A Phase 3, Open-Label, Randomized, Parallel Group Study to Evaluate the Efficacy and Safety of Intrapleural Administration of Adenovirus-Delivered Interferon Alpha-2b (rAd-IFN) in Combination With Celecoxib and Gemcitabine in Patients With Malignant Pleural Mesothelioma
Phase: PHASE3
Conditions: Malignant Pleural Mesothelioma
Sponsor: Ferring Ventures Limited

Clinicaltrials.gov 
Cover Page for Protocol  
Sponsor Name 
Ferring Ventures Limited 
Official Title of the Study 
A Phase 3, Open-Label, Randomized, Parallel Group Study to 
Evaluate the Efficacy and Safety of Intrapleural 
Administration of Adenovirus-Delivered Interferon Alpha-2b 
(rAd-IFN) in Combination with Celecoxib and Gemcitabine in 
Patients with Malignant Pleural Mesothelioma 
NCT Number 
NCT03710876 
Date of Document 
11 December 2023 
 

CLINICAL STUDY PROTOCOL 
 
A Phase 3, Open-Label, Randomized, Parallel Group Study to 
Evaluate the Efficacy and Safety of Intrapleural Administration of 
Adenovirus-Delivered Interferon Alpha-2b (rAd-IFN) in 
Combination with Celecoxib and Gemcitabine in Patients with 
Malignant Pleural Mesothelioma 
Study Drugs: Nadofaragene firadenovec (Recombinant adenovirus vector containing the human 
interferon alpha-2b gene: rAd-IFN), celecoxib, and gemcitabine 
Protocol Number: rAd-IFN-MM-301 
EudraCT Number: 2017-003169-82 
IND Number: 13854 
 
Sponsor: 
Trizell, Ltd. 
Drayton Hall, Church Road 
West Drayton 
UB7 7PS 
United Kingdom 
Telephone: +44 (0) 73 939 55692 
 
Version 1.0: 26 February 2018 
Version 2.0: 12 June 2018 
Version 3.0: 10 September 2018 
Version 4.0: 14 August 2019 
Version 5.0: 20 May 2020 
Version 6.0: 28 April 2021 
Version 7.0: 13 July 2023 
Version 8.0: 11 December 2023 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Trizell, Ltd. (Trizell) except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical study for Trizell. You are allowed 
to disclose the contents of this document only to your Institutional Review Board or Independent 
Ethics Committee and study personnel directly involved with conducting this protocol. Persons 
to whom the information is disclosed must be informed that the information is confidential and 
proprietary to Trizell and that it may not be further disclosed to third parties. 

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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Trizell to study personnel under my supervision. I will discuss this material with them to ensure 
they are fully informed about the study product and study procedures. I will let them know that 
this information is confidential and proprietary to Trizell and that it may not be further disclosed 
to third parties. I understand that the study may be terminated or enrollment suspended at any time 
by Trizell, with or without cause, or by me if it becomes necessary to protect the best interests of 
the study patients. 
I agree to conduct this study according to this protocol and to comply with its requirements, subject 
to ethical and safety considerations and guidelines, and to conduct the study in accordance with 
the Declaration of Helsinki, International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (ICH E6), and applicable regional regulatory requirements. 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
______________________________________________ 
Investigator’s Printed Name 
______________________________________________ 
______________________________________________ 
______________________________________________ 
Investigational Site/Address 
 
 
  

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SYNOPSIS 
TITLE: A Phase 3, Open-Label, Randomized, Parallel Group Study to Evaluate the Efficacy and 
Safety of Intrapleural Administration of Adenovirus-Delivered Interferon Alpha-2b (rAd-IFN) in 
Combination with Celecoxib and Gemcitabine in Patients with Malignant Pleural Mesothelioma 
PROTOCOL NUMBER: rAd-IFN-MM-301 
STUDY DRUGS: Nadofaragene firadenovec (Recombinant adenovirus vector containing the 
human interferon alpha-2b gene: rAd-IFN), celecoxib, and gemcitabine 
PHASE: 3 
INDICATION: Malignant pleural mesothelioma (MPM) 
OBJECTIVES: 
The primary objective of this study is to compare the overall survival (OS) associated with 
rAd-IFN, when administered with celecoxib and gemcitabine, versus that associated with 
celecoxib and gemcitabine alone for the treatment of patients with MPM who have received a 
minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have 
been an anti-folate and platinum combination regimen. 
The secondary objectives of this study are:  
 To compare between rAd-IFN, when administered with celecoxib and gemcitabine, versus that 
associated with celecoxib and gemcitabine alone for the treatment of patients with MPM who 
have received a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 
1 of which must have been an anti-folate and platinum combination regimen, with respect to: 
o Survival rate at 12 months and every 6 months thereafter; 
o Progression-free survival (PFS); 
o Best response (complete response, partial response, or stable disease); and 
o Safety of rAd-IFN; and 
 To evaluate rAd-IFN, when administered with celecoxib and gemcitabine, in a sub-set of 
patients with MPM who have received a minimum of 1 treatment regimen and a maximum of 
2 treatment regimens, 1 of which must have been an anti-folate and platinum combination 
regimen, with respect to viral shedding and biodistribution.  

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The exploratory objectives of this study are: 
 To compare between rAd-IFN, when administered with celecoxib and gemcitabine, versus that 
associated with celecoxib and gemcitabine alone for the treatment of patients with MPM who 
have received a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 
1 of which must have been an anti-folate and platinum combination regimen, with respect to: 
o Health-related Quality-of-Life, 
o The relationship between immunological status and response to treatment, and 
o Biocorrelates of response to treatment. 
POPULATION: 
The study population is patients with MPM and confirmed epithelioid or biphasic histology (if 
biphasic, histology must be predominantly [50%] epithelioid) who have received a minimum of 
1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an 
anti-folate and platinum combination regimen. 
STUDY DESIGN AND DURATION: 
The study is an open-label, randomized, parallel group study conducted in patients with MPM and 
confirmed epithelioid or biphasic histology (if biphasic, histology must be predominantly [50%] 
epithelioid) who have received a minimum of 1 treatment regimen and a maximum of 2 treatment 
regimens, 1 of which must have been an anti-folate and platinum combination regimen. 
Screening assessments must be completed within 28 days prior to Study Day 1, and eligible 
patients will be randomized to either: 
1. Treatment group: rAd-IFN (Study Day 1) + celecoxib (Study Days 1 to 14) + gemcitabine 
(Study Days 14 and 21 [i.e., Days 1 and 8 of the first gemcitabine treatment cycle], 
gemcitabine will be administered on a 21-day cycle, unless the cycle is modified due to 
toxicity/delay, and repeated every 3 weeks until disease progression/early termination [ET]); 
or 
2. Control group: celecoxib (Study Days 1 to 14) + gemcitabine (Study Days 14 and 21 
[i.e., Days 1 and 8 of the first gemcitabine treatment cycle], gemcitabine will be administered 
on a 21-day cycle, unless the cycle is modified due to toxicity/delay, and repeated every 
3 weeks until disease progression/ET). 
An extension to the Screening Period will be permitted on a case-by-case basis following 
discussion between the Investigator, the Medical Monitor, and/or the Sponsor. The reason(s) for 
the extension is to be clearly documented. 
The target interval between randomization and Study Day 1 should be up to 7 days and no greater 
than 14 days. Any extension beyond 14 days will be considered on a case-by-case basis, following 
discussion between the Investigator, Medical Monitor, and Sponsor. 
Treatment Phase 
Patients randomized to receive rAd-IFN (treatment group) will have an intrapleural catheter (IPC) 
or similar device either previously in place or inserted for the study, permitting drug administration 
to an accessible pleural space. The rAd-IFN will be diluted to a volume of 25 mL using sterile 

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normal saline and will be administered directly to the pleural space via the IPC or similar device. 
The IPC or similar device will then be flushed with up to 20 mL of sterile normal saline. 
Patients will receive gemcitabine until disease progression/ET. All adverse events will be captured 
from the time of the main study’s informed consent through 30 days after the last dose of study 
treatment (rAd-IFN, celecoxib, and gemcitabine). All treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs) will be followed until resolution or stabilization. 
Clinical Follow-Up Phase  
Following disease progression/ET, patients in the rAd-IFN treatment group will be followed every 
6 months (±14 days) for survival and safety for up to 5 years after receiving the first dose of 
rAd-IFN, assuming consent has not been withdrawn. All previously recorded TEAEs and SAEs 
will be followed until resolution or stabilization. Patients in the control group will not continue in 
the clinical Follow-up phase and study participation will conclude after end of study treatment. 
Discontinuation of Screening and Enrollment Into the Study 
The study opened to recruitment in January 2019 and was scheduled to complete recruitment by 
May 2021, with a target of approximately 300 patients. As of April 2021, a total of 53 patients 
have been randomized to treatment, of whom 30 have discontinued the study. After careful 
consideration and a thorough evaluation of available options, Trizell has decided to discontinue 
screening and enrollment into the study, while continuing to treat and collect study data from 
randomized patients as per the Schedule of Procedures.  
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Patients randomized to the treatment group will receive rAd-IFN (3 × 1011 viral particles) on Study 
Day 1, diluted to a total volume of 25 mL using sterile normal saline and administered into the 
pleural space via an IPC or similar device. The IPC or similar device will then be flushed with up 
to 20 mL of sterile normal saline. 
All study patients (treatment and control) will receive: 
 Celecoxib administered at a dose of 400 mg twice daily orally on Study Days 1 to 14; and 
 Gemcitabine starting on Study Day 14, using the following treatment regimen: 1250 mg/m2 
administered intravenously on Days 1 and 8 of a 21-day gemcitabine cycle, unless the cycle is 
modified due to toxicity/delay, and continued every 3 weeks until disease progression/ET. 
CCI

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ENDPOINTS:  
The primary endpoint is OS, defined as time to death (from any cause) from randomization. 
Secondary endpoints include efficacy and safety endpoints. 
The secondary efficacy endpoints are:  
 To evaluate survival rate at 12 months, defined as the number of deaths (from any cause) at 
12 months from randomization, and every 6 months thereafter; 
 To evaluate PFS, defined as the time from randomization to the time when the modified 
Response Evaluation Criteria in Solid Tumors 1.1 criteria for disease progression are first met, 
or when death from any cause occurs; and 
 To evaluate best response, defined as the best response after randomization (complete 
response, partial response, or stable disease). 
The secondary safety endpoints are: 
 To evaluate the number of patients with Common Terminology Criteria for Adverse Events 
Grade 3 or 4, and 
 To evaluate post-treatment levels of rAd-IFN-related viral DNA in biological samples 
collected up to 28 days after Study Day 1 in a sub-set of patients. 
The exploratory efficacy endpoints are: 
 Change in total score and individual components of the EQ-5D-5L and Lung Cancer Symptom 
Scale-mesothelioma (patient and observer) from baseline (randomization) to each successive 
cycle of gemcitabine, 
 Correlation between the presence of adenovirus type 5 neutralizing antibodies prior to 
treatment and survival (death from any cause), 
 Correlation between pre- and post-treatment levels of serum mesothelin and treatment 
outcomes, and 
 Correlation between pre- and post-treatment levels of serum fibulin-3 and treatment outcomes. 
SAFETY VARIABLES: 
Safety assessments will include the assessment of adverse events including adverse events of 
special interest, as well as physical examinations, vital sign measurements, clinical laboratory 
assessments, and electrocardiographic data through electrocardiogram. 
STATISTICAL ANALYSES: 
The primary analysis of the primary endpoint is a comparison of the OS curves between the 
2 treatment groups using a log-rank test. A Cox proportional hazards model with treatment as an 
explanatory variable will be used to assess the magnitude of the treatment difference in OS. The 
hazard ratio and the associated 95% confidence interval obtained from the Cox proportional 
hazards model will be presented.  

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The median OS and the 95% confidence interval for each treatment group will be estimated using 
the Kaplan-Meier method and summarized by treatment group. Plots of the Kaplan-Meier curve 
of OS will be presented by treatment group. 
Secondary analyses of the primary endpoint will include a comparison of the survival rates at 
various time points since randomization. 
Secondary time-to-event endpoints will be analyzed in the same manner as the primary efficacy 
endpoint. 
Categorical efficacy endpoints will be summarized and compared between groups using Fisher’s 
exact test. 
The nature, incidence, severity, relatedness, expectedness, seriousness, and outcome of TEAEs 
will be summarized by treatment group for safety analyses. 
SAMPLE SIZE DETERMINATION: 
It is anticipated that approximately 44 events (equivalent to 89% of the planned 50 enrolled 
patients) will be observed 24 months after the last patient is randomized. The final analysis of the 
study will be conducted after the forty-fourth event (death) or 30 months after the last patient is 
randomized, whichever occurs first. 
DATA AND SAFETY MONITORING BOARD: 
An independent Data and Safety Monitoring Board (DSMB) will be convened for this study to 
monitor safety, efficacy, and study integrity. All aspects of the DSMB’s scope of review and 
procedures will be detailed in a DSMB charter.  
SITES: Up to 45 sites globally 
SPONSOR: 
Trizell, Ltd. 
Drayton Hall, Church Road 
West Drayton 
UB7 7PS 
United Kingdom 
Telephone: +44 (0) 73 939 55692 
CCI

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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents ............................................................................................................................ 9 
List of Tables ................................................................................................................................ 14 
List of Figures ............................................................................................................................... 15 
List of Abbreviations and Definition of Terms............................................................................. 16 
1 Introduction and Background Information ............................................................................. 18 
1.1 
Overview of Nonclinical Studies .................................................................................. 19 
1.2 
Overview of Clinical Studies ........................................................................................ 19 
1.2.1 Celecoxib ........................................................................................................... 21 
1.2.1.1 Rationale for celecoxib dosing ............................................................ 22 
1.2.2 Gemcitabine ...................................................................................................... 22 
1.2.2.1 Rationale for gemcitabine dosing ....................................................... 23 
1.3 
Rationale for rAd-IFN Dosing ...................................................................................... 23 
1.4 
Risk/Benefit ................................................................................................................... 24 
1.4.1 Potential Risks of rAd-IFN ............................................................................... 24 
1.4.1.1 Viral shedding ..................................................................................... 24 
1.4.1.2 Inclusion of patients with pre-existing adenovirus neutralizing 
antibody titers ...................................................................................... 25 
1.4.2 Potential Benefits of rAd-IFN ........................................................................... 25 
1.4.3 Potential Risks and Benefits of Celecoxib ........................................................ 26 
1.4.4 Potential Risks and Benefits of Gemcitabine .................................................... 26 
1.5 
Coronavirus Disease 2019 ............................................................................................. 27 
2 Objectives ............................................................................................................................... 28 
2.1 
Primary Objective ......................................................................................................... 28 
2.2 
Secondary Objectives .................................................................................................... 28 
2.3 
Exploratory Objectives .................................................................................................. 28 
3 Study Description.................................................................................................................... 29 
3.1 
Summary of Study Design ............................................................................................ 29 
3.1.1 Overview ........................................................................................................... 29 

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3.1.2 Viral Shedding Cohort ...................................................................................... 30 
3.1.3 Study Duration and End of Study ..................................................................... 30 
3.1.4 Discontinuation of Screening and Enrollment Into the Study ........................... 31 
3.2 
Data and Safety Monitoring Board ............................................................................... 31 
3.3 
Stopping Rules .............................................................................................................. 32 
3.4 
Study Indication ............................................................................................................ 32 
4 Selection and Withdrawal of Patients ..................................................................................... 33 
4.1 
Inclusion Criteria ........................................................................................................... 33 
4.2 
Exclusion Criteria .......................................................................................................... 35 
4.3 
Withdrawal Criteria ....................................................................................................... 36 
5 Study Treatments and Intrapleural Catheter or Similar Device Procedures ........................... 38 
5.1 
Nadofaragene Firadenovec (rAd-IFN) .......................................................................... 38 
5.1.1 Formulation, Packaging, and Handling ............................................................. 38 
5.1.2 Dosage and Administration ............................................................................... 38 
5.1.2.1 Intrapleural catheter or similar device placement ............................... 38 
5.1.2.2 rAd-IFN administration via intrapleural catheter or similar device .... 39 
5.1.3 Intrapleural Catheter or Similar Device Removal Post-rAd-IFN 
Administration ................................................................................................... 39 
5.1.4 Patient Preparation and Monitoring .................................................................. 39 
5.2 
Celecoxib ....................................................................................................................... 40 
5.3 
Gemcitabine .................................................................................................................. 41 
5.4 
Storage and Accountability ........................................................................................... 41 
5.4.1 rAd-IFN Biosafety Precautions ......................................................................... 41 
5.5 
Treatment Groups .......................................................................................................... 42 
5.5.1 Treatment Compliance ...................................................................................... 42 
5.5.2 Treatment of Overdose ...................................................................................... 43 
5.6 
Dose Modification and Treatment Delay ...................................................................... 43 
5.6.1 rAd-IFN ............................................................................................................. 43 
5.6.2 Celecoxib ........................................................................................................... 43 
5.6.3 Gemcitabine ...................................................................................................... 43 
5.7 
Randomization and Blinding ......................................................................................... 44 
5.8 
Breaking the Blind ........................................................................................................ 44 
5.9 
Prior and Concomitant Medications and/or Procedures ................................................ 44 

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5.9.1 Excluded Medications and/or Procedures ......................................................... 44 
5.9.2 Restricted Medications and/or Procedures ........................................................ 45 
5.9.2.1 rAd-IFN and COVID-19 vaccination ................................................. 45 
5.9.2.2 Celecoxib and COVID-19 vaccination ............................................... 46 
5.9.2.3 Gemcitabine and COVID-19 vaccination ........................................... 46 
5.9.3 Allowed Medications and/or Procedures .......................................................... 46 
5.9.4 Documentation of Prior and Concomitant Medication Use .............................. 47 
6 Study Procedures .................................................................................................................... 48 
6.1 
Informed Consent .......................................................................................................... 48 
6.2 
Screening (Study Days -28 to 0) ................................................................................... 48 
6.3 
Treatment Period ........................................................................................................... 49 
6.3.1 Study Day 1 ....................................................................................................... 49 
6.3.2 Study Day 2 (rAd-IFN Treatment Group Only) ................................................ 51 
6.3.3 Study Day 7 ....................................................................................................... 52 
6.3.4 Study Days 14 to 28 (Gemcitabine Cycle 1) ..................................................... 52 
6.3.4.1 Study Day 14 (Gemcitabine Cycle 1 Day 1) ...................................... 52 
6.3.4.2 Study Day 21 (Gemcitabine Cycle 1 Day 8) ...................................... 53 
6.3.4.3 Study Day 28 (Gemcitabine Cycle 1 Day 15) .................................... 54 
6.3.5 Gemcitabine Cycle 2, 3, 4, and Beyond ............................................................ 54 
6.3.5.1 Gemcitabine Cycle 2, 3, 4, and Beyond Day 1 ................................... 54 
6.3.5.2 Gemcitabine Cycle 2, 3, 4, and Beyond Day 8 ................................... 55 
6.4 
Post-Randomization CT Scans ...................................................................................... 55 
6.5 
End of Treatment (Disease Progression) Visit .............................................................. 55 
6.6 
Clinical Follow-Up Visits ............................................................................................. 56 
6.7 
Early Termination ......................................................................................................... 56 
7 Efficacy Assessments .............................................................................................................. 58 
7.1 
Archival Tumor or Biopsy at Screening ....................................................................... 58 
7.2 
Tumor Assessments ....................................................................................................... 58 
8 Safety Assessments ................................................................................................................. 60 
8.1 
Adverse Events .............................................................................................................. 60 
8.1.1 Adverse (Drug) Reaction .................................................................................. 60 
8.1.2 Unexpected Adverse Drug Reaction ................................................................. 61 

