
neurotoxicity , 
refer to NCI 
CTCAE 
version 4.03 
for defining 
the CTC 
grade/severity 
 
Any Grade  
 
 
 
 
 
 
General Guidance 
- 
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes and medications, etc.)  
- 
Monitor patient  for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness) 
- 
Consider appropriate diagnostic testing (e.g. 
electromyogram and nerve conduction investigations) 
- 
Symptomatic treatment with neurological consult as 
appropriate 
 
Grade 1 
 No dose modifications 
See “Any Grade” recommendations above 
Grade 2 
For acute motor 
neuropathies or  
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to ≤ Grade 
1 
 
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study drug/study regimen 
dose until resolution to ≤ 
Grade 1. 
• 
If toxicity worsens 
then treat as Grade 3 
or Grade 4  
Study drug/study regimen 
can be resumed once 
event improves to Grade 
≤1 and after completion of 
steroid taper 
- 
Discuss with the study physician  
- 
Obtain  Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.) 
- 
Promptly start systemic steroids prednisone 1-2mg/kg/day 
PO or IV equivalent  
- 
If no improvement within 3-5 days despite 1-2mg/kg/day 
prednisone PO or IV equivalent consider additional workup 
and promptly treat with additional immunosuppressive 
therapy (e.g. IVIG)  
 
 
Grade 3 
Hold Study drug/study 
regimen dose until 
resolution to ≤ Grade 1 
Permanently discontinue 
study drug/study regimen 
if Grade 3 irAE does not 
resolve to ≤ Grade 1 
within 30 days. 
 
For Grade 3 or 4: 
- 
Discuss with study physician 
- 
Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent  
- 
If no improvement within 3-5 days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (e.g. IVIG)  


Version 2.4 01-Oct2019 
 
 
 
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 Appendix E. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 4 
 
 
Permanently 
discontinue study 
drug/study regimen 
- 
Once stable, gradually taper steroids over ≥4 weeks 
Immune-
mediated 
peripheral 
neuromotor 
syndromes, 
such as 
Guillain-
Barre and 
Myasthenia 
Gravis 
 
General Guidance 
- 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients 
may unpredictably experience acute decompensations 
which can result in substantial morbidity or in the worst 
case, death. Special care should be taken for certain 
sentinel symptoms which may predict a more severe 
outcome, such as prominent dysphagia, rapidly progressive 
weakness, and signs of respiratory insufficiency or 
autonomic instability 
- 
Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes and medications, etc.). 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 
neurological consult 
- 
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  
- 
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 IVIG and followed by plasmapheresis if not responsive 
to IVIG  
Grade 1 
No dose modification 
- 
Discuss with the study physician 
- 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above 
- 
Obtain a neurology consult unless the symptoms are very 
minor and stable 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to ≤ Grade 1 
 
Permanently discontinue 
study drug/study regimen 
if it does not resolve to ≤ 
Grade 1 within 30 days or 
if there are signs of 
respiratory insufficiency 
or autonomic instability 
 
Grade 2  
- 
Discuss with the study physician  
- 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above 
- 
Obtain a Neurology Consult  
- 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia 
Gravis. 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 


Version 2.4 01-Oct2019 
 
 
 
135 
 
 Appendix E. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIG. 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 present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE:  
o 
Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should be 
started with IVIG and followed by plasmapheresis if not 
responsive to IVIG. 
Grade 3 
Hold study drug/study 
regimen dose until 
resolution to ≤ Grade 1 
 
Permanently discontinue 
Study drug/study regimen 
if Grade 3 irAE does not 
resolve to ≤ Grade 1 
within 30 days or if there 
are signs of respiratory 
insufficiency or autonomic 
instability 
For severe or life threatening (Grade 3 or 4) events:  
- 
Discuss with study physician 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological consult 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia 
Gravis.  It 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 IVIG. 
o 
If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
GUILLAIN-BARRE:  
Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should be 
started with IVIG and followed by plasmapheresis if not 
responsive to IVIG 
Grade 4 
Permanently discontinue 
study drug/study regimen  
 
 
 
 


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Appendix E. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
Infusion-Related Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
- 
Management per institutional standard at the discretion of 
investigator 
- 
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, skin rashes etc.) and anaphylaxis (e.g., 
generalized urticaria, angioedema, wheezing, hypotension, 
tachycardia, etc.) 
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 1 or Grade 2: 
- 
Acetaminophen and/or antihistamines may be administered 
per institutional standard at the discretion of the investigator  
- 
Consider premedication per institutional standard prior to 
subsequent doses 
- 
Steroids should not be used for routine premedication of 
≤Grade 2 infusion reactions 
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 
Grade 3/4 
Permanently discontinue study drug/study 
regimen 
For Grade 3 or 4: 
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid) 
 
 
Appendix E. Dosing Modification and Toxicity Management Guidelines for Immune-mediated, 
Infusion Related, and Non Immune-mediated Reactions for Durvalumab Monotherapy 
Non-immune Mediated Reactions 
(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 Study Physician”  
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modification 
Toxicity Management 
Any Grade 
Note: dose modifications are not required for adverse events 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  
1 
No dose adjustment  
Treat accordingly as per 
institutional standard  
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per 
institutional standard  
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to 
≤ Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen 
Treat accordingly as per 
institutional standard  
 
 
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision 
to discontinue would be based on accompanying clinical 
signs/symptoms and as per Investigator’s clinical judgment and in 
consultation with the sponsor)  
Treat accordingly as per 
institutional standard  
Abbreviations: 


Version 2.4 01-Oct2019 
 
 
 
137 
 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline phosphatase; 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = computed tomography; GI = gastrointestinal; 
IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = intramuscular; irAE = immune-related adverse event; 
IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PO = by 
mouth; TNF = tumor necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal. 
 
i ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by 
Michael Postow MD  
ii NCI CTCAE version 4.03 
iii ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by 
Michael Postow MD 
ibFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – 
Premarketing Clinical Evaluation NCI CTCAE version 4.03 iv