Phase I Trial With Expansion Cohort of OBP-301 (Telomelysin™) and Definitive Chemoradiation for Patients With Locally Advanced Esophageal and Gastroesophageal Cancer Who Are Not Candidates for Surgery
Phase: PHASE1
Conditions: Advanced Esophageal Adenocarcinoma, Advanced Gastroesophageal Junction Adenocarcinoma, Clinical Stage II Esophageal Adenocarcinoma AJCC v8, Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8, Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8, Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage III Esophageal Adenocarcinoma AJCC v8, Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage II Esophageal Adenocarcinoma AJCC v8, Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage III Esophageal Adenocarcinoma AJCC v8, Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8, Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage II Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage III Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Esophageal Adenocarcinoma AJCC v8, Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8, Unresectable Gastroesophageal Junction Adenocarcinoma, Squamous Cell Carcinoma, Squamous Cell Cancer
Sponsor: NRG Oncology

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NRG ONCOLOGY 
 
NRG-GI007 
 
(ClinicalTrials.gov Identifier NCT #04391049) 
 
Phase I Trial with Expansion Cohort of OBP-301 (Telomelysin) and Definitive 
Chemoradiation for Patients with Locally Advanced Esophageal And Gastroesophageal 
Cancer Who are Not Candidates for Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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NRG ONCOLOGY  
NRG-GI007 
(ClinicalTrials.gov NCT #04391049) 
 
PHASE I TRIAL WITH EXPANSION COHORT OF OBP-301 (TELOMELYSINTM) AND 
DEFINITIVE CHEMORADIATION FOR PATIENTS WITH LOCALLY ADVANCED 
ESOPHAGEAL AND GASTROESOPHAGEAL CANCER WHO ARE NOT 
CANDIDATES FOR SURGERY 
 
This trial is sponsored by the National Cancer Institute (NCI) and will be led by NRG Oncology.  
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103  
 
Study Team (19-MAY-2023)  
Principal Investigator/Medical 
Oncology 
Geoffrey Ku, MD 
Memorial Sloan Kettering Cancer Center 
300 E. 66th Street, Rm 1035 
New York, NY 10065  
646-888-4588/FAX 646-888-4258 
kug@mskcc.org  
 
Translational Science Co-Chair 
Prasad S Adusumilli, MD  
Memorial Sloan Kettering Cancer Center 
1275 York avenue, C-863 
New York, NY 10065  
212-639-8093/ FAX 646-422-2340 
adusumip@mskcc.org  
 
Medical Physics Co-Chair 
Adam D Yock, PhD 
Vanderbilt Ingram Cancer Center 
2220 Pierce Avenue, B-948 
Nashville, TN 37232 
615-875-8650 
adam.d.yock@vanderbilt.edu  
 
 
Radiation Oncology Co-Chair 
Terence Williams, MD, PhD 
City of Hope National Medical Center  
1500 E. Duarte Road 
Duarte, CA 91010 
626-218-5677 
terwilliams@coh.org  
 
Gastroenterology Co-Chair 
Makoto Nishimura, MD 
Memorial Sloan Kettering Cancer Center 
127 York Avenue, H-710 
New York, NY 10065 
212-639-6029/ FAX 212-639-2766 
nishimum@mskcc.org 
 
Statistician 
Kathryn Winter, MS 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3198/FAX 215-574-3198 
WinterK@NRGOncology.org  
 
 
 
 
 

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NRG Oncology Contact Information 
 
Data Management 
For questions concerning eligibility or 
data submission 
Wendy Bergantz, RN 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3230 
BergantzW@NRGOncology.org  
  
RTQA 
For questions concerning RT data 
submission 
 
Susan McNulty, BS, RT(R)(T), CMD 
IROC Philadelphia – RT QA Center 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-940-8907 
smcnulty@acr.org 
RT Credentialing 
 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org  
RT data submission to TRIAD 
 
Triad-Support@acr.org 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & 
amendments 
Kathryn Okrent 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0856 
okrentk@nrgoncology.org  
Gastrointestinal (Non-Colorectal) 
Committee Chair 
Current Chair starting January 2020 
Theodore S. Hong, MD 
Massachusetts General Hospital 
100 Blossom St., Cox 3 
Boston, MA 02114 
617-726-6050/Fax:  617-726-3603 
Tshong1@mgh.harvard.edu    
 
Prior Chair 
Christopher Crane, MD 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue, Box 22 
New York, NY 10065  
212-639-2112 
 
cranec1@mskcc.org   
 
 
 
 
 

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Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
OBP-301 
Oncolys BioPharma 809930 
19404 
NRG  
Carboplatin 
Commercial 
241240 
Paclitaxel 
Commercial 
673089 
 
Participating Sites (19-MAY-2023) 
 U.S. 
 Canada 
 Approved International Member Sites 
 
Document History 
 
Version Date 
Amendment 6 
July 10, 2023 
Amendment 5 
May 19, 2023 
Amendment 4 
January 11, 2022 
Amendment 3 
July 26, 2021 
Amendment 2 
January 6, 2021 
Amendment 1 
December 7, 2020 
Initial 
 May 05, 2020 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol was designed and developed by NRG Oncology. It is intended to 
be used only in conjunction with institution-specific IRB approval for study 
entry.  No other use or reproduction is authorized by NRG Oncology nor does 
NRG Oncology assume any responsibility for unauthorized use of this protocol. 

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CONTACT INFORMATION (19-MAY-2023) 
 
For regulatory 
requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission 
Portal: (Sign in at 
www.ctsu.org, and select  
Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
 
Contact the CTSU 
Regulatory Help Desk at 1-
866-651-2878, or 
CTSURegHelp@coccg.orgfo
r regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email : 
1-888-823-5923, or 
ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  
Refer to the data submission 
section of the protocol for 
further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page located on the CTSU members’ website 
(https://www.ctsu.org).   
 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the Roster Maintenance application and in 
most cases viewable and manageable via the Roster Update Management System (RUMS) on 
the CTSU members’ website.   
 
For clinical questions (i.e., patient eligibility or treatment-related)  
Contact the Study Data Manager of the Lead Protocol Organization  
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 

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TABLE OF CONTENTS  
 
SCHEMA .........................................................................................................................................9 
1. 
OBJECTIVES ....................................................................................................................10 
1.1 
Primary Objective ..............................................................................................................10 
1.2 
Secondary Objectives .........................................................................................................10 
1.3 
Exploratory Objectives ......................................................................................................10 
2. 
BACKGROUND ...............................................................................................................10 
2.1 
Definitive Chemoradiation .................................................................................................10 
2.2 
Platinum/Taxane with Radiation ........................................................................................11 
2.3 
Oncolytic viruses ...............................................................................................................11 
2.4 
OBP-301: Background .......................................................................................................12 
2.5 
OBP-301: Clinical Experience ...........................................................................................14 
2.6 
Combining OBP-301 with Chemoradiation.......................................................................14 
3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA ..........................................................15 
3.1 
Eligibility Criteria ..............................................................................................................15 
3.2 
Ineligibility Criteria ...........................................................................................................16 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........18 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION ..........................................................21 
5.1 
Treatment Summary ...........................................................................................................21 
5.2 
Systemic Therapy ...............................................................................................................23 
5.3 
Radiation Therapy ..............................................................................................................26 
5.4 
General Concomitant Medication and Supportive Care Guidelines ..................................37 
5.5 
Duration of Therapy ...........................................................................................................38 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT .....................................................38 
6.1 
General Guidelines  ............................................................................................................38 
6.2 
OBP-301 ............................................................................................................................42 
6.3 
Radiation Therapy  .............................................................................................................42 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................43 
7.1 
Protocol Agents ..................................................................................................................43 
7.2 
Adverse Events and Serious Adverse Events ....................................................................43 
7.3 
Adverse Events for Investigational Study Agent: OBP-301 .............................................44 
7.4 
Adverse Events for Commercial Study Agents: Paclitaxel and Carboplatin .....................44 
7.5 
Expedited Reporting of Adverse Events ............................................................................44 
7.6 
Routine Reporting Requirements for Adverse Events .......................................................47 
7.7 
Pregnancy ...........................................................................................................................47 

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8. 
REGISTRATION AND STUDY ENTRY PROCEDURES  ............................................47 
8.1    Cancer Trials Support Unit Registration Procedures .........................................................48 
8.2 
RT-Specific Pre-Registration Requirements  .....................................................................52 
8.3 
Patient Enrollment  ............................................................................................................53 
9. 
DRUG INFORMATION ...................................................................................................55 
9.1 
Investigational Study Agent: OBP-301  ............................................................................55 
9.2 
Commercial Agent: Paclitaxel ...........................................................................................58 
9.3 
Commercial Agent: Carboplatin ........................................................................................59 
10.  
PATHOLOGY/BIOSPECIMEN .......................................................................................59 
10.1 
Biospecimen Submission Tables .......................................................................................59 
11. 
SPECIAL STUDIES (NON-TISSUE) ...............................................................................61 
12. 
MODALITY REVIEWS ...................................................................................................61 
12.1 
Medical Oncology Modality Quality Assurance Reviews .................................................61 
12.2 
Radiation Therapy Quality Assurance Reviews ................................................................61 
13. 
DATA AND RECORDS ...................................................................................................61 
13.1 
Data Management/Collection  ...........................................................................................61 
13.2 
Summary of Data Submission ...........................................................................................62 
13.3 
Data Quality Portal  ...........................................................................................................63 
13.4 
Global Reporting/Monitoring ............................................................................................64 
14. 
STATISTICAL CONSIDERATIONS...............................................................................64 
14.1 
Study Design ......................................................................................................................64 
14.2 
Study Endpoints .................................................................................................................64 
14.3 
Primary Objectives Study Design ......................................................................................64 
14.4 
Study Monitoring of Primary Objectives ...........................................................................66 
14.5 
Accrual/Study Duration Considerations ............................................................................67 
14.6 
Dose Level Guidelines .......................................................................................................67 
14.7 
Secondary or Exploratory Endpoints (including correlative science aims) .......................67 
14.8 
Exploratory Hypothesis and Endpoints .............................................................................68 
14.9 
Gender/Ethnicity/Race Distribution ...................................................................................68 
REFERENCES ..............................................................................................................................69 
APPENDIX I: PHARMACY MANUAL  .....................................................................................72 
APPENDIX II: BIOSAFETY LEVEL II SUMMARY INFORMATION FOR INSTITUTIONAL 
BIOSAFETY COMMITTEE REVIEW ............................................................................79 
APPENDIX III: HANDLING GUIDELINES/UNIVERSAL PRECAUTIONS FOR 
BIOSAFETY LEVEL 2 AGENTS ....................................................................................80 
APPENDIX IV: GUIDELINES FOR USE AND COMPLETION OF CLINICAL TRIAL 
MATERIAL (DRUG) DESTRUCTION CERTIFICATE.................................................88 
APPENDIX V: CARBOPLATIN DOSE CALCULATION INSTRUCTIONS ...........................90 

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APPENDIX VI: CORRELATIVE IMMUNE ASSSAYS ............................................................92 
 
 
 

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NRG-GI007 
SCHEMA 
 
REGISTRATION 
↓ 
OBP-301 via Endoscopy 
+ 
Carboplatin / Paclitaxel  
+ 
Radiation   
See full treatment details in Section 5. 
 
 
 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objective 
To determine if the addition of OBP-301 to chemoradiation with carboplatin/paclitaxel is 
safe. 
 
1.2 
Secondary Objectives 
1.2.1 To assess toxicities associated with the addition of OBP-301 to chemoradiation. 
1.2.2 To assess the number of clinical complete responses (cCR). 
1.2.3 To assess the number of patients alive/without progression (PFS) and the number of  
            patients alive (OS) at 1 and 2 years. 
 
1.3 
Exploratory Objectives 
To report correlate outcomes – cCR, PFS and OS – with immune and virus-based 
correlative assays 
 
2. BACKGROUND 
 
2.1 
Definitive Chemoradiation (11-JAN-2022) 
 
In the U.S., esophageal cancer is a rare but deadly malignancy. In 2020, it is estimated 
that 18,440 patients will be diagnosed, with 16,170 deaths (Siegel 2020). It ranks as the 
seventh cause of cancer deaths, despite its rarity, underlining the challenge of treating 
such patients. These poor outcomes are in part because approximately half of patients in 
the U.S. are diagnosed with metastatic disease. 
 
 
For patients with localized disease, surgery remains the cornerstone of curative therapy. 
However, esophageal cancer is a disease of older patients, many of whom cannot tolerate 
the morbidity of an esophagectomy because of underlying cardiopulmonary 
comorbidities or because of a borderline performance status. Complications include 
respiratory problems in 11% to 20%, anastomotic leak in 3% to 7%, and wound infection 
in 5%. Operative mortality ranges from zero to 4%, even in high-volume institutions 
(Mathisen 1988, Griffin 2002, Nichols 2005). 
 
As such, a standard-of-care that has emerged for patients with locally advanced 
esophageal and gastroesophageal junction (GEJ) cancer who are medically inoperable is 
definitive chemoradiation. This approach is based on the seminal Radiation Therapy 
Oncology Group (RTOG) 85-01 study, which revealed superior outcomes for 5-
fluorouracil (FU)/cisplatin chemotherapy and radiation vs. radiation alone (Herskovic 
1992); long-term survival was reported in both squamous cell cancer (SCC) patients and 
the small group of adenocarcinoma patients treated on this study (Cooper 1999).  
 
Definitive chemoradiation is a particularly strong consideration for patients with 
esophageal SCC. Many of these patients have co-morbidities associated with alcohol and 

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tobacco use, and surgery carries with it a higher rate of post-operative mortality following 
neoadjuvant chemoradiation secondary to increased risks of cardiopulmonary 
complications. In addition, observation for patients with esophageal SCC who achieve a 
clinical complete response to chemoradiation is supported by the results of two 
randomized European trials, which did not show a clear improvement in overall survival 
for surgery following chemoradiation (Stahl 2005, Bedenne 2007). 
 
 
2.2 
Platinum/Taxane with Radiation (11-JAN-2022) 
 
While the RTOG 85-01 study treated patients with 5-FU/cisplatin and radiation, the 
Dutch CROSS study established carboplatin/paclitaxel as a contemporary reference 
chemotherapy regimen in combination with radiation prior to surgery for operable tumors 
(van Hagen 2012). This regimen resulted in a 23% and 49% pathologic complete 
response rate (pCR) respectively in patients with esophageal adenocarcinomas and SCC. 
Compared to surgery alone, it also reduced the risk of distant metastases by 6% 
(Oppedijk 2014). 
 
Of note, the widespread adoption of this regimen is in large part because it was very well-
tolerated. For example, the rate of grade 3/4 esophagitis was only 1% and there was only 
1 esophageal perforation in 171 patients. The grade 3/4 nausea rate was also only 1%. 
Unfortunately, the relatively low pCR rate with chemoradiation means that the majority 
of patients who do not undergo surgery will have locally persistent/recurrent disease, 
which is a source of significant morbidity, including dysphagia and bleeding. In addition, 
these patients are at significant risk for developing metastatic disease. As such, this 
population represents a high unmet medical need in what is already a highly malignant 
disease. 
 
Relatively few studies have focused on this population as the majority of studies have 
mandated pre-operative therapy prior to surgery. A recent exception is the RTOG 0436 
study, which randomized 344 patients (62% of whom had adenocarcinomas) to 
cisplatin/paclitaxel and radiation to 50.4 Gy (1.8 Gy/fraction ×28 fractions) with or 
without cetuximab, an antibody against epidermal growth factor receptor 
(Suntharalingam 2017). The study demonstrated there was no improvement in overall 
survival (OS), which was the primary endpoint; the 24-month OS rate was about 44%. 
Similarly, the clinical CR (cCR) rate – defined as endoscopic clearance of the primary 
tumor – was about 56% in both arms and the 24-month local failure rate for all patients 
was about 48%. 
 
2.3 
Oncolytic viruses 
 
Oncolytic immunotherapy employs viruses that are designed to preferentially replicate in 
and lyse cancer cells and through this process trigger anti-tumor immunity. Following the 
first description of a virus engineered to replicate selectively in cancer cells over 20 years 
ago, the field of oncolytic immunotherapy has expanded dramatically. Over 10 different 

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viral species have now been assessed or are under assessment in human studies, including 
the H101 adenovirus product, which was approved for use in combination with 
chemotherapy as a treatment for head and neck cancer by the Chinese State Food and 
Drug Administration in November 2005.   
 
More recently, a phase III pivotal trial of talimogene laherparepvec, an oncolytic herpes 
virus expressing granulocyte-macrophage colony stimulating factor (GM-CSF) in 
patients with advanced melanoma met its primary endpoint, demonstrating a significant 
improvement in durable response rate versus GM-CSF alone (16% vs 2%, p<0.0001) in 
patients with advanced melanoma (Andtbacka 2015). Based on these results, in October 
2015, it was granted approval as the first oncolytic viral therapy in the U.S. as local 
therapy for recurrent melanoma. The European Medicines Agency also approved 
talimogene laherparepvec for the treatment of adults with unresectable melanoma.  
 
Conditionally replicable oncolytic viruses are engineered for selective replication in 
cancer cells that express certain oncogenic phenotypes (Hawkins 2001, Nemunaitis 
2010).  To this end, multiple viral backbones have been employed, although the most 
commonly utilized is derived from the adenovirus serotype 5 (Ad5).   
 
2.4 
OBP-301: Background 
 
OBP-301 (TelomelysinTM) is a novel, condition-restricted, replication-competent 
adenovirus serotype 5-based adenoviral construct that incorporates a human telomerase 
reverse transcriptase gene (hTERT) promoter. hTERT encodes the catalytic protein 
subunit of telomerase, a polymerase that acts to stabilize telomere lengths and is highly 
expressed in tumors but not in normal, differentiated adult cells. Thus infection with 
OBP-301 leads to viral cytolytic activity preferentially in cancer cells but not normal 
cells. 
 
The adenoviral reproductive cycle is a highly orchestrated process. At the molecular 
level, the adenoviral genome contains 8 transcriptional units that are activated at different 
phases of infection. They are referred to as early (E1A), immediate early (E1B, E2, E3, 
E4), intermediate (IX and IVa2), and late genes. It has been reported previously that the 
transcriptional control of the E1A expression via the hTERT promoter could restrict 
adenoviral replication to telomeres-positive cells and efficiently lyse tumor cells 
(Fujiwara 2007). In the construct of OBP-301, the normal transcriptional regulatory 
element of the E1A gene is replaced by the hTERT promoter and additional 
modifications to enhance specificity include the replacement of the normal transcriptional 
element of viral E1B gene by an internal ribosomal entry site (IRES) sequence to 
minimize “leakiness”). Furthermore, OBP-301 is the first replication-competent 
adenovirus that retains a fully functional viral E3 region, which codes for proteins that 
regulate the immune response to the virally infected cell (Hawkins 2001). 