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8.1.3 Assessment of Adverse Events by the Investigator .......................................... 61 
8.1.4 Adverse Events of Special Interest .................................................................... 62 
8.2 
Serious Adverse Events ................................................................................................. 63 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 63 
8.4 
Pregnancy Reporting ..................................................................................................... 64 
8.5 
Expedited Reporting ...................................................................................................... 65 
8.6 
Safety Assessments ....................................................................................................... 65 
8.7 
Clinical Laboratory Evaluations .................................................................................... 65 
8.8 
Vital Signs ..................................................................................................................... 65 
8.9 
Electrocardiograms ........................................................................................................ 65 
8.10 Physical Examinations .................................................................................................. 66 
8.11 Viral Shedding Evaluation ............................................................................................ 66 
8.12 Patient Preparation and Monitoring (rAd-IFN Treatment Group Only) ....................... 66 
9 Statistics .................................................................................................................................. 68 
9.1 
Analysis Populations ..................................................................................................... 68 
9.2 
Statistical Methods ........................................................................................................ 68 
9.2.1 Analysis of Efficacy .......................................................................................... 68 
9.2.1.1 Primary efficacy analysis .................................................................... 68 
9.2.1.2 Secondary efficacy analysis ................................................................ 68 
9.2.2 Analysis of Safety ............................................................................................. 68 
9.2.3 Analysis Timing ................................................................................................ 69 
9.2.3.1 Interim analysis ................................................................................... 69 
9.2.3.2 Final analysis ...................................................................................... 69 
9.2.4 Data and Safety Monitoring Board ................................................................... 69 
9.2.5 Sample Size Determination ............................................................................... 69 
10 Data Management and Record Keeping ................................................................................. 70 
10.1 Data Management ......................................................................................................... 70 
10.1.1 Data Handling ................................................................................................... 70 
10.1.2 Computer Systems ............................................................................................. 70 
10.1.3 Data Entry ......................................................................................................... 70 
10.1.4 Medical Information Coding ............................................................................. 70 
10.1.5 Data Validation ................................................................................................. 70 

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10.2 Record Keeping ............................................................................................................. 70 
11 Investigator Requirements and Quality Control ..................................................................... 71 
11.1 Ethical Conduct of the Study ........................................................................................ 71 
11.2 Ethics and Regulatory Review ...................................................................................... 71 
11.3 Informed Consent .......................................................................................................... 71 
11.4 Study Monitoring Requirements ................................................................................... 72 
11.5 Disclosure of Data ......................................................................................................... 72 
11.6 Retention of Records ..................................................................................................... 73 
11.7 Publication Policy ......................................................................................................... 73 
11.8 Financial Disclosure ...................................................................................................... 73 
11.9 Financing and Insurance ................................................................................................ 73 
12 Study Administrative Information .......................................................................................... 74 
12.1 Protocol Amendments ................................................................................................... 74 
12.2 Address List ................................................................................................................... 74 
12.2.1 Sponsor .............................................................................................................. 74 
12.2.2 Contract Research Organization ........................................................................ 74 
12.2.3 Serious Adverse Event Reporting ..................................................................... 74 
12.2.4 Biological Specimens ........................................................................................ 75 
12.2.5 rAd-IFN Manufacturer ...................................................................................... 75 
12.2.6 Gemcitabine and Celecoxib Supplier (Where Supplied Centrally) .................. 76 
13 References ............................................................................................................................... 77 
Appendix A: Schedule of Procedures ........................................................................................... 81 
Appendix B: Clinical Laboratory Analytes .................................................................................. 85 
Appendix C: Modified RECIST 1.1 Criteria Adapted to the Growth Pattern of Malignant 
Pleural Mesothelioma ............................................................................................................. 86 
Appendix D: Cytochrome P450 Inhibitors, Inducers, and Substrates .......................................... 92 
Appendix E: Grading and Management of Cytokine Release Syndrome ..................................... 93 
Appendix F: Dose Modification Strategies for Celecoxib and Gemcitabine ............................... 95 
Appendix G: Pleural Fluid Sample Collection Procedure ............................................................ 97 

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LIST OF TABLES 
Table 1. 
Schedule of Procedures ............................................................................................... 81 
Table 2. 
Summary of Key Points for Modified Response Evaluation Criteria in Solid 
Tumors 1.1 .................................................................................................................. 91 
Table 3. 
Inhibitors, Inducers, and Substrates of Cytochrome P450 1A2, 2C9, and 2D6 ......... 92 
Table 4. 
Cytokine Release Syndrome Revised Grading System .............................................. 93 
Table 5. 
High Vasopressor Doses ............................................................................................. 93 
Table 6. 
Dose Modification Strategies for Celecoxib and Gemcitabine for All Toxicities ...... 95 
Table 7. 
Dose Modification of Gemcitabine Due to Hematological Toxicities for All Cycles 95 

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LIST OF FIGURES 
Figure 1. Study Schematic.......................................................................................................... 29 
Figure 2. Treatment Algorithm for Management of Cytokine Release Syndrome Based on the 
Cytokine Release Syndrome Revised Grading System .............................................. 94 
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
Ad5 
Adenovirus type 5 
Ad.muIFN-β 
Adenoviral vector containing the mouse interferon beta gene 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
CD 
Cluster of differentiation 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
COX 
Cyclooxygenase 
CRA 
Clinical Research Associate 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EPD 
Extended pleurectomy/decortication 
EPP 
Extrapleural pneumonectomy 
ET 
Early termination 
FAP 
Familial adenomatous polyposis 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IFN-α2b 
Interferon alpha-2b 
IFN-β 
Interferon beta 
IFN-γ 
Interferon gamma 
IL 
Interleukin 
INR 
International normalized ratio 
IPC 
Intrapleural catheter 
IRB 
Institutional Review Board 

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Abbreviation 
Definition 
IRT 
Interactive Response Technology 
LCSS-Meso 
Lung Cancer Symptom Scale-mesothelioma 
MOS 
Median overall survival 
MPM 
Malignant pleural mesothelioma 
nAb 
Neutralizing antibody 
NMIBC 
Non-muscle invasive bladder cancer 
NSAID 
Nonsteroidal anti-inflammatory drug 
OS 
Overall survival 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free survival 
PGE2 
Prostaglandin E2 
QoL 
Quality-of-Life 
rAd-IFN 
Recombinant adenovirus vector containing the human interferon
alpha-2b gene 
rAd-IFN-β 
Recombinant adenovirus vector containing the interferon beta gene 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
Syn3 
A clinical polyamide surfactant excipient 
TEAE 
Treatment-emergent adverse event 
Th1 
T helper type 1 
TPL 
Tripartite leader 
ULN 
Upper limit of normal 
US 
United States 
vp 
Viral particles 
WHO 
World Health Organization 
 

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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Malignant pleural mesothelioma (MPM) is an aggressive tumor of the serosal surface of the 
thoracic cavity. Asbestos is the principal carcinogen associated with MPM, causing up to 80% of 
cases, although other agents, such as simian virus 40, may also be implicated in the disease 
etiology. Estimates of the annual incidence of MPM range from 8 to 29 cases per million people 
in the population.1 The annual incidences in Europe and the United States (US) are 18 and 15 cases 
per million people in the population, respectively.2 There are approximately 3000 and 5000 new 
cases per year in the US and Europe, respectively. Analysis of mesothelioma mortality recorded 
by the World Health Organization (WHO) between 1994 and 2008 yielded an age-adjusted 
mortality rate of 4.9 per million, a mean age of death of 70 years, and a male to female ratio 
of 3.6:1.3 
Malignant pleural mesothelioma typically presents with shortness of breath, unexplained pleural 
effusion, pleural or chest pain, weight loss, and fatigue and is usually diagnosed through 
video-assisted thoracoscopic surgery and tumor biopsy. There are 3 major histological tumor 
sub-types: epithelioid, sarcomatoid, and biphasic; the proportion of each is approximately 60%, 
20%, and 20%, respectively.4 Where feasible, patients with MPM are initially treated by surgical 
resection of the tumor, using either extrapleural pneumonectomy (EPP) (en bloc removal of 
parietal and visceral pleura, involved lung, mediastinal lymph nodes, diaphragm, and pericardium) 
or extended pleurectomy/decortication (EPD) (removal of visceral and parietal pleura, mediastinal 
pleura, pericardium, and diaphragm). Both procedures leave residual tumor and are considered 
equally effective in “maximal cytoreduction.” An analysis of 663 consecutive patients treated with 
EPP or EPD showed no statistical difference in survival by procedure at any stage; 5-year overall 
survival (OS) was 12%.5 
Platinum plus multi-targeted anti-folate regimens are standard first-line therapy worldwide for 
patients with advanced or unresectable MPM and have a good performance status. The 
EMPHACIS trial of pemetrexed plus cisplatin, versus cisplatin alone, in chemotherapy-naïve 
patients with MPM who were not eligible for surgery demonstrated statistically significant 
improvements in response rate (41.3% versus 16.7%) and median overall survival (MOS) 
(12.1 versus 9.3 months) in the combination-treated patients.6 A similar study of raltitrexed plus 
cisplatin, versus cisplatin alone, also showed improved response rates (23.6% versus 13.6%) and 
MOS (11.4 versus 8.8 months) in patients receiving combination therapy. In relapsed or refractory 
disease, typically a gemcitabine or vinorelbine-based regimen is used in patients with good 
performance status; however, there are no published Phase 3 clinical trials that have shown 
improvements in OS associated with second-line therapies.7 Therefore, there remains a significant 
unmet need for new treatments in patients with relapsed MPM. 
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adenovirus viral vector itself also elicits additional “danger signals,” further potentiating 
anti-tumor immune responses.14 This multi-modal approach alters the tumor microenvironment, 
kills tumor cells, and stimulates the innate and adaptive immune systems. 
1.1 
Overview of Nonclinical Studies 
 
 
1.2 
Overview of Clinical Studies 
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anti-tumor humoral immune responses in 7 out of 8 patients; clinical responses characterized by 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2.1 
Celecoxib 
Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, 
analgesic, and anti-pyretic activities in animals. The mechanism of action of celecoxib is believed 
to be related to inhibition of cyclooxygenase (COX)-2, which is expressed at high levels in 
inflamed tissues, where it is induced by mediators of inflammation. It also plays physiological 
roles in a limited number of tissues, including the female reproductive tract, the kidney, and 
possibly the vascular endothelium. Celecoxib is indicated in adults for the symptomatic relief in 
the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. In some regions, 
it is also indicated for the management of acute pain in adults and for the treatment of primary 
dysmenorrhea, as well as for juvenile rheumatoid arthritis in patients 2 years and older. In addition 
to its approved uses in inflammatory pain conditions, celecoxib has also been shown to reduce the 
number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP), when 
administered at a dose of 400 mg BID as an adjunct to usual care (e.g., endoscopic surveillance 
and surgery).20 
Cyclooxygenase-2 is known to be overexpressed in various malignancies, including pancreatic, 
gastric, prostate, lung, colon, breast, liver, brain, and esophageal cancer. The mechanisms by which 
COX-2 inhibition results in anti-tumor activity include direct inhibition of tumor cell growth, 
blockade of angiogenesis, suppression of apoptosis, and decreased carcinogenic metabolite 
production.21 In addition to the observed anti-tumor effects of COX-2 inhibition, prostaglandins 
derived from arachidonic acid through the COX enzymes have very potent immunosuppressive 
properties, particularly prostaglandin E2 (PGE2). Prostaglandin E2 has been shown to inhibit 
T-cell proliferation and interferon gamma (IFN-γ) and interleukin (IL)-2 production, while 
enhancing IL-4 and IL-10 production, thereby promoting a T helper type 2 response over a Th1 
anti-tumor response. Furthermore, PGE2 has been shown to prevent the maturation and ability of 
dendritic cells to present antigen and to produce IL-12 and IFN-γ.22 
Human mesothelioma tumors have been shown to overexpress COX-2, and high levels of COX-2 
protein have been demonstrated to be a prognostic factor indicating poor outcome in this tumor, 
suggesting that COX-2 may contribute to the pathogenesis of malignant mesothelioma.23,24 
Blockade of COX-1 and/or COX-2 has some direct anti-proliferative effects on human 
mesothelioma cell lines and has been reported to restore depressed lymphokine-activated killer 
cell activity ex vivo.25 
The potential interaction between immunotherapy and COX-2 inhibition has been evaluated in a 
mouse model of MPM. In these experiments, mice were injected with MPM cells in the flank 
region. When flank tumors were established, treatment with a combination of COX-2 inhibition 
and Ad-IFN resulted in complete eradication of tumors.  
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Celecoxib 400 mg BID has been studied in patients with FAP. In a study of celecoxib administered 
for 6 months to patients with FAP, administration of a dose of 400 mg BID was well tolerated, and 
there were no significant differences in the incidence of any adverse event between the celecoxib 
groups (100 mg BID and 400 mg BID) and the placebo group.20 
Based on the potential role of COX-2 in the pathogenesis and prognosis of MPM and the 
encouraging nonclinical data supporting the beneficial effects of COX-2 inhibition combined with 
immunotherapy, celecoxib was included in the second clinical study of rAd-IFN in patients with 
MPM. In this study, patients received celecoxib orally at a dose of 400 mg BID for a period of 
14 days, starting 3 days before the first dose of rAd-IFN. The outcomes of this study indicated that 
administration of rAd-IFN appeared to have an acceptable tolerability profile when given in 
combination with celecoxib 400 mg BID and followed by treatment with chemotherapy. Efficacy 
outcomes also appeared encouraging, with an MOS in the entire study population of 13 months. 
1.2.1.1 
Rationale for celecoxib dosing 
 
1.2.2 
Gemcitabine 
Gemcitabine is used across a range of solid tumors as a single agent or in combination with other 
anti-neoplastic agents. In addition, a number of nonclinical studies have indicated that gemcitabine 
has immuno-modulatory properties that make it an attractive agent to combine with IFN-α2b, 
which itself stimulates immune-mediated anti-tumor effects: 
1. B-cell proliferation and antibody production in response to tumor antigens is inhibited by 
gemcitabine, a phenomenon that may skew anti-tumor immunity towards beneficial T-cell 
responses;26,27 
2. The frequency of CD11b+GR1+ myeloid-derived suppressor cells is reduced by gemcitabine; 
these cells have been shown to induce tumor-associated antigen-specific CD8+ T-cell 
tolerance;28 
3. Through its effects on apoptosis of established tumors, gemcitabine may enhance the dendritic 
cell dependent cross-presentation of tumor antigens to T-cells;29 and 
4. The range of tumor antigens eliciting cytotoxic T-lymphocyte responses in vivo is expanded 
by gemcitabine and it promotes infiltration of tumor-specific T-cells.30 
The effects of co-administration of rAd-IFN and gemcitabine (plus cisplatin) have been studied in 
a mouse model of MPM. In this model, the combination of rAd-IFN and gemcitabine (plus 
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cisplatin) had a statistically better response than chemotherapy alone or rAd-IFN alone (p<0.05). 
All 6 mice in the combination therapy group were cured.31 
In the second study of rAd-IFN in 40 patients with MPM, 15 patients received second-line 
gemcitabine (±platinum). In this cohort of second-line patients, MOS was 10 months 
(95% confidence interval, 4 to 21), which compares favorably with placebo response rates 
observed in the second-line treatment setting.32,33 Furthermore, approximately 20% of second-line 
patients receiving gemcitabine-based chemotherapy were alive at 24 months, suggesting a 
prolonged immunologic phenomenon. While patients who received pemetrexed as a second-line 
therapy also demonstrated encouraging MOS (26 months; 95% confidence interval, 3 to ∞), the 
number of patients was small (n=7), and these patients had previously responded to pemetrexed as 
first-line therapy, and therefore had good response characteristics. 
Although there are no approved treatments for MPM in the second-line setting, the National 
Comprehensive Cancer Network Clinical Practice Guidelines for MPM recommend gemcitabine 
as an appropriate second-line treatment.34 
1.2.2.1 
Rationale for gemcitabine dosing 
Based on the known immune-modulatory properties of gemcitabine and its activity when 
combined with rAd-IFN in a mouse model of MPM, observed clinical outcomes in patients treated 
with rAd-IFN followed by gemcitabine as second-line therapy, and national guidelines supporting 
its use, gemcitabine has been selected as suitable second-line therapy for all patients participating 
in the proposed study. Given that the key comparison in the study is between patients who receive 
and who do not receive rAd-IFN, it is considered appropriate for all enrolled patients to receive 
gemcitabine. Thus, the study will not draw conclusions on the effectiveness of gemcitabine alone 
in the second-line setting. 
1.3 
Rationale for rAd-IFN Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
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the cycle is modified due to toxicity/delay. Biocorrelates of response to intrapleural rAd-IFN will 
also be evaluated. 
1.4 
Risk/Benefit 
1.4.1 
Potential Risks of rAd-IFN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.1.1 
Viral shedding 
In the context of providing a comprehensive risk assessment, additional monitoring will be 
performed during this study, notably to assess viral shedding in an initial cohort of patients prior 
to exposing a larger number of patients to rAd-IFN. 
The 28-day sampling duration for viral shedding is based on data with a similar vector containing 
the IFN-β gene, where vector shedding was observed on skin at 24 days and longer in the pleural 
fluid of some patients. It is anticipated that some shedding may occur at and/or around the IPC or 
similar device site; however, available data indicate that no shedding in other biological materials 
is expected. The study containment processes are intended to prevent horizontal transmission from 
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the site of administration. The sample size for the Viral Shedding Cohort will be approximately 
10 patients. Samples will be analyzed by polymerase chain reaction. 
1.4.1.2 
Inclusion of patients with pre-existing adenovirus neutralizing antibody titers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.2 
Potential Benefits of rAd-IFN 
 
 
 
 
 
 
 
 
 
 
 
 
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1.4.3 
Potential Risks and Benefits of Celecoxib 
The risk/benefit balance favors inclusion of celecoxib at a dose of 400 mg BID for 14 days in the 
proposed Phase 3 clinical study. There is a sound scientific rationale supporting the role of COX-2 
in MPM pathogenesis, and preclinical evidence from 2 mouse models supports the potential 
synergy of IFN-based gene therapy when administered with COX-2 inhibition.
 
In accordance with the labelled contraindications to celecoxib use, patients who i) have 
experienced asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria, or other 
allergic-type reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors; 
ii) have a history of ulcer disease or gastrointestinal bleeding; iii) have significant renal or hepatic 
impairment; iv) have New York Heart Association class III or IV congestive heart failure; v) have 
a history of myocardial infarction in the past 12 months or unstable angina; vi) have uncontrolled 
or poorly controlled hypertension requiring 3 or more anti-hypertensive drugs; or vii) have known 
hypersensitivity to celecoxib or sulfonamides will be excluded from the study, thus further 
reducing the likelihood of patients experiencing adverse effects relating to celecoxib treatment. 
1.4.4 
Potential Risks and Benefits of Gemcitabine 
The risk/benefit balance favors inclusion of gemcitabine at a dose of 1250 mg/m2 on Days 1 and 8 
of a repeating 21-day cycle in the proposed Phase 3 clinical study. Data from a mouse model of 
MPM indicate that addition of gemcitabine to a treatment regimen of rAd-IFN and celecoxib 
results in a very pronounced suppression of tumor growth. In a clinical trial of rAd-IFN in MPM, 
patients who received second line treatment with gemcitabine showed encouraging outcomes with 
respect to MOS, comparing favorably to historical controls and other second line trials. 
In accordance with the labelled contraindications to gemcitabine use, patients with known 
hypersensitivity to gemcitabine or who are breastfeeding will be excluded from the study. Patients 
with significantly impaired renal function, impaired hepatic function, or stage IV extrathoracic 
metastatic disease will also be excluded, reflecting special warnings and precautions for 
gemcitabine. Patients will undergo regular safety monitoring on Days 1 and 8 of each gemcitabine 
treatment cycle, allowing for the detection of adverse effects of treatment. Additionally, the dose 
of gemcitabine can be modified based on the results of safety laboratory results or observed 
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toxicity. Gemcitabine will be permanently discontinued in patients who develop posterior 
reversible encephalopathy syndrome, capillary leak syndrome, or hemolytic uremic syndrome. 
1.5 
Coronavirus Disease 2019 
In March 2020, the Coronavirus Disease 2019 (COVID-19), caused by infection with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), was characterized as a pandemic by the 
WHO. The COVID-19 pandemic continues to impact clinical studies worldwide due to 
quarantines, clinical site closures, travel limitations, diversion of resources, and/or general 
interruptions in study-specific procedures. Any impacts on the outcomes of this study, including 
any protocol deviations that result from COVID-19 illness and/or COVID-19 control measures, 
will be discussed in the Clinical Study Report. 
If any patient is suspected of contracting COVID-19 or has a confirmed diagnosis of COVID-19, 
this information should be communicated to Medpace immediately. This information must be 
documented and recorded as an adverse event with the relevant concomitant medications 
prescribed clearly documented in the patient’s source notes. 

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2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to compare the OS associated with rAd-IFN, when 
administered with celecoxib and gemcitabine, versus that associated with celecoxib and 
gemcitabine alone for the treatment of patients with MPM who have received a minimum of 
1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an 
anti-folate and platinum combination regimen. 
2.2 
Secondary Objectives 
The secondary objectives of this study are:  
 To compare between rAd-IFN, when administered with celecoxib and gemcitabine, versus that 
associated with celecoxib and gemcitabine alone for the treatment of patients with MPM who 
have received a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 
1 of which must have been an anti-folate and platinum combination regimen, with respect to: 
o Survival rate at 12 months and every 6 months thereafter; 
o Progression-free survival (PFS); 
o Best response (complete response, partial response, or stable disease); and 
o Safety of rAd-IFN; and 
 To evaluate rAd-IFN, when administered with celecoxib and gemcitabine, in a sub-set of 
patients with MPM who have received a minimum of 1 treatment regimen and a maximum of 
2 treatment regimens, 1 of which must have been an anti-folate and platinum combination 
regimen, with respect to viral shedding and biodistribution. 
2.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
 To compare between rAd-IFN, when administered with celecoxib and gemcitabine, versus that 
associated with celecoxib and gemcitabine alone for the treatment of patients with MPM who 
have received a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 
1 of which must have been an anti-folate and platinum combination regimen, with respect to: 
o Health-related Quality-of-Life (QoL), 
o The relationship between immunological status and response to treatment, and 
o Biocorrelates of response to treatment. 

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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
3.1.1 
Overview 
The study is an open-label, randomized, parallel group study conducted in patients with MPM and 
confirmed epithelioid or biphasic histology (if biphasic, histology must be predominantly [50%] 
epithelioid) who have received a minimum of 1 treatment regimen and a maximum of 2 treatment 
regimens, 1 of which must have been an anti-folate and platinum combination regimen. 
Screening assessments must be completed within 28 days prior to Study Day 1, and eligible 
patients will be randomized to either: 
1. Treatment group: rAd-IFN (Study Day 1) + celecoxib (Study Days 1 to 14) + gemcitabine 
(Study Days 14 and 21 [i.e., Days 1 and 8 of the first gemcitabine treatment cycle], gemcitabine 
will be administered on a 21-day cycle, unless the cycle is modified due to toxicity/delay, and 
repeated every 3 weeks until disease progression/early termination [ET]); or 
2. Control group: celecoxib (Study Days 1 to 14) + gemcitabine (Study Days 14 and 21 
[i.e., Days 1 and 8 of the first gemcitabine treatment cycle], gemcitabine will be administered 
on a 21-day cycle, unless the cycle is modified due to toxicity/delay, and repeated every 
3 weeks until disease progression/ET). 
An extension to the Screening Period will be permitted on a case-by-case basis following 
discussion between the Investigator, the Medical Monitor, and/or the Sponsor. The reason(s) for 
the extension is to be clearly documented. 
The target interval between randomization and Study Day 1 should be up to 7 days and no greater 
than 14 days. Any extension beyond 14 days will be considered on a case-by-case basis, following 
discussion between the Investigator, Medical Monitor, and Sponsor. 
The design of the study is summarized in Figure 1. 
Figure 1. Study Schematic 
 
BID = twice daily; ET = early termination; i.v. = intravenous; MPM = malignant pleural mesothelioma; po = oral; 
rAd-IFN = recombinant adenovirus interferon alpha-2b; vp = viral particles. 
Treatment Phase 
Patients randomized to receive rAd-IFN (treatment group) will have an IPC or similar device either 
previously in place or inserted for the study, permitting drug administration to an accessible pleural 

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space. The rAd-IFN will be diluted to a volume of 25 mL using sterile normal saline and will be 
administered directly to the pleural space via the IPC or similar device. The IPC or similar device 
will then be flushed with up to 20 mL of sterile normal saline. 
Patients will receive gemcitabine until disease progression/ET. All adverse events will be captured 
from the time of the main study’s informed consent through 30 days after the last dose of study 
treatment (rAd-IFN, celecoxib, and gemcitabine). All TEAEs and SAEs will be followed until 
resolution or stabilization. 
Clinical Follow-Up Phase 
Following disease progression/ET, patients in the rAd-IFN treatment group will be followed every 
6 months (±14 days) for survival and safety for up to 5 years after receiving the first dose of 
rAd-IFN, assuming consent has not been withdrawn. All previously recorded TEAEs and SAEs 
will be followed until resolution or stabilization. Patients in the control group will not continue in 
the clinical Follow-up phase and study participation will conclude after end of study treatment. 
The study will be conducted in up to 45 sites globally. 
3.1.2 
Viral Shedding Cohort 
A sub-set of patients randomized to the rAd-IFN treatment group will be asked to participate in 
the Viral Shedding Cohort to assess rAd-IFN viral vector shedding. Patients in the Viral Shedding 
Cohort will be required to sign an additional section of the main study informed consent form 
(ICF) prior to performing any viral shedding-related procedures. The Viral Shedding Cohort will 
include the first 10 patients randomized to the rAd-IFN treatment group who consent to 
participation. The evaluations will include collection of blood (for biodistribution), saliva, urine, 
pleural access site swab, and pleural fluid sample as indicated in the Schedule of Procedures 
(Table 1). The pleural fluid sample will be collected using the IPC or similar device (if the IPC or 
similar device is still in place). See Appendix G for pleural fluid sample collection procedure. 
3.1.3 
Study Duration and End of Study 
The study will consist of the following periods: 
 Screening Period of up to 28 days; 
An extension to the Screening Period will be permitted on a case-by-case basis following 
discussion between the Investigator, the Medical Monitor, and/or the Sponsor. 
 14-day treatment period with rAd-IFN (Study Day 1) + celecoxib (Study Days 1 to 14) in 
treatment group and celecoxib (Study Days 1 to 14) in control group; 
 21-day gemcitabine treatment cycles, unless the cycle is modified due to toxicity/delay, 
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 Clinical Follow-Up Visits every 6 months (±14 days) for up to 5 years: 
o Patients in the rAd-IFN treatment group will be followed for survival and safety after 
receiving the first dose of rAd-IFN; and 
o Patients in the control group will not continue with clinical Follow-up Visits and study 
participation concludes after the end of study treatment. 
Note: Under previous Protocol versions all patients were to be followed for survival and safety 
every 3 months, including patients who have withdrawn prior to commencing Study Day 1 
treatment. 
Patients will discontinue study treatment at the time of disease progression or ET 
(i.e., development of an unacceptable toxicity, withdrawal of consent, or termination of the study). 
A patient's participation in the study will conclude after the completion of clinical Follow-up Visits 
(rAd-IFN treatment group), end of study treatment (control group), or if the withdrawal criteria 
are met (see Section 4.3). The end of the study (study completion) is defined as the last visit of the 
last patient.  
The final analysis will be conducted after the forty-fourth event (death) or at least 30 months after 
the last patient is randomized, whichever occurs first. The long-term safety follow-up data will be 
collected. 
3.1.4 
Discontinuation of Screening and Enrollment Into the Study 
 
 
 
 
 
 
 
 
 
3.2 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be convened for this study to 
monitor safety, efficacy, and study integrity. All aspects of the DSMB’s scope of review and 
procedures will be detailed in a DSMB charter. 
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3.3 
Stopping Rules 
The DSMB may recommend that the study stop recruitment if any emergent safety issue is 
identified that changes the benefit/risk balance to study patients (see Section 9.2.4 for additional 
details). 
3.4 
Study Indication 
The indication for this study is MPM. 

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4 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Aged 18 years or older at the time of consent; 
2. Able to give informed consent;  
3. Has a confirmed histological diagnosis of MPM with histological type epithelioid or biphasic 
(if biphasic, histology must be predominantly [50%] epithelioid). Histological diagnosis of 
MPM will be confirmed centrally using specimens or slides from tumor specimens obtained at 
the time of initial presentation or a subsequent procedure. Central confirmation of diagnosis 
with immunohistochemistry will be performed, and independent central confirmation will be 
required for study entry;  
4. Measurable disease, per modified Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 
(see Section 7) for pleural mesothelioma;42 
5. Has received a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 
which may have been chemotherapeutic and/or immunotherapeutic treatment regimens for 
MPM which included at least 1 anti-folate and platinum combination regimen; 
 Adjuvant or neoadjuvant therapy represent 1 line of therapy each; 
 Patients who have undergone primary surgical resection and/or radiation therapy to the 
pulmonary site are eligible to participate. For clarity, surgical resection and/or radiation 
therapy to the pulmonary site are not exclusionary and are not considered a line of therapy;  
 Treatment that is split between pre-surgical resection and post-surgical resection and is the 
same regimen will be counted as 1 regimen. Patients meeting this condition should be 
discussed with the Medical Monitor prior to including the patient in the study;  
6. Has a pleural space accessible for IPC or similar device insertion. Patients with a previously 
inserted IPC or similar device may be enrolled, and the pre-existing IPC or similar device can 
be used for vector administration as long as it is functional and has no evidence of local 
infection; 
7. Life expectancy 12 weeks in the judgement of the Investigator; 
8. Eastern Cooperative Oncology Group (ECOG) status of 1 or 0; 
9. Female and male patients: 
 Female patients of childbearing potential must have a negative pregnancy test upon entry 
into this study and agree to use a highly effective method of contraception from Screening 
until 1 month after the last dose of gemcitabine; 
o Highly effective methods of contraception that result in a low failure rate (i.e., <1% 
per year) when used consistently and correctly include combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, or 

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implantable), intrauterine device, intrauterine hormone-releasing system, bilateral 
tubal occlusion, vasectomized partner, or sexual abstinence;  
o True abstinence, when in line with the preferred and usual lifestyle of the patient, 
is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of study participation and for 
1 month after the last dose of gemcitabine. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, and post-ovulation method) and withdrawal are not 
acceptable methods of contraception; and 
 Female patients of non-childbearing potential must be either postmenopausal (no menstrual 
period for a minimum of 12 months) or surgically sterile upon entry into the study; 
 Male patients must be either surgically sterile or agree to use a double-barrier contraception 
method from Screening until 6 months after the last dose of gemcitabine;  
o Where available and in accordance with local practice, male patients must be 
advised to seek further advice regarding cryoconservation of sperm prior to 
gemcitabine treatment due to the possibility of infertility after therapy with 
gemcitabine; and 
10. Adequate laboratory values at Screening: 
 Hemoglobin 9 g/dL; 
 White blood cell count 3500/µL; 
 Absolute neutrophil count 1500/µL; 
 Platelet count 100,000/µL; 
 International normalized ratio (INR) and activated partial thromboplastin time (aPTT) 
below the upper limit of normal (ULN). It is expected that patients receiving 
anticoagulation therapy will not have INR and aPTT results that fall within normal limits. 
It is not intended to exclude these patients and, therefore, medical discretion is permitted 
for patients who have clinically acceptable results in regards to their current concomitant 
anticoagulant therapy; 
 Aspartate aminotransferase (AST) 3 × ULN; 
 Alanine aminotransferase (ALT) 3 × ULN; 
 Total bilirubin 2 × ULN;  
 Estimated glomerular filtration rate (calculated using the Modification of Diet in Renal 
Disease study equation [see Appendix B]) 50 mL/min/1.73 m2; and 
 Serum albumin 2.5 g/dL. 

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4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Is “treatment-naïve” (i.e., has not received at least 1 anti-folate and platinum combination 
regimen); 
2. Has previously received 3 or more lines of systemic chemotherapeutic or immunotherapeutic 
treatment. Treatment that is split between pre-surgical resection and post-surgical resection 
and is the same regimen will be counted as 1 regimen. Patients meeting this condition should 
be discussed with the Medical Monitor prior to including the patient in the study;  
3. Has previously received treatment with gemcitabine; 
4. Has stage IV extrathoracic metastatic disease; 
5. Inadequate pulmonary function of clinical significance as per Investigator review; 
6. Clinically significant pericardial effusion (i.e., as judged by the Investigator and/or requiring 
drainage) detected by computed tomography (CT) scan at Screening. Standard of care CT 
scans completed within 2 weeks prior to Screening may be used in place of the Screening CT 
scan on a case-by-case basis as agreed with the Medical Monitor; 
7. Prior therapy(ies), if applicable, must be completed according to the criteria below prior to 
vector administration: 
 Cytotoxic chemotherapy, at least 21 days from last dose; 
 Non-cytotoxic chemotherapy (e.g., small molecule inhibitor), at least 14 days from last 
dose; 
 Monoclonal antibody, at least 30 days from last dose; 
 Non-antibody immunotherapy (e.g., tumor vaccine), at least 42 days from last dose; 
 Radiotherapy, at least 14 days from last local site radiotherapy; 
 Hematopoietic growth factor, at least 14 days from last dose; or 
 Study drug, 30 days or 5 half-lives, whichever is longer, from last dose; 
8. Patient previously treated with IFNs (e.g., for chronic active hepatitis); 
9. Suspected/known hypersensitivity to IFN-α2b or rAd-IFN (including any of its excipients);  
10. Known hypersensitivity to celecoxib (including any of its excipients) or sulfonamides; 
11. Known hypersensitivity to gemcitabine (including any of its excipients); 
12. Impaired cardiac function or clinically significant cardiac disease including the following: 
 New York Heart Association class III or IV congestive heart failure; 
 Myocardial infarction within the last 12 months; and 
 Patients known to have impaired left ventricular ejection fraction per institutional standards 
and of clinical significance as per Investigator review; 
13. Women who are pregnant or breastfeeding; 

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14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, depression, 
or psychiatric illness/social situations within the last 12 months; 
15. Patients with active, known, or suspected auto-immune disease or a syndrome that requires 
systemic or immunosuppressive agents (oral prednisolone or equivalent at a dose of 10 mg 
per day is permitted);  
Note: patients with vitiligo, residual hypothyroidism due to auto-immune disease only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
16. History of asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria, or other 
allergic-type reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 
inhibitors; 
17. History of ulcer disease or gastrointestinal bleeding; 
18. Uncontrolled or poorly controlled hypertension (i.e., blood pressure >160/100 mmHg) 
requiring 3 or more anti-hypertensive drugs; 
19. Heart rate corrected QT interval using Fridericia’s formula >470 ms on resting 12-lead 
electrocardiogram (ECG); 
20. Patients receiving lithium;  
21. Any significant disease which, in the opinion of the Investigator, would place the patient at 
increased risk of harm if he/she participated in the study; 
22. History of a prior malignancy for which treatment was completed <2 years prior to Screening 
or for which the patient has continued evidence of disease, or concurrent malignancy that is 
clinically unstable and requires tumor-directed treatment; 
23. Has a congenital or acquired immunodeficiency, including patients with known history of 
infection with human immunodeficiency virus; 
24. Has both serum albumin 2.5 to 3.5 g/dL and total bilirubin >1.5  ULN;  
25. History of clinically significant inflammatory bowel disease requiring systemic (parenteral) 
immunosuppressive therapy within 5 years prior to Screening; or 
26. History of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. 
4.3 
Withdrawal Criteria 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
 The patient withdraws consent or requests discontinuation from the study for any reason; 
 Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol; 
 Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition that indicates to the Investigator that continued participation 
is not in the best interest of the patient; 

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 Pregnancy; 
 Requirement of prohibited concomitant medication; 
 Patient failure to comply with protocol requirements or study-related procedures; or  
 Termination of the study by the Sponsor or the regulatory authority. 
If a patient withdraws prematurely from the study, after commencing Study Day 1 treatment and 
prior to disease progression, due to the above criteria or any other reason, study staff should make 
every effort to complete the full panel of assessments scheduled for the ET Visit. The reason for 
patient withdrawal must be documented in the electronic case report form (eCRF). Where 
applicable, patients in the rAd-IFN treatment group who have withdrawn from study treatment, 
not including those who have withdrawn prior to commencing Study Day 1 treatment, will be 
asked if they would agree to continue to be followed for survival and safety every 6 months 
(14 days) for up to 5 years.  
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records. 
Withdrawn patients will not be replaced. 

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5 
STUDY TREATMENTS AND INTRAPLEURAL CATHETER OR SIMILAR 
DEVICE PROCEDURES 
5.1 
Nadofaragene Firadenovec (rAd-IFN) 
 
 
 
 
 
 
 
 
5.1.1 
Formulation, Packaging, and Handling 
 
 
 
 
5.1.2 
Dosage and Administration 
 
 
 
 
 
5.1.2.1 
Intrapleural catheter or similar device placement 
Patients with a previously inserted IPC or similar device may be enrolled, and the pre-existing IPC 
or similar device can be used for vector administration as long as it is functional and has no 
evidence of local infection. 
For patients allocated to the rAd-IFN treatment group that do not have an existing IPC or similar 
device in situ, an IPC or similar device will be inserted under local anesthesia as an outpatient 
visit. Sedation and analgesia may be administered as needed for the patient’s comfort. 
If this is not technically feasible, an IPC or similar device may be inserted via thoracoscopy under 
general anesthesia. Some cases may require interventional radiology for the placement of a 
tunneled or non-tunneled catheter (depending on each individual case).  
Patients with minimally accessible pleural space as a result of pleurodesis or prior surgery may 
require video-assisted thoracoscopic placement of the IPC or similar device. 
CCI
CCI
CCI
CCI

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In each circumstance (i.e., patients with a previously inserted or a newly inserted IPC or similar 
device), the correct position of the IPC or similar device will be confirmed by the Investigator or 
an appropriately qualified designee, in accordance with local institutional practice. 
After IPC or similar device insertion (if not already in situ) and prior to vector instillation, patients 
will be monitored carefully for dyspnea, chest pain, infection, and rapid symptomatic 
re-accumulation of the malignant pleural effusion. 
5.1.2.2 
rAd-IFN administration via intrapleural catheter or similar device 
rAd-IFN administration will be performed under sterile conditions and will include the following 
steps: 
1. Maximally drain the pleural space prior to rAd-IFN infusion; 
Note: If the Investigator determines the pleural space cannot be drained sufficiently (i.e., to 
accommodate up to 45 mL of fluid [25 mL of rAd-IFN and up to 20 mL saline flush]), the 
patient will be withdrawn from the study. 
2. Clamp the IPC or similar device after drainage is complete; 
3. Attach syringe with rAd-IFN to the stop-cock; 
4. Infuse rAd-IFN over 2 to 5 minutes, as tolerated by the patient; 
5. Flush the IPC or similar device with up to 20 mL of sterile normal saline; 
6. Clamp the IPC or similar device; and 
7. Re-dress site as per standard of care. 
It is recommended that the pleural space is not drained within the first 24 hours post-rAd-IFN 
administration, unless deemed necessary by the Investigator. 
5.1.3 
Intrapleural Catheter or Similar Device Removal Post-rAd-IFN Administration 
At the discretion of the Investigator, the IPC or similar device may be removed at any time during 
the 6-hour post-rAd-IFN administration observation period or at the Study Day 2 Visit for patients 
in the rAd-IFN treatment group. The Investigator may keep the IPC or similar device in situ beyond 
the Study Day 2 Visit if required for clinical purposes.  
5.1.4 
Patient Preparation and Monitoring 
Immediately before (within 10 minutes prior to the start time of rAd-IFN administration), during, 
and immediately after (within 10 minutes after the start time of rAd-IFN administration) rAd-IFN 
administration, 
 Patients should be monitored using pulse oximetry, 
 Oxygen via nasal cannula should be administered at approximately 2 L/min as required, and 
 Cardiac telemetry may also be used to monitor patients as per the Principal Investigator’s 
discretion.  
These safety procedures should be continued post-rAd-IFN administration as per the Principal 
Investigator’s or designee’s discretion.  

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An intravenous cannula should be placed prior to rAd-IFN administration, and normal saline (or 
equivalent as per local institutional standards) should be administered slowly.  
Analgesia may be administered as required, in accordance with local institutional standards. 
Post-rAd-IFN administration, 
 Body temperature will be monitored every hour (±10 minutes) for 6 hours; and 
 Blood pressure, respiratory rate, pulse rate, and oxygen saturation will be measured and 
recorded every 15 minutes (±5 minutes) for the first 2 hours; every 30 minutes (±10 minutes) 
for the next 2 hours; then, every hour (±10 minutes) for the remainder of the inpatient 
monitoring period up to 6 hours post-rAd-IFN administration (unless further surveillance is 
required as per the Principal Investigator’s discretion). 
After 6 hours of observation, the patient can go home if vital signs and oxygen saturation are within 
acceptable limits, as per local institutional practice and guidelines, following assessment by the 
Investigator or an appropriately qualified designee. After leaving the facility, the patient may use 
acetaminophen or equivalent (as per local institutional standards) for the management of pyrexia, 
should it occur. rAd-IFN treatment group patients will return to the site to be reviewed 
approximately 24 hours after rAd-IFN administration (see Section 6.3.2). 
In the event the patient experiences CRS, see Appendix E for details on CRS grading. Local 
guidelines for the management and treatment of CRS should be followed. In the absence of any 
such appropriate guidelines, see Appendix E for details on the therapeutic strategy for the 
management of CRS. 
5.2 
Celecoxib 
All patients will take oral celecoxib 400 mg BID on Study Days 1 to 14; no celecoxib should be 
taken after Study Day 14. The first dose of celecoxib will be administered 1 to 2 hours prior to 
rAd-IFN administration (rAd-IFN treatment group) or on Study Day 1 (control group). The patient 
will be provided with the remainder of the 14-day treatment to be taken at home. The patient will 
be provided with a celecoxib diary and instructed that the next dose should be taken approximately 
12 hours post-rAd-IFN administration (rAd-IFN treatment group) or approximately 12 hours after 
the first celecoxib dose (control group) and 400 mg orally BID, at approximately 12-hour intervals, 
thereafter. If the patient receives the first dose of celecoxib late on Study Day 1, such that the 
patient is only able to take 1 dose of celecoxib on Study Day 1, the patient must not take a celecoxib 
dose on Study Day 15, regardless of whether or not the patient has taken all planned celecoxib 
doses. If BID dosing does not occur on Study Day 1 for this reason, it will not be considered a 
protocol deviation. 
If, during treatment with celecoxib, patients experience Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 3 or higher deterioration in renal or hepatic function, appropriate 
measures should be taken, and celecoxib therapy should be discontinued. Celecoxib should be 
discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of 
hypersensitivity. It should be noted that celecoxib may mask fever and other signs of inflammation. 
If the patient vomits after taking celecoxib, the patient should not replace that dose; instead, the 
patient should wait until the next scheduled time point to take their next scheduled celecoxib dose. 
Storage and administration should be done in compliance with the instructions provided by the 
manufacturer. 

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5.3 
Gemcitabine 
Gemcitabine will be administered for all patients starting on Study Day 14 (gemcitabine Cycle 1 
Day 1) with intravenous administration of 1250 mg/m2 on Days 1 and 8 of a 21-day gemcitabine 
cycle, unless the cycle is modified due to toxicity/delay, and continued every 3 weeks until disease 
progression/ET.  
The regimen will be administered in compliance with local clinical practice and manufacturer 
guidelines. Dose banding may be permitted for gemcitabine in accordance with local policy. 
Gemcitabine will be permanently discontinued in patients who develop posterior reversible 
encephalopathy syndrome, capillary leak syndrome, or hemolytic uremic syndrome at any time in 
the study, and supportive measures will be implemented. Supportive measures will include blood 
pressure control and anti-seizure therapy for posterior reversible encephalopathy. If pulmonary 
effects, such as pulmonary edema, interstitial pneumonitis, or adult respiratory distress syndrome, 
develop at any time during the study, the Investigator should discuss with the Sponsor and consider 
discontinuing gemcitabine. Treatment with gemcitabine should be discontinued if there is 
unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity. See Appendix F 
for further details regarding suggested dose modification strategies for gemcitabine. 
See Section 5.6 for details regarding gemcitabine treatment delay. 
The use of myeloid growth factors is not prohibited; however, their use within the first 30 days 
after rAd-IFN administration must be discussed with the Medical Monitor and Sponsor.  
Gemcitabine (1 g powder for solution) for infusion contains sodium. This should be taken into 
consideration by patients on a controlled sodium diet. 
Storage, handling, and preparation will be done in compliance with local practice and manufacturer 
guidelines.  
5.4 
Storage and Accountability 
The rAd-IFN concentrate should be stored frozen (below -60°C [-76°F]) and thawed under 
ambient temperature and light at the time of preparation. 
An accurate and current accounting of the receipt, storage, and administration of all study drugs 
for each patient will be maintained on an ongoing basis by a member of the study site staff on the 
Investigational Product Accountability Record. Chain of custody will be documented at all stages. 
The study monitor will verify these documents throughout the course of the study. 
5.4.1 
rAd-IFN Biosafety Precautions 
Adenoviruses are classified as Risk Group 2 out of the 4 Risk Group categories (European Union 
Directive 2000/54/EC; National Institutes of Health Recombinant DNA Guidelines 2016; WHO 
Laboratory Safety Manual 3rd Ed, 2004).45,46,47 Risk Group 2 biological agents are usually 
associated with human disease that is rarely serious and for which preventive or therapeutic 
interventions are often available.46 Although viral vectors, such as adenoviruses, may be 
replication deficient, there is always a risk of replication-competent viruses arising from 
spontaneous recombinant events. Because of this, it is recommended that vectors are handled at 
the same biosafety level as the parent virus from which they are derived. In the case of 
adenoviruses, and specifically rAd-IFN, this is Risk Group 2.47 

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All biosafety precautions and procedures required by the Institutional Biosafety Committee and/or 
local regulatory authorities must be observed. 
Biosafety procedures and policies already established at the sites are sufficient for the management 
of rAd-IFN; however, the rAd-IFN Clinical Biosafety Precautions described in the current 
Investigator’s Brochure48 provide an overview of safety practices, safety equipment, and facility 
requirements that are advised during the handling, preparation, and administration of rAd-IFN and 
in the event of spillage. 
See Section 3.3 of the Investigator’s Brochure for further details related to rAd-IFN Biosafety 
Precautions.  
5.5 
Treatment Groups 
Patients will be randomized to either: 
 Treatment group: rAd-IFN (Study Day 1) + celecoxib (Study Days 1 to 14) + gemcitabine 
(Study Days 14 and 21 [i.e., Days 1 and 8 of the first gemcitabine treatment cycle], gemcitabine 
will be administered on a 21-day cycle, unless the cycle is modified due to toxicity/delay, and 
repeated every 3 weeks until disease progression/ET); or 
 Control group: celecoxib (Study Days 1 to 14) + gemcitabine (Study Days 14 and 21 
[i.e., Days 1 and 8 of the first gemcitabine treatment cycle], gemcitabine will be administered 
on a 21-day cycle, unless the cycle is modified due to toxicity/delay, and repeated every 
3 weeks until disease progression/ET). 
5.5.1 
Treatment Compliance 
rAd-IFN will be administered via the intrapleural route by the Principal Investigator or designee 
and recorded in the source documents and eCRF. 
The first dose of celecoxib will be administered orally 1 to 2 hours prior to rAd-IFN administration 
(rAd-IFN treatment group) or on Study Day 1 (control group) and provided to the patient by 
hospital staff while in the hospital. The patient will be provided with the remainder of the 14-day 
treatment to be taken at home. The patient will be provided with a celecoxib diary and instructed 
that the next dose should be taken approximately 12 hours post-rAd-IFN administration (rAd-IFN 
treatment group) or approximately 12 hours after the first celecoxib dose (control group) and 
400 mg orally BID, at approximately 12-hour intervals, thereafter. If the patient receives the first 
dose of celecoxib late on Study Day 1, such that the patient is only able to take 1 dose of celecoxib 
on Study Day 1, the patient must not take a celecoxib dose on Study Day 15, regardless of whether 
or not the patient has taken all planned celecoxib doses. If BID dosing does not occur on Study 
Day 1 for this reason, it will not be considered a protocol deviation. The dosing diary and unused 
celecoxib capsules will be returned to the site staff at the next visit to check for compliance. 
Gemcitabine will be administered for all patients intravenously by site staff on a standard 3-week 
cycle regimen as per local clinical practice and manufacturer guidelines. This will be recorded in 
the source documents and eCRF. See Section 5.6 for details regarding gemcitabine treatment 
delay. 

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5.5.2 
Treatment of Overdose 
In the event of an overdose of rAd-IFN, gemcitabine, or celecoxib, the Investigator should contact 
the Medical Monitor immediately and monitor the patient for possible adverse events/SAEs. 
5.6 
Dose Modification and Treatment Delay 
5.6.1 
rAd-IFN 
No dose modifications of rAd-IFN will be allowed during the study.  
5.6.2 
Celecoxib 
Patients who develop gastrointestinal side effects considered by the Investigator to be attributable 
to celecoxib may be given a proton pump inhibitor or other suitable symptomatic relief at the 
discretion of the Investigator.  
Dose modifications to celecoxib will be considered on an individual basis after discussion between 
the Investigator and Medical Monitor.  
If, during treatment with celecoxib, patients experience CTCAE Grade 3 or higher deterioration in 
renal or hepatic function, appropriate measures should be taken, and celecoxib therapy should be 
discontinued. Celecoxib should be discontinued at the first appearance of skin rash, mucosal 
lesions, or any other sign of hypersensitivity. 
See Appendix F for further details regarding suggested dose modification strategies for celecoxib. 
5.6.3 
Gemcitabine 
Gemcitabine dose level reductions required due to toxicity should be made following the 
guidelines in Appendix F. 
Recommended dose modifications of gemcitabine due to hematological toxicities and adjustments 
related to other toxicities are also provided in Appendix F. 
The following rules will be applied if any of the following gemcitabine doses are missed in the 
21-day gemcitabine cycle: 
 Day 1 of any cycle can be delayed by a maximum of 7 days to accommodate a maximum of 
21 days between the Day 1 dose and the previous cycle’s Day 8 dose; 
 Day 8 of any cycle can be delayed by a maximum of 7 days to accommodate a maximum of 
14 days between the Day 1 dose and the Day 8 dose of the same cycle; and 
 If Day 8 of any cycle is delayed, then the Day 1 dose for the next cycle must occur at least 
14 days and up to a maximum of 21 days after the previous cycle’s Day 8 dose. 
If the maximum delay between a scheduled dose and the next dose is greater than what is described 
above, then this would be considered a missed dose. 
If the time required for recovery from gemcitabine toxicity is more than 21 days, consideration 
should be given to permanently discontinue the patient from study treatment, unless the patient is 
demonstrating benefit overall; in which case, the possibility of remaining on study treatment 
should be discussed between the Investigator, Medical Monitor, and Sponsor after review of the 
associated risks and benefits. 

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Gemcitabine will be permanently discontinued in patients who develop posterior reversible 
encephalopathy syndrome, capillary leak syndrome, or hemolytic uremic syndrome at any time in 
the study, and supportive measures will be implemented. Supportive measures will include blood 
pressure control and anti-seizure therapy for posterior reversible encephalopathy. If pulmonary 
effects, such as pulmonary edema, interstitial pneumonitis, or adult respiratory distress syndrome, 
develop at any time during the study, the Investigator should discuss with the Sponsor and consider 
discontinuing gemcitabine. Treatment with gemcitabine should be discontinued if there is 
unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity.  
Any changes in dose or regimen should be recorded in the source documents and eCRF. 
5.7 
Randomization and Blinding 
This is an open-label study. Eligible patients will be randomized to 1 of the 2 treatment groups. 
Selection bias will be minimized by randomizing patients via an Interactive Response Technology 
(IRT) system. The IRT will stratify patients based on disease stage – stage I/II versus stage III/IV 
(without extrathoracic metastasis). Randomization via the IRT will ensure equal representation of 
disease stages in each treatment group such that there is not preferential allocation of patients with 
better prognosis to one treatment group or the other. Each study site will not know the randomized 
allocation for a patient until they have committed that patient for randomization.  
While this is an open-label study, bias due to study personnel knowing the treatment allocation 
will be reduced by restricting that knowledge on a need-to-know basis. The schedule of assessment 
of tumor response is identical for both treatment groups.  
Bias due to informative censoring of OS will be minimized by performing active follow-up to 
pre-specified data cut-offs and censoring survival at that cut-off. Every effort will be made to trace 
patients. Patients will be informed of the importance of being followed up for survival, and where 
applicable, patients will be asked to confirm if they will agree to survival follow-up even if they 
withdraw from other study activities.  
Appropriate adjustments to the statistical analyses will be made for other factors that may affect 
response to treatment (e.g., age, gender, tumor histology, response to first-line treatment). 
5.8 
Breaking the Blind 
This is an open-label study. Investigators, study staff, and patients will be aware of drug 
assignment. 
5.9 
Prior and Concomitant Medications and/or Procedures 
5.9.1 
Excluded Medications and/or Procedures 
The following medications and products will be prohibited during the study: 
 Other anticancer therapy, including cytotoxic, antibody, retinoid, or hormonal treatment; 
 Other investigational therapeutic agents; and 
 Lithium. 

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5.9.2 
Restricted Medications and/or Procedures 
During the period of celecoxib administration, the following medications and products will be 
restricted: 
 Celecoxib should not be taken, other than as indicated in the protocol; and 
 Other COX-2 inhibitors, standard doses of acetylsalicylic acid, and NSAIDs should not be 
taken. Patients who are receiving low doses of acetylsalicylic acid for cardiovascular 
prophylaxis may continue treatment during the period of celecoxib administration. 
During the period of celecoxib administration and for 72 hours afterwards, the following 
medications and products will be restricted: 
 Patients should not receive concomitant potent inhibitors of cytochrome P450 (CYP)2C9 
(i.e., fluconazole) (see Appendix D); 
 Caution should be taken in patients receiving concomitant substrates of CYP2D6, including 
tamoxifen, beta blockers, anti-depressants, and anti-psychotics (see Appendix D); 
 Blood pressure should be monitored in patients receiving angiotensin converting enzyme 
inhibitors, angiotensin receptor blockers, and beta-blockers; 
 Renal function should be monitored in patients receiving angiotensin-converting enzyme 
inhibitors and angiotensin receptor blockers; 
 Patients receiving concomitant furosemide and thiazide diuretics should be monitored to assure 
diuretic efficacy including antihypertensive effects; and 
 Patients receiving digoxin should have serum digoxin levels monitored. 
During the period of gemcitabine treatment, yellow fever vaccine and other live attenuated 
vaccines are not recommended. 
The use of myeloid growth factors is not prohibited in the event of gemcitabine-related toxicity; 
however, their use within the first 30 days after rAd-IFN administration must be discussed with 
the Medical Monitor and Sponsor. 
5.9.2.1 
rAd-IFN and COVID-19 vaccination 
Although the combination of rAd-IFN and newly approved COVID-19 vaccines has not been 
studied, the use of an approved COVID-19 vaccine is likely to have a positive benefit/risk ratio in 
this vulnerable patient population and is recommended. 
The use of any newly approved COVID-19 vaccine will be determined on an individual basis 
according to the Investigator’s medical judgment, their interpretation of the published information 
available for the vaccine, and in agreement with current regulatory guidelines and local 
institutional practices. 
A temporary, non-specific inflammatory response may be induced by exposure to any adenovirus 
vector. As a general rule, the use of any vaccine should be separated from rAd-IFN treatment by 
2 weeks, if possible. If a COVID-19 vaccine is administered during the study, it should be recorded 
as a concomitant medication in the patient’s eCRF. 

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Therefore, the following actions apply if vaccinating a study patient for COVID-19 and/or if a 
study patient becomes infected with SARS-CoV-2: 
 Administer only approved vaccines. Experimental and/or non-approved COVID-19 
vaccinations should not be administered. 
5.9.2.2 
Celecoxib and COVID-19 vaccination 
The reference safety information for celecoxib warns that its use may mask fever and other signs 
of inflammation and the current product information for celecoxib makes no mention of any 
interaction or potential interaction with vaccines.49,50 
It is the opinion of the Sponsor that the use of celecoxib by patients in this study poses no additional 
risk in the context of any COVID-19 vaccination currently in use and that the benefits of receiving 
such vaccine are fully maintained. 
5.9.2.3 
Gemcitabine and COVID-19 vaccination 
The reference safety information for gemcitabine warns that its use can suppress bone marrow 
function as manifested by leukopenia, thrombocytopenia, and anemia. As such, patients receiving 
gemcitabine should be monitored prior to each dose for platelet, leukocyte and granulocyte counts. 
Suspension or modification of therapy should be considered when drug-induced bone marrow 
depression is detected. However, myelosuppression is short lived and usually does not result in 
dose reduction and rarely in discontinuation. The use of live attenuated vaccines is not 
recommended in patients treated with gemcitabine.51,52 The COVID-19 vaccinations currently in 
use are not live attenuated vaccines and it is unlikely that any future formulations will be of that 
type. 
Current guidance from the Macmillan Cancer Support Organisation states that the COVID-19 
vaccines that are currently available can be given to people who are receiving cancer treatment. 
While it is possible that COVID-19 vaccines may be slightly less effective for patients receiving 
chemotherapy or other cancer treatments, it is still expected that the vaccine will give useful 
protection against the virus. In addition, experts on cancer immunotherapy have recommended that 
patients who are receiving immunotherapy or who are receiving (or have received) targeted 
therapies, including antibody treatments, as part of their therapy should receive the COVID-19 
vaccines. Although the vaccines can be given before, during, or after cancer treatment, if a patient 
has been recommended to start a treatment that affects the immune system (i.e., chemotherapy, 
immunotherapy), receiving a COVID-19 vaccine before the start of treatment may improve its 
effectiveness.53 The benefits of receiving a COVID-19 vaccine for patients in the study outweigh 
any potential additional risk posed by the use of gemcitabine. 
5.9.3 
Allowed Medications and/or Procedures  
The following medications and procedures will be allowed: 
 Patients receiving warfarin should be monitored closely for symptoms or signs of bleeding 
during the period of celecoxib administration and for 72 hours afterwards; 
 No precautions are required with respect to co-administration of CYP1A2 substrates with 
celecoxib; 

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 Supportive care measures including low dose corticosteroids up to 10 mg daily, if clinically 
indicated, and symptomatic treatment for any treatment-related toxicity; 
 Oral prednisolone or equivalent at a dose of 10 mg per day for patients with active, known, 
or suspected auto-immune disease or a syndrome that requires systemic or immunosuppressive 
agents; 
 Prophylactic use of standard anti-emetics; 
 Intermittent use of dexamethasone is permitted as an anti-emetic;  
 Blood and platelet transfusions, as needed per the judgment of the Investigator; and 
 Palliative radiation therapy will be permitted for pain or severe symptom control. It should be 
noted that toxicity has been reported when radiation therapy is administered together with or 
within 7 days of gemcitabine treatment. Radiation will be limited to non-target lesions only 
and will be documented in the eCRF. 
5.9.4 
Documentation of Prior and Concomitant Medication Use 
Medications used within 28 days of Screening will be recorded. All concomitant medications will 
be recorded on the eCRF as indicated in Appendix A. 