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∆E1 = delta E1 adenovirus vector, E1A, E1B = transcriptional units, hTERT = human telomerase 
reversetranscriptase, IRES = internal ribosomal entry site, ITR = inverted terminal repeat 
Figure 1. The construct of OBP-301 
 
Telomerase activation is considered to be a critical step in carcinogenesis and its activity 
is closely correlated with hTERT expression. Thus, expression of hTERT is generally 
low in differentiated adult cells and active in cells with proliferative capacity such as 
tumors, gastrointestinal endothelium, or stem cells;(Shay 1997, Shay 2001) the majority 
of malignant tumors shown to demonstrate high telomerase activity. Previous studies 
have demonstrated control over the expression of exogenous genes to telomerase-positive 
cancer cells by the hTERT promoter (Kamradt 2003) and the hTERT promoter is an 
excellent candidate for generating cancer-specific oncolytic adenovirus.  
 
There are several mechanisms by which adenoviruses in general, and OBP-301 in 
particular, can destroy tumor cells in vivo. Direct cell lysis occurs following viral 
replication and data from animal models have shown that non-replicating adenovirus in 
rodent tissue will induce both an acute (2-4 days) and chronic (14 days) inflammatory 
infiltration. During the acute phase, tumor necrosis factor (TNF-α) and interleukin (IL)-1 
and IL-6 are produced in high concentrations locally within the tissue. These cytokines 
have both direct cytopathic effects and indirect effects through immune effector cell 
recruitment into the local tissue. Finally, adenovirus infection of a tumor cell may 
augment tumor antigen presentation and enhance tumor antigenicity, leading in turn to 
immunogenic cell death, which leads to release of danger-associated molecular patterns, 
thereby attracting innate immune cells, particularly dendritic cells to the tumor and 
leading to the recruitment and maturation of tumor specific T-cells in the tumor 
microenvironment, improved recognition and destruction of tumors by cytotoxic T cells 
(van Vloten 2018). 
 
In vitro studies have validated the selective infectivity and direct cytolysis of OBP 301 in 
cancer cells and in vivo, intratumoral injection has demonstrated anti-tumor activity 
without significant toxicity. Additionally, distant viral uptake was observed following 
E1A 
hTERT promoter 
IRES 
E1B 
ΔE1 
ITR 
ITR 
Adenovirus type 5 genome  

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intratumoral injection, evidenced by the presence of adenoviral protein in non-injected 
tumors following treatment of the contralateral tumor. These encouraging pre-clinical 
findings of safety and directed anti-tumor activity were supportive of the continuing 
clinical development of OBP 301 as an oncolytic therapeutic agent (Fujiwara 2007).   
 
2.5 
OBP-301: Clinical Experience 
In a phase I study, OBP-301-001, (OBP-301), 16 patients were treated with single intra-
tumoral injections of OBP-301(Nemunaitis 2010). No grade 3/4 toxicities were observed 
and common grade 1/2 toxicities included injection site reactions and systemic symptoms 
(fevers/chills in 6 patients). Viral DNA was transiently detected in 13 of the 16 patients. 
Of 11 patients with RECIST-evaluable lesions, 1 patient had a partial response, while 7 
had stable disease.  
In OBP-301-003-CV (OBP-301 + Radiation phase I/II study), OBP-301 was combined 
with radiation to 60 Gy in Japanese esophageal cancer patients who were assessed not to 
be candidates for surgery or chemoradiation. OBP-301 were administered at three dose 
levels; 1 mL of 1x1010 viral particles (vp)/mL, 1 mL of 1x1011 vp/mL, and 1mL of 1x1012 
vp/mL, administered 3 times via endoscopic injection (Tanabe 2019). In total, 13 patients 
were treated (3 at the highest dose level of 1×1012 vp/ml). Toxicities were manageable. 
The only observed grade 3/4 toxicities were leukopenia (8%) and lymphopenia (77%). 
Grade 1/2 toxicities include transient fever without evidence of infection (62%), chills 
(15%), nausea (25%), esophagitis (31%) anorexia (39%) and pneumonitis (23%). Of the 
13 patients treated, 8 achieved a local cCR to the combination of OBP-301 and radiation 
and 3 patients have achieved a partial response. The overall response rate was 91.7%. 
The clinical CR was 83.3 % in stage I and 60% in stages II and III. These results compare 
favorably with a historical cCR rate of about 37.2% for stages I-IV with radiation alone 
(Toh 2020, Fujiwara 2019). 
Beyond augmenting the local effects of radiation, OBP-301 has been shown in vitro to 
inhibit DNA repair mechanisms, which may sensitize the infected tumor cells to radiation 
(Kuroda 2010), leading to synergistic effect. In addition to a local effect, OBP-301 may 
also potentiate immune responses. Viral replication is highly immunogenic and oncolysis 
induced by such viruses releases tumor epitopes and provides costimulatory danger 
signals (Endo 2008).  
 
2.6 
Combining OBP-301 with Chemoradiation (11-JAN-2022) 
Given the excellent safety profile of both carboplatin/paclitaxel and radiation and OBP-
301 with radiation (in an elderly population that was assessed not to be a eligible for even 
chemoradiation alone), there is a compelling rationale to combine OBP-301 with 
carboplatin/paclitaxel and radiation as definitive therapy for patients with 
esophageal/GEJ cancer who are not surgical candidates. In addition to improvement in 
locoregional control, there is also the potential to augment anti-tumor immunity, which 
may also impact positively on distant micrometastatses through an abscopal effect. 
 

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3. ELIGIBILITY AND INELIGIBILITY CRITERIA 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page). For radiation therapy-related eligibility 
questions, please contact RTQA (see protocol cover page).  
 
3.1 
Eligibility Criteria (19-MAY-2023) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
3.1.1 Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma or 
squamous cell carcinoma (SCC) of the esophagus or gastroesophageal junction (GEJ) within 90 
days prior to registration;  
• Gastroesophageal junction tumors must be Siewert Type I/II; 
 
3.1.2 Required diagnostic workup for study entry: 
• History/physical examination prior to registration; 
• CT of the chest/abdomen with intravenous contrast within 28 days prior to registration; 
If CT contrast is contraindicated MRI of the chest/abdomen without contrast is 
permitted;  
• Bronchoscopy for squamous cell carcinoma (SCC) tumors that are adjacent to the 
airway to exclude a tracheoesophageal fistula within 42 days prior to registration; 
• Endoscopic ultrasound (if technically feasible) within 90 days prior to registration; 
• Whole body PET/CT scan within 42 days prior to registration: Note: scan will be 
used for radiation treatment planning, in addition to ruling out metastatic disease; 
 
3.1.3 Age ≥ 18; 
 
3.1.4 ECOG Performance Status of 0-2 within 14 days prior to registration; 
 
3.1.5 Adequate hematologic function within 14 days prior to registration defined as follows: 
• Absolute Neutrophil Count ≥1,500/mcL 
• Hemoglobin ≥ 9 gm/dL 
• Platelets ≥ 100,000/mcL 
 
3.1.6 Adequate renal function within 14 days prior to registration defined as follows: 
• Creatinine clearance of ≥50 ml/min (as calculated by Cockcroft-Gault equation) 
 
3.1.7 Adequate hepatic function within 14 days prior to registration defined as follows: 
• Total Bilirubin ≤ 1.5 x ULN (patients with known Gilbert Syndrome can have a Total 
Bilirubin <2.5 x ULN) 
• AST/ALT ≤ 2.5 x ULN 
 

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3.1.8   Patients for whom non-operative management is a viable option in the opinion of a thoracic 
surgeon and/or multidisciplinary team and are candidates for chemoradiation; this does not 
preclude patients from receiving surgery after chemoradiation if felt to me medically 
indicated; 
 
3.1.9 Patients must, in the opinion of a treating gastroenterologist, have a tumor that is amenable 
to intratumoral injection with at least 1 mL (1 x1012 vp/mL) of OBP-301 and be a candidate 
for 3 endoscopy procedures. 
 
3.1.10  Female patients of child bearing potential must have a negative serum/urine pregnancy test 
within 14 days prior to study entry. A female not of childbearing potential is one who has 
undergone a hysterectomy, bilateral oophorectomy, tubal ligation, or who has had no 
menses for 12 consecutive months.   
 
3.1.11    Patients of reproductive potential must agree to use effective contraception for the duration 
of study treatment as well as 6 months (for women) or 12 months (for men) after the last 
administered injection of OBP-301.  Effective contraception includes oral contraceptives, 
implantable hormonal contraception, double-barrier method or intrauterine device. 
 
3.1.12 The patient must provide study-specific informed consent prior to study entry. 
 
3.1.13  Patients with a prior or concurrent malignancy whose natural history or treatment does not 
have the potential to interfere with the safety or efficacy assessment of the investigational 
regimen are eligible for this trial. 
 
3.1.14  Known acute or chronic hepatitis B or C infection (testing not required prior to study entry 
in patients with no known history of hepatitis B or C);  
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated.  
• For patients with a history of hepatitis C virus (HCV) infection, they must (i) have been 
treated and cured, (ii) for patients with HCV infection who are  currently on treatment, 
they are eligible if they have an undetectable HCV viral load 
 
3.1.15  HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months prior to study entry are eligible for this trial. 
 
3.2 
Ineligibility Criteria (11-JAN-2022) 
Patients with any of the following conditions are NOT eligible for this study. 
 
3.2.1 Definitive clinical or radiologic evidence of metastatic disease including; 
• Positive malignant cytology of the pleura, pericardium or peritoneum; 
• Radiographic evidence of involvement of any adjacent mediastinal structure, e.g. aorta, 
trachea, which would increase the risk of repeated endoscopic interventions; 
• Tracheoesophageal fistula 
• Radiographic evidence of distant organ involvement; 

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• Non-regional lymph nodes that cannot be contained within a radiation field; 
 
3.2.2   More than 1 esophageal lesion; 
 
3.2.3 Prior systemic chemotherapy for the study cancer;  
 
3.2.4 Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields; 
 
3.2.5   Biopsy-proven tumor invasion of the tracheobronchial tree or presence of 
tracheoesophageal fistula or recurrent laryngeal or phrenic nerve paralysis.  
 
3.2.6   For patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, a New York Heart Association Functional Classification 
2C or worse. 
 
3.2.7  Uncontrolled diabetes; 
 
3.2.8   Infection requiring IV antibiotics at the time of registration; 
  
3.2.9   Patients requiring immunosuppressive medications including chronic suppressive steroid 
therapy (greater than the equivalent of 20mg/day of prednisone), methotrexate, 
azathioprine and TNF-α blockers   within 7 days prior to study entry; See section 5.4.2 
for further details; 
 
3.2.10  Received live vaccine within 30 days prior to registration; 
 
3.2.11 Received a blood transfusion, hematopoietic agent; granulocyte-colony stimulating factor 
(G-CSF), and/or oxygen supplementation within 7 days before the screening lab. 
 
3.2.12  Breast feeding females. 
 
 

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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  
(19-MAY-2023) 
 
PRE-TREATMENT ASSESSMENTS 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to Initial OBP-301 
Injection 
(calendar days) 
Optional Patient History 
Form (Patient Reported)*  
 
X 
Endoscopy with biopsy  
90 
 
Endoscopic Ultrasound (If 
technically feasible) 
90 
 
Bronchoscopy (for SCC 
tumors that are adjacent to the 
airway) 
42 
 
Whole body PET/CT scan 
42 
 
CT/MRI chest/abdomen** 
28 
 
CBC (to include absolute 
neutrophil count, Hgb and 
platelets) 
14 
 
CMP (to include creatinine, 
AST/ALT, and total bilirubin) 
14 
 
History and physical exam 
X 
 
ECOG Performance status 
14 
 
Concomitant Medications* 
14 
 
Urine or Serum Pregnancy 
test 
14 (for women of child 
bearing potential) 
X 
Optional collection of 
archival tumor tissue  
(see Section 10) 
 
 
Optional Blood Collection 
(see Section 10) 
 
≤2  
*In person preferred; may be conducted by telehealth visit at the discretion of the site-identified 
qualified healthcare professional. 
 
**CT of the chest/abdomen with intravenous contrast. If CT contrast is contraindicated, MRI of 
the chest/abdomen without contrast is permitted. 
 
 
 
 
 

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ASSESSMENTS DURING TREATMENT 
Assessments 
Prior to OBP-301 injection 
Weekly during concurrent 
chemotherapy and radiation 
Physical exam per 
Institutional Standard 
 
X 
ECOG PS assessment 
 
X 
Adverse Event Assessment 
 
X 
Concomitant Medications 
 
X 
 CBC (to include WBC, 
absolute neutrophil count, 
Hgb and platelets) 
X (see section 5.2) 
X 
 CMP (to include creatinine, 
AST/ALT, and total 
bilirubin) 
 
X 
Optional Collection of tumor 
and blood for correlative 
assays 
 
X(see Section 10) 
 
Urine or Serum Pregnancy 
test 
Only prior to first OBP-301 
treatment only (for women of 
child bearing potential) 
 
 
 
 

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ASSESSMENTS IN FOLLOW UP 
Assessment 
1 week 
post 
chemoRT 
6-8 weeks 
post RT 
completion 
Q 3 mo 
from end 
RT X 2 
YRS 
Q 3-6 mo 
from end 
RT X 2 YRS 
Q 6 mo 
from end 
RT X 2 
YRS 
Physical Exam 
X 
 
 
 
 
CBC and CMP 
X 
X 
 
 
 
 
Whole Body 
PET/CT (if not 
covered by insurance 
CT/MRI is allowed 
and must include 
chest, abdomen, and 
pelvis) 
 
X 
 
 
 
CT or MRI 
chest/Abdomen 
 
 
 
 
X 
Endoscopy with 
/without Biopsy (see 
definition of disease 
assessments below) 
 
X 
 
X (only for 
clinical 
complete 
responders at 
6-8 weeks post 
RT 
completion) 
 
Physical Exam 
 
X 
X 
 
 
Adverse Event 
Evaluation 
 
X 
X 
 
 
ECOG PS  
 
X 
X 
 
 
Optional Collection 
of Tumor and Blood 
for Correlative 
Assays (See Section 
10) 
 
X 
 
 
 
 
Definition of Disease Assessments 
The same method of imaging assessment and the same technique should be used to characterize 
baseline and post-treatment extent of disease. Imaging-based evaluation is preferred to 
evaluation by clinical exam when both methods have been used to assess the anti-tumor effect of 
therapy. 
 
While it is recognized that it is not always possible to obtain pathologic proof of progressive 
disease, biopsy or autopsy material confirming recurrent cancer is preferred and every reasonable 
attempt to obtain such is encouraged. 
 
Local Disease 

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6-8 weeks post RT completion for clinical complete response (cCR) 
At the time of the 6-8 weeks post RT completion endoscopy, a visual inspection of the 
site of the original primary disease must be documented. Patients will be scored as 
follows: 
• Those patients who are found to be grossly free of disease are NOT required to 
undergo biopsy and will be scored as achieving a clinical complete response 
• Patients deemed to have residual disease or suspicion of residual disease must 
undergo a biopsy in order to pathologically confirm findings. Any patient with 
pathologically confirmed residual disease will be scored as a local failure. Patients 
who are pathologically proven to have no evidence of disease will be scored as 
achieving a clinical complete response 
 
Follow-up after initial cCR assessment 
• Clinical complete responders: If there is evidence or suspicion of disease on follow-
up CT/MRI scans, biopsy is required to confirm recurrence of disease. In the 
absence of clinical symptoms or radiographic findings, patients should undergo a 
surveillance EGD every 6 months for up to 2 years from the start of protocol 
therapy. 
• Patients with residual disease:  These patients should be followed for local disease 
per institution’s standard of care.  
 
Distant Disease 
In the absence of histologic or cytologic proof of recurrence, clinical evidence (including e.g. 
new masses on CT scan, new lesions on bone scan, ascites not explained by other causes or 
enlarging mass by endoscopic ultrasound) should be considered highly suspicious of recurrent 
disease. It is strongly suggested that these findings lead to a biopsy to confirm progression. 
However, if the patient’s clinical condition does not allow biopsy to be performed and these 
findings are unequivocal, they may be acceptable as progression of disease. 
 
5.  TREATMENT PLAN/REGIMEN DESCRIPTION 
Protocol treatment must begin within 2 weeks after protocol registration. 
 
5.1 Treatment Summary (19-MAY-2023) 
Patients undergo an intra-tumoral injection via endoscopy (EGD) with OBP-301 (1×1012 
vp/mL).  
Patients will then receive chemoradiation with carboplatin and paclitaxel administered on a 
Monday or Tuesday and radiation administered Monday through Friday. 
 
 
 
 
 
 
 

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TREATMENT SCHEMA FOR INTIAL COHORT 
 
 
 
*Surgery is permitted post-chemoradiation if medically indicated. 
 
 
 
Treatment Regimen with Initial OBP-301 Dose Level:OBP-301 injection must start 
Thursday or Friday. Chemoradiation must start Monday or Tuesday. 
 
 
 
Week 
1 
Week 2 
Week 
3 
Week 4 
Week 
5 
 
Day -3 
(+/- 1 
day) 
Day 1 
(+/- 1 
day) 
Day 8 
(+/- 2 
day) 
Day 12 
(+/- 1 
day) 
Day 15 
(+/- 2 
day) 
Day 22 
(+/- 2 
day) 
Day 26 
(+/- 1 
day) 
Day 29 
(+/- 2 
day) 
OBP-301 by EGD 1 x1012 
vp/mL (q14d ±1 day)  
× 
 
 
× 
 
 
× 
 
Carboplatin AUC 2  
 
× 
× 
 
× 
× 
 
× 
Paclitaxel 50mg/m2 
 
× 
× 
 
× 
× 
 
× 
Radiation 1.8 Gy/fraction 
 
Daily Monday-Friday for 5 ½ weeks (28 fractions) 

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IF NEEDED; Treatment Regimen with DE-ESCALATED OBP-301 Dose Level : 
 
 
 
Week 
1 
Week 2 
Week 
3 
Week 4 
Week 
5 
 
Day -3 
(+/- 1 
day) 
Day 1 
(+/- 1 
day) 
Day 
8 
(+/-
2day) 
Day 
12 
(+/- 1 
day) 
Day 
15 
(+/- 2 
day) 
Day 
22 
(+/- 2 
day) 
Day 26 
(+/- 1 
day) 
Day 29 
(+/- 2 
day) 
OBP-301 by EGD 1 x1011 
vp/mL (q14d ±1 day)  
× 
 
 
× 
 
 
× 
 
Carboplatin AUC 2 
 
× 
× 
 
× 
× 
 
× 
Paclitaxel 50mg/m2 
 
× 
× 
 
× 
× 
 
× 
Radiation 1.8 Gy/fraction 
 
Daily Monday-Friday  for 5 ½ weeks (28 fractions) 
 
5.2 
Systemic Therapy (26-JUL-2021) 
 
5.2.1   OBP-301 Treatment 
 
OBP-301 (1×1012 vp/mL) is administered as intratumoral injection into a primary esophageal 
tumor mass that is suitable for injection, and in a location amenable for endoscopic injection.  
Irrespective of the size of the tumor, every effort should be made to inject 1.0 to 2 ml of OBP-
301; the maximal volume of 2 ml is preferred and should be injected as long as this is technically 
possible. 
 
Pre-injection planning is the key to success, therefore, a sketch of the tumor and the planned 
injection sites should be made. The sketch will be helpful in determining the total quantity of study 
drug to inject. Please refer to Appendix I. 
 
The optimum technique for injection of a primary tumor is to inject the viral particles into the 
lesion.  This will ensure that the viral particle will maximally penetrate into the lesion.   
Endoscopists who perform a polypectomy will be eligible to perform the procedure.  A training 
video (prepared by Oncolys Biopharma) is available as well.    
 
The procedure will be performed in the Endoscopy Unit with standard sterilization procedures. A 
standard gastroscope and needle (e.g. GIF-HQ190 Olympus gastroscope with 23 or 25 gauge 
injection needle made by Boston Scientific/ or Olympus (NeedleMaster) is used for the 
procedure.  
Guidelines for each injection procedure are provided below: 
 
Pre-Injection   
• Review of medications  
• Abbreviated physical exam and performance status   

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• Vital signs  
 
Post-Injection  
• Monitor patient for 60-90 minutes for any symptoms of injection site pain, bleeding, 
nausea.   
• Vital signs (except weight)  
 
Standard sedation procedures used for endoscopy will be used, and consists of monitored 
anesthesia care with an anesthesiologist and the patient monitored at all times.  
 
For patients who consent to the optional collection of tumor (see Section 10), biopsy of the 
primary tumor should be performed prior to OBP-301 injection. Up to 3 biopsies should be 
performed and processed by Pathology per standard procedure. If <3 core biopsies are 
performed, the reason should be documented in the procedure note. 
 
The tumor area to be injected will be ≥1 cm and can be mapped into (preferably at least) 5 
sections. The dose (volume) delivered to the lesion should be within the range of 1.0 to 2.0 mL. 
 
Refer to the OBP-301 Pharmacy Manual (Appendix I) for details to complete the endoscopic 
injection of OBP-301. 
 
Parameters for Treatment 
 A CBC is required within 3 days prior to OBP-301 administration. 
Parameters for treatment on Day -3 are as follows: 
• WBC ≥3,000/µL 
• ANC ≥1,500/µL 
• Platelets ≥100,000/µL 
• Hgb ≥9 g/dL 
Parameters for treatment on any other subsequent day are as follows and based on a CBC 
obtained at any time during that week prior to OBP-301 administration. 
• ANC ≥1,000/µL 
• Platelets ≥75,000/µL 
 
 
FOR THE DE-ESCALATED COHORT:  
Preparation Step: Use injection syringe to suck the 1 ml from 1x1012 vp/mL vial and use diluted 
solution syringe to suck the 9 mL D5W. 
 
Dilution Step: Slowly push 1 mL OBP-301 to Diluted solution syringe, and mix (The 
concentration of diluted solution syringe would be 1 x 1011 vp/mL). 
 

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   Injection syringe        T shape stop cock or luer lock connector      Diluted solution (D5W) syringe  
                       1 mL                                                                                                     9 mL 
 
 
 
 
 
Dose Levels 
Dose Level 
for DLT 
Assessment 
Number 
of OBP-
301 Doses 
Details 
Initial 
COHORT 
3 
 OBP-301 1×1012 viral particles (vp)/mL (up to 2mL of OBP-
301 should be injected based on the tumor volume.) will be 
given by an intra-tumoral injection via EGD every 14 days on 
Days -3, 12 and 26 (±1 day). 
 
IF NEEDED; 
DE-
ESCALATED 
COHORT 
 
3 
 OBP-301 1×1011 viral particles (vp)/mL (up to 2mL of OBP-
301 should be injected based on the tumor volume)) will be 
given by an intra-tumoral injection via EGD every 14 days on 
Days -3,12 and 26 days (±1 day).  
 
 
5.2.2    Paclitaxel/Carboplatin Chemotherapy 
 
Paclitaxel  
Paclitaxel will be administered at a fixed dose of 50 mg/m2 over 60 minutes weekly; 
rounding dose down to the nearest 10 mg is permitted as long as within 10% of the 
calculated dose. This is the recommended dose administration guidance but sites may 
follow institutional standards. 
 
The paclitaxel infusion is administered prior to the carboplatin infusion. 
 
The first dose will be given on Monday or Tuesday during the first week of radiation. 
Subsequent doses will be given every 7 days +/-1 day for a total of 5 doses. 
 
Recommended pre-medications or per institutional standards:  

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• Dexamethasone 10mg IVP, completed 30 minutes prior 
• Diphenhydramine 50mg IVP or equivalent 
• H-2 blocker of choice (Cimetidine 300mg IV or ranitidine 50mg IV or famotidine 
20mg IV) 30 minutes prior  
 
Carboplatin 
See Carboplatin Dose Calculation Instruction in Appendix IV 
Carboplatin will be administered at a fixed dose AUC 2 over 30 minutes weekly. The 
first dose will be given on either Monday or Tuesday during the first week of radiation. 
Subsequent doses will be given every 7 days +/-1 day for a total of 5 doses.  
The maximum dose of carboplatin will be capped at 300 mg. 
 
Recommended pre-medications or per institutional standards:  
• Antiemetic regimen including a 5HT3-antagonist and steroid  
 
5.3 
Radiation Therapy (10-JUL-2023) 
Radiation must begin on a Monday or Tuesday following the first intratumoral 
injection with OBP-301. 
 
Radiation Therapy Schema 
Radiation will be given in 1.8 Gy/fraction ×28 fractions (50.4 Gy total)- 5 fractions/week 
Monday-Friday starting on Day 1. Radiation can either precede or follow chemotherapy 
on days when they are given concurrently. 
 
5.3.1 Treatment Technology 
Proton treatments are not allowed, IMRT only.  
 
Photon beam intensity modulated radiation therapy (IMRT) /VMAT with effective 
energies between 6 and 10 MV is required.  IMRT may be delivered using multiple fixed 
fields employing dynamic multi-leaf collimator, helical arc therapy or volumetric 
modulated arc therapy using any of the commercially available delivery systems.  Daily 
image-guidance (IGRT) is also required for all patients. 
 
5.3.2 Immobilization and Simulation 
Proper immobilization is important for this protocol.  Patient setup reproducibility must 
be achieved using appropriate clinical devices.   
Assessment and Management of Internal Organ Motion 
Special considerations must be made to account for the effect of internal organ motion 
(e.g., primarily breathing associated motion) on target positioning and reproducibility. As 
a first step, it is required that the treatment team quantify the specific motion of a target 
so as to determine if management strategies are needed. The patient should be in normal 
free breathing at the time of initial tumor motion assessment. Deep inspiration or 
expiration breath hold is not allowed for initial tumor motion assessment as such 
assessment generally overestimates free breathing tumor motion. Options for motion 

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assessment include real time fluoroscopy and 4D CT scanning.  Any strategy, including 
4D CT should incorporate appropriate image review and quality assurance to ensure 
suitability for treatment planning and target delineation. 
 
In some tumor locations, tumor motion measurement may demonstrate motion exceeding 
the required small tumor expansions per this protocol (resulting in marginal miss or 
excessive volume of irradiation) unless a motion management strategy is employed. 
Acceptable maneuvers for motion management include reliable abdominal compression, 
accelerator beam gating with the respiratory cycle, tumor tracking, and active breath-
holding techniques or other methods approved by the study committee.  These measures 
are recommended in cases where the extent of motion quantified on motion assessment 
exceeds 1 cm. Internal organ management maneuvers must be reliable enough to insure 
that the GTV does not deviate beyond the confines of the PTV with any significant 
probability (i.e., < 5%). 
Table 5.3.2 highlights the recommended and minimum requirements for motion 
assessment and treatment planning imaging. 
Table 5.3.2  Motion Assessment/Management Guidelines for Simulation 
Treatment 
Technique 
Recommended 
Method for Motion 
Assessment During 
Simulation 
Minimum Method 
for Motion 
Assessment During 
Simulation 
Scan(s) 
Recommended  for 
Treatment Planning 
Free breathing 
treatment 
using an 
internal gross 
target volume 
(IGTV) 
approach, 
including 
abdominal 
compression 
4D CT or fluoroscopy 
as long as tumor can be 
directly visualized 
Repeated slow 
acquisition CT 
scanning through 
the target (to sample 
motion) fused to the 
planning CT dataset  
Average intensity 
projection (AveIP) scan 
from a full field of view 
4D CT for dose 
calculations; the 
maximum intensity 
projection (MIP) scan may 
be desirable to aid IGTV 
definition; Free-breathing 
scans are not 
recommended for 
treatment planning.   
Gating with a 
gating window 
4D CT 
Exhale CT plus 
fluoroscopy (free-
breathing + 
fluoroscopy strongly 
discouraged due to 
baseline shift) 
Reconstructed average of 
gating window scans from 
4D CT.    
Breath hold 
(i.e. ABC) 
Reproducibility of 
breath hold confirmed 
(examples: multiple low 
dose scans over tumor, 
N/A 
Scan in breath hold 
position (inhale 
recommended since it 
maximizes lung volume). 

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repeat fluoroscopy or 
scout images) 
Tracking 
4D CT or breath hold 
CT 
N/A 
4D CT or breath hold CT 
 
Simulation Imaging  
Motion assessment during simulation should be performed on all patients to account for 
the tumor and nodal excursion with respiration and the appropriate type of treatment 
planning CT required. Respiratory motion may be significant for esophageal (particularly 
distal) and GE junction lesions.  When 4D-CT planning or other motion management 
techniques are used, margins may be modified to account for observed motion and may 
also be reduced if justified.  The 4D-CT data may also be used to create an internal target 
volume (IGTV) from which subsequent clinical target volume (CTV) and planning target 
volume (PTV) expansions can be made. 
 
A motion management technique-specific treatment planning CT (e.g., 4D-CT, breath-
hold, gated CT, etc.) should be used during simulation to define gross tumor volume 
(GTV),internal gross tumor volume (IGTV), clinical target volume (CTV), and planning 
target volume (PTV) (see definitions in Section 5.3.4). Contiguous CT slices, having no 
more than 3 mm thickness are to be obtained starting from the level of the cricoid 
cartilage and extending inferiorly through the entire liver and kidney(s) volume. The field 
of view must be large enough so that none of the patient’s anatomy along the path of the 
treatment beams is cut off.   
 
A treatment planning FDG PET/CT scan (or FDG-PET alone) (if available for 
simulation) with the patient in the treatment position is encouraged for treatment 
planning. In the case where the PET/CT is obtained in the treatment position as part of 
radiation simulation, the CT from this study may be used as the planning CT scan, but a 
motion management technique-specific treatment planning CT should still be done.   
 
Intravenous contrast during the planning CT is optional provided a diagnostic chest CT 
was done with contrast to delineate the major blood vessels. If not, intravenous contrast 
should be given during the planning CT. If contrast is used, the densities or RLSPs 
should be over-ridden or the contrast scan must be registered to a non-contrast scan for 
planning purposes. 
 
5.3.3 Imaging for Structure Definition, Image Registration/Fusion  
Limited extent FDG-PET/CT +/- contrast (unless contraindicated) imaging will be 
preferred as part of staging and to assist in volume delineation in all eligible patients. CT 
+ contrast (unless contraindicated) will be allowed as a substitute if for some reason 
FDG-PET is not able to be acquired.  
 
5.3.4 Definition of Target Volumes and Margins 
Note: All structures must be named for digital RT data submission as listed in the table 
below.  The structures marked as “Required” in the table must be contoured and 

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submitted with the treatment plan.  Structures marked as “Required when applicable” 
must be contoured and submitted when applicable. 
Resubmission of data may be required if labeling of structures does not conform to the 
standard DICOM name listed.  Capital letters, spacing and use of underscores must be 
applied exactly as indicated. 
 
Standard 
Name 
Description 
Validation Required/Required 
when applicable/Optional 
GTVp_5040 
Primary disease GTV to 
receive 5040 cGy 
 
Required 
GTVn_5040 
Nodal disease GTV (if 
applicable) as confirmed 
by PET/CT or EUS 
FNA to receive 5040 
cGy. Peritumoral nodal 
disease are included 
with the GTVp. 
Required 
IGTVp_5040 
Primary disease GTV 
that accounts for motion 
over the respiratory 
cycle to receive 5040 
cGy. 
 
Required if 4D-CT used to 
assess and account for GTV 
motion.  Not required if 4D-
CT is not obtained or motion 
is minimal on 4D-CT 
(<10mm).  If treatment is to 
be delivered with breath hold 
or gated techniques, this is not 
required. 
IGTVn_5040 
Nodal disease GTV (if 
applicable) as confirmed 
by PET/CT or EUS 
FNA that accounts for 
over the respiratory 
cycle to receive 5040 
cGy. Peritumoral nodal 
disease are included 
with the IGTVp_5040. 
Required if 4D-CT used to 
assess and account for GTV 
motion. Not required if 4D-
CT is not obtained or motion 
is minimal on 4D-CT 
(<10mm).  If treatment is to 
be delivered with breath hold 
or gated techniques, this is not 
required. 
GTV_5040 
and 
IGTV_5040 
Sum of 
GTVp/IGTVp_5040 and 
GTVn/IGTVn_5040, 
which is the volume 
enveloping all GTV(s) 
or IGTV(s). 
Required for GTV_5040.  
Required for IGTV_5040, 
unless IGTVs not made. 
CTV_5040 
CTV to receive 5040 
cGy 
Required 

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PTV_5040 
PTV to receive 5040 
cGy 
Required 
 
Detailed Specifications  
Target volumes: The definitions of volumes will be in accordance with the 1999 
ICRUReport#62. 
 
GTVp_5040 and IGTVp_5040: The GTVp includes the GTV defined as the primary 
tumor in the esophagus as delineated on planning scan and other pre-treatment diagnostic 
studies (e.g. PET/CT, EUS). GTVp should be contoured on the primary CT dataset (see 
Section 5.3.8 for definition). When 4DCT simulation is performed for non-gated free-
breathing delivery, the phases of the breath cycle could be used to construct the 
composite primary GTV volume (IGTVp).  Ideally, targets should be contoured on all 
phase images in order to construct IGTVp.  Some commercial software may be used to 
populate the physician’s GTVp contour on one phase images to the other phase images. If 
such software is unavailable, at least 4 phase images (end of inspiration, mid-inspiration, 
end of expiration and mid-expiration) should be used to assure IGTVp accuracy. 
Maximum Intensity Projected (MIP) images should not be used to generate IGTV (see 
Chen X, Lu H, Tai A, et al. Determination of internal target volume for radiation 
treatment planning of esophageal cancer by using 4-dimensional computed tomography 
(4DCT). Int J Radiat Oncol Biol Phys. 2014;90(1):102-9). 
 
GTVn_5040 and IGTVn_5040:  The GTVn defined as any grossly involved regional 
lymph nodes, either considered suspicious on PET/CT or proven by EUS biopsy.  GTVn 
should be contoured on the primary CT dataset (see 5.3.8 for definition). When 4DCT 
simulation is performed for non-gated free-breathing delivery, the phases of the breath 
cycle could be used to construct the composite nodal GTV volume (IGTVn).  Ideally, 
targets should be contoured on all phase images in order to construct IGTVn.  Some 
commercial software may be used to populate the physician’s GTVn contour on one 
phase images to the other phase images. If such software is unavailable, at least 4 phase 
images (end of inspiration, mid-inspiration, end of expiration and mid-expiration) should 
be used to assure IGTVn accuracy. Maximum Intensity Projected (MIP) images should 
not be used to generate IGTVn (see Chen X, Lu H, Tai A, et al. Determination of internal 
target volume for radiation treatment planning of esophageal cancer by using 4-
dimensional computed tomography (4DCT). Int J Radiat Oncol Biol Phys. 
2014;90(1):102-9). 
 
CTV_5040:  The CTV is defined as the GTVp with a 3.5-4.0 cm expansion superiorly 
and inferiorly along the length of the esophagus and cardia and a 1.0-1.5 cm radial 
expansion. It should also include GTVn with a 1.0-1.5 cm expansion in all dimensions. 
This CTV expansion needs to be trimmed away from the edges of anatomic boundaries of 
microscopic disease spread, including major blood vessels, vertebral body, pericardial 
lining/heart, pleura, liver, pancreas, kidneys and spleen.  This volume should be 
expanded if needed to cover the paraesophageal, celiac and supraclavicular lymph node 
regions. If not involved, the celiac nodes (for distal and gastroesophageal junction 

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tumors) or the bilateral supraclavicular nodes (for upper thoracic tumors) are 
recommended to be included for N0 status, but required to be covered for N+ status. Such 
rules also apply to any large mid esophageal tumors with extension to either upper 
thoracic or distal esophagus.  The 3.5-4 cm superior and inferior expansion should follow 
the contour of the esophagus and proximal stomach. The intent is to extend the margin 
along the length of the esophagus and proximal stomach to provide a margin for coverage 
of submucosal extension of tumor and lymphatics. For cervical esophageal cancer, nodal 
coverage of the cervical lymph node regions in the head and neck (e.g. neck levels 3, 4, 
etc.) is at the discretion of the treating physician, but recommended for N+ status.   
 
PTV_5040: Additional margin shall be added to the CTV for set up error and movement. 
This expansion should be 0.5 to 1.0 cm and does not need to be uniform in all 
dimensions. 4DCT data is allowed to customize PTV expansion.   
 
5.3.5 Definition of Critical Structures and Margins 
Note: All structures must be named for digital RT data submission as listed in the table 
below.  The structures marked as “Required” in the table must be contoured and 
submitted with the treatment plan. Structures marked as “Required when applicable” 
must be contoured and submitted when applicable.   
Resubmission of data may be required if labeling of structures does not conform to the 
standard DICOM name listed.  Capital letters, spacing and use of underscores must be 
applied exactly as indicated. 
 
Standard Name 
Description 
Validation 
Required/Required when 
applicable/Optional 
SpineCanal 
Spinal Canal 
Required 
Lungs 
Right + Left Lung 
Required 
Lung_R 
Right Lung 
Required 
Lung_L 
Left Lung 
Required 
Esophagus-GTV 
Esophagus minus 
GTV 
Required 
Esophagus-IGTV 
Esophagus minus 
IGTV 
Required if IGTV made 
Heart 
Heart 
Required 
Liver 
Liver 
Required for all mid/distal 
tumors 
Kidney_R 
Right Kidney 
Required for all mid/distal 
tumors 

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Kidney_L 
Left Kidney 
Required for all mid/distal 
tumors 
Spleen 
Spleen 
Required for all mid/distal 
tumors 
Stomach-
GTV/IGTV 
Stomach minus 
GTV/IGTV 
Stomach-GTV required for 
all mid/distal tumors. 
Stomach-IGTV required if 
IGTV made. 
Bowel_Small 
Small bowel 
Required for all mid/distal 
tumors 
Bowel_Large 
Large bowel 
Required for all mid/distal 
tumors 
 
Detailed Specifications 
SpineCanal: Boundaries: Cranial:1st slice of CT; Caudal: last slice of CT; 
Lungs:  Boundaries:  Cranial: From apex bilaterally; Caudal: to bottom of L2 
Esophagus-GTV/IGTV: Boundaries: Cranial: Bottom of cricoid; Caudal: GE junction; subtract 
IGTV from structure 
Heart:  Boundaries:  Base: Bottom of the aortic arch; Inferior: Apical most of the ventricle 
Liver:  Boundaries: Cranial: From dome; Caudal:  Inferior tip 
Kidneys:  Entire kidneys contoured separately as Kidney_R and Kidney_L 
Spleen:  Entire spleen  
Stomach-GTV/IGTV: Boundaries: whole stomach minus GTV/IGTV 
Bowel_Small: Boundaries: Level of PTV 
Bowel_Large: Boundaries: Level of PTV 
 
5.3.6 Dose Prescription 
Note: The information provided in this section can be used for adjusting the dose constraints for 
treatment planning purposes.  This table together with the planning priority table should be used 
during dose optimization.  It is important to remember that ideal plans might not be achievable in 
all cases.  Thus, the Compliance Criteria table could be different than the information given here.  
Cases will be scored using the Compliance Criteria table. 
 