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6 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Appendix A. 
Disease assessments will be performed as indicated in the Schedule of Procedures (Table 1). 
6.1 
Informed Consent 
Informed consent will be obtained prior to performance of any study-related procedures.  
An optional pre-Screening ICF will be available for patients choosing to submit their archival 
tumor tissue for histological assessment prior to consenting to the study. The pre-Screening ICF 
will not include consent for any other study-related procedures. 
Patients may choose to forego the optional pre-Screening ICF and only sign the main study ICF. 
All patients will need to sign the main study ICF in order to proceed with any other study-related 
procedures. The main study ICF will allow patients to complete Screening procedures in parallel 
with submitting their archival tumor tissue.  
The main study ICF will also contain a section for patients to confirm their consent to participate 
in the Viral Shedding Cohort. The Viral Shedding Cohort is an optional cohort for those patients 
who are randomized to the rAd-IFN treatment group. Not all patients who consent to the Viral 
Shedding Cohort will be included in this cohort as it will depend on their treatment randomization 
and whether any slots remain in this cohort. Medpace will confirm availability of slots for those 
patients randomized to the rAd-IFN treatment group.  
See Section 11.3 for details on informed consent. 
6.2 
Screening (Study Days -28 to 0) 
The following assessments will be performed at Screening: 
 Obtain informed consent; 
 Obtain informed consent specifically allowing viral shedding-related procedures (Viral 
Shedding Cohort only); 
 Record demographics information; 
 Review medical history (including history of prior exposure to checkpoint inhibitors);  
 Perform physical examination; 
 Record vital signs including weight and height; 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation) and local serum pregnancy test (for female patients of childbearing potential 
only); 
Note: Laboratory assessments must be performed within 28 days prior to Study Day 1. 
Estimated glomerular filtration rate will be calculated using the Modification of Diet in Renal 
Disease study equation at Screening only (see Appendix B). 
 Collect urine sample for urinalysis; 
Note: Laboratory assessments must be performed within 28 days prior to Study Day 1. 

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 Perform ECG (resting); 
 Submit archival tumor block or 3 to 5 unstained slides from archival tumor block for central 
pathology review if patient did not sign pre-Screening ICF and archival tumor sample has not 
already been submitted (confirmation of tumor histology is required for inclusion criterion 
number 3); 
 Perform radiographic assessment of tumor by CT scan of the chest, abdomen, and pelvis (see 
Section 7.2 and Appendix C); 
Note: CT scan must be performed within 28 days prior to Study Day 1. The CT scan performed 
during Screening will be used as the patient’s baseline modified RECIST 1.1 assessment. 
Standard of care CT scans completed within 2 weeks prior to Screening may be used in place 
of the Screening CT scan on a case-by-case basis as agreed with the Medical Monitor. 
 Assess pleural space for ability to site an IPC or similar device for patients who do not have a 
pre-existing IPC or similar device; 
 Record the ECOG performance status;  
 Assess QoL using EQ-5D-5L and Lung Cancer Symptom Scale-mesothelioma (LCSS-Meso) 
(patient and observer) questionnaires; 
 Record adverse events and concomitant medications; and 
 Submit all CT scans to central archive. 
During the Screening Period, after tumor histology results are received, and the patient is 
confirmed to be eligible for the study, the following should be completed in preparation for Study 
Day 1: 
 Randomize via IRT, and 
Note: The target interval between randomization and Study Day 1 should be up to 7 days and 
no greater than 14 days. Any extension beyond 14 days will be considered on a case-by-case 
basis, following discussion between the Investigator, Medical Monitor, and Sponsor. 
 Schedule IPC or similar device placement (rAd-IFN treatment group only), if required. 
Note: An IPC or similar device must be inserted on or before Study Day 1 for patients who do 
not have a pre-existing IPC or similar device. 
An extension to the Screening Period will be permitted on a case-by-case basis following 
discussion between the Investigator, the Medical Monitor, and/or the Sponsor. The reason(s) for 
the extension is to be clearly documented. 
6.3 
Treatment Period 
6.3.1 
Study Day 1 
Study Day 1 will be a maximum of 28 days after the start of Screening unless an extension is 
approved by the Sponsor or Medical Monitor. 

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The following assessments will be performed for all patients before starting study treatment on 
Study Day 1 or within 24 hours before starting study treatment (i.e., the following Study Day 1 
assessments may be split over 2 days): 
 Record vital signs; 
 Perform physical examination; 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation), serum mesothelin and fibulin-3 measurement, and local serum pregnancy test 
(for female patients of childbearing potential only); 
 Collect blood sample for Ad5 nAbs (samples collected and stored for later analysis, antibody 
status not required for study enrollment); 
 Collect urine sample for urinalysis; 
 Perform ECG (resting); 
 Record adverse events and concomitant medications; and 
 Insert IPC or similar device if not previously inserted (rAd-IFN treatment group only). 
Note: For all rAd-IFN treatment group patients (i.e., patients with a previously inserted or a 
newly inserted IPC or similar device), the correct position of the IPC or similar device will be 
confirmed by the Investigator or an appropriately qualified designee, in accordance with local 
institutional practice. 
The following procedure must be performed on Study Day 1: 
 Administer the first dose of celecoxib (400 mg) orally.  
Note: The first dose of celecoxib will be administered 1 to 2 hours prior to rAd-IFN 
administration for the rAd-IFN treatment group. 
rAd-IFN will be administered via the intrapleural route by the Principal Investigator or designee 
according to Section 5.1.2 and recorded in the source documents and eCRF (rAd-IFN treatment 
group only). It is recommended that the pleural space is not drained within the first 24 hours 
post-rAd-IFN administration, unless deemed necessary by the Investigator. 
See Section 5.1.4 for instructions to prepare the patient and to monitor the patient before, during, 
and after rAd-IFN administration. 
At the discretion of the Investigator, the IPC or similar device may be removed at any time during 
the 6-hour post-rAd-IFN administration observation period or at the Study Day 2 Visit. The 
Investigator may keep the IPC or similar device in situ beyond the Study Day 2 Visit if required 
for clinical purposes.  
The following assessments will be performed on Study Day 1 for all patients (post-rAd-IFN 
administration for the rAd-IFN treatment group): 
 Provide patient with the remainder of celecoxib for at home dosing and instruct patient that 
dosing should be 400 mg orally BID, at approximately 12-hour intervals; 
Note: If the patient receives the first dose of celecoxib late on Study Day 1, such that the patient 
is only able to take 1 dose of celecoxib on Study Day 1, the patient must not take a celecoxib 

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dose on Study Day 15, regardless of whether or not the patient has taken all planned celecoxib 
doses. If BID dosing does not occur on Study Day 1 for this reason, it will not be considered a 
protocol deviation. If the patient vomits after taking celecoxib, the patient should not replace 
that dose; instead, the patient should wait until the next scheduled time point to take their next 
scheduled celecoxib dose. 
 Provide patient with a celecoxib diary and instruct patient that the next dose should be taken 
approximately 12 hours post-rAd-IFN administration (rAd-IFN treatment group) or 
approximately 12 hours after the first celecoxib dose (control group); and 
 Record adverse events and concomitant medications. 
For patients in the rAd-IFN treatment group participating in the Viral Shedding Cohort, the 
following assessments will also be performed: 
 Collect urine sample for viral shedding 2 to 3 hours post-rAd-IFN administration; 
 Collect saliva and pleural access site swab for viral shedding 2 to 3 hours post-rAd-IFN 
administration; and 
 Collect blood sample for biodistribution 2 to 3 hours post-rAd-IFN administration. 
6.3.2 
Study Day 2 (rAd-IFN Treatment Group Only) 
For patients randomized to the rAd-IFN treatment group only, the following assessments will be 
performed on Study Day 2 (approximately 24 hours after rAd-IFN administration): 
 Record vital signs; 
 Perform physical examination; 
 Review diary/complete capsule count to calculate compliance and accountability; and 
Note: Retrain patients with <100% compliance (unless the only reason compliance is <100% 
is a result of the patient taking the first dose of celecoxib late on Study Day 1, such that the 
patient is only able to take 1 dose of celecoxib on Study Day 1). 
 Record adverse events and concomitant medications. 
For patients in the rAd-IFN treatment group participating in the Viral Shedding Cohort, the 
following assessments will also be performed: 
 Collect urine sample for viral shedding approximately 24 hours post-rAd-IFN administration; 
 Collect saliva and pleural access site swab for viral shedding approximately 24 hours 
post-rAd-IFN administration;  
 Collect pleural fluid sample using the IPC or similar device (if the IPC or similar device is still 
in place) approximately 24 hours post-rAd-IFN administration. See Appendix G for collection 
procedure; and 
 Collect blood sample for biodistribution approximately 24 hours post-rAd-IFN administration. 

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6.3.3 
Study Day 7 
The following assessments will be performed on Study Day 7 (±1 day) for all patients: 
 Record vital signs; 
 Perform physical examination; 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation); 
 Collect urine sample for urinalysis; 
 Review diary/complete capsule count to calculate compliance and accountability; and 
Note: Retrain patients with <100% compliance (unless the only reason compliance is <100% 
is a result of the patient taking the first dose of celecoxib late on Study Day 1, such that the 
patient is only able to take 1 dose of celecoxib on Study Day 1). 
 Record adverse events and concomitant medications. 
For patients in the rAd-IFN treatment group participating in the Viral Shedding Cohort, the 
following assessments will also be performed: 
 Collect urine sample for viral shedding;  
 Collect saliva and pleural access site swab for viral shedding; 
 Collect pleural fluid sample using the IPC or similar device (if the IPC or similar device is still 
in place). See Appendix G for collection procedure; and 
 Collect blood sample for biodistribution. 
6.3.4 
Study Days 14 to 28 (Gemcitabine Cycle 1) 
6.3.4.1 
Study Day 14 (Gemcitabine Cycle 1 Day 1) 
The following assessments will be performed on gemcitabine Cycle 1 Day 1 (±1 day) for all 
patients: 
 Record vital signs including weight; 
 Perform physical examination; 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation) and local serum pregnancy test (for female patients of childbearing potential 
only); 
 Collect urine sample for urinalysis; 
 Perform ECG (resting); 
 Administer gemcitabine 1250 mg/m2 intravenously; 
 Assess QoL using EQ-5D-5L and LCSS-Meso (patient and observer) questionnaires;  

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 Review diary/complete capsule count to calculate compliance and accountability; and 
Note: Retrain patients with <100% compliance (unless the only reason compliance is <100% 
is a result of the patient taking the first dose of celecoxib late on Study Day 1, such that the 
patient is only able to take 1 dose of celecoxib on Study Day 1). 
 Record adverse events and concomitant medications. 
For patients in the rAd-IFN treatment group participating in the Viral Shedding Cohort, the 
following assessments will also be performed: 
 Collect urine sample for viral shedding; 
 Collect saliva and pleural access site swab for viral shedding;  
 Collect pleural fluid sample using the IPC or similar device (if the IPC or similar device is still 
in place). See Appendix G for collection procedure; and 
 Collect blood sample for biodistribution. 
6.3.4.2 
Study Day 21 (Gemcitabine Cycle 1 Day 8) 
The following assessments will be performed on gemcitabine Cycle 1 Day 8 (±1 day) for all 
patients: 
 Record vital signs including weight; 
 Perform physical examination; 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation); 
 Collect urine sample for urinalysis; 
 Administer gemcitabine 1250 mg/m2 intravenously; 
 Review diary/complete capsule count to calculate compliance and accountability; and 
 Record adverse events and concomitant medications. 
For patients in the rAd-IFN treatment group participating in the Viral Shedding Cohort, the 
following assessments will also be performed: 
 Collect urine sample for viral shedding;  
 Collect saliva and pleural access site swab for viral shedding;  
 Collect pleural fluid sample using the IPC or similar device (if the IPC or similar device is still 
in place). See Appendix G for collection procedure; and 
 Collect blood sample for biodistribution. 

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6.3.4.3 
Study Day 28 (Gemcitabine Cycle 1 Day 15) 
The following assessments will be performed on gemcitabine Cycle 1 Day 15 (±3 days) for all 
patients: 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation);  
 Collect urine sample for urinalysis; and 
 Record adverse events and concomitant medications. 
For patients in the rAd-IFN treatment group participating in the Viral Shedding Cohort, the 
following assessments will also be performed: 
 Collect urine sample for viral shedding;  
 Collect saliva and pleural access site swab for viral shedding; 
 Collect pleural fluid sample using the IPC or similar device (if the IPC or similar device is still 
in place). See Appendix G for collection procedure; and 
 Collect blood sample for biodistribution. 
6.3.5 
Gemcitabine Cycle 2, 3, 4, and Beyond 
6.3.5.1 
Gemcitabine Cycle 2, 3, 4, and Beyond Day 1 
The following assessments will be performed on gemcitabine Cycle 2, 3, 4, and Beyond Day 1 
(±3 days) for all patients: 
 Record vital signs including weight; 
 Perform physical examination; 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation) and local serum pregnancy test (for female patients of childbearing potential 
only); 
 Collect urine sample for urinalysis; 
 Collect blood sample for serum mesothelin and fibulin-3 measurement; 
 Perform ECG (resting); 
 Perform radiographic assessment of tumor by CT scan of the chest, abdomen, and pelvis on 
gemcitabine Cycle 3 Day 1 (±3 days) only (see Section 7.2 and Appendix C); 
 Administer gemcitabine 1250 mg/m2 intravenously; 
 Assess QoL using EQ-5D-5L and LCSS-Meso (patient and observer) questionnaires; 

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 Record adverse events and concomitant medications; and 
 Submit all CT scans to central archive. 
Note: All CT scans will be submitted for central archiving on an ongoing basis throughout the 
study. Any CT scans completed for standard of care purposes after disease progression/ET will 
not be collected for the central archive. 
6.3.5.2 
Gemcitabine Cycle 2, 3, 4, and Beyond Day 8 
The following assessments will be performed on gemcitabine Cycle 2, 3, 4, and Beyond Day 8 
(±3 days) for all patients: 
 Record vital signs including weight; 
 Perform physical examination; 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation); 
 Collect urine sample for urinalysis; 
 Administer gemcitabine 1250 mg/m2 intravenously; and 
 Record adverse events and concomitant medications. 
6.4 
Post-Randomization CT Scans 
The following assessments will be performed for all patients: 
 Perform radiographic assessment of tumor by CT scan of the chest, abdomen, and pelvis (see 
Section 7.2 and Appendix C); and 
Note: The first CT scan after randomization will be performed at gemcitabine Cycle 3 Day 1 
(±3 days).  
Subsequent CT scans will be performed every 9 weeks (±3 days) until disease progression/ET. 
The CT scan schedule of every 9 weeks (±3 days) from gemcitabine Cycle 3 Day 1 will be 
maintained regardless of gemcitabine dose delays or interruptions. 
 Submit all CT scans to central archive. 
Note: All CT scans will be submitted for central archiving on an ongoing basis throughout the 
study. Any CT scans completed for standard of care purposes after disease progression/ET will 
not be collected for the central archive. 
6.5 
End of Treatment (Disease Progression) Visit 
The following assessments will be performed at the End of Treatment (Disease Progression) 
Visit (±3 days) for all patients: 
 Record vital signs; 
 Perform physical examination; 

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 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation) and local serum pregnancy test (for female patients of childbearing potential 
only); 
 Collect urine sample for urinalysis; 
 Perform ECG (resting); 
 Record adverse events and concomitant medications; and 
 Submit all CT scans to central archive. 
Note: All CT scans will be submitted for central archiving on an ongoing basis throughout the 
study. Any CT scans completed for standard of care purposes after disease progression/ET will 
not be collected for the central archive. 
6.6 
Clinical Follow-Up Visits 
Following the End of Treatment (Disease Progression) Visit or ET, patients in the rAd-IFN 
treatment group will continue to have clinical Follow-up Visits every 6 months (±14 days) for 
survival and safety for up to 5 years after receiving the first dose of rAd-IFN, assuming consent 
has not been withdrawn. Cause and date of death will be recorded where possible. Concomitant 
medications specific for mesothelioma treatment will be recorded. All previously recorded TEAEs 
and SAEs will be followed until resolution or stabilization. Clinical Follow-up Visits can be 
performed face-to-face, through physician contact, or by telephone. Patients in the control group 
will not continue with clinical Follow-up Visits and study participation concludes after end of 
study treatment.  
6.7 
Early Termination 
For patients who are withdrawn from study treatment after commencing Study Day 1 treatment 
and prior to disease progression, the following procedures will be performed at an ET Visit: 
 Record vital signs; 
 Perform physical examination; 
 Collect blood sample for routine laboratory assessments (hematology, clinical chemistry, and 
coagulation) and local serum pregnancy test (for female patients of childbearing potential 
only); 
 Collect urine sample for urinalysis; 
 Perform ECG (resting); 
 Record adverse events and concomitant medications; and 
 Submit all CT scans to central archive. 
Note: All CT scans will be submitted for central archiving on an ongoing basis throughout the 
study. Any CT scans completed for standard of care purposes after disease progression/ET will 
not be collected for the central archive. 
For patients who have withdrawn consent to the study after commencing Study Day 1 treatment 
and prior to disease progression, all attempts should be made to complete the above procedures. 

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For patients who have withdrawn prior to commencing Study Day 1 treatment, the above 
procedures do not need to be completed. 
Where applicable, patients in the rAd-IFN treatment group who have withdrawn from study 
treatment, not including those who have withdrawn prior to commencing Study Day 1 treatment, 
will be asked if they would agree to continue to be followed for survival and safety every 6 months 
(14 days) for up to 5 years. 

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7 
EFFICACY ASSESSMENTS 
The primary endpoint is OS, defined as time to death (from any cause) from randomization. 
The secondary efficacy endpoints are:  
 To evaluate survival rate at 12 months, defined as the number of deaths (from any cause) at 
12 months from randomization, and every 6 months thereafter; 
 To evaluate PFS, defined as the time from randomization to the time when the modified 
RECIST 1.1 criteria for disease progression are first met, or when death from any cause occurs; 
and 
 To evaluate best response, defined as the best response after randomization (complete 
response, partial response, or stable disease). 
The exploratory efficacy endpoints are: 
 Change in total score and individual components of the EQ-5D-5L and LCSS-Meso (patient 
and observer) from baseline (randomization) to each successive cycle of gemcitabine, 
 Correlation between the presence of Ad5 nAbs prior to treatment and survival (death from any 
cause), 
 Correlation between pre- and post-treatment levels of serum mesothelin and treatment 
outcomes, and 
 Correlation between pre- and post-treatment levels of serum fibulin-3 and treatment outcomes. 
7.1 
Archival Tumor or Biopsy at Screening 
Archival tumor samples will be requested at Screening from all patients enrolled in the study. The 
diagnostic pathology block or tumor tissue obtained at the time of the patient's initial diagnosis 
and/or at the time of subsequent procedures is acceptable. If a tumor block is not available, 
3 to 5 unstained paraffin-embedded tumor tissue containing slides may be provided. Fresh tumor 
biopsies will not be taken as part of this study.  
The archival tissue or unstained slides will be reviewed by a central pathologist to confirm 
histological diagnosis. The Sponsor or its designee will return all blocks/tissue samples to the 
originating site upon completion of the associated analyses. Confirmation of tumor histology is 
required prior to inclusion into the study. 
The archival tumor samples will also be assessed for programmed death-ligand 1 (PD-L1) 
expression by a central pathologist, and the data will be retained for exploratory analysis. 
Programmed death-ligand 1 expression is not required prior to inclusion into the study.  
A Laboratory Manual detailing the tumor sample collection, preparation, storage, and shipping 
process will be provided. 
7.2 
Tumor Assessments 
Tumor assessments will be performed locally in accordance with modified RECIST 1.1 based on 
diagnostic CT examinations performed of the chest, abdomen, and pelvis (see Appendix C).42 
Contrast-enhanced examinations are preferred when possible. Standard of care CT scans 
completed within 2 weeks prior to Screening may be used in place of the Screening CT scan on a 

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case-by-case basis as agreed with the Medical Monitor. All CT scans will be submitted for central 
archiving on an ongoing basis throughout the study. Any CT scans completed for standard of care 
purposes after disease progression/ET will not be collected for the central archive. 

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8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of the main study’s informed consent through 30 days after the last dose 
of study treatment (rAd-IFN, celecoxib, and gemcitabine). All TEAEs will be followed until 
resolution or stabilization. Patients should be instructed to report any adverse event that they 
experience to the Investigator. Beginning with Screening, Investigators should make an assessment 
for adverse events at each visit and record the event on the appropriate adverse event eCRF. 
Disease progression should not be reported as an adverse event/SAE; however, when a patient dies 
from disease progression, the event will be captured as an outcome on an eCRF for deaths due to 
disease progression. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the adverse event eCRF. 
However, if an observed or reported sign or symptom is not considered a component of a specific 
disease or syndrome by the Investigator, it should be recorded as a separate adverse event on the 
eCRF. Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, 
endoscopy, tooth extraction, or transfusion) should be recorded as an adverse event, not the 
procedure.  
Any medical condition already present at Screening should not be reported as an adverse event 
unless the medical condition or signs or symptoms present at baseline changes in severity, 
frequency, or seriousness at any time during the study. In this case, it should be reported as an 
adverse event. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study, or are present at Screening and significantly worsen during the study, 
should be reported as adverse events. The Investigator will exercise his or her medical and 
scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Any abnormal test that is determined to be an error does not require 
reporting as an adverse event. 
8.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 

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8.1.2 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For rAd-IFN, the reference safety 
information is included in Section 6.9 of the Investigator’s Brochure currently in force. The 
reference safety information will be reviewed yearly and the periodicity of the review will be 
harmonized with the reporting period of the Development Safety Update Report. 
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, 
severe, life-threatening, or death and will also categorize each adverse event as to its potential 
relationship to study drug using the categories of yes or no. 
Assessment of Severity 
The severity of all adverse events should be graded according to the CTCAE Version 4.03, with 
the exception of CRS. See Appendix E for details on CRS grading. The CTCAE can be found at 
http://ctep.cancer.gov/reporting/ctc.html. For those adverse events not listed in the CTCAE, the 
following grading system should be used: 
 Mild (CTCAE Grade 1): Transient symptoms, awareness of signs/symptoms, but easily 
tolerated and no interference with patient’s daily activities. 
 Moderate (CTCAE Grade 2): Marked signs/symptoms that interfere with patient’s usual 
activities, but still acceptable. 
 Severe (CTCAE Grade 3): Incapacitating signs/symptoms which cause considerable 
interference with the patient’s daily activities, unacceptable. 
 Life-threatening (CTCAE Grade 4): Life-threatening or disabling adverse event. 
 Death (CTCAE Grade 5): Death-related adverse event. 
Causality Assessment 
The relationship of an adverse event to the administration of each study drug (rAd-IFN, celecoxib, 
and gemcitabine) is to be assessed according to the following definitions: 
No (unrelated, not related, no relation)  The time course between the administration of each study 
drug and the occurrence or worsening of the adverse event rules out a causal relationship and 
another cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (related) – The time course between the administration of each study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship, and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 

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The following factors should also be considered: 
 The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
 Underlying, concomitant, intercurrent diseases- 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
 Concomitant drug- 
o The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 
 Known response pattern for this class of study drug- 
o Clinical and/or nonclinical data may indicate whether a particular response is likely to be 
a class effect. 
 Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 
 The pharmacology and pharmacokinetics of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) 
of the study drug should be considered. 
8.1.4 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) must be recorded in the eCRF. An AESI will be 
recorded within the first 30 days of rAd-IFN treatment for patients who are randomized to rAd-IFN 
treatment and received the rAd-IFN dose. Adverse events of special interest will be followed up 
to resolution.  
For this study, AESIs include: 
 Laboratory results, signs, and symptoms associated with CRS; 
 Laboratory results, signs, and symptoms associated with transaminitis (defined as 
ALT >3.0 × ULN and/or AST >3.0 × ULN); and 
 Infection at IPC or similar device site. 

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8.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
 Death, 
 A life-threatening adverse event, 
o Note: An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
 Requires hospitalization or prolongation of existing hospitalizations, 
o Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded 
as an SAE under this criterion, nor will hospitalization for a procedure scheduled or 
planned before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
adverse events and assessed for seriousness. Admission to the hospital for social or 
situational reasons (i.e., no place to stay, live too far away to come for hospital visits) will 
not be considered inpatient hospitalizations.  
 A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions, 
 A congenital anomaly/birth defect, or 
 An important medical event. 
o Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent 1 of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalizations, or the development 
of drug dependency. 
o Note: Disease progression should not be reported as an adverse event/SAE; however, when 
a patient dies from disease progression, the event will be captured as an outcome on an 
eCRF for deaths due to disease progression. 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
Serious adverse events will be captured from the time of the main study’s informed consent 
through 30 days after the last dose of study treatment (rAd-IFN, celecoxib, and gemcitabine). All 
SAEs must be reported to Medpace Clinical Safety within 24 hours of the knowledge of the 
occurrence (this refers to any adverse event that meets any of the aforementioned serious criteria). 
All SAEs will be followed until resolution or stabilization. 

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To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is saved, Medpace Safety personnel will be notified 
electronically and will retrieve the form. If the event meets serious criteria and it is not possible to 
access 
the 
EDC 
system, 
send 
an 
e-mail 
to 
Medpace 
Safety 
at 
Medpace-safetynotification@medpace.com or call the Medpace SAE reporting line (telephone 
number listed below) and fax the completed paper SAE form to Medpace (fax number listed 
below) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available.  
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE reporting line  USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
e-mail: medpace-safetynotification@medpace.com 
 
Medpace SAE reporting line  Europe: 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
e-mail: medpace-safetynotification@medpace.com 
Follow-Up Reports 
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the patient 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(e.g., patient discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
8.4 
Pregnancy Reporting 
If the patient or partner of a patient participating in the study becomes pregnant during the study 
or within 30 days of the last dose of study drug (rAd-IFN, celecoxib, and gemcitabine), the 
Investigator should report the pregnancy to Medpace Clinical Safety within 24 hours of being 
notified. Medpace Clinical Safety will then forward the Exposure In Utero form to the Investigator 
for completion.  
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and ET study procedures will be performed. 
The patient or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Medpace Clinical Safety. At the completion of the pregnancy, the Investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 

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8.5 
Expedited Reporting 
The Sponsor will report all relevant information about all suspected unexpected serious adverse 
reactions (fatal, life-threatening, or other) to the respective health authority, Principal 
Investigators, ethics committees, and other local authorities as per local guidelines within the 
expected reporting timeframes.  
8.6 
Safety Assessments 
The secondary safety endpoints are: 
 To evaluate the number of patients with CTCAE Grade 3 or 4, and 
 To evaluate post-treatment levels of rAd-IFN-related viral DNA in biological samples 
collected up to 28 days after Study Day 1 in a sub-set of patients. 
Safety assessments will also include the assessment of adverse events including AESIs, as well as 
physical examinations, vital sign measurements, clinical laboratory assessments, and 
electrocardiographic data through ECG. 
8.7 
Clinical Laboratory Evaluations 
Blood for chemistry, hematology, and coagulation panels will be obtained as indicated in 
Appendix A and sent to the site’s clinical laboratory per institutional guidelines for analysis. See 
Appendix B for a complete list of analytes. Estimated glomerular filtration rate will be calculated 
using the Modification of Diet in Renal Disease study equation at Screening only (see 
Appendix B). 
Urine will be obtained as indicated in Appendix A and sent to each site’s clinical laboratory per 
institutional guidelines for complete urinalysis. See Appendix B for a complete list of analytes.  
A local laboratory serum pregnancy test will be performed for female patients of childbearing 
potential only prior to their participation in the study (Screening and Study Day 1), on Day 1 of all 
gemcitabine cycles, and at the End of Treatment (Disease Progression)/ET Visit.  
Laboratory results will be collected for the clinical study database. 
8.8 
Vital Signs 
Vital sign measurements will be taken after at least a 5-minute rest in a sitting or supine position. 
Measurements will include blood pressure, respiratory rate, pulse rate, and body temperature. 
Weight and height will be measured at Screening (see Appendix A). Weight will also be measured 
on Day 1 and Day 8 of all gemcitabine cycles and can be used to calculate the gemcitabine dose 
for that visit. 
8.9 
Electrocardiograms 
Standard ECGs will be performed. Patients will rest for 5 minutes prior to each ECG reading (see 
Appendix A). 

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8.10 
Physical Examinations 
The physical examination appropriate to the physical condition of the patient will be performed by 
either the Investigator or a Sub-Investigator who is a physician (see Appendix A). 
8.11 
Viral Shedding Evaluation 
A sub-set of patients randomized to the rAd-IFN treatment group will be selected to participate in 
the Viral Shedding Cohort to assess rAd-IFN viral vector shedding. The Viral Shedding Cohort 
will include the first 10 patients randomized to the rAd-IFN treatment group who consent to 
participation. The viral shedding evaluation will include collection of saliva, urine, pleural access 
site swab, and blood samples for biodistribution, taken at designated time points 2 to 3 hours 
post-rAd-IFN administration (Study Day 1); approximately 24 hours post-rAd-IFN administration 
(Study Day 2); and on Study Days 7, 14, 21, and 28. A pleural fluid sample will be collected using 
the IPC or similar device (if the IPC or similar device is still in place) approximately 24 hours 
post-rAd-IFN administration (Study Day 2) and on Study Days 7, 14, 21, and 28. See Appendix G 
for pleural fluid sample collection procedure. 
8.12 
Patient Preparation and Monitoring (rAd-IFN Treatment Group Only) 
Immediately before (within 10 minutes prior to the start time of rAd-IFN administration), during, 
and immediately after (within 10 minutes after the start time of rAd-IFN administration) rAd-IFN 
administration, 
 Patients should be monitored using pulse oximetry, 
 Oxygen via nasal cannula should be administered at approximately 2 L/min as required, and 
 Cardiac telemetry may also be used to monitor patients as per the Principal Investigator’s 
discretion.  
These safety procedures should be continued post-rAd-IFN administration as per the Principal 
Investigator’s or designee’s discretion.  
An intravenous cannula should be placed prior to rAd-IFN administration, and normal saline (or 
equivalent as per local institutional standards) should be administered slowly.  
Analgesia may be administered as required, in accordance with local institutional standards. 
Post-rAd-IFN administration, 
 Body temperature will be monitored every hour (±10 minutes) for 6 hours; and 
 Blood pressure, respiratory rate, pulse rate, and oxygen saturation will be measured and 
recorded every 15 minutes (±5 minutes) for the first 2 hours; every 30 minutes (±10 minutes) 
for the next 2 hours; then, every hour (±10 minutes) for the remainder of the inpatient 
monitoring period up to 6 hours post-rAd-IFN administration (unless further surveillance is 
required as per the Principal Investigator’s discretion).  
After 6 hours of observation, the patient can go home if vital signs and oxygen saturation are within 
acceptable limits, as per local institutional practice and guidelines, following assessment by the 
Investigator or an appropriately qualified designee. After leaving the facility, the patient may use 
acetaminophen or equivalent (as per local institutional standards) for the management of pyrexia, 

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should it occur. rAd-IFN treatment group patients will return to the site to be reviewed 
approximately 24 hours after rAd-IFN administration (see Section 6.3.2). 
In the event the patient experiences CRS, see Appendix E for details on CRS grading. Local 
guidelines for the management and treatment of CRS should be followed. In the absence of any 
such appropriate guidelines, see Appendix E for details on the therapeutic strategy for the 
management of CRS. 

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9 
STATISTICS 
9.1 
Analysis Populations 
The study population is patients with MPM and confirmed epithelioid or biphasic histology (if 
biphasic, histology must be predominantly [50%] epithelioid) who have received a minimum of 
1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an 
anti-folate and platinum combination regimen. 
The Full Analysis Set comprises all patients appropriately randomized into the study who have 
received at least 1 dose of study drug (rAd-IFN, celecoxib, or gemcitabine). 
The Safety Analysis Set comprises all patients who have received at least 1 dose of study drug 
(rAd-IFN, celecoxib, or gemcitabine). 
9.2 
Statistical Methods 
A Statistical Analysis Plan (SAP) will be finalized before database lock. Any changes to the 
methods described in the final SAP will be described and justified as needed in the Clinical Study 
Report. 
9.2.1 
Analysis of Efficacy 
9.2.1.1 
Primary efficacy analysis 
The primary analysis of the primary endpoint is a comparison of the OS curves between the 
2 treatment groups using a log-rank test. A Cox proportional hazards model with treatment as an 
explanatory variable will be used to assess the magnitude of the treatment difference in OS. The 
hazard ratio and the associated 95% confidence interval obtained from the Cox proportional 
hazards model will be presented. 
The median OS and the 95% confidence interval for each treatment group will be estimated using 
the Kaplan-Meier method and summarized by treatment group. Plots of the Kaplan-Meier curve 
of OS will be presented by treatment group. 
Secondary analyses of the primary endpoint will include a comparison of the survival rates at 
various time points since randomization. 
9.2.1.2 
Secondary efficacy analysis 
Secondary time-to-event endpoints will be analyzed in the same manner as the primary efficacy 
endpoint. 
Categorical efficacy endpoints will be summarized and compared between groups using Fisher’s 
exact test. 
9.2.2 
Analysis of Safety 
The nature, incidence, severity, relatedness, expectedness, seriousness, and outcome of TEAEs 
will be summarized by treatment group. 

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9.2.3 
Analysis Timing 
9.2.3.1 
Interim analysis 
No interim analysis is planned due to the premature termination of enrollment for the study.  
9.2.3.2 
Final analysis 
The final analysis will be conducted after the forty-fourth event (death) or at least 30 months after 
the last patient is randomized, whichever occurs first. The long-term safety follow-up data will be 
collected. 
9.2.4 
Data and Safety Monitoring Board 
An independent DSMB will be convened for this study to monitor safety, efficacy, and study 
integrity. The DSMB will consist of individuals, experts in relevant fields, including but not 
limited to mesothelioma, drug safety, and biostatistics. It will convene on a regular basis and will 
review all safety and study conduct information to determine whether the study should continue 
unchanged or whether protocol modifications are required to ensure patient safety and study 
integrity.  
All aspects of the DSMB’s scope of review and procedures will be detailed in a DSMB charter, to 
be finalized before the first patient is randomized. 
9.2.5 
Sample Size Determination 
The planned sample size is approximately 50 patients. The sample size is not based on statistical 
considerations. Patient recruitment into the study has been significantly slower than expected due 
to several technical study challenges. Therefore, Trizell has decided to discontinue screening and 
enrollment into the study after a total of approximately 50 patients have been randomized to 
treatment. 
It is anticipated that approximately 44 events (equivalent to 89% of the approximately 50 enrolled 
patients) will be observed 24 months after the last patient is randomized. The final analysis of the 
study will be conducted after the forty-fourth event (death) or 30 months after the last patient is 
randomized, whichever occurs first. 

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10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the Clinical Research Associate (CRA) 
during monitoring visits. The CRAs will verify data recorded in the EDC system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in an 
audit trail in the EDC system. An eCRF will be considered complete when all missing, incorrect, 
and/or inconsistent data has been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
 Medical Dictionary for Regulatory Activities for medical history and adverse events, and 
 WHO Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  

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11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human patients. Compliance 
with this standard provides public assurance that the rights, safety, and wellbeing of study patients 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible.  
11.2 
Ethics and Regulatory Review 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of patients. 
The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, 
Investigator’s Brochure, ICF, advertisements (if applicable), written information given to the 
patients, safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the Investigator. 
International regulations and International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an IRB/IEC prior to participation of patients in research studies. 
Prior to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for 
patient recruitment, and any other written information regarding this study to be provided to a 
patient or patient’s legal guardian must be approved by the IRB/IEC. 
No drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by the Sponsor or other approval has been granted, as applicable, according to national 
regulations. 
It is the responsibility of the Sponsor or their designee (i.e., Medpace) to obtain the approval of 
the responsible ethics committees according to the national regulations.  
The study will only start at the respective sites once the respective ethics committee’s written 
approval has been obtained, and the respective applicable national regulatory authority(ies) has 
been notified and its approval has been obtained as required per national requirements for clinical 
trials and for genetically modified organisms.  
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed by the 
Sponsor or designee and the IRB/IEC prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements. 
An optional pre-Screening ICF will be available for patients choosing to submit their archival 
tumor tissue for histological assessment prior to consenting to the study. The pre-Screening ICF 
will not include consent for any other study-related procedures. If the patient chooses to consent, 
the consent form should be signed and personally dated by the patient prior to submission of his/her 
archival tumor tissue for histological assessment. 
Patients may choose to forego the optional pre-Screening ICF and only sign the main study ICF. 
All patients will need to sign the main study ICF in order to proceed with any other study-related 

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procedures. The main study ICF will allow patients to complete Screening procedures in parallel 
with submitting their archival tumor tissue.  
The main study ICF will also contain a section for patients to confirm their consent to participate 
in the Viral Shedding Cohort. The Viral Shedding Cohort is an optional cohort for those patients 
who are randomized to the rAd-IFN treatment group. Not all patients who consent to the Viral 
Shedding Cohort will be included in this cohort as it will depend on their treatment randomization 
and whether any slots remain in this cohort. Medpace will confirm availability of slots for those 
patients randomized to the rAd-IFN treatment group. 
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRBs/IECs and/or regulatory 
agencies. A copy of the signed ICF will be given to the patient. 
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, Directive 2001/20/EC and applicable regulatory 
requirements, and that valid data are entered into the eCRFs. 
To achieve this objective, the CRA’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any patient in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the CRA and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the Sponsor or their designee, 
applicable regulatory authorities, and the IRB/IEC, as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 

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Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, or 
as specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
11.8 
Financial Disclosure 
Each Investigator (including Principal and any Sub-Investigators) directly involved in the 
treatment or evaluation of study patients is required to provide financial disclosure information to 
the Sponsor to permit the Sponsor to fulfill its US obligations under 21 CFR Part 54. In addition, 
Investigators must commit to promptly updating this information if any relevant changes occur 
during the study and for a period of 1 year after the completion of the study. 
11.9 
Financing and Insurance  
The financing and insurance for this study are outlined in the Clinical Study Agreement. 

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12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
relevant competent authority(ies) and/or IRB/IEC, as applicable, unless immediate 
implementation of the change is necessary for patient safety, in compliance with local 
requirements. In this case, the situation must be documented and reported to the IRB/IEC within 
5 working days (or other local requirement as applicable). 
12.2 
Address List 
12.2.1 
Sponsor 
Trizell (UK), Ltd. 
Drayton Hall, Church Road 
West Drayton 
UB7 7PS 
United Kingdom 
Telephone: +44 (0) 73 939 55692 
12.2.2 
Contract Research Organization 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227 
United States 
Telephone: +1-513-579-9911 
Fax: +1-513-579-0444 
12.2.3 
Serious Adverse Event Reporting 
Central Postal Address: 
Medpace Clinical Safety 
5375 Medpace Way 
Cincinnati, OH 45227 
United States 
 
Medpace SAE reporting line – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
e-mail: medpace-safetynotification@medpace.com 
 
Medpace SAE reporting line – Europe: 
Telephone: +49 89 89 55 718 44 
Fax: +49 89 89 55 718 104 
e-mail: medpace-safetynotification@medpace.com 

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Version 8.0, 11 December 2023 
75 
12.2.4 
Biological Specimens 
Medpace Reference Laboratories 
5365 Medpace Way 
Cincinnati, OH 45227 
United States 
Telephone: +1-513-366-3270 
Fax: +1-513-366-3273 
 
Medpace Laboratories BVBA 
Technologielaan 19 
B-3001 Leuven 
Belgium 
Telephone: +32 16 407775 
Fax: +32 16 407781 
 
Medpace Singapore Pte. Ltd. 
Block 72, #06-05/07 
Bendemeer Road 
Singapore 339941 
Telephone: +65 6578 5178 
Fax: +65 3158 0045 
 
Q2 Solutions – Specialty Center of Excellence (Ad5 nAb assay) 
33608 Ortega Highway 
San Juan Capistrano, CA 92675 
United States 
Telephone: +1-844-833-9520 
 
Geneuity Clinical Research Services (Pathology) 
250 E. Broadway 
Maryville, TN 37804 
United States 
Telephone: +1-865-380-9746, Extension 160 
Fax: +1-865-273-1123 
12.2.5 
rAd-IFN Manufacturer 
FinVector Oy 
Microkatu 1 
70210 Kuopio 
Finland 
Telephone: +358 (0) 50 4336447 

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12.2.6 
Gemcitabine and Celecoxib Supplier (Where Supplied Centrally) 
Catalent Pharma Solutions 
Lancaster Way, Wingates Industrial Estate 
Westhoughton, Bolton BL5 3XX 
United Kingdom 
Telephone: +44 (0) 7816 179 918 
 
Catalent Pharma Solutions 
1 Inchwood Park 
Bathgate, West Lothian EH48 2FY 
United Kingdom 
 
Catalent Germany Schorndorf GmbH 
Clinical Supply Services 
Steinbeisstraße 1 
73614 Schorndorf  
Germany 
 
Catalent Philadelphia 
Packaging and labeling facility: 
10381 Decatur Road 
Philadelphia, PA 19114 
United States 
 
Catalent Philadelphia 
Receipt, storage, and distribution: 
3031 Red Lion Road 
Philadelphia, PA 19114 
United States 

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13 
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APPENDIX A: SCHEDULE OF PROCEDURES 
Table 1. 
Schedule of Procedures 
Study Visit Day 
Screening 
Day 11 
Day 2 
Day 7 
Day 14 
Day 21 
Day 28 
 
 
EOT (Disease 
Progression)/ 
ET Visit 
Clinical 
Follow-Up 
Visit2 
Gemcitabine Cycle3 
 
 
 
 
C1, D1 
C1, D8 
C1, 
D15 
C2, 3, 4, 
etc., D1 
C2, 3, 4, 
etc., D8 
 
 
Visit Window (Days) 
-28 to 04 
 
 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±14 
Informed consent5 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X6 
X 
X 
X 
 
X 
X 
X 
 
Vital signs7 
X 
X 
X6 
X 
X 
X 
 
X 
X 
X 
 
Clinical chemistry, hematology, 
coagulation, and urinalysis 
X8 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (serum)9 
X 
X 
 
 
X 
 
 
X 
 
X 
 
ECG (resting) 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Confirmation of tumor histology, 
including PD-L1 expression10 
X 
 
 
 
 
 
 
 
 
 
 
CT scan of chest, abdomen, and 
pelvis (radiographic tumor 
assessment) 
X11 
 
 
 
 
 
 
X12 
 
 
 
Assessment of pleural space for 
ability to site an IPC or similar 
device 
X 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
 
 
Randomization13 
X 
 
 
 
 
 
 
 
 
 
 
Serum mesothelin and fibulin-3 
 
X 
 
 
 
 
 
X 
 
 
 
Adenovirus type 5 neutralizing 
antibodies 
 
X 
 
 
 
 
 
 
 
 
 
Viral shedding and biodistribution 
(Viral Shedding Cohort only)14 
 
X 
X6 
X 
X 
X 
X 
 
 
 
 
Insert IPC or similar device6 
X15 
 
 
 
 
 
 
 
 
 
rAd-IFN administration6,16 
 
X 
 
 
 
 
 
 
 
 
 
IPC or similar device removal6 
 
X17 
 
 
 
 
 
 
 
 
Celecoxib18 
 
X 
 
 
 
 
 
 
Gemcitabine19 
 
 
 
 
X 
X 
 
X 
X 
 
 
QoL assessment (EQ-5D-5L and 
LCSS-Meso [patient and observer]) 
X 
 
 
 
X 
 
 
X 
 
 
 

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Table 1. 
Schedule of Procedures (Continued) 
Study Visit Day 
Screening 
Day 11 
Day 2 
Day 7 
Day 14 
Day 21 
Day 28 
 
 
EOT (Disease 
Progression)/ 
ET Visit 
Clinical 
Follow-Up 
Visit2 
Gemcitabine Cycle3 
 
 
 
 
C1, D1 
C1, D8 
C1, 
D15 
C2, 3, 4, 
etc., D1 
C2, 3, 4, 
etc., D8 
 
 
Visit Window (Days) 
-28 to 04 
 
 
±1 
±1 
±1 
±3 
±3 
±3 
±3 
±14 
Review diary/complete capsule count 
to calculate compliance and 
accountability 
 
 
X6,20 
X20 
X20 
X 
 
 
 
 
 
Adverse events21 
X 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X22 
Concomitant medications 
X 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X23 
Submit all CT scans to central 
archive24 
X 
 
 
 
 
 
 
X 
 
X 
 
Survival25 
 
 
 
 
 
 
 
 
 
 
X 
Note: Informed consent will be obtained prior to performance of any study-related procedures. An optional pre-Screening ICF will be available for patients choosing to submit 
their archival tumor tissue for histological assessment prior to consenting to the study. The pre-Screening ICF will not include consent for any other study-related procedures. 
Patients may choose to forego the optional pre-Screening ICF and only sign the main study ICF. All patients will need to sign the main study ICF in order to proceed with any 
other study-related procedures. The main study ICF will allow patients to complete Screening procedures in parallel with submitting their archival tumor tissue.  
Assessments that are scheduled to be performed on treatment days may be completed on non-treatment days as long as the assessment is completed within the visit window. 
1. 
The following assessments will be performed for all patients before starting study treatment on Study Day 1 or within 24 hours before starting study treatment (i.e., the 
following Study Day 1 assessments may be split over 2 days): vital signs; physical examination; clinical chemistry, hematology, coagulation, and urinalysis; serum mesothelin 
and fibulin-3 measurement; adenovirus type 5 neutralizing antibodies; pregnancy test; ECG (resting); adverse events; concomitant medications; and IPC or similar device 
insertion (if not previously inserted [rAd-IFN treatment group only]). The first dose of celecoxib (400 mg) will be administered orally 1 to 2 hours prior to rAd-IFN 
administration (rAd-IFN treatment group) or on Study Day 1 (control group). rAd-IFN will be administered via the intrapleural route by the Principal Investigator or designee 
and recorded in the source documents and eCRF. The following assessments will be performed on Study Day 1 for all patients (post-rAd-IFN administration for the rAd-IFN 
treatment group): celecoxib dosing (at home), provide celecoxib diary, viral shedding and biodistribution (for Viral Shedding Cohort only), adverse events, and concomitant 
medications. Study Day 1 will be a maximum of 28 days after the start of Screening unless an extension is approved by the Sponsor or Medical Monitor. 
2. 
Following the EOT (Disease Progression) Visit or ET, patients in the rAd-IFN treatment group will continue to have clinical Follow-up Visits every 6 months (±14 days) for 
survival and safety for up to 5 years after receiving the first dose of rAd-IFN, assuming consent has not been withdrawn. Cause and date of death will be recorded where 
possible. Clinical Follow-up Visits can be performed face-to-face, through physician contact, or by telephone. 
3. 
Patients will receive gemcitabine on a 21-day cycle, unless the cycle is modified due to toxicity/delay, that will continue every 3 weeks until disease progression/ET.  
4. 
An extension to the Screening Period will be permitted on a case-by-case basis following discussion between the Investigator, the Medical Monitor, and/or the Sponsor. The 
reason(s) for the extension is to be clearly documented. 
5. 
The main study ICF will also contain a section for patients to confirm their consent to participate in the Viral Shedding Cohort. The Viral Shedding Cohort is an optional 
cohort for those patients who are randomized to the rAd-IFN treatment group. Not all patients who consent to the Viral Shedding Cohort will be included in this cohort as it 
will depend on their treatment randomization and whether any slots remain in this cohort. Medpace will confirm availability of slots for those patients randomized to the 
rAd-IFN treatment group. 
6. 
rAd-IFN treatment group only. 
7. 
Vital sign measurements will be taken after at least a 5-minute rest in a sitting or supine position. Measurements will include blood pressure, respiratory rate, pulse rate, and 
body temperature. Weight and height will be measured at Screening. Weight will also be measured on Day 1 and Day 8 of all gemcitabine cycles and can be used to calculate 
the gemcitabine dose for that visit. 
8. 
Assessment must be performed within 28 days prior to Study Day 1. Estimated glomerular filtration rate will be calculated using the Modification of Diet in Renal Disease 
study equation at Screening only. 

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9. 
Local serum pregnancy test for female patients of childbearing potential only. Confirmation of negative pregnancy test must be obtained within 24 hours prior to dosing with 
rAd-IFN. 
10. Tumor histology will be confirmed centrally using specimens or slides from tumor specimens obtained at the time of initial presentation or a subsequent procedure. Fresh 
tumor biopsies will not be taken as part of this study. Confirmation of tumor histology is required prior to inclusion into the study. Information on PD-L1 tumor expression 
should be collected but is not required prior to inclusion into the study.  
11. CT scan must be performed within 28 days prior to Study Day 1. The CT scan performed during Screening will be used as the patient’s baseline modified Response 
Evaluation Criteria in Solid Tumors 1.1 assessment. Standard of care CT scans completed within 2 weeks prior to Screening may be used in place of the Screening CT scan 
on a case-by-case basis as agreed with the Medical Monitor. 
12. The first CT scan after randomization will be performed at gemcitabine Cycle 3 Day 1 (±3 days). Subsequent CT scans will be performed every 9 weeks (±3 days) until 
disease progression/ET. The CT scan schedule of every 9 weeks (±3 days) from gemcitabine Cycle 3 Day 1 will be maintained regardless of gemcitabine dose delays or 
interruptions. 
13. During the Screening Period, after tumor histology results are received, and the patient is confirmed to be eligible for the study, randomization via IRT will take place. The 
target interval between randomization and Study Day 1 should be up to 7 days and no greater than 14 days. Any extension beyond 14 days will be considered on a 
case-by-case basis, following discussion between the Investigator, Medical Monitor, and Sponsor.  
For patients randomized to the rAd-IFN treatment group who do not have a pre-existing IPC or similar device, schedule IPC or similar device placement for either on or 
before Study Day 1. 
14. For patients in the rAd-IFN treatment group participating in the Viral Shedding Cohort only. Viral shedding evaluations will include collection of saliva, urine, pleural access 
site swab, and blood samples for biodistribution, taken at designated time points 2 to 3 hours post-rAd-IFN administration (Study Day 1); approximately 24 hours 
post-rAd-IFN administration (Study Day 2); and on Study Days 7, 14, 21, and 28. A pleural fluid sample will be collected using the IPC or similar device (if the IPC or 
similar device is still in place) approximately 24 hours post-rAd-IFN administration (Study Day 2) and on Study Days 7, 14, 21, and 28.  
15. For patients in the rAd-IFN treatment group who do not have a pre-existing IPC or similar device, an IPC or similar device must be inserted on or before Study Day 1, prior to 
rAd-IFN administration. For all rAd-IFN treatment group patients (i.e., patients with a previously inserted or a newly inserted IPC or similar device), the correct position of 
the IPC or similar device will be confirmed by the Investigator or an appropriately qualified designee, in accordance with local institutional practice. 
16. rAd-IFN will be administered as described in Section 5.1.2. It is recommended that the pleural space is not drained within the first 24 hours post-rAd-IFN administration, 
unless deemed necessary by the Investigator.  
See Section 5.1.4 for instructions to prepare the patient and to monitor the patient before, during, and after rAd-IFN administration. 
17. At the discretion of the Investigator, the IPC or similar device may be removed at any time during the 6-hour post-rAd-IFN administration observation period or at the Study 
Day 2 Visit. The Investigator may keep the IPC or similar device in situ beyond the Study Day 2 Visit if required for clinical purposes.  
18. All patients will take oral celecoxib 400 mg BID on Study Days 1 to 14; no celecoxib should be taken after Study Day 14. The first dose of celecoxib will be administered 1 to 
2 hours prior to rAd-IFN administration (rAd-IFN treatment group) or on Study Day 1 (control group). The patient will be provided with the remainder of the 14-day 
treatment to be taken at home. The patient will be provided with a celecoxib diary and instructed that the next dose should be taken approximately 12 hours post-rAd-IFN 
administration (rAd-IFN treatment group) or approximately 12 hours after the first celecoxib dose (control group) and 400 mg orally BID, at approximately 12-hour intervals, 
thereafter. If the patient receives the first dose of celecoxib late on Study Day 1, such that the patient is only able to take 1 dose of celecoxib on Study Day 1, the patient must 
not take a celecoxib dose on Study Day 15, regardless of whether or not the patient has taken all planned celecoxib doses. If BID dosing does not occur on Study Day 1 for 
this reason, it will not be considered a protocol deviation. If the patient vomits after taking celecoxib, the patient should not replace that dose; instead, the patient should wait 
until the next scheduled time point to take their next scheduled celecoxib dose. 
19. 1250 mg/m2 administered intravenously on Days 1 and 8 of a 21-day gemcitabine cycle, unless the cycle is modified due to toxicity/delay. See Section 5.6 for details 
regarding gemcitabine treatment delay. 
20. Retrain patients with <100% compliance (unless the only reason compliance is <100% is a result of the patient taking the first dose of celecoxib late on Study Day 1, such that 
the patient is only able to take 1 dose of celecoxib on Study Day 1). 
21. All adverse events will be monitored and documented from the time of the main study’s informed consent through 30 days after the last dose of study treatment (rAd-IFN, 
celecoxib, and gemcitabine). 
22. All previously recorded treatment-emergent adverse events and SAEs will be followed until resolution or stabilization. 
23. Concomitant medications specific for mesothelioma treatment. 

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24. All CT scans will be submitted for central archiving on an ongoing basis throughout the study. Any CT scans completed for standard of care purposes after disease 
progression/ET will not be collected for the central archive. 
25. Where applicable, patients in the rAd-IFN treatment group who have withdrawn from study treatment, not including those who have withdrawn prior to commencing Study 
Day 1 treatment, will be asked if they would agree to continue to be followed for survival and safety every 6 months (14 days) for up to 5 years. 
BID = twice daily; C = cycle; CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report 
form; EOT = end of treatment; ET = early termination; ICF = informed consent form; IPC = intrapleural catheter; IRT = Interactive Response Technology; LCSS-Meso = Lung 
Cancer Symptom Scale-mesothelioma; PD-L1 = programmed death-ligand 1; QoL = Quality-of-Life; rAd-IFN = recombinant adenovirus vector containing the human interferon 
alpha-2b gene; SAE = serious adverse event.

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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen (or local equivalent) 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate [1, 2] 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphorus 
Lipase 
Magnesium 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Total cholesterol 
Triglycerides 
Uric acid (or local equivalent) 
1. 
Estimated glomerular filtration rate will be calculated using the Modification of Diet in Renal Disease study equation, 
i.e., Estimated glomerular filtration rate (mL/min/1.73 m2) = 175  (serum creatinine/88.4)-1 154  (Age)-0 203  (0.742 if 
female)  (1.212 if African American), where serum creatinine is reported in mol/L. 
2. 
Estimated glomerular filtration rate will be calculated at Screening only. 
 
Hematology 
Absolute neutrophil count 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
Reticulocyte 
White blood cell count and differential [1] 
 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of reference 
range. 
 
Coagulation 
Activated partial thromboplastin time 
International normalized ratio 
Prothrombin time 
 
 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
1. 
Microscopy is performed only as needed based on initial positive test results. 
 
Pregnancy Test 
Serum pregnancy tests will be performed for female patients of childbearing potential only. 
 

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APPENDIX C: MODIFIED RECIST 1.1 CRITERIA ADAPTED TO THE 
GROWTH PATTERN OF MALIGNANT PLEURAL MESOTHELIOMA 
The baseline computed tomography (CT) scan of chest, abdomen, and pelvis performed during 
Screening will be used to determine restaging of the disease. Only those patients with no evidence 
of malignant pleural mesothelioma outside of the thoracic cavity will be eligible for the study. The 
baseline CT scan performed during Screening and all other CT scans performed for the patient 
during the study will be required to be submitted to a central archive. Details are provided in the 
Imaging Manual. If patients have clinical symptoms of metastatic disease (e.g., bone pain), this 
should be evaluated before the patient is enrolled in the study. 
This study seeks to evaluate therapy response by measuring tumor response to therapy in patients 
with malignant pleural mesothelioma (with no extrathoracic disease). Imaging evaluations will 
employ the modified Response Evaluation Criteria in Solid Tumors guideline (version 1.1), which 
is tailored to this disease. All patients enrolled in this study will be evaluated for therapy response 
approximately every 9 weeks, with measurements of target lesions performed locally. Changes in 
longest radial diameter for pleural lesions, longest diameter for thoracic non-pleural, thoracic 
non-nodal measurements, and shortest diameter in the case of malignant thoracic lymph nodes will 
be assessed for target lesions identified at baseline for each re-imaging time point over the course 
of the study. 
General Guidelines for Measurement of Disease Response 
Timing of disease measurement: Baseline imaging (i.e., CT scan of the chest, abdomen, and 
pelvis) must be performed within 28 days prior to Study Day 1. The CT scan performed during 
Screening will be used as the patient’s baseline modified Response Evaluation Criteria in Solid 
Tumors 1.1 assessment. Standard of care CT scans completed within 2 weeks prior to Screening 
may be used in place of the Screening CT scan on a case-by-case basis as agreed with the Medical 
Monitor. The purpose of baseline imaging is to exclude ineligible patients with extrathoracic 
disease and identify measurable sites of disease that will be followed over time for evidence of 
response. The first CT scan after randomization will be performed at gemcitabine Cycle 3 Day 1 
(±3 days). Subsequent CT scans will be performed every 9 weeks (±3 days) until disease 
progression/early termination. The CT scan schedule of every 9 weeks (±3 days) from gemcitabine 
Cycle 3 Day 1 will be maintained regardless of gemcitabine dose delays or interruptions. 
Identifying sites of measurable disease: Measurable disease is defined by the presence of at least 
1 measurable lesion. In addition to identifying the sites of disease, the evaluator must decide if the 
disease is measurable. In choosing sites of measurable disease, it is vital to choose sites that allow 
for reproducible measurement since slight variations in lesion measurement can introduce 
unwanted variability in response assessment. This is of particular importance in the case of pleural 
disease. 
Measurement technique: All measurements will be recorded in metric notation using millimeters 
by use of a ruler or calipers. Radial measurements of the pleural thickness will be made with 
measurement trajectories perpendicular to the surface of the pleura using the same orientation of 
measurement for all subsequent follow-up scans. In order to ensure reproducibility for subsequent 
measurements, it is advised that a screenshot of the measurements be retained. 

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Modalities used for measurement: CT scan is the mandated modality for tumor imaging 
assessments in this study. The measurability of lesions on a CT scan provided in this Clinical Study 
Protocol is based on the assumption that the CT slice thickness is 5 mm.  
Computed tomography imaging protocol recommendations: The modality of choice for 
imaging evaluation in this study is diagnostic CT scan performed on multidetector CT and obtained 
with intravenous contrast enhancement when possible. The same imaging technique will be used 
to acquire CT images at baseline and for imaging acquired on therapy for tumor response 
assessment. Images of the chest should be acquired at full inspiration with coverage of the entire 
chest and include the abdomen and pelvis. Axial, coronal, and sagittal reconstructions with 1 mm 
slice thickness are recommended, and the maximum allowable slice thickness is 5 mm.  
Definitions of Disease Measurements 
The following are definitions relevant to therapy response assessment in this study. Measurable 
disease is necessary for sites of disease to qualify as target lesions. 
Measurable disease (pleural): Measurable disease in the pleural space is defined as a lesion with 
a minimum pleural thickness of 7 mm. This measurement of pleural thickness is measured radially, 
perpendicular to the curvature of the pleural surface. Care should be taken to accurately 
discriminate between pleural tumor and adjacent pleural plaque, complex pleural fluid, atelectatic 
lung, and chest wall soft tissues. Target lesions should be chosen at locations with anatomical 
landmarks that allow for reproducible measurement longitudinally. This sometimes may mean that 
the target lesion chosen is not the largest lesion available. In general, it is preferable to choose 
lesions away from pleural fluid and not in proximity to the diaphragm, since the curvature of the 
diaphragm can be variable based on the degree of inspiration. In addition, the curvature of the 
pleura at the lung apex can result in measurement error. The preferred site of pleural measurement 
is as follows: 
 Superior to the level of the left atrium (to minimize inspiratory effort and pleural curvature), 
and 
 Below the level of the aortic arch (to minimize the impact of pleural curvature). 
All tumor measurements must be recorded in millimeters. In the case of bilateral disease, the pleura 
of both hemithoraces are considered 1 organ. 
Measurable disease (thoracic non-pleural, thoracic non-nodal): Thoracic non-nodal lesions 
outside of the pleural space must measure at least 10 mm in the longest dimension to be considered 
measurable for assignment as target lesions. All tumor measurements must be recorded in 
millimeters.  
Measurable disease (thoracic nodal): To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in the short axis. At baseline and in follow-up examinations, only 
the short axis will be measured and followed.  
New lesions: New lesions represent new sites of malignant involvement. If a new site of disease 
is in question but not certain to be malignant, then this lesion should be considered a “finding” 
rather than a “new lesion” since the later term automatically implies progressive disease (PD). If 
a “finding” is later discovered to represent a site of disease, it should be re-categorized as a “new 
lesion” dating from the time it first manifested. An enlarging lymph node should not be considered 
a “new lesion” if it is <15 mm in the short axis. If the newly enlarged lymph node has been 

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biopsy-proven to be malignant, the newly enlarged lymph node is considered a “new lesion” even 
if the short axis is <15 mm. 
Non-measurable disease: Sites of malignant disease that are smaller than the threshold to be 
considered measurable (i.e., pleural disease <7 mm in radial thickness; thoracic nodal disease 
10 mm but <15 mm in the short axis; or thoracic non-nodal, thoracic non-pleural disease <10 mm 
in the long axis) are considered non-measurable disease and can be followed as non-target lesions. 
Also included in this category are lesions at sites of disease that are measurable in size but are in 
excess of the allowed number of target lesions at that site.  
Evaluable for therapy response assessment: Only patients with measurable disease present at 
baseline who have received at least 1 cycle of therapy and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified according 
to the definitions stated below.  
Assessment of Baseline Imaging 
All baseline evaluations should be performed as close as possible to the beginning of treatment 
and never more than 28 days prior to Study Day 1, unless there is prior agreement with the Medical 
Monitor as stated in this protocol. At baseline, prior to the start of therapy, sites of measurable 
disease must be determined and target lesions as well as non-target lesions must be defined. These 
are the lesions that will be assessed, longitudinally, over the course of therapy to determine tumor 
response to therapy. At baseline, the determination will be made as to whether the patient has 
measurable disease and can be a candidate for this study. Tumor lesions will be assigned as 
follows. 
Target lesions: If the patient has exclusively pleural disease, all measurable pleural lesions up to 
6 lesions can be included as target lesions using the following rule: no more than 2 lesions 
measured per slice and image slices should be chosen at least 1 cm apart. Pleural lesions should 
be chosen in locations with anatomical landmarks that are reproducible for longitudinal 
assessments to maintain accuracy in assessment of therapy response. 
In patients with a mix of pleural and thoracic non-pleural disease, all measurable lesions up to a 
maximum of 2 lesions per organ and 5 lesions in total can be included as target lesions. For 
measurable target lesions that are both pleural and thoracic non-pleural, the pleura (inclusive of 
both hemithoraces) are considered 1 organ. Target lesions should be chosen so that they are 
representative of all of the organs involved to convey the changes in overall tumor burden. As with 
pleural disease, lesions should be chosen in locations with anatomical landmarks that are 
reproducible for longitudinal assessments. 
Non-target lesions: Disease that is evaluable but does not meet the criteria for measurable disease, 
or exceeds the allowed number of target lesions for a specified organ, can be assigned as a 
non-target lesion. These lesions will be assessed for presence, absence, and significant change in 
burden over time. Although, patients with only non-target lesions will not be enrolled in the study. 
Assessment of Tumor Response to Therapy 
In order to determine the tumor response to therapy, the diameters of the target lesions are summed 
at each time point beginning with the baseline imaging. At each subsequent post-therapy time 
point, the new post-therapy sum is compared to the baseline sum, and the percent change is 
calculated. This percent change is used to assign an objective response for that time point.  

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Target lesions: At each post-therapy time point, the target lesions that are identified at baseline 
will be measured using millimeter measurements. The same measurement technique and imaging 
modality will be made for these serial measurements.  
 Pleural lesions that remain detectable but are too small to measure are indicated as “too small,” 
and a default measurement of 2 mm is assigned to that lesion for that time point. If the lesion 
can be measured, it should be measured, and the measurement should be recorded. Lesions 
that disappear completely are termed “disappeared.”  
 Thoracic non-pleural, thoracic non-nodal lesions that are detectable but are too small to 
measure are indicated as “too small,” and a default measurement of 5 mm is assigned to that 
lesion for that time point. If the lesion can be measured, it should be measured, and the 
measurement should be recorded. Lesions that disappear completely are termed “disappeared.”  
 For thoracic lymph nodes, a decrease in size such that the short axis measurement is <10 mm 
is considered “disappeared.”  
Non-target lesions: All baseline evaluations of non-target lesions will be recorded separate from 
the time point sum. These lesions are not measured but rather are qualitatively assessed at each 
time point with a determination made as to whether they are stable, significantly progressed, 
significantly regressed, or disappeared.  
 For thoracic non-pleural lesions, these non-target lesions may be individually identified.  
 For pleural lesions, if these non-target lesions represent a few discrete lesions beyond those 
measured as target lesions, they may be individually identified as non-target lesions. In cases 
where there is extensive pleural nodularity or pleural tumor cannot be discriminated from 
adjacent diaphragm or complex pleural effusion, specific descriptors characterizing this 
disease should be used such as “circumferential pleural thickening” or “tumor 
indistinguishable from diaphragm.” 
 For thoracic nodal lesions considered to be malignant, lymph nodes 10 mm in the short axis 
but <15 mm may be considered non-target lesions. 
Assignment of objective time point response: target lesions  
Progressive disease: The criteria for an assessment of PD are met if either of the following are 
true: 
 The time point sum of target lesion diameters increased by at least 20% taking as reference the 
smallest time point sum in the course of the study (including the baseline, if that is the smallest 
sum on study), which must be at least a 5 mm increase in sum when compared to the baseline 
sum; or 
 New lesions are present. 
Stable disease (SD): The criteria for an assessment of SD are met if the following is true: 
 The criteria for complete response (CR), partial response (PR), or PD are not met (i.e., <20% 
increase or <30% decrease in time point sum, or >20% increase in time point sum but the 
increase is not at least 5 mm, taking as reference the smallest time point sum in the course of 
the study [including the baseline, if that is the smallest sum on study]).  

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Partial response: The criteria for an assessment of PR are met if the following are true: 
 There is a >30% decrease in the time point sum of the target lesion diameters taking as 
reference the baseline sums, and  
 Criteria for PR are met on 2 sequential re-imaging assessments performed >4 weeks apart. 
Complete response: The criteria for an assessment of CR are met if the following are true: 
 There is complete disappearance of the target lesion (if thoracic non-nodal), 
 There is regression of thoracic nodal disease such that all malignant thoracic lymph nodes have 
a short axis <10 mm, and 
 Criteria for CR are met on 2 sequential re-imaging assessments performed >4 weeks apart. 
Assignment of time point response: non-target lesions 
In the majority of cases, the overall time point response will be determined by the assessment of 
the changes in the target lesion sums. However, there may be rare cases of marked enlargement of 
a non-target lesion that is considered unequivocal progression and will result in an assessment of 
PD. 
Progressive disease: The criteria for PD are fulfilled if the following are true: 
 Appearance of 1 new lesion, and/or  
 Unequivocal progression of existing non-target lesions. 
Note: Marked enlargement of the non-target lesion must be comparable to an increase in 
disease that would be considered progression for a target lesion. Non-target disease evaluation 
should not normally trump target lesion status. The non-target disease evaluation must be 
representative of overall disease status change, not a single lesion increase. 
Non-CR/non-PD: The criteria for non-CR/non-PD are fulfilled if the following is true: 
 There is persistence of non-target lesions, and the criteria for PD or CR are not met. 
Complete response: The criteria for CR are fulfilled if the following are true: 
 There is complete disappearance of all non-target lesions (if thoracic non-nodal), and 
 There is regression of thoracic nodal disease such that all malignant thoracic lymph nodes have 
a short axis <10 mm. 
Assignment of best overall response 
The best overall response represents the best response recorded from the start of the treatment until 
completion of the patient’s involvement in the study. For assignment of CR, PR, and SD, there is 
a requirement of confirmation with a CT at least 4 weeks later. 

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Table 2. 
Summary of Key Points for Modified Response Evaluation Criteria in Solid 
Tumors 1.1 
Minimum lesion size for target lesions 
Pleural (radial pleural thickness): 7 mm 
Thoracic non-pleural, thoracic non-nodal (longest 
diameter): 10 mm 
Thoracic nodal (short axis): 15 mm 
Default measurement for target lesions that become too 
small to measure 
Pleural: 2 mm 
Thoracic non-pleural, thoracic non-nodal: 5 mm 
Thoracic lymph nodes become “disappeared” when 
<10 mm in the short axis 
Number of target lesions to include in time point sum 
If only pleural disease: 6 lesions1 
If mix of pleural and thoracic non-pleural: maximum 
of 5 target lesions and no more than 2 per organ2 
1. 
When measuring pleural lesions, no more than 2 lesions per image slice. Image slices should be at least 1 cm apart. 
2. 
Pleura count as 1 organ, even if bilateral disease. 
Source: Armato SG, Nowak AK. Revised modified Response Evaluation Criteria in Solid Tumors for assessment of response in 
malignant pleural mesothelioma (version 1.1). J Thorac Oncol. 2018 Jul;13(7):1012-1021. 

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APPENDIX D: CYTOCHROME P450 INHIBITORS, INDUCERS, AND 
SUBSTRATES 
A listing of cytochrome P450 inhibitors, inducers, and substrates can be found using the following 
link: http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
Table 3. 
Inhibitors, Inducers, and Substrates of Cytochrome P450 1A2, 2C9, and 2D6 
Cytochrome 
P450 
Substrate 
Inhibitor 
Inducer 
1A2 
Amitriptyline, caffeine, clomipramine, 
clozapine, cyclobenzaprine, duloxetine, 
estradiol, fluvoxamine, haloperidol, 
imipramine N-DeMe, mexiletine, 
nabumetone, naproxen, olanzapine, 
ondansetron, phenacetin, 
acetaminophen, NAPQI, propranolol, 
riluzole, ropivacaine, tacrine, 
theophylline, tizanidine, triamterene, 
verapamil, (R)warfarin, zileuton, 
zolmitriptan 
Fluvoxamine, ciprofloxacin, 
cimetidine, amiodarone, 
efavirenz, fluoroquinolones, 
fluvoxamine, furafylline, 
interferon, methoxsalen, 
mibefradil, ticlopidine 
Broccoli, brussel 
sprouts, 
carbamazepine, 
char-grilled meat, 
insulin, 
methylcholanthrene, 
modafinil, nafcillin, 
beta-naphthoflavone, 
omeprazole, 
rifampin, tobacco 
2C9 
Diclofenac1, ibuprofen, lornoxicam, 
meloxicam, S-naproxen, piroxicam, 
suprofen, tolbutamide, glipizide, 
losartan, irbesartan, glyburide, 
glibenclamide, glipizide, glimepiride, 
tolbutamide, amitriptyline, celecoxib, 
fluoxetine, fluvastatin, glyburide, 
nateglinide, phenytoin-4-OH2, 
rosiglitazone, tamoxifen, torsemide, 
valproic acid, S-warfarin, zafirlukast 
Fluconazole, amiodarone, 
efavirenz, fenofibrate, 
fluconazole, fluvastatin, 
fluvoxamine, isoniazid, 
lovastatin, metronidazole, 
paroxetine, phenylbutazone, 
probenecid, sertraline, 
sulfamethoxazole, 
sulfaphenazole, teniposide, 
voriconazole, zafirlukast 
Carbamazepine, 
enzalutamide, 
nevirapine, 
phenobarbital, 
rifampin, 
secobarbital, 
St. John's Wort 
2D6 
Tamoxifen, carvedilol, S-metoprolol, 
propafenone, timolol, amitriptyline, 
clomipramine, desipramine, fluoxetine, 
imipramine, paroxetine, venlafaxine, 
haloperidol, perphenazine, risperidone, 
thioridazine, zuclopenthixol, 
alprenolol, amphetamine, aripiprazole, 
atomoxetine, bufuralol, 
chlorpheniramine, chlorpromazine, 
clonidine, codeine, debrisoquine, 
dexfenfluramine, dextromethorphan, 
donepezil, duloxetine, encainide, 
flecainide, fluvoxamine,  
lidocaine, metoclopramide, 
methoxyamphetamine, mexiletine, 
minaprine, nebivolol, nortriptyline, 
ondansetron, oxycodone, perhexiline, 
phenacetin, phenformin, promethazine, 
propafenone, propranolol, risperidone, 
sparteine, tramadol 
Bupropion, cinacalcet, 
fluoxetine, paroxetine, 
quinidine, duloxetine, 
sertraline, terbinafine, 
amiodarone, cimetidine, 
celecoxib, chlorpheniramine, 
chlorpromazine, citalopram, 
clemastine, clomipramine, 
cocaine, diphenhydramine, 
doxepin, doxorubicin, 
escitalopram, halofantrine, 
haloperidol, histamine H1 
receptor antagonists, 
hydroxyzine, 
levomepromazine, methadone, 
metoclopramide, mibefradil, 
midodrine, moclobemide, 
perphenazine, promethazine, 
ranitidine, 
reduced-haloperidol, ritonavir, 
ticlopidine, tripelennamine 
Dexamethasone, 
rifampin 
NAPQI = N-acetyl-p-benzoquinone imine. 
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx 

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APPENDIX E: GRADING AND MANAGEMENT OF CYTOKINE 
RELEASE SYNDROME 
Table 4. 
Cytokine Release Syndrome Revised Grading System 
Grade 
Toxicity 
Grade 1 
Symptoms are not life-threatening and require symptomatic treatment only (e.g., fever, nausea, 
fatigue, headache, myalgias, malaise) 
Grade 2 
Symptoms require and respond to moderate intervention 
Oxygen requirement <40% or 
Hypotension responsive to fluids or low dose of 1 vasopressor or 
Grade 2 organ toxicity 
Grade 3 
Symptoms require and respond to aggressive intervention 
Oxygen requirement 40% or 
Hypotension requiring high dose1 or multiple vasopressors or 
Grade 3 organ toxicity or grade 4 transaminitis 
Grade 4 
Life-threatening symptoms 
Requirement for ventilator support or 
Grade 4 organ toxicity (excluding transaminitis) 
Grade 5 
Death 
Note: Grade 2 through Grade 4 organ toxicity and Grade 4 transaminitis refer to Common Terminology Criteria for Adverse 
Events v4.03 grading.  
1. 
High vasopressor doses are defined in Table 5. 
Source: Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-95. 
 
Table 5. 
High Vasopressor Doses 
Pressor 
Dose 
Norepinephrine monotherapy 
20 g/min 
Dopamine monotherapy 
10 g/kg/min 
Phenylephrine monotherapy 
200 g/min 
Epinephrine monotherapy 
10 g/min 
If on vasopressin 
Vasopressin and norepinephrine equivalent of 10 g/min1 
If on combination vasopressors (not vasopressin) 
Norepinephrine equivalent of 20 g/min1 
Note: All doses are required for 3 hours. 
1. 
Vasopressin and Septic Shock Trial vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine 
(g/min)] + [dopamine (g/kg/min)/2] + [epinephrine (g/min)] + [phenylephrine (g/min)/10]. 
Source: Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-95. 

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Figure 2. Treatment Algorithm for Management of Cytokine Release Syndrome Based on 
the Cytokine Release Syndrome Revised Grading System 
 
Note: Grade 2 through Grade 4 organ toxicity and Grade 4 transaminitis refer to Common Terminology Criteria for Adverse 
Events v4.03 grading. 
CRS = cytokine release syndrome. 
Source: Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-95. 

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APPENDIX F: DOSE MODIFICATION STRATEGIES FOR CELECOXIB 
AND GEMCITABINE 
Table 6. 
Dose Modification Strategies for Celecoxib and Gemcitabine for All Toxicities 
 
Celecoxib 
Gemcitabine 
Temporary discontinuation 
Not applicable 
For severe (CTCAE Grade 3 or 4) 
non-hematological toxicity, except nausea/vomiting, 
treatment with gemcitabine should be withheld or 
decreased depending on the judgment of the 
Investigator. Treatment should be withheld until 
toxicity has resolved. 
Permanent discontinuation 
1. Appearance of skin 
rash, mucosal lesions, or 
any other sign of 
hypersensitivity 
2. CTCAE Grade 3 or 
higher deterioration in 
renal or hepatic function 
1. Unexplained new or worsening dyspnea or 
evidence of severe pulmonary toxicity 
2. Severe hepatic toxicity 
3. Posterior reversible encephalopathy syndrome 
4. Capillary leak syndrome 
5. Hemolytic uremic syndrome 
If pulmonary effects, such as pulmonary edema, 
interstitial pneumonitis, or adult respiratory distress 
syndrome, develop at any time during the study, the 
Investigator should discuss with the Sponsor and 
consider discontinuing gemcitabine. 
Dose modification 
Not applicable 
Dose modifications due to hematological toxicities 
for all cycles should be performed in accordance 
with Table 7. 
CTCAE = Common Terminology Criteria for Adverse Events. 
 
Table 7. 
Dose Modification of Gemcitabine Due to Hematological Toxicities for All Cycles 
Absolute Granulocyte or Neutrophil Count (109/L) 
 
Platelet Count (109/L) 
% of Total Dose 
>1 
and 
>100 
100 
0.5-1 
or 
50-100 
75 
<0.5 
or 
<50 
Withhold1 
1. 
Withheld treatment will not be reinstated within a cycle before the absolute granulocyte count reaches at least 0.5  109/L 
and the platelet count reaches 50  109/L. 
Gemcitabine Missed Doses and Treatment Delay 
The following rules will be applied if any of the following gemcitabine doses are missed in the 
21-day gemcitabine cycle: 
 Day 1 of any cycle can be delayed by a maximum of 7 days to accommodate a maximum of 
21 days between the Day 1 dose and the previous cycle’s Day 8 dose; 
 Day 8 of any cycle can be delayed by a maximum of 7 days to accommodate a maximum of 
14 days between the Day 1 dose and the Day 8 dose of the same cycle; and 
 If Day 8 of any cycle is delayed, then the Day 1 dose for the next cycle must occur at least 
14 days and up to a maximum of 21 days after the previous cycle’s Day 8 dose. 
If the maximum delay between a scheduled dose and the next dose is greater than what is described 
above, then this would be considered a missed dose. 

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If the time required for recovery from gemcitabine toxicity is more than 21 days, consideration 
should be given to permanently discontinue the patient from study treatment, unless the patient is 
demonstrating benefit overall; in which case, the possibility of remaining on study treatment 
should be discussed between the Investigator, Medical Monitor, and Sponsor after review of the 
associated risks and benefits. 

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APPENDIX G: PLEURAL FLUID SAMPLE COLLECTION PROCEDURE 
The following steps are instructions to access the intrapleural catheter (IPC) or similar device and 
drain the pleural fluid: 
1. Remove dressing; 
2. Clean the skin area with ChloraPrep, povidone-iodine, or a suitable alternative; 
3. Clean the IPC or similar device with ChloraPrep, povidone-iodine, or a suitable alternative; 
4. Gown and glove; 
5. Prepare sterile field; 
6. Remove valve cap; 
7. Clean the IPC or similar device tip with at least 3 alcohol swabs; 
8. Clamp drainage line set and attach to the IPC or similar device. Insert the tip of the drainage 
tube into the valve. Continue to push the tip into the valve until you hear a click indicating that 
the valve and drainage tube are firmly connected; 
9. Attach a 3-way stop cock to the drainage line; 
10. Use a syringe of suitable volume to aspirate up to 20 mL of fluid for research specimens. If 
fluid is not obtained, see instructions below for pleural lavage; 
11. Clamp drainage line; 
12. If vacuum bottle is required to drain pleura, remove syringe and place a 16 gauge needle (or 
suitable alternative). Insert the needle into the vacuum bottle, release the clamp in the bottle, 
and release the clamp in the drainage tube. Fluid will immediately flow into the bottle; 
13. When drainage is complete, grasp the drainage tube and pull the tip out of the IPC or similar 
device valve; 
14. Wipe the valve with at least 3 alcohol swabs; 
15. Place a new cap on the valve; and 
16. Dress the IPC or similar device site as per local standard of care.