Target 
Standard Name 
Dose (Gy) 
Fraction Size 
(Gy) 
# of 
fractions 
Frequency 
Dose specification 
technique 
PTV_5040 
50.4 
1.8 
28 
Daily 
Covering 95% of 
PTV* 
CTV_5040 
50.4 
1.8 
28 
Daily 
Covering 95-99% 
of CTV 
IGTVp_5040 
IGTVn_5040 
IGTV_5040 
50.4 
1.8 
28 
Daily 
Covering  >=99% 
of IGTV 

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GTVp_5040 
GTVn_5040 
GTV_5040 
50.4 
1.8 
28 
Daily 
Covering  >=99% 
of GTV 
*Prescribe to the isodose line that covers 95% of the PTV, or inverse plan to cover 95% of the PTV with the 
prescription dose 
 
5.3.7 Compliance Criteria 
The compliance criteria listed here will be used to score each case.  Given the limitations 
inherent in the treatment planning process, the numbers given in this section can be different than 
the prescription table.  The Per Protocol and Variation Acceptable categories are both considered 
to be acceptable.  The Per Protocol cases can be viewed as ideal plans, and the Variation 
Acceptable category can include more challenging plans that do not fall at or near the ideal 
results.  A final category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable. Plans falling in this category are 
considered to be suboptimal and additional treatment planning optimization is recommended. 
 
Normalization of Dose: The plan is normalized such that 95% of the PTV_5040 volume 
receives prescription dose of 50.4 Gy. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met 
 
Target Volume Constraints and Compliance Criteria 
Name of Structure 
Dosimetric parameter 
Per Protocol 
Variation 
Acceptable* 
PTV_5040 
D0.03cc[%]  
<= 110% Rx Dose 
<= 113% Rx Dose 
 
V50.4Gy[%] 
>=95% 
>90% 
*Per Protocol range is excluded from Variation Acceptable range. 
 
Normal Structure Constraints and Compliance Criteria 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable* 
Lungs 
D0.03cc[%] 
<= 110% Rx 
Dose 
<= 113% Rx Dose 
 
Mean[Gy] 
<= 20 Gy 
<= 21 Gy 
 
V30Gy[%] 
<= 20% 
<= 25% 
 
V20Gy[%] 
<= 30% 
<= 35% 
 
V10Gy[%] 
<= 50% 
<= 55% 
 
V5Gy[%] 
<= 65% 
<= 75% 
Heart 
D0.03cc[Gy] 
<= 52Gy 
<= 54 Gy 
 
Mean[Gy] 
<= 38 Gy 
<= 40 Gy 
 
V40Gy[%] 
<= 50% 
<= 55% 
Kidney_L 
D0.03cc[Gy] 
<= 45 Gy 
<= 50 Gy 

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Mean[Gy] 
<= 18 Gy 
<= 20 Gy 
 
V20Gy[%] 
<= 30% 
<= 40% 
Kidney_R 
D0.03cc[Gy] 
<= 45 Gy 
<= 50 Gy 
 
Mean[Gy] 
<= 18 Gy 
<= 20 Gy 
 
V20Gy[%] 
<= 30% 
<= 40% 
SpineCanal 
D0.03cc[Gy] 
<= 45 Gy 
<= 50 Gy 
Liver 
Mean[Gy] 
<= 21 Gy 
<= 25 Gy 
 
V30Gy[%] 
<= 30% 
<= 40% 
Bowel_Small 
D0.03cc[Gy] 
<= 52Gy 
<= 54 Gy 
Bowel_Large 
D0.03cc[Gy] 
<= 52Gy 
<= 54 Gy 
Stomach-GTV/IGTV 
(parameters apply to 
Stomach-IGTV if made, 
otherwise they apply to 
Stomach-GTV) 
Mean[Gy] 
<= 40 Gy 
<= 45 Gy 
Spleen 
Mean[Gy] 
<= 45 Gy 
<= 50 Gy 
*Per Protocol range is excluded from Variation Acceptable range. 
 
Recommended dose acceptance criteria for other normal tissue, but not to be used for plan 
score. 
Heart 
Mean [Gy] <=30 Gy  
Lungs 
Mean [Gy] <=18 Gy 
 
 
Delivery Compliance criteria 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Radiation Start date  
Day 1 
2-3 days 
>3 days 
Overall Treatment time 
≤40 days 
41-52 days 
>52 days 
Interruptions 
None 
≤1 week 
>1 week 
 
5.3.8 Treatment Planning Priorities and Instructions 
 
Critical Structure and Target priorities are listed in order of decreasing importance. Use these 
priorities when not all planning constraints can be met: 
1. 
Spinal Cord 
2. 
PTV 
3. 
Lungs 
4. 
Heart 
 
- Required algorithms  
The dose calculation algorithm in treatment planning system (TPS) should be one of those 

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approved by IROC, which includes Convolution Superposition, Collapsed Cone Convolution, 
AAA and Monte Carlo (see http://rpc.mdanderson.org/RPC/home.htm for details). These 
algorithms have been tested using the IROC lung phantom to provide acceptable dose calculation 
accuracy within a heterogeneous medium. The dose calculation algorithms like Clarkson or 
pencil beam should not be used for photon treatment planning.  
 
For Convolution/Superposition type algorithms, dose should be reported as computed inherently 
by the given algorithm.   For Monte Carlo or Grid Based Boltzmann Solver algorithms, 
conversion of Dm (dose-to-medium) to Dw (dose-to-water) should be avoided.  Dm, computed 
inherently by these algorithms, should be reported.  
 
- Primary dataset for dose calculation 
The primary dataset for dose calculation must be a free-breathing CT that is generated from 
4DCT, such as an average intensity pixel CT (AveIP), mid-ventilation CT or, the breath-
hold/gated CT, or the free-breathing CT acquired with no other motion management. Maximum 
Intensity Pixel (MIP) generated images from 4DCTs may not be used as the primary dose 
calculation dataset. In the case in which contrast is present during the treatment planning CT, the 
density of the contrast should be overridden to a representative background electron density or 
RSLP. 
 
-Dose matrix resolution 
Dose grid size should be ≤ 3 mm in all directions. 
 
Planning Procedures  
• Using a motion management technique-specific treatment planning CT from the 
simulation, primary tumor motion should be evaluated.   
• For tumor motion > 1.0 cm, motion management techniques such as breathhold or 
respiratory gating techniques should be considered for planning and treatment but not 
required, as long as the primary tumor motion is accounted for in the planning for both 
modalities and that daily image guidance and weekly anatomic imaging verification are 
done to ensure proper set up and targeting.   
 
Planning Procedures  
 
• For IMRT (multiple fixed fields or arc therapy) the PTV will be treated with any 
combination of coplanar, non-coplanar, or dynamically arcing fields. Please refer to 
Section 8.4 for credentialing requirements.  Margins to be used are stated in Section 
5.3.4. 
 
5.3.9 Patient-Specific QA 
Any patient-specific QA that needs to be acquired should follow institutional guidelines 
and AAPM task group report recommendations. Patient specific QA is highly 
recommended. The recommended patient specific QA criteria is for ≥90% of the 
comparison points to pass a ±3%/3mm Gamma Index analysis. 
 

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5.3.10 Daily Treatment Localization/IGRT 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate 
accuracy and precision throughout its entire process. In this section we use the 
terminology IGRT to focus on image-guidance at the time of radiation delivery to ensure 
its adherence to the planned treatment, with computer assisted process, i.e. image 
handling together with calculation of shift and rotations (if available) must be determined 
with computer assistance.  
 
 Daily IGRT is required for all treatments on this protocol and may be achieved using any 
one or more of the following techniques: 
o Orthogonal kilovoltage (KV) images, e.g. ExacTrac; on-board imagers (OBI) or 
similar systems; 
o Linear-accelerator mounted kV and MV conebeam CT images; 
o Linear-accelerator mounted MV CT images (e.g., Tomotherapy); 
o MRI-on-rails, ViewRay and MR-Linac. 
 
 The institution’s procedure to register treatment day image dataset with the reference 
dataset should comply with the following recommendations: 
o Region-of-Interest (ROI) or “clip box” for fusion should be set to encompass the high 
dose PTV and adjacent vertebral bodies.  (Note:  The same strategy should be used 
for repeat CT scans required for verification, QA or replanning.) 
o If the fusion software allows the user to create an irregular ROI (e.g., ExacTrac), 
treatment room objects seen on in-room X-rays should be excluded from the 
registration. 
o Automatic (e.g., based on mutual information bone or soft tissue fusion) types of 
registration should be used; the result of the fusion must be visually checked for 
alignment of the target or bony structures, such as vertebral bodies when appropriate.  
Manual adjustments (using drag-and-drop capabilities) should be made when 
necessary.   
 
 Following the registration, the translational and (if the appropriate technology is available) 
rotational corrections should be applied to the treatment couch. If all the variances are less 
than 3 mm, the treatment can proceed without correction. If one or more corrections are 3-
5 mm, adjustment is necessary prior to treatment; however, re-imaging is not 
recommended. If one or more of the corrections are larger than 5 mm, the imaging can be 
repeated in addition to performing table/positioning adjustments. 
 If orthogonal projection imaging is used for setup, this fact should be communicated to the 
therapists (i.e. bony anatomy or fiducial). The relationship between the image surrogate of 

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internal anatomy and the soft tissue targets shall be verified, at a minimum, as part of the 
repeat CTs done for QA, verification or replanning. 
 If in-room CT is available but orthogonal projection X-ray imaging is used for daily setup, 
weekly verification of soft tissue with setup surrogate is recommended.  
 If in-room CT is used for daily setup, the setup surrogate needs to be communicated to the 
therapists (i.e. bony anatomy, IGTV, or other). If, due to changing anatomy, a compromise 
must be made between multiple target structures, the therapists shall be guided by the 
treating physician as to the best compromise. 
5.4 
General Concomitant Medication and Supportive Care Guidelines (19-MAY-2023) 
 
5.4.1 Permitted Supportive/Ancillary Care, Concomitant Medications, and Post-
Chemoradiation Resection 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
 
Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes 
and hormone replacement therapy) is acceptable. 
 
Surgery is permitted post-chemoradiation if medically indicated. 
 
5.4.2 Prohibited Therapies 
 Any other investigational anti-cancer therapy 
 Any other concurrent chemotherapy, radiotherapy, immunotherapy, biologic or 
hormonal therapy for cancer treatment other than the treatments stated in this 
protocol.  
 Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses exceeding 20 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and TNF-α blockers. Use of immunosuppressive medications in subjects 
with contrast allergies is acceptable. In addition, use of inhaled and intranasal 
corticosteroids is permitted. The shortest possible duration of steroids will be allowed 
for different indications, at the discretion of the principal investigator (e.g., chronic 
obstructive pulmonary disease, radiation, nausea, etc.)    
 Live attenuated vaccines within 30 days of OBP-301 dosing, i.e., 30 days prior to the 
first dose, during treatment with OBP-301 and for 30 days post discontinuation of 
OBP-301. Inactivated vaccines, such as the injectable influenza vaccine, are 
permitted 
 
5.4.3   Nutritional and Herbal Supplements  
The concomitant use of herbal therapies is not recommended, as their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown. However the 
use of general nutritional foundation supplements will be allowed including: calcium with 

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vitamin D and/or minerals, Omega3s (fish oil), Vitamin B6, Vitamin B12, a basic 
multivitamin, L-glutamine, or probiotics oral supplements will be permitted as long as at 
or below recommended dosing by a healthcare provider. Herbal-based multivitamins are 
not allowed.  
 
5.4.4 Participation in Other Trials  
Patients are not to participate in other therapeutic trials during this study.  However, trials 
that do not add experimental agents are allowed (e.g. imaging trials, quality of life, etc).  
 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment; 
• Unacceptable adverse event(s), as described in Section 6; 
• Patient decides to withdraw consent for participation in the study, or 
• General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator; 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT  
 
6.1 
General Guidelines (26-JUL-2021) 
The following side effects are anticipated: nausea, vomiting, myelosuppression (including 
lymphopenia), esophagitis, dysphagia, mucositis and fatigue.  
• If doses of chemotherapy are missed, they should not be made up.  
• Any delay of > 3 weeks requires discontinuing paclitaxel and carboplatin 
chemotherapy. If a dose is missed it will not be made up once RT is completed; 
• If chemotherapy needs to be permanently discontinued, patients may continue with 
radiation and OBP-301 alone if it is considered to be in the patient’s best interests.  
 
Use of filgrastim is recommended, at the discretion of the treating investigator if 
chemoradiation is held for neutropenia. All dose reductions are permanent, i.e. drug doses 
will not be re-escalated after resolution of toxicity. 
 
Dose levels for carboplatin and paclitaxel are as follows: 
Dose level 
Weekly dose 
Carboplatin 
Paclitaxel 
0 
AUC 2 
50 mg/m2 
-1 
AUC 1.5 
40 mg/m2 
There will not be any additional dose reductions. 
 
6.1.1 Hematologic toxicity 
Week 2-5 blood counts during chemoradiation 
Dosage 

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ANC 
 
Platelet count 
≥1,000/μL 
AND 
≥75,000/μL 
Chemotherapy at full dose 
<1,000/μL 
OR 
<75,000/μL 
First occurrence 
Hold all treatments (chemo,OBP-301 
and RT). Re-check CBC. Consider 
filgrastim. When ANC ≥1,000/μL 
and platelets ≥75,000/μL, resume 
chemotherapy at dose level -1 
 
Second occurrence 
Hold all treatments and resume when 
ANC≥1,000 and platelets ≥75,000. 
Continue chemo at the -1 dose level, 
i.e. no further dose reductions are 
permitted.  
 
6.1.2      Non-hematologic toxicity 
Toxicity 
CTCAE version 
5 grade 
Modality 
Modification 
Nausea/vomiting, 
dehydration 
(despite maximum 
medical support) 
≥3 
Carboplatin 
Paclitaxel 
OBP-301    
Radiation 
Therapy 
First occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Resume chemo at dose level -
1.  OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
Second and further occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Continue chemo at the -1 dose 
level, i.e. no further dose 
reductions are permitted. 
OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
Esophagitis 
>3 
Carboplatin 
Paclitaxel 
OBP-301    
Radiation 
Therapy 
First occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Resume chemo at dose level -
1.  OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
Second and further occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 

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Continue chemo at the -1 dose 
level, i.e. no further dose 
reductions are permitted. 
OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
If grade ≥3 in last week of 
treatment-Hold chemo but 
continue the RT at the 
discretion of the treating 
physician. 
Mucositis (despite 
maximum 
supportive care 
> 3 
Carboplatin 
Paclitaxel 
OBP-301    
Radiation 
Therapy 
First occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Resume Carboplatin and 
Paclitaxel at dose level -1. 
OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
Second and further occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Continue Carboplatin and 
Paclitaxel at the -1 dose level, 
i.e. no further dose reductions 
are permitted. 
OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
Fatigue 
≥3 
Carboplatin 
Paclitaxel 
OBP-301    
Radiation 
Therapy 
First occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Resume Carboplatin and 
Paclitaxel chemo at dose level 
-1.  OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
Second and further occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Continue Carboplatin and 
Paclitaxel at the -1 dose level, 
i.e. no further dose reductions 
are permitted. 
OBP-301 injections will 

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resume at the next previously 
scheduled time-point. 
Any other toxicity 
≥3 
Carboplatin 
Paclitaxel 
OBP-301    
Radiation 
Therapy 
First occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Resume Carboplatin and 
Paclitaxel at dose level -1. 
OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
Second and further occurrence 
Hold all treatment until 
toxicities improve to grade ≤2. 
Continue Carboplatin and 
Paclitaxel at the -1 dose level, 
i.e. no further dose reductions 
are permitted. 
OBP-301 injections will 
resume at the next previously 
scheduled time-point. 
Diarrhea (despite 
maximum medical 
support) 
≥3 
Paclitaxel 
Only 
First occurrence  
Hold Paclitaxel until diarrhea 
improves to grade ≤2. Dose 
reduce Paclitaxel by 1 dose 
level. 
Second occurrence 
Hold all Paclitaxel until 
toxicities improve to grade ≤2. 
Continue Paclitaxel at the -1 
dose level, i.e. no further dose 
reductions are permitted 
Hepatotoxicity 
(ALT, AST, blood 
bilirubin) 
≥1 
Paclitaxel 
Only 
Decrease paclitaxel by 1 dose 
level. Resume paclitaxel if 
Total Bili ≤1.5× ULN OR 
AST/ALT ≤2.5× UL N. 
Carboplatin dose will remain 
at current dose level. 
Sensory 
neuropathy 
2 
Paclitaxel 
Only 
Hold Paclitaxel. When toxicity 
is grade ≤1, resume Paclitaxel 
at -1 dose level for all 
subsequent cycles. Carboplatin 
dose will remain at current 
dose level. 
≥3 
Patients will not receive any 
more paclitaxel.  

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Infusion related 
reaction  
≥3 
Carboplatin 
Paclitaxel 
Permanently discontinue 
Paclitaxel and Carboplatin.  
 
Hypersensitivity Reaction Management per Institutional Standard 
Hypersensitivity reactions include anaphylactic-like reactions. Tachycardia, 
bronchoconstriction, hypotension, facial edema and erythema may occur and should be 
treated with antihistamine, corticosteroids, and epinephrine as per institutional 
hypersensitivity management protocol. If the treating Physician feels that it is appropriate 
to continue with protocol therapy, options include pre-medication with steroids and 
diphenhydramine the night before and at the time of carboplatin or paclitaxel infusion. For 
patients who develop a grade 1/2 carboplatin reaction, a desensitization protocol can be 
considered, after consultation with the Principal Investigator 
 
6.2 
OBP-301 
OBP-301 injection will be delayed for any ongoing non-hematologic Grade 3 toxicity or 
hematologic Grade 4 toxicity (except for Grade 4 Lymphopenia) at the time of the next 
scheduled injection.  Patients who require a delay of OBP-301 injection of > 4 weeks (i.e., 
approximately 6 weeks from the previous injection) due to lack of resolution to Grade < 2 
toxicity will not receive subsequent OBP-301 treatments.   
 
Any patient who experiences any of the following grade ≥3 toxicities directly attributable 
to OBP-301 and/or endoscopic injections will not receive further OBP-301 treatments: 
• Perforation 
• Bleeding 
• Infection 
• Pain lasting >3 days despite maximal medical management 
 
If a dose of OBP-301 is missed within the 2 day window, unless there is a specific reason 
that OBP-301 administration via EGD is contraindicated, administration during the same 
calendar week is permitted but must not be on the same day as chemotherapy 
administration. 
 
Injection site pain is the one of the more common adverse events in connection with 
intratumoral injections.  Therefore, the following pain control measures are suggested to 
improve the comfort of the patient. 
1. Review the analgesics already prescribed for the patient and determine the level of pain 
control. 
2. Additional pain medication will with all likelihood be needed during the day of the 
intratumoral injections and for several days afterwards. Local anesthesia may be 
required just before or during the intratumoral injection at the discretion of the treating 
gastroenterologist. 
 
6.3 
Radiation Therapy (26-JUL-2021) 
Radiation therapy will typically continue as prescribed without modifications while these 
drug-related adverse events are being managed.  

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Fatigue, esophagitis, cough, nausea and vomiting can be common acute side effects of 
radiation to the esophagus.   
 
For nausea and vomiting, anti-emetics should be initiated at the onset of symptoms and 
continued as directed by the treating physician until resolution of symptoms to grade 0-1. 
Additional supportive care measures, e.g. oral or intravenous rehydration, etc., should be 
instituted as required by the patient’s clinical condition. Additional medical evaluation is 
recommended for those patients with continued > grade 2 nausea/vomiting, lasting > 48 
hours despite institution of optimal supportive care measures. Primary prophylaxis should 
be initiated once nausea or vomiting has occurred with the prior treatment. Admit to 
hospital and administer IV fluids and all supportive measures for symptoms unresponsive 
to medication and signs of dehydration. 
 
For cough, dextromethorphan with or without guaifenesin, benzonatate, or mild narcotic 
medications (e.g. codeine syrup) can be used. 
 
Esophagitis can be managed by the preference of the treating physician and may 
commonly include medications such as sucralfate, Magic Mouthwash (e.g. custom mix of 
Benadryl, Maalox, lidocaine/xylocaine), proton pump inhibitors, or narcotics for pain. 
 
In the unlikely event that radiation must be permanently discontinued, patients will  
discontinue all treatment. 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 
Protocol Agents 
Investigational Agent 
The investigational agent OBP-301 administered in NRG-GI007 is being made available 
under an IND sponsored by NRG Oncology.  For OBP-301, determination of whether an 
adverse event meets expedited reporting criteria, see the reporting table in section 7.5 of 
the protocol. 
Commercial Agents 
The commercial agents in NRG-GI007 are carboplatin and paclitaxel.  
 
7.2 
Adverse Events and Serious Adverse Events 
 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (Aes), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 

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or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.3 
Adverse Events for Investigational Study Agent: OBP-301 (07-DEC-2020) 
Identified Risks of OBP-301 
• Administration site reaction 
• Lymphocyte count decrease 
 
Potential Risks of OBP-301 
• Accidental exposure of a third party to OBP-301 
• Spread of OBP-301 to close contacts or healthcare providers after direct contact 
with patients  
• Adenovirus infection affecting the entire body in patients with impaired immune 
function 
• Inflammatory lesions in virus-infected organs (liver, kidney, lung) 
• Influenza-like symptoms 
 
For more details see Investigator’s Brochure. 
 
7.4 
Adverse Events for Commercial Study Agents: Paclitaxel and Carboplatin  
Refer to the package insert for detailed pharmacologic and safety information 
 
7.5 
Expedited Reporting of Adverse Events (11-JAN-2022) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 

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made to the NRG Oncology by phone at: 1-215-574-3191. An electronic report must be 
submitted immediately upon re-establishment of the Internet connection. 
 
7.5.1 Expedited Reporting Methods 
 
• Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERS 24-hour 
notification must be submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS-24-Hour Notification must be followed by a complete report within 1 
day.  
• Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Deidentified supporting source documentation is uploaded to 
the source document portal via CTEP-AERS.   
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
• NRG Oncology reports serious adverse events to Oncolys within 24 hours of report 
completion. Additionally, NRG Oncology reports applicable adverse events to FDA 
per 21 CFR 312.32 and submits the FDA report to Oncolys within 3 days for life 
threatening or fatal adverse events and within 7 days for all other FDA reportable 
adverse events following Oncolys’ initial receipt of the information. 
 
7.5.2 Expedited Reporting Requirements for Adverse Events  
 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 

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Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 Aes 
Expedited 10 calendar day reports for: 
• 
Grade 2 Aes resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements 
 Not applicable 
 
7.5.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
 
7.5.4 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  

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Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy). Second malignancies require ONLY routine 
AE reporting unless otherwise specified. 
 
7.6 
Routine Reporting Requirements for Adverse Events 
All Adverse Events must be reported in routine study data submissions.  Aes reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
7.7 
Pregnancy 
Any pregnancy occurring in a patient or patient’s partner from start of protocol treatment 
to 90 days after the last study treatment must be reported expeditiously as a grade 3 SAE 
coded in the CTCAE as “pregnancy, puerperium and perinatal conditions, other—
pregnancy” in CTEP-AERS and also submit the Pregnancy Information Form found at 
this link: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyRep
ortFormUpdated.pdf 
 
The form should be submitted within 14 days of notification AND the form should also 
be uploaded to the patient case file in RAVE in the source documentation upload 
folder.  NRG Oncology will report the pregnancy to Oncolys within 1 business day of 
notification of the event. Newborn infants should be followed until 8 weeks old and the 
pregnancy outcome for patients on study should be reported to NRG Oncology. NRG 
Oncology will report the status to Oncolys. 
 
8. REGISTRATION AND STUDY ENTRY PROCEDURES (19-MAY-2023) 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing to 
NCI-sponsored trials to register with their qualifications and credentials and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. Investigators and clinical site staff who are significant 
contributors to research must register in the Registration and Credential Repository (RCR). 
The RCR is a self-service online person registration application with electronic signature and 
document submission capability. RCR utilizes five person registration types. 
• Investigator (IVR) — MD, DO, or international equivalent; 
• Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) 
or graduate level researchers (e.g., PhD); 
• Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications such as the  Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 

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• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster; 
• Selection as the treating, credit, or drug shipment investigator or consenting person in 
OPEN; 
• Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval. 
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, must be rostered at the 
enrolling site with a participating organization. 
 
Refer to the NCI RCR page on the CTEP website for additional information. For questions, 
please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
8.1   Cancer Trials Support Unit Registration Procedures ( 19-MAY-2023) 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on the person and site roster assignment housed in the Roster Maintenance 
application and in most cases viewable and manageable via the Roster Update Management 
System (RUMS) on the Cancer Trials Support System  Unit (CTSU) members’ website. 
 
This study is supported by the NCI CTSU.  
 
IRB Approval  
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program 
(CTEP) and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 

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Research Bases. In addition, U.S.-based sites must accept the NCI CIRB review to activate 
new studies at the site after March 1, 2019. Local IRB review will continue to be accepted 
for studies that are not reviewed by the CIRB, or if the study was previously open at the site 
under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria for the site to be able to have an 
Approved status following processing of the IRB/REB approval record: 
• Have an active CTEP status; 
• Have an active status at the site(s) on the IRB/REB approval on at least one 
participating organization’s roster; 
• If using NCI CIRB, be active  on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements for Protocol NRG-GI007 Site Registration 
Additional requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 

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• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• Training for Gastroenterologists, who will perform intra-tumoral injection of OBP-
301, are required to view the video produced by Oncolys BioPharma Inc. They are 
also required to have direct communication via email or telephone call with the 
Gastroenterology Co-Chair, Dr. Makoto Nishimura, to ensure there is clear 
understanding of the procedure for intra-tumoral injection. Documentation that they 
have fulfilled both of these criteria must be submitted to Dr. Nishimura at 
nishimum@mskcc.org who will review, contact the Gastroenterologist and correct 
any procedural errors with them. Gastroenterologist certification documents can be 
found on the NRG Oncology website; Documents & Materials tab of the NRG-GI007 
homepage. If the gastroenterologist demonstrates competency he/she will be notified 
of the certification approval to perform the procedure. The certification form will be 
signed by Dr. Nishimura and provided to NRG Oncology. NRG Oncology will 
submit the required documentation to CTSU. Only gastroenterologists who are 
credentialed in this manner are permitted to administer OBP-301. The video and 
further credentialing details are posted on the NRG protocol website. 
• Per “NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules” this trial falls under a Risk Group 2 category given OBP-301 is a virus. 
Therefore, IBC approval is needed prior to patient enrollment. Upon receipt of 
Institutional Biosafety Committee (IBC) approval documentation should be 
submitted to CTSU (see below for submission details). 
• An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• Compliance with all applicable protocol-specific requirements (PSRs). 
 
• Requirements for the Initial Shipment of OBP-301 for ALL sites  
Institutions must electronically complete (versus hand write) and submit a Drug 
Request form to the Oncolys contact listed in the form. The Oncolys contact will 
work directly with the drug distributor to arrange OBP-301 shipment to sites. 
The Drug Request form is available on the NRG protocol website. 
 
The following items must be submitted to NRG Regulatory (Regulatory-
PHL@nrgoncology.org)  
o 1572 for each investigator conducting the study 
o CV for each investigator conducting the study 
 
• This is a study with a radiation and/or imaging (RTI) component and the enrolling 
site must be aligned to an RTI provider. To manage provider associations or to add 
or remove associated providers, access the Provider Association page from the 

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Regulatory section on the CTSU members’ website at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at least 
one Imaging and Radiation Oncology Core (IROC) credentialed provider to 
participate on trials with an RTI component. Enrolling sites are responsible for 
ensuring that the appropriate agreements and IRB approvals are in place with their 
RTI provider. An individual with a primary role on any roster is required to update 
provider associations, though all individuals at a site may view provider 
associations. To find who holds primary roles at your site, please view the Person 
Roster Browser under the RUMS section on the CTSU members’ website. 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC to 
begin the modality credentialing process.  
To complete protocol-specific credentialing the RTI provider or enrolling site should 
follow instructions in the protocol to submit documentation or other materials to the 
designated IROC Quality Assurance (QA) center. Upon the IROC QA center 
approving the RTI provider for the study modality, IROC will automatically send the 
approval to the Regulatory and Roster Maintenance applications to comply with the 
protocol-specific requirement, unless otherwise noted at the bottom of the IROC 
Credentialing Approval notification. IROC will continue to copy the provider and/or 
enrolling site on modality approvals. 
Upon site registration approval in the Regulatory application, the enrolling site may 
access Oncology Patient Enrollment Network (OPEN) to complete enrollments. If 
the study is using the IROC integration suite, the enrolling site will select their 
credentialed provider treating the subject in the OPEN credentialing screen and may 
need to answer additional questions related to treatment in the eligibility checklist.   
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and their  associated investigators and staff on a 
participating roster. To view/download site registration forms:   
• Log on to the CTSU members’ website (https://www.ctsu.org); 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, 
or 
o Click on the By Lead Organization folder to expand, then select NRG and 
protocol number NRG-GI007. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.)  
 

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Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  
• Click on Regulatory at the top of your screen; 
• Click on Site Registration; and 
• Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
 
8.2 RT-Specific Pre-Registration Requirements (19-MAY-2023) 
For detailed information on the specific technology requirement required for this study, please 
refer to the table below and utilize the web link provided for detailed instructions. The check 
marks under the treatment modality columns indicate whether that specific credentialing 
requirement is required for this study. Specific credentialing components may require you to 
work with various QA centers; however, IROC Houston will notify your institution when all 
credentialing requirements have been met and the institution is RT credentialed to enter 
patients onto this study.  The credentialing notification document (email) must be uploaded 
by the site to the CTSU Regulatory Submission Portal for RSS to be updated.   
RT 
Credentialing 
Requirements 
 
Web Link for Procedures and Instructions:   http://irochouston.mdanderson.org 
 
Treatment 
Modality 
 
Photons 
Key Information 
 
Credentialing 
Status Inquiry 
x 
To determine if your institution has completed the requirements above, please 
complete a “Credentialing Status Inquiry Form” found under Credentialing on the 

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8.2.1 Digital RT Data Submission to NRG Using TRIAD 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 
images as they are transferred. 
TRIAD Access Requirements: 
• Active CTEP registration with the credentials necessary to access secure NCI/CTSU 
IT systems; 
• Registration type of: Associate (A), Associate Plus (AP), Non-Physician Investigator 
(NPIVR), or Investigator (IVR). Refer to the CTEP Registration Procedures section 
for instructions on how to request a CTEP-IAM account and complete registration in 
RCR; and 
• TRIAD Site User role on an NCTN,  ETCTN, or other relevant roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 
to TRIAD, and may submit images for credentialing purposes, or for enrollments to 
which the provider is linked in OPEN. 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account and 
RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.3 
Patient Enrollment ( 19-MAY-2023) 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
Form 
IROC Houston QA Center website (http://irochouston.mdanderson.org). 
Facility 
Questionnaire 
x 
The IROC Houston electronic facility questionnaire (FQ) should be completed or 
updated with the most recent information about your institution.  To access this FQ, 
email irochouston@mdanderson.org to receive your FQ link. 
Phantom 
Irradiation 
        X 
An IMRT thorax phantom study provided by the IROC Houston QA Center must be 
successfully completed. Instructions for requesting and irradiating the phantom are 
found on the IROC Houston web site (http://irochouston.mdanderson.org). 
 
Credentialing Issued to: 
Institution 
 
x 
Institution will be credentialed for the treatment modality that they intend to use on all 
patients. IROC Houston QA Center will notify the institution and NRG Headquarters 
that all desired credentialing requirements have been met. 

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criteria have been met, informed consent is obtained, and the study site is listed as 
‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.  
 
Informed Consent: Patients must be aware of the neoplastic nature of their disease and 
informed of the procedure(s) to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side-effects, risks, and discomforts prior to signing the 
informed consent in accordance with institutional and federal guidelines. Current 
IRB/RE/REC approval of this protocol and a consent form is required prior to patient 
consent and registration. The model consent form created for this study adheres to the 
NCI informed consent template requirements. 
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs’ registration/randomization systems for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar.  Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 

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CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the patient enrollment in OPEN. Prior to discussing protocol entry with 
the patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that 
a slot on the protocol is available to the patient. Once a slot reservation confirmation is 
obtained, site staff may then proceed to enroll the patient to this study.  
 
9.0 DRUG INFORMATION  
 
9.1 
Investigational Study Agent: OBP-301 (19-MAY-2023) 
To supplement the toxicity information contained in this document, investigators must 
obtain the current version of the Investigator Brochure for comprehensive pharmacologic 
and safety information 
The Investigator Brochure can be obtained from the protocol specific page of the NRG 
website. 
 
9.1.1    Adverse Events 
See Section 7.3 and consult the Investigator Brochure for comprehensive information. 
The OBP-301 clinical study material and product is generated according to current Good 
Manufacturing Practice (cGMP).  Below shows an overview of OBP-301.  OBP-301 will 
be provided by Oncolys BioPharma Inc.   
Investigational 
product code: 
OBP-301 
Content: 
2 mL/vial (1×1012 Viral Particles/mL) 
Dosage form: 
Solution; formulated in 20 mM Tris pH 8.0, 25 mM NaCl with 
2.5% glycerin, USP by volume, filled in each 5 mL glass vial 
Storage method for 
the investigational 
product: 
Store at ≤ -60°C 
 
9.1.2    Supply, Packaging, Accountability, and Drug Ordering 
This study will be conducted under IND# 19404 to be held by NRG and will require FDA 
submission and approval as part of the IND. 
 
            Study Supplies 
Oncolys BioPharma Inc. will be responsible for the preparation and labelling of the 
Investigational Product (IP) in accordance with local regulatory requirements.  Oncolys 
BioPharma Inc. will also provide details of batch numbers and all associated safety and 
stability data.  
Oncolys BioPharma Inc. in coordination with the drug distributor, Catalant, is responsible 
for packaging and shipment of the IP to the site(s).  Due to product specific requirements, 
shipments of IP will be made on dry ice using a validated container and temperature 

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monitoring.  An official shipping form to be completed by the study Investigator or 
designee (e.g., pharmacist) will be included in each shipment and returned to the drug 
distributor per instructions on the form. (See Appendix I: Pharmacy Manual, for receipt 
procedures). 
              Storage Conditions 
The study Investigator or designee is responsible for receiving each shipment of IP.  
Upon receipt of the IPs at the investigational site, the receipt procedures should be 
completed and IPs stored appropriately at ≤ -60°C.  A record to account for all dispensing 
and return of unused IPs will be maintained by the investigational sites.  At the end of the 
study the IPs will be reconciled and a copy of the record submitted to Oncolys BioPharm, 
Inc. at t.biran@oncolys.com. The Investigator will be fully responsible for the security, 
accessibility, and storage of the IPs while they are at the investigational facility.   
Vials must be stored in the original vial storage boxes to facilitate supply tracking.  It is 
recommended to leave the vial storage boxes in the original leak-proof bag or in a 
substitute leak-proof container, particularly if the supplies are not segregated (i.e., in a 
separate section of the freezer) from other products or biological samples. 
The freezer should be in a locked or secured area, with limited access.  Additionally, the 
freezer should have a temperature recorder and an alarm system.  The temperature plot 
should be properly maintained and checked.  Documentation for calibration of the freezer 
at installation and at each maintenance inspection should be available (at least annually or 
as per manufacturer’s recommendations).  A biohazard symbol should be affixed to the 
outside of the storage compartment.   
Accountability and Compliance 
The Investigator, pharmacist, or designee may only dispense clinical supplies in 
accordance with this protocol.  The NCI’s Investigational Agent Accountability Record 
(located on CTEP/PMB website) must be used for accountability. 
The Investigator, pharmacist, or designee, is responsible for maintaining an accurate and 
current record of all clinical supplies received from the drug distributor, dispensed to the 
Investigator or destroyed.  Accountability records must be maintained throughout the 
course of the study, showing receipt and disposition of the clinical supplies. 
Refer to the pharmacy manual (Appendix I) for specific disposal and destruction 
information. 
Drug Ordering 
A standard amount of study material will be provided to each site upon request at the 
beginning of the study. Sites must submit a drug request form to the contact listed in the 
form with a copy to the NRG-GI007 study mailbox (NRG-GI007@NRGOncology.org). 
Catalent will be the drug distributor and will ship OBP-301 to each site. Please allow 4 
weeks for receipt of initial supply. The Drug Request form is available on the NRG 
website. 
 

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The site may request additional OBP-301 study material when the supply is low (i.e. 
study material on site is only enough for 1 participant). Please allow four weeks for 
preparation and delivery to site. To request additional study material supplies, the site 
will contact the assigned supplier using the Drug Request Form (located on the NRG 
website).  
 
9.1.3   Agent Specific Information: OBP-301 
Refer to the Pharmacy Manual (Appendix I) and the Investigator Brochure for 
detailed information  
 
Other Names: Suratadenoturev (pending trade name Telomelysin TM), hereafter referred to 
as OBP-301 
 
Classification:  Adenovirus 
 
Description:  Adenoviral vector containing the adenoviral E1A and E1B gene linked with 
an internal ribosome entry site (IRES) under the control of the human Telomerase 
Reverse Transcriptase (hTERT) promoter. 
 
Mode of Action: The normal transcriptional regulatory element of the Ad5 E1A gene is 
replaced by the human Telomerase Reverse Transcriptase gene (hTERT) promoter, and 
the normal transcriptional element of the E1B gene is replaced by an IRES (Internal 
Ribosomal Entry Site) sequence.  
How Supplied:  OBP-301 will be provided as a frozen viral suspension formulated in 20 
mM Tris pH 8.0, 25 mM NaCl with 2.5% Glycerin, USP by volume.  The product is 
packaged using a 5 mL glass vial, siliconized gray butyl-rubber stoppered vials, an 
aluminum seal, and yellow flip-top plastic cap.  Each vial contains a volume of 2.0 mL at 
a concentration of 1 x 1012 viral particles (vp)/mL. The product in this configuration is 
stored at ≤ -60° C prior to administration. 
Preparation: OBP-301 should be prepared according to Biosafety Level 2 Guidelines, 
unless local regulations require a more rigorous containment level. See Appendix I and 
Appendix II. 
Storage: See Appendix I and section 9.1.2. 
Route of Administration:  Injection into the tumor 
 
Method of Administration:  OBP-301 is administered as intratumoral injection into a 
primary esophageal tumor mass that is suitable for injection, e.g. greater than 1 cm2 in 
size and in a location amenable for endoscopic injection. 
 
Administration Instructions can be found in the pharmacy manual (Appendix I) 
 
9.1.4    Destruction of Used and Unused Investigational Product 
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Empty or partially used vials should be destroyed, by the study pharmacy, in accordance 
with institutional biosafety policy and procedures for biohazardous waste management.  
Proper accounting of the vials must be performed immediately using the NCI 
Investigational Agent Accoountability Record. 
 
Written authorization must be obtained from Oncolys BioPharma Inc. before any 
destruction of unused clinical material supplies.  This will occur at the completion of 
the clinical study or when the expiration date has been reached and could not be 
prolonged by Oncolys BioPharma Inc. based on updated stability information.  In 
addition, destruction of unused supplies may only be performed after product 
reconciliation by the monitor.  
 
The unused vials must be destroyed by the study pharmacy, in accordance with 
institutional Biosafety policy and procedures for biohazardous waste management or 
returned to Oncolys BioPharma Inc. Unless approved by Oncolys BioPharma Inc., 
unused drug cannot be saved for future use. 
 
The Investigator or designee must fill in, sign, and date the appropriate section of Clinical 
Trial Material Destruction Certificate.  Discrepancies in vial accountability must be 
explained in writing by the Investigator or designee.  A copy will be retained for the site 
study file. 
 
9.2 
Commercial Agent: Paclitaxel 
 
 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
 
9.2.1 Product Description: Paclitaxel injection is a clear colorless to slightly yellow viscous 
solution. 
 
9.2.2    Solution Preparation: Paclitaxel injection should be diluted in 0.9% Sodium Chloride 
Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride 
Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 
mg/mL. 
 
9.2.3     Route of Administration:  Intravenous 
 
9.2.4    Agent Ordering/Availability: Commercially available 
Please see Section 5.2.2 for administration instructions. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage. 
 
9.2.5    Adverse Events 
 
Please refer to the package insert. 
 

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9.3 
Commercial Agent: Carboplatin 
 
 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
 
9.3.1 Product Description: Carboplatin injection is a premixed aqueous solution of 10 mg/mL 
carboplatin. 
 
9.3.2    Solution Preparation: Carboplatin aqueous solution can be further diluted to 
concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D 5W) or 0.9% Sodium 
Chloride Injection. 
 
9.3.3     Route of Administration; Intravenous 
 
9.3.4     Agent Ordering/Availability; Commercially available 
Please see Section 5.2.2 for administration instructions. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage. 
 
9.3.5    Adverse Events 
 
Please refer to the package insert. 
 
10. PATHOLOGY/BIOSPECIMEN 
10.1 
Biospecimen Submission Tables (07-DEC-2020) 
10.1.1 Optional Specimen Submissions  
 
 
Optional Study Description #1 FFPE Tumor tissue for Immunofluorescence/IHC Assays (See Appendix VI 
for details) 
 
Why specimen is being collected: To identify potential biomarkers of response.  
Specimens and Processing: Tumor specimens will be collected and prepared following standard pathology 
practices and sent to NRG Biospecimen Bank – San Francisco 
Required Forms: Specimen Transmittal Form and copy of pathology report with accession number and date of 
procedure visible. All other PHI information should be redacted. 
Kits and Shipping costs: Sites are responsible for all FFPE shipping costs 
Shipping Days: Sites can ship FFPE samples Monday-Friday 
 
Residual Material:  Sites can request blocks and any un-used slides be returned once study is completed and the 
pre-planned analyses are complete.  Sites will be responsible for return FFPE shipping costs. Sites must check 
with their pathology department to ensure they can release the FFPE material for all patients that consent. FFPE 
Blocks will be returned to sites after the end of study testing is completed. 
 
Ship FFPE samples to:  
Attn: NRG Oncology Biospecimen Bank – San Francisco 
2340 Sutter Street- Room S341 
San Francisco, CA 94115 
415-476-7864/Fax 415-476-5271 
Email: NRGBB@ucsf.edu 
 
For questions, please contact the San Francisco Bank at:  

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Email: NRGBB@ucsf.edu 
415-476-7864/Fax 415-476-5271 
  
Specimen Type  
Collection Time Points 
 
Collection Information and 
Requirements/Instructions 
for Site 
Shipping  
 
H&E Slide and FFPE 
Tumor block  
 
 
Baseline:  
From diagnostic biopsy. 
 
Pre-treatment: Biopsy of 
the primary tumor prior to 
first OBP-301 injection. 
 
During Treatment: Biopsy 
of the primary tumor prior 
to each OBP-301 injection 
on Days 12 and 26 (up to 1 
day before) 
 
Post Treatment: 6-8 weeks 
post RT if applicable per 
disease assessment 
 
 
Paraffin-embedded block.  
If site is unable to send block 
site must send 15-20 five 
micron unstained slides at the 
end of treatment to ensure they 
are cut immediately prior to 
shipment. Sites must submit an 
ST form to the biobank stating 
they will be submitting 
unstained slides for all 
timepoints. 
Store all samples and 
batch ship ambient to 
NRGBB_SF at end of 
treatment. 
 
 
Optional Study Description #2 Whole Blood for PBMC isolation and Plasma Assays. (See Appendix VI for 
details) 
 
Why specimen is being collected: To identify potential biomarkers of response. 
Required Forms: Specimen Transmittal Form 
Kits: CPT tubes and shipping supplies can be requested from the NRG Biospecimen Bank- San Francisco. Allow 
5-10 business days for receipt of kits from California by Fed Ex Ground. If sites need kits expedited they must 
provide a shipping label or Fed Ex account number.  
Shipping costs: Priority overnight Fed Ex labels for shipment to MSK lab can be requested for all timepoints 
from the NRG Biobank (NRGBB@ucsf.edu) once a patient is screened.  
Shipping Days: Fresh Blood must be shipped ambient overnight courier Monday-Thursday.  
Notice of anticipated shipment must be provided at least 24 hours and tracking information must be sent day of 
shipment to the Immune Monitoring Facility at wongp@mskcc.org. 
Residual Material: Blood samples will be destroyed once the study is completed and the pre-planned analyses 
are complete. 
 
Ship Samples to: 
Phil Wong 
Immune Monitoring Facility, Memorial Sloan Kettering Cancer Center 
Zuckerman Research Building, Z-1513 
408 E. 69th St. 
New York, NY 10065 
Phone: 646-888-3514 
Email: wongp@mskcc.org 
 
For questions, contact the Immune Monitoring Facility at : wongp@mskcc.org 
 
Specimen Type  
Collection Time Points 
 
Collection Information and  
Requirements/Instructions 
Shipping  
 

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for Site 
5-10 mL Whole Blood 
drawn into 4 CPT tubes. 
 
 
Pre Treatment: Prior to 
first OBP-301 injection 
on Day -3  
 
During Treatment: Prior 
to OBP-301 injection on 
Days 12 and 26 (up to 1 
day before) 
 
Post Treatment: 6-8 
weeks post RT 
Collect whole blood, label 
with identifier and time of 
collection, and place in 
insulated tube box inside 
biohazard specimen transport 
bag. Store at ambient 
temperature until ready to 
ship. Samples must be 
shipped on day of collection. 
Ship ambient via 
overnight courier to 
Immune Monitoring 
Facility, MSKCC   
 
 
11. SPECIAL STUDIES (NON-TISSUE) 
 
Not Applicable 
 
12. MODALITY REVIEWS 
 
12.1 
Medical Oncology Modality Quality Assurance Reviews 
The Medical Oncology Chair, Geoffrey Ku, MD will perform a Systemic Therapy 
Assurance Review for OBP-301(TelomelysinTM),Carboplatin and Paclitaxel for all patients 
who receive systemic therapy in this trial.  The goal of the review is to evaluate protocol 
compliance.  The review process is contingent on timely submission of systemic therapy 
treatment data. The scoring mechanism is: 1) Per Protocol, 2) Acceptable Variation, 3) 
Unacceptable Deviation, and 4) Not Evaluable.   
 
Dr. Ku will perform a Quality Assurance Review after NRG Data Management Center has 
received complete data for cases enrolled. The reviews will be ongoing and performed 
remotely. The final cases will be reviewed within 3 months after this study has reached the 
target accrual or as soon as NRG Data Management Center has received complete data for 
all cases enrolled, whichever occurs first. 
 
12.2 
Radiation Therapy Quality Assurance Reviews 
The Radiation Oncology Co-Chair will perform an RT Quality Assurance Review after 
IROC Philadelphia-RT has received complete data in TRIAD.  The RT reviews will be 
ongoing and performed remotely. The scoring mechanism is: Per Protocol, Variation 
Acceptable, and Deviation Unacceptable. 
 
13. DATA AND RECORDS 
 
13.1 
Data Management/Collection (19-MAY-2023) 
Medidata Rave is the clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments. Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; and  

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• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
 
Rave role requirements: 
• Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• Rave Read Only or Rave SLA role must have at a minimum an Associate (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
Upon initial site registration approval for the study in the Regulatory application, all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
e-mail from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, 
and click on the accept link in the upper right-corner of the iMedidata page. Site staff will 
not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. If an eLearning is required and has not yet been taken, the link to the 
eLearning will appear under the study name in iMedidata instead of the Rave EDC link; 
once the successful completion of the eLearning has been recorded, access to the study in 
Rave will be granted, and a Rave EDC link will display under the study name.  
Site staff who have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in the Regulatory application will receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website in the Data Management section under the 
Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU members’ website 
in the Data Management > Rave section at or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
13.2 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Sections 7.5 and 7.6 for information about expedited and 
routine reporting.   
 
Summary of All Data Submission: Refer to the NRG Protocol website 

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See Section 8 for TRIAD account access and installation instructions. See data 
submission table for TRIAD below. 
 
 
DICOM Items 
DICOM CT Image 
Due Within 1 week of start 
 
 
of RT. Triad Time Point: 
  DICOM Structure 
 
       RT Digital Plan 
 
DICOM Dose 
 
 
DICOM Plan  
 
All required structures must be labeled per the tables in Sections 
5.3.4 
 
5.3.5 
 
Imaging needed for RT review: 
Any imaging used for target delineation in the RT Planning process 
must be submitted along with RT Digital Plan 
 
Upon submission of the digital data via TRIAD, complete an online  
Digital Data Submission Information Form (DDSI): 
https://www.irocqa.org/Resources/TRIAD 
 
 
 
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES WILL BE 
KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED. 
 
13.3 
Data Quality Portal (19-MAY-2023) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status, and 
timeliness reports. Site staff should review the DQP modules on a regular basis to 
manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to 
the CTSU website. Staff who have Rave study access can access the Rave study 
data via direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice 
a month. These notifications serve as alerts that queries and/or delinquent forms 
require site review, providing a summary count of queries and delinquent forms 

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for each Rave study that a site is participating in. Additional site staff can 
subscribe and unsubscribe to these notifications using the CTSU Report and 
Information Subscription Portal on the CTSU members’ website. 
To learn more about DQP use and access, click on the Help Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms. DQP Form 
Status, and DQP Reports modules. 
 
13.4 
Global Reporting/Monitoring  
Required submission of patient demographic data for this study will be submitted 
automatically via OPEN.   
 
Note: Serious adverse events must be submitted via CTEP-AERS per protocol 
guidelines. 
 
14. STATISTICAL CONSIDERATIONS  
 
14.1 
Study Design (11-JAN-2022) 
This is a limited multicenter phase I study of OBP-301 and chemoradiation (CRT) with 
carboplatin/paclitaxel for patients with locally advanced esophageal/GEJ cancer, for 
whom surgery is not planned. Up to 2 OBP-301 dose regimens will be assessed.  If either 
dose regimen is determined to be safe, additional patients will be accrued to that dose 
regimen. 
 
14.2 
Study Endpoints 
14.2.1 Primary Endpoint: Dose limiting toxicity to assess the safety of OBP-301 given in 
combination with chemoradiation. 
 
14.2.2  Secondary Endpoints:  
 Adverse events as measured by CTCAE v5.0 
 Clinical complete response (cCR) – if one of the OBP-301 regimens is declared to be 
safe. 
 Number of patients alive without progression and number of patients alive at 1 and 2 
years - if one of the OBP-301 regimens is declared to be safe. 
 
14.3 
Primary Objectives Study Design 
14.3.1 Primary Hypothesis and Endpoints 
The primary hypothesis is that OBP-301 given in combination with chemoradiation using 
carboplatin and paclitaxel is safe. 
 
14.3.2 How Primary Endpoint Will Be Analyzed 
To assess the safety endpoint, the initial cohort of patients to be assessed will receive 3 
doses of OBP-301 at 1 x1012 vp/mL in conjunction with chemoradiation.  
 
The dose-limiting toxicity (DLT) assessment period is from start of protocol treatment 

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until 30 days after the completion of CRT (total of ~10 weeks).   
 
DLT is defined as the following that are definitely or probably attributed to OBP-301: 
• Any grade ≥3 toxicity EXCEPT for the following: 
o Grade 3 nausea/vomiting  
o Grade 3 esophagitis or dehydration  
o The first occurrence of grade 3/4 neutropenia 
o Grade 3/4 lymphopenia (since this is a known toxicity of chemoradiation and 
OBP-301)  
• Any toxicity that leads to a >14-day cumulative delay in chemoradiation 
Evaluable patients for the safety endpoint will be defined as (i) patients who started all 
study treatment (OBP-301 and CRT) and had a DLT and (ii) patients who started all 
study treatment (OBP-301 and CRT) and completed DLT evaluation period without a 
DLT. If ≤1 of 6 evaluable patients in the 3 doses of OBP-301 at 1 x1012 vp/mL cohort 
have a dose limiting toxicity, then the regimen will be declared safe and an expansion 
cohort of 9 more patients will be treated on this regimen to further evaluate toxicity and 
to get preliminary data on cCR.   
 
If ≥2 of these 6 evaluable patients have a dose limiting toxicity, then the 3 doses of OBP-
301 at 1 x1012 vp/mL will be deemed too toxic and a second cohort will assess 3 doses of 
OBP-301 at 1 x1011 vp/mL in conjunction with chemoradiation. If ≤1 of 6 evaluable 
patients in the 3 doses of OBP-301 at 1 x1011 vp/mL cohort have a dose limiting toxicity, 
then the regimen will be declared safe and an expansion cohort of 9 more patients will be 
treated on this regimen to further evaluate toxicity and to get preliminary data on cCR. If 
≥2 of 6 evaluable patients in this cohort have a dose limiting toxicity, then the 3 doses of 
OBP-301 at 1 x1011 vp/mLwill be deemed too toxic, no more patients will be accrued, 
and the results will be reported.   
 
If a grade 5 AE and/or 2 or more grade 4 AEs occur within 30 days of OBP-301  
administration, there will be a pause in accrual in order for NRG to discuss these  
events with the FDA via teleconference. 
 
If a safe OBP-301 dose is determined, then cCR will be evaluated and reported for the 
cohort of 15 patients treated at that dose, including the 6 used for the DLT assessment.  
 
14.3.3 Sample Size and Power Calculations:  
The DLT portion of the trial will accrue 6 or 12 evaluable patients, depending on whether 
or not the OBP-301 doses needs to be reduced. If a regimen is determined to be safe, 
based on the DLT endpoint, then the total number of evaluable patients accrued to the 
trial will be 15 patients, if OBP-301 3 doses at 1 x1012 vp/mL is the DLT safe dose, or 21 
patients, if OBP-301 3 doses at 1 x1011 vp/mL is the DLT safe dose. 
 
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when the true toxicity rate is ≥42% is at least 80%. If the true toxicity rate is ≤18%, the 
probability that the treatment will be deemed to be safe is at least 70%.    
 
Study reports focusing on accrual and adverse event data will be prepared regularly and 
the PI/NRG study team will have regular conference calls (biweekly or at most monthly) 
to review the accrual/safety data.  Information from these calls will be reviewed regularly 
by the NRG Oncology Early Phase Oversight Committee. 
 
14.4 
Study Monitoring of Primary Objectives 
Interim Reporting 
Interim reports will be prepared twice each year until the final analysis has been accepted 
for presentation or publication. In general, these reports will contain information about the 
accrual rate with projected completion date for the accrual phase, exclusion rates, 
pretreatment characteristics of patients accrued, and the frequency and severity of AEs.  
 
Required submission of patient demographic data for this study will be submitted 
automatically via OPEN.   
 
Note: Serious adverse events must be submitted via CTEP-AERS per protocol guidelines. 
After the start of the accrual or 8 weeks following protocol activation, whichever comes 
first, the study team, including the study chairs, study statisticians, data managers will hold 
at least monthly conference calls to review the overall conduct of the study lead by the 
study statistician.  A representative from each participating site will be invited to these 
calls.  Data on accrual, eligibility, patient demographics, treatment dose delivery, and 
reported adverse events will be reviewed on the calls.  Brief minutes of each meeting will 
be written by the study PI to document the review of information and any decisions that 
are made. The meeting minutes will be provided to the NRG Early Phase Trial Oversight 
Committee for review. 
 

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14.5 
Accrual/Study Duration Considerations 
 
It is anticipated that 1-2 patients will be accrued per month, after a 3 month ramp-up 
period. There will be a staggered enrollment of a 3 week duration for the first 3 patients 
enrolled onto the study to monitor for acute and subacute AEs. 
 
The projected duration to accrue and assess DLTs for a given regimen is estimated to be 
5.5-8.5 months.  If both regimens need to be assessed, the projected maximum time from 
study activation to reporting the primary endpoint is ~ 20 months.  This trial will have 
finite follow-up for each patient of 2 years from start of treatment. 
 
The required number of evaluable patients is as follows: 
 15, if the initial cohort is deemed to be safe (6 for DLT and 9 expansion) 
 21, if the initial cohort is not deemed to be safe, but the reduced cohort is deemed 
to be safe (12 for DLT and 9 expansion) 
 12, if neither cohort is deemed to be safe (12 for DLT and no expansion) 
 
14.6 
Dose Level Guidelines 
 Initial Dose Level: 3 doses of OBP-301 with chemoradiation, as specified in Section 
5.2.1 
 De-escalated Dose Level (IF NEEDED): 3 doses of OBP-301 with chemoradiation, as 
specified in Section 5.2.1 
  
14.7 
Secondary or Exploratory Endpoints (including correlative science aims) 
14.7.1 Secondary Hypotheses and Endpoints:  
 Adverse events as measured by CTCAE v5.0 
 Clinical complete response (cCR) – if one of the OBP-301 regimens is declared to be 
safe. 
 Number of patients alive without progression (PFS) and number of patients alive 
(OS) at 1 and 2 years - if one of the OBP-301 regimens is declared to be safe. 
 
14.7.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Adverse events 
Adverse events (AE) will be evaluated using the CTCAE v 5.0.  Counts of all AEs by grade 
will be provided by treatment arm.  Counts and frequencies will be provided for the worst 
grade AE experienced by the patient by treatment arm and within the subset of AEs related 
to treatment.  Severe AEs will be any grade 4 or greater non-hematologic toxicities and 
will be summarized by frequency tables by treatment arm.  No formal statistical testing 
will be performed on these summary data. 
 
Clinical Complete Response (cCR) 
 
For the regimen that is determined to be safe, out of all patients accrued to that  
 
regimen, the number of cCRs will be reported. No formal statistical testing will be  
 
performed on these summary data. 
 
 
Progression-free Survival (PFS) 

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For the regimen that is determined to be safe, out of all patients accrued to that  
 
regimen, the number of patients that are alive without progression at 1 and 2 years  
 
will be reported.  No formal statistical testing will be performed on these summary  
 
data. 
 
 
Overall Survival (OS) 
 
For the regimen that is determined to be safe, out of all patients accrued to that  
 
regimen, the number of patients that are alive at 1 and 2 years will be reported.  No formal 
statistical testing will be performed on these summary data.  
 
14.7.5 Expected Sample Size or Patient Cohorts: 6 evaluable patients will be accrued for up to 2 
dose levels.  If a dose level is determined to be safe, an additional 9 patients will be 
accrued at that dose level. 
 
14.8 
Exploratory Hypothesis and Endpoints 
Tumor and blood immune and virus-based correlative assays will be performed (see 
Section 10). 
These analyses will allow for the following exploratory hypotheses to be evaluated: 
• Correlate qualitative and semi-quantitative in the tumor micro-environment and 
persistence of adenovirus infection with outcomes to identify biomarkers of response 
• Correlate changes in immune cell subsets via multi-parameter flow cytometry with 
outcomes to identify biomarkers of response 
• Correlates changes in cytokine profile via multiplex ELISA with outcomes to identify 
biomarkers of response 
 
14.9 
Gender/Ethnicity/Race Distribution 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
1 
0 
0 
1 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
1 
2 
0 
0 
3 
White  
2 
12 
0 
2 
16 
More Than One Race 
0 
0 
0 
0 
0 
Total 
3 
16 
0 
2 
21 
 
 
 
 

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REFERENCES (11-JAN-2022) 
 
Andtbacka RH, HL Kaufman, Collichio F, et al. Talimogene Laherparepvec Improves 
Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015 33(25): 
2780-2788. 
 
Bedenne L, Michel P, Bouché O, Milan C, et al.  Chemoradiation followed by surgery 
compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J 
Clin Oncol. 2007 25(10):1160-1168. 
 
Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal 
cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation 
Therapy Oncology Group. Jama. (1999) 281(17): 1623-1627. 
 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0  U. D. o. H. a. H. 
S. N. I. o. H. N. C. Institute. (2010). 
 
EndoY, Sakai YR, Ouchi M, et. al. Virus-mediated oncolysis induces danger signal and 
stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation. Oncogene. 
2008. 27(17): 2375-2381. 
 
Fujiwara T, Urata Y, Tanaka N. Telomerase-specific oncolytic virotherapy for human cancer 
with the hTERT promoter. Curr Cancer Drug Targets. (2007);7(2):191-201  
 
Fujiwara T. Multidisciplinary oncolytic virotherapy for gastrointestinal cancer. Ann 
Gastroenterol Surg. 2019 Jul 5;3(4):396-404. 
 
Griffin S. M., Shaw IH and Dresner SM. Early complications after Ivor Lewis subtotal 
esophagectomy with two-field lymphadenectomy: risk factors and management. J Am Coll 
Surg. 2002. 194(3): 285-297. 
 
Hawkins LK., Johnson L, Bauzon M, Nye JA, et al. Gene delivery from the E3 region of 
replicating human adenovirus: evaluation of the 6.7 K/gp19 K region. Gene Ther. (2001). 
8(15): 1123-1131. 
 
Herskovic A, Martz K, al-Sarraf M, Leichman L,et al.Combined chemotherapy and 
radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N 
Engl J Med. (1992). 326(24): 1593-1598. 
 
Kamradt J, Drosse C, Kalkbrenner S, Rohde V,et al. Telomerase activity and telomerase 
subunit gene expression levels are not related in prostate cancer: a real-time quantification 
and in situ hybridization study. Lab Invest. (2003). 83(5): 623-633. 
 
Kuroda S, Fujiwara T, Shirakawa Y, Yamasaki Y, et al. Telomerase-dependent oncolytic 
adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair 

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machinery. Cancer Res. (2010).70(22): 9339-9348. 
 
Mathisen DJ, Grillo HC, Wilkins, Jr EW, Moncure AC and Hilgenberg AD. Transthoracic 
esophagectomy: a safe approach to carcinoma of the esophagus. Ann Thorac Surg 
(1988).45(2): 137-143. 
 
Nemunaitis J, Tong AW, Nemunaitis M, Senzer N, Phadke AP, et al. A phase I study of 
telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various 
solid tumors. Mol Ther. (2010). 18(2): 429-434. 
 
Nichols FC, Allen MS, Deschamps C, Cassivi SD, et al. Ivor Lewis esophagogastrectomy. 
Surg Clin North Am. 2005.85(3): 583-592. 
 
Oppedijk V, Van der Gaast A, Van Lanschot JJ,Van Hagen P, et al. Patterns of recurrence 
after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. 
J Clin Oncol. 2014. 32(5): 385-391. 
 
Services, U. D. o. H. a. u. The Health Insurance Portability and Accountability Act (HIPAA) 
of 1996 (P.L. 104-191). 1996.  [HIPAA]. 
 
Shay JW and Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer 
1997. 33(5): 787-791. 
 
Shay JW, Zou Y, E. Hiyama E and Wright WE. Telomerase and cancer. Hum Mol Genet 
2001. 10(7): 677-685. 
 
Siegel RL, Miller KD and Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020 70(1):7-
30. 
 
Stahl M, Stuschke M, Lehmann N, Hans-Meyer H-J, et al. Chemoradiation with and without 
surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin 
Oncol. 2005. 23(10):2310-2317. 
 
Suntharalingam M, Winter K, Ilson D, Dicker AP, et al. (2017). Effect of the Addition of 
Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal 
Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial. JAMA Oncol. 
2017 3(11): 1520-1528. 
 
Tanabe S, Tazawa H, Kanaya N, Noma K, et al. Endoscopic intratumoral injection of OBP-
301 (telomelysin) with radiotherapy in esophageal cancer patients unfit for standard 
treatments. J Clin Oncol 2019. 2019. 36: 130 [abstr]. 
 
Toh Y, Numasaki H, Tachimori Y. Current status of radiotherapy for patients with thoracic 
esophageal cancer in Japan, based on the Comprehensive Registry of Esophageal Cancer in 
Japan from 2009 to 2011 by the Japan Esophageal Society. Esophagus. 2020 Jan;17(1):25-

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32. doi 
 
Van Hagen P, Hulshof MC, Van Lanschot JJ, Steyerberg EW, et al.  Preoperative 
chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012. 366(22): 2074-
2084. 
 
Van Vloten JP, Workenhe ST, Wootton SK, et al. Critical Interactions between immunogenic 
cancer cell death, Oncolytici virsues, and the immune system define the rationale the design 
of combination immunotherapies. J. Immunol 2018. 200: 450-458 
  
 

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APPENDIX I: PHARMACY MANUAL (19-MAY-2023) 
 
1. Telomelysin (OBP-301) 
Summary of Investigational Product 
OBP-301 (Telomelysin, hereafter referred to as OBP-301) is an adenoviral vector containing the 
adenoviral E1A and E1B gene linked with an internal ribosome entry site (IRES) under the 
control of the human telomerase reverse transcriptase (hTERT) promoter. 
 
Packaging and Labeling 
OBP-301 will be provided as a frozen viral suspension formulated in 20 mM Tris pH 8.0, 25 mM 
NaCl with 2.5% Glycerin, USP by volume.  The product is packaged using a 5 mL glass vial, 
siliconized gray butyl-rubber stoppered vials and an aluminum seal with a plastic cap.  Each vial 
contains a volume of 2.0 mL at a concentration of 1 x 1012 viral particles (vp) / mL. The product 
in this configuration is stored at ≤ -60° C prior to administration 
Vials will be labeled with the following information: 
 
Vial label: 
Name of the Sponsor, Protocol No., Contents, Nominal Concentration, Content, 
Route of Administration, Batch No., Lot No., Storage Condition 
 
Label for storage box: 
Caution: For Clinical Trial Use Only,  
Name of the Sponsor, Protocol No., Contents, Nominal Concentration, Content, 
Route of Administration, Batch No., Lot No., Storage Condition 
 
STUDY AGENT RECEIPT PROCEDURES 
Shipping Conditions 
Each vial is boxed in an upright position within a small box. Each storage box is placed in a 
plastic self-sealing leak-proof bag with an adequate number of absorbent pads in the event of 
leakage during shipping. The storage boxes are shipped to the clinical sites in leak-proof foam-
lined cardboard boxes. 
Due to product specific requirements, the shipments are made on dry ice.  Within each shipment 
there will be an official shipping form to be completed by the study investigator or designee (e.g. 
pharmacist).  
 
Receipt Procedures 
The study investigator or designee is responsible for receiving each OBP-301 shipment.  Prior to 
each shipment, the drug distributor, Catalent, will contact the assigned personnel with the 
delivery information. 
 
Upon receipt the following should be performed: 
1. Always wear disposable gloves when handling OBP-301. 

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2. Examine the outside of the shipment package(s) for integrity. If the shipment package or 
contents are not intact: 
• The outer surfaces of all containers should be decontaminated with a virucidal 
disinfectant such as CaviCide. 
• If a vial is damaged in any way, it should be placed in a biohazardous waste container for 
sharps, and destroyed immediately according to institutional and local regulations for 
biohazardous waste management.  Be sure to record the destruction of any clinical 
material on the Clinical Trial Material Destruction Certificate (located on the NRG 
website). See Appendix III Guidelines for use and completion of Clinical Trial Material 
Destruction Certificate for instructions to complete the form. 
• Contact the drug distributor, Catalent, to report the damage. 
3. Open the shipment package(s). 
4. Confirm the package still contains dry-ice. 
5. Transfer the leak-proof package to a Biological Safety Cabinet (BSC). 
6. Remove the storage box from the plastic bag(s).  
7. OBP-301 will be provided in glass, chlorobutyl rubber stoppered vials, with an aluminum seal 
as a frozen viral suspension.  It will be transported to the pharmacy, following the current 
International Airway Transport Association (IATA) regulations.   
8. Promptly, inventory the vials of OBP-301 contained in the storage box and examine the 
integrity of the vials.  If the shipment package or contents are not intact, follow the steps listed 
above in step 2.  If the shipment does not match the detailed description, the site should 
contact the drug distributor, Catalent. 
9. Transfer vials to the appropriate location in the assigned ≤ -60°C freezer.  The vials must be 
stored in the original storage box to facilitate supply tracking.   
10.Wearing gloves, dispose of the dry ice, according to institutional procedures. 
11.Decontaminate the biological safety cabinet with a virucidal disinfectant. 
12.Complete the lower portion of the official shipping form, email it to the originator of the form 
as instructed and retain the original document in the site file. 
13.Enter the number of vials of clinical trial material received on the NCI’s Investigational 
Agent Accountability Record (located on CTEP/PMB website).  
 
Storage Conditions 
Prior to dilution, the vials of OBP-301 must be stored in a ≤ -60°C freezer, in an upright position.  
The vials must be stored in the original vial storage boxes to facilitate supply tracking.  It is 
recommended to leave the vial storage boxes in the original leak-proof bag or in a substitute leak-
proof container, particularly if the supplies are not segregated (i.e. in a separate section of the 
freezer) from other products or biological samples. 
The freezer should be in a locked or secured area, with limited access.  Additionally, the freezer 
should have a temperature recorder and an alarm system.  The temperature plot should be properly 
maintained and checked.  Documentation for calibration of the freezer at installation and at each 
maintenance inspection is required, (at least annually or as per manufacturer’s recommendations).  
A biohazard symbol should be affixed to the outside of the storage compartment. 
 

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PREPARATION NOTES 
OBP-301 should be prepared according to Biosafety Level 2 Guidelines, unless local regulations 
require a more rigorous containment level. An outline of Biosafety Level 2 precautions is located 
in Appendix III: Handling Guidelines/Universal Precautions for Biosafety Level 2 Agents. 
 
Disinfectant 
A disinfectant that has been qualified as an effective virucide for adenoviruses should be used for 
any decontamination procedure. The recommended exposure time should be at least 5 to 15 
minutes.  However, if the handling precautions recommended by the manufacturer differ, the 
manufacturer’s instructions should be followed. 
 
Study Material Expiration After Thaw 
The duration that OBP-301 remains at room temperature should be minimized.  It is recommended 
that OBP-301 be administered as soon as possible (within 4 hours) after reconstitution.  
Immediately prior to injection, it may be warmed by rolling the syringe between the palms of the 
hands, which may facilitate comfort of administration. 
 
Aseptic Procedures 
Aseptic techniques must be followed at all times during the preparation and transport to the 
treatment area. 
 
Biosafety Level 2 
As there is the potential of creating infectious aerosol during the preparation procedure, all work 
involving OBP-301 must be performed inside a properly maintained class II Biological Safety 
Cabinet (BSC). Biosafety Level 2 guidelines should be adhered to, unless local regulations require 
a more rigorous containment level.  An outline of Biosafety Level 2 guidelines is given in 
Appendix II. 
 
Universal Precautions 
Universal precautions should always be adhered to, as defined by federal, state and institutional 
and local regulations. 
 
Biohazardous Waste Management 
All OBP-301 wastes are considered biohazardous and consequently must be handled by the site 
according to federal, state and local regulations on management of biohazardous materials. 
 
Syringe Label 
According to local practice, a label will be affixed either to each injection syringe containing the 
final OBP-301 suspension or to the leak-proof plastic bags used in the transfer of the syringes.  
Care should be taken not to cover the graduation markings on the syringe with the label.  
The label should include but is not limited to the following information: 

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- Patient name or initials 
 
- Patient study number 
 
- Study investigational product: OBP-301 
 
- Dose (vp) and volume of injection 
 
- Expiration date 
 
- Lot number  
 
MATERIALS REQUIRED 
1. Vials of OBP-301 
2. Labels for injection syringes 
3. Disposable needles with bore 22-25 Gauge 
4. Self-sealing leak-proof plastic bags 
5. Puncture resistant leak-proof container for transport from pharmacy to treatment area 
6. Virucidal Disinfectant 
7. Biological Safety Cabinet (Class II) for OBP-301 preparation 
8. Polypropylene syringe(s) 
 
PREPARATION PROCEDURES  
1. Prior to assembly and placement of the OBP-301 preparation material, wipe Biological 
Safety Cabinet work surface with an appropriate disinfectant, following manufacturer’s 
instructions.  Allow to dry. 
2. Wipe all outside surfaces of materials with an appropriate disinfectant, following 
manufacturer’s instructions, prior to placement of study material inside the biological safety 
cabinet.  Arrange materials for preparation toward the back of the cabinet in order to protect 
from contamination. 
3. Remove the vial(s) of OBP-301 from the ≤ -60°C freezer on the day of administration, 
following confirmation that the patient will be treated on that day.  Transfer the vials in a 
puncture resistant leak-proof container to the preparation area.  
4. Prepare labels. 
5. Assemble the appropriate needles and syringes. 
6. Thaw vial containing OBP-301 by rolling the vial between the palms of the hands and 
mixing 10 times by inverting the vial.  The OBP-301 should be allowed to thaw completely 
prior to removing the aluminum seal. Before proceeding, visually inspect the solution in the 
vials to ensure there are no ice particles.  Remove the seal on the OBP-301 vials. 

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7. As there is a “dead space” of up to 1.5 ml in the tubing and syringe, it will be necessary to 
utilize 2 vials of OBP-301, drawing up 2 mL from vial 1 and 1.5 mL from vial 2. At the end 
of the endoscopy procedure, any OBP-301 in the syringe, tubing and the 2nd vial that has not 
been administered should be disposed of per biosafety protocols. 
8.   Using polypropylene syringe(s), aseptically pierce the rubber cap(s) with the needle(s) and 
draw up the required volume.  Caution should be used to avoid excessive shear forces in 
aspirating and discharging through needles.   
9. According to local practice, label either the OBP-301 syringe and/or the plastic transfer bag 
with a patient label. 
10. Place the syringe into the primary self-sealing leak-proof plastic bag and seal tightly.  Place 
this bag into the second transfer bag. Seal outer transfer bag tightly, assuring that the labels 
can easily be read. 
11. When the syringe is to be transported to the treatment area, the transfer bags should be placed 
in a puncture resistant leak-proof container, marked with a biohazard label.  Effort should be 
made to minimize the time that the OBP-301 is placed at room temperature. 
12. Immediately after use in the preparation procedure, the OBP-301 vials should be placed in a 
biohazardous waste container.  Thereafter, the local procedures for handling of biohazardous 
wastes must be followed. 
13. Immediately dispose of all materials used in the preparation of the syringe, according to 
practices established by local health authorities and/or hospital for disposal of biohazardous 
waste. 
14. Clean and disinfect the Biological Safety Cabinet with a virucidal disinfectant. 
15. Record dispensing of study material on the NCI Investigational Agent Accountability Record. 
16. If you have any questions concerning the preparation procedure, please contact NRG 
Oncology. 
 
INJECTION TECHNIQUE 
Please read Appendix II: Handling Guidelines/Universal Precautions for Biosafety Level 2 
Agents before injecting OBP-301.   
 
Pre-injection planning is the key to success, therefore, a sketch of the tumor and the planned 
injection sites should be made.  (The sketch will be helpful in determining the total quantity of 
study drug to inject.) 
 
Irrespective of the size of the tumor, every effort should be made to inject 1.0-2.0 mL of OBP-
301; the maximal volume of 2.0 mL is preferred and should be injected as long as this is 
technically possible 
 
 
 

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Figure 1.  Example of Mapping into up to 5 Tracks 
 
Specific endoscopic instructions are provided in a separate training document and video. 
 
Pain Management for Intratumoral Injections with OBP-301 
Injection site pain is the one of the more common adverse events in connection with intratumoral 
injections.  Therefore, the following pain control measures are suggested to improve the comfort 
of the patient. 
1. Review the analgesics already prescribed for the patient and determine the level of pain 
control. 
Additional pain medication will with all likelihood be needed during the day of the 
intratumoral injections and for a couple of days afterwards. Local anesthesia or nerve block 
may very well be required just before or during the intratumoral injection. 
 
DISPENSING AND ACCOUNTABILITY 
The study investigator, pharmacist, or designee may only dispense clinical supplies in 
accordance with the protocol.   
The study investigator, pharmacist, or designee, is responsible for maintaining an accurate and 
current record of all clinical supplies received from the sponsor, dispensed to the investigator or 
destroyed.  Accountability records must be maintained throughout the course of the study, 
showing receipt and disposition of the clinical supplies. At the end of the study, it must be 
possible to reconcile delivery records with that of used, unused and destroyed clinical supplies.  
① 
⑤ 
② 
③ 
④ 

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The NCI’s Investigational Agent Accountability Record (located on CTEP/PMB website) must 
be used for accountability and destruction certificate to be completed upon destruction (located 
on the NRG website).  
During site monitoring visits, the drug accountability forms will be verified and checked for 
accuracy and consistency. 
 
DESTRUCTION OF EMPTY OR PARTIALLY USED VIALS 
Immediately after use, the used vials should be placed in a biohazardous waste container.  Empty 
or partially used vials should be destroyed by the study pharmacy, in accordance with institutional 
biosafety policy and procedures for biohazardous waste management. Proper accounting of the 
vials must be performed immediately using the Investigational Agent Accountability Record. 
 
DESTRUCTION OF UNUSED VIALS 
Written authorization must be obtained from  Oncolys before any destruction of unused 
clinical material supplies.   
This will occur at the completion of the clinical study or when the expiration date has been 
reached and could not be prolonged by the sponsor based on updated stability information.  In 
addition, destruction of unused supplies may only be performed after product reconciliation by 
the pharmacist.  
The unused vials must be destroyed by the study pharmacy, in accordance with institutional 
Biosafety policy and procedures for biohazardous waste management. 
The investigator or designee must fill in, sign and date the appropriate section of Clinical Trial 
Material Destruction Certificate (located on the study-specific page on the NRG website).  
Discrepancies in vial accountability are to be explained in writing by the investigator or 
designee.  The original will be retained for the site study file. 
 
 

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APPENDIX II: BIOSAFETY LEVEL II SUMMARY INFORMATION FOR 
INSTITUTIONAL BIOSAFETY COMMITTEE REVIEW 
 
The site at which this trial is being conducted will ensure that an Institutional Biosafety 
Committee (IBC) is in place that is composed of at least 5 appropriately-qualified members.  The 
IBC will ensure that the site conforms to the requirements set forth in the Section IV-B-2 of the 
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, 
promulgated by the NIH/Office of Biotechnology Activities (NIH/OBA).  The Principal 
Investigator at the site will be responsible for petitioning the IBC and obtaining approval prior to 
enrolling any subject in the study.  The Principal Investigator will also be required to obtain and 
follow all biohazard safety guidelines promulgated by the IBC, and to report all findings as 
required to the IBC and to NRG Oncology for reporting to NIH/OBA. 
This protocol and any accompanying material provided to the subject (such as subject 
information sheets, Informed Consent Form, or descriptions of the study used to obtain informed 
consent) will be submitted by the Principal Investigator to the legally constituted and chartered 
Institutional Biosafety Committee (IBC).  Additional materials, such as the Investigator’s 
Brochure, will be submitted to the IBC according to the specific Committee and federal (United 
States’ National Institutes of Health or foreign equivalent) requirements.  Each site will be 
approved by the IBC in accordance with local procedures and country specific regulatory 
requirements.  Documentation of IBC approval must be in place with both the CTSU and locally 
prior to subject enrollment.  At the discretion of the specific IBC and within federal 
requirements, IBC oversight of individual sites may be terminated provided (1) all subjects at 
that site have completed dosing by at least 90 days, and (2) all investigational materials have 
been fully accounted for and either returned to the distributor, destroyed on site, or shipped to a 
duly licensed destruction facility and a shipping and inventory reconciliation records have been 
filed. 
Precautions appropriate to a Risk Group 2 virus are recommended for the OBP-301 (US NIH 
Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules).  There 
are 4 risk groups, with Risk Group 1 posing the least danger and Risk Group 4 being the most 
dangerous to work with.  RG-2 viruses are defined as those agents that are associated with 
human disease which is rarely serious and for which preventive or therapeutic interventions are 
often available.  For comparison purposes, herpes simplex virus and hepatitis B virus are also 
classified as Risk Group 2 viruses.  Dealing with Risk Group 2 viruses requires certain 
precautions referred to as Biosafety Level 2 (BSL-2) practices.   These practices are summarized 
below.  Further information can be obtained from the local site Institutional Biosafety 
Committee. 
 
 
 

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APPENDIX III: HANDLING GUIDELINES/UNIVERSAL PRECAUTIONS FOR 
BIOSAFETY LEVEL 2 AGENTS 
Introduction 
This document is designed to serve as a guide for pharmacists, laboratory staff, and healthcare 
workers involved with work involving agents of moderate potential hazard to personnel and the 
environment. It gives an overall view of the type of safety procedures and precautions that are 
recommended with work with these types of agents. 
These instructions are based on two documents: Biosafety in Microbiological and Biomedical 
Laboratories and Guidelines for Isolation Precautions in Hospitals. Both documents are from the 
US Centers for Disease Control and Prevention (CDC) which should be consulted for further 
reference if needed. 
Detailed specific study product preparation procedures are provided to the study pharmacist in 
the Pharmacy Brochure. 
 
Overview 
The following schema highlights key points for hospital team members participating directly or 
indirectly in patient care. 
 
 
 BIOHAZARD/INFECTIOUS 
    WASTE MANAGEMENT 
      
     Institutional procedures 
     Local authorities 
MANUFACTURE 
SITE 
HOSPITAL 
PHARMACY 
STUDY PRODUCT 
ADMINISTRATION 
DISPOSAL OF  
WASTE MATERIAL 
 TRANSPORT IN A 
DURABLE, LEAK- 
   PROOF PLASTIC BAG  
 SHIPPING  
 IATA REGULATIONS 
 ROUTINE  LAB 
 Biological Safety 
Level II 
 Disinfectant validated 
   for adenoviruses 
 PREPARATION 
BIOLOGICAL SAFETY 
LEVEL II 
  BIOSAFETY CABINET II 
“PREPARATION OF 
CLINICAL SUPPLIES” 
 PRECAUTIONS 
   Institutional procedures 
 
   Universal precautions 
    Primary barriers 
   (gloves, gowns, masks) 
   Disinfectant validated 
   for adenoviruses 
 
 

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                           Biosafety Level 2 Guidelines 
Standard Practices 
Special Practices 
Safety Equipment 
(Primary Barriers) 
Laboratory Facilities 
(Secondary Barriers) 
• Limited or restricted 
access 
• Hand washing 
• No eating, drinking, 
storing food, 
smoking, handling 
contact lenses, or 
applying cosmetics 
• Mouth pipetting 
prohibited 
• Minimize creation of 
aerosols, splashes 
• Procedures creating 
infectious aerosols 
or splashes to be 
conducted in BSC. 
• Work surfaces 
decontaminated 
• Wastes 
decontaminated 
before disposal 
• Insect and rodent 
control 
• Policies and 
procedures 
• Hazard warning 
sign 
• Serum monitoring 
program  
• Biosafety manual 
• Appropriate 
training 
• Limit sharps 
• Use leak-proof 
containers 
• Decontaminate 
equipment and 
work surfaces 
• Report spills and 
accidents to 
appropriate hospital 
personnel 
• Biosafety cabinets 
(BSC), preferably 
class II, and/or 
personal protective 
equipment 
• Face/eye protection 
for work outside 
BSC 
• Designated 
laboratory garments 
worn and removed 
before leaving lab 
• Gloves worn when 
handling materials, 
removed before 
leaving lab 
• Sink available in 
room 
• Lab designed for 
easy cleaning 
• Impervious bench 
tops 
• Windows fitted 
with screens 
• Method for 
decontamination of 
waste available 
• Eyewash facility 
readily available 
 
                              Universal Precautions 
Patient Placement: 
Single room 
Handwashing: 
After contact 
After glove removal 
Gloves: 
Wear when handling patient/contaminated items 
Wear when entering room, change after contact, remove when leaving,  
Mask/Eye Protection: 
When splashes or sprays are anticipated 

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Gown: 
When splashes or sprays are anticipated 
Patient-care Equipment: 
Avoid contact with surfaces, ensure proper disposal/ decontamination 
Environmental Control: 
Procedures for routine care, cleaning, and disinfection 
Linen: 
Proper handling, transport, and processing 
Occupational Health: 
Blood borne pathogens, sharps control, resuscitation devices 
 
All Departments 
All staff potentially working with agents of moderate potential hazard to personnel and the 
environment should receive appropriate training, regarding the potential hazards associated with 
the work involved and the necessary precautions to prevent exposures.  The staff should receive 
additional training as necessary for procedural or policy changes.  
 
Pharmacy Facilities 
1. Properly maintained Level 2 Biological Safety Cabinets (BSC) and other appropriate 
physical containment devices and personal protective equipment are used, unless local 
regulations require a more rigorous containment level. 
2. A method of decontamination of the infectious material is available (e.g., autoclave, 
chemical disinfection, incinerator, or other approved decontamination system). 
3. The preparation room contains a sink for hand-washing. 
4. The room is designed so that it can be easily cleaned. 
5. Bench tops are impervious to water and resistant to acids, alkalis, organic solvents, and 
moderate heat. 
6. An eyewash facility is readily available. 
7. A hazard warning sign, incorporating the universal biohazard symbol is posted on the access 
door to the preparation room.  The hazard warning sign identifies the infectious agent, lists 
the name and telephone number of the responsible pharmacist or other responsible person(s), 
and indicates the requirement(s) for entering the room. 
8. If the area has windows that open, they are fitted with fly screens. 
9. Access to the preparation room is limited or restricted, at the discretion of the responsible 
pharmacist, when preparation is in progress. 

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General Recommendations for Product Preparation and Handling 
1. Protective coats, gowns, smocks, or uniforms designated for pharmacy use should be worn 
while in the preparation room.  This protective clothing is removed and left in the 
preparation room before leaving for another area (e.g. cafeteria, library, administrative 
offices).  All protective clothing is either disposed into a biohazard waste container in the 
preparation room or laundered by the institution according to hospital policy and local 
regulations for garments potentially contaminated with infectious agents.  Personnel must 
never take protective garments home. 
2. Gloves must be worn and disposed of when contaminated, removed when work is 
completed, and are not worn outside the preparation room.  Disposable gloves are not 
washed or reused. 
3. Persons wash their hands after handling potentially infectious material, after removing 
gloves, and before leaving the preparation room. 
4. Persons who wear contact lenses should also wear goggles or a face shield. 
5. All procedures are performed carefully to minimize the creation of splashes or aerosols, 
Furthermore, face protection (goggles, mask, face shield, or other splatter guards) is used for 
anticipated splashes or sprays to the face 
6. This is a sterile product for injection; therefore aseptic procedures should be followed at all 
times during the preparation of the required specific dose. 
7. Mouth pipetting is prohibited. Mechanical pipette devices must be used. 
8. A high degree of precaution should always be taken with any sharp items, including needles 
and syringes, slides, pipettes, capillary tubes, and scalpels.  Needles and syringes or other 
sharp instruments should be restricted in the pharmacy for use only when there is no 
alternative.  Plastic ware should be substituted for glassware whenever possible. 
a) Only needle-locking syringes or disposable syringe-needle units (i.e., needle is integral to 
the syringe) are used for injection or aspiration of infectious materials.  If avoidable, used 
disposable needles should not be bent, sheared, broken, recapped, removed from 
disposable syringes, or otherwise manipulated by hand before disposal; rather, they 
should be carefully placed in conveniently located puncture-resistant containers used for 
sharps disposal.  Non-disposable sharps should be placed in a hard-walled container for 
transport to a processing area for decontamination, preferably by autoclaving. 
b) Syringes that re-sheathe the needle, needle-less systems, and other safe devices should be 
used when appropriate. 
c) Broken glassware should not be handled directly by hand, but should be removed by 
mechanical means, such as a brush and dustpan, tongs, or forceps. 
 
Accidental Inoculation  
If an accidental inoculation (or blood spillage on broken skin) occurs: 

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1. The offending needle should be removed quickly. 
2. The wound should be soaked as soon as possible in a good skin disinfectant for at least 15 
minutes. 
3. All actions that could lead to a deeper penetration (rubbing, scrubbing, etc.) should be 
avoided. 
4. Apply a waterproof dressing. 
5. Such incidents should be reported officially in accordance with the standard institutional 
procedures. 
6. A blood sample should be taken and stored for possible future analysis. 
7. The wound site should be monitored and a follow-up clinical evaluation should be performed 
2 weeks after the incident. 
Any accidental blood spillages onto unbroken skin should be washed off with water into a 
suitable receptacle. The skin should then be washed with soap and water. An accident form 
should be filled out in accordance with institutional policy. 
 
Decontamination Procedures 
1. Gloves are worn when handling contaminated surfaces or equipment.  Gloves are disposed of 
when contaminated.  Disposable gloves are not washed or reused.  
2. Pharmacy equipment and work surfaces should be decontaminated with an appropriate 
disinfectant after work with these agents is finished and especially after overt spills, splashes, 
or other contamination.  Contaminated equipment should be decontaminated according to 
hospital regulations before it is sent for repair or maintenance or packaged for transport in 
accordance with applicable local or country regulations before removal from the facility. 
3. All stocks and other regulated wastes will be double-bagged in biohazard bags, marked with 
a biohazard label and sealed before removal for destruction in accordance with institutional 
regulations on biohazardous waste management.   
4. Materials to be decontaminated outside the pharmacy are to be placed in a durable, leak-
proof container, marked with a biohazard label and closed for transport from the pharmacy. 
5. All sharps (contaminated needles, sharp equipment, broken glass, etc.) should be placed in 
leak-proof, puncture-resistant sharps containers marked with a biohazard label.  When 
procedures are finished, the container should be sealed and put into a biohazard waste bag.  
The bag is then sealed, marked with a biohazard label, and sent for destruction in accordance 
with institutional regulations on biohazardous waste management. 
6. Routine daily cleaning procedures may be carried out as determined by hospital policy and 
local regulations. 
 
Decontamination of Spills 
Small Spills on Hard Surfaces 
Blood or bodily fluids spilled on hard surfaces should be wiped up immediately with paper 

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towels (while wearing gloves, eye protection, mask, and a gown), and the area washed with a 
virucidal disinfectant.  The material used in the clean-up procedure should be double-bagged in 
biohazard bags, sealed, marked with a biohazard label, and sent for destruction according to 
institutional regulations for biohazardous waste management.  
 
Small Spills in Safety Cabinet 
1. Close the cabinet sash and allow the ventilation system to operate for 20 to 30 minutes to 
remove any aerosolized material. 
2. Wearing eye protection and gloves, cover the spill with absorbent material and saturate with 
disinfectant. 
3. After 20 to 30 minutes of contact time, remove the absorbent and contained liquid. 
4. Clean the area with disinfectant. 
5. All material used in the clean-up should be double-bagged in biohazard bags, marked with a 
biohazard label, sealed, and sent for destruction according to institutional regulations for 
biohazardous waste management.  
Large Spills 
1. Evacuate the area.  Wait for 20 to 30 minutes prior to entry to allow aerosols to settle. 
2. Enter the area wearing full protective clothing, including eye protection and mask. 
3. Place absorbent material on liquid and saturate with disinfectant. 
4. Use mechanical means to pick up broken glassware or other sharps. 
5. After 20 to 30 minutes of contact time, remove the absorbent and contained liquid. 
6. Clean the area with disinfectant. 
All material used in the clean-up should be double-bagged in biohazard bags, marked with a 
biohazard label, sealed, and sent for destruction according to institutional regulations for 
biohazardous waste management. 
 
Transport, Reception and Handling of Biological Samples by Laboratory Staff 
It is recommended that all biological samples be handled and disposed of according to Biosafety 
Level 2 guidelines, unless local regulations require a more rigorous containment level.  Training 
and regular updating on the potential hazards associated with the work involved, the necessary 
precautions to prevent exposures, and the exposure evaluation procedures should be performed. 
An outline of Biosafety Level 2 precautions is given below: 
1. All specimens should be double-bagged and labeled with a biohazard label.  Request cards 
also appropriately labeled. 
2. Samples should be transported in a covered, leak-proof, autoclavable container, marked with 
a biohazard label. 
3. In the laboratory, samples should be stored separately in autoclavable or disposable racks. 

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4. The reception area in the laboratory should have disposable gloves, disinfectant, and 
absorbent material ready to deal with contamination. 
5. Gloves, eye protection, masks, and gowns should be worn when handling/transporting all 
biological samples, i.e., blood, urine, sputum and stools. 
6. All materials containing or having come into contact with samples are discarded in sack 
holders containing doubled biohazard waste bags.  These bags should be sealed, marked with 
a biohazard label, and sent for destruction according to institutional regulations for 
biohazardous waste management.  
7. Contaminated needles, sharp equipment, and broken glass are placed in leak-proof, puncture-
resistant sharps containers, which are closed securely, placed in biohazard bags, sealed, 
marked with a biohazard label, and sent for destruction according to institutional regulations 
for biohazardous waste management. 
 
Clinical Waste  
Universal Precautions should be observed when handling blood, urine, stool, and other bodily 
matter, unless local regulations require special procedures. An outline of Universal Precautions 
and Biosafety disposal guidelines is provided below: 
1. The disposable gowns, gloves, and masks worn by the staff should be discarded in a 
biohazard waste bag kept on a regular holder with a lid just inside the door.  When the holder 
is full, it should be sealed, marked with a biohazard label, and sent for destruction in 
accordance with institutional regulations on biohazardous waste management. 
2. If re-usable gowns are worn they should be disinfected and laundered according to hospital 
policy and local regulations for garments potentially contaminated with infectious agents. 
3. Sharps are a potential inoculation hazard; therefore extreme care should be taken in handling 
them.  A leak-proof, puncture-resistant container for disposing sharps should be kept beside 
the patient’s bed.  When half full it should be sealed and put into a biohazard waste bag.  The 
bag is then sealed, marked with a biohazard label and sent for destruction in accordance with 
institutional regulations on biohazardous waste management. 
4. Used linen, whether it is soiled or not, should be handled, transported, and laundered as 
determined by hospital policy and local regulations for linen with an infectious risk. 
5. Used dressings should be sealed securely in a plastic bag before disposal in a biohazard 
waste bag.  The biohazard bag is then sealed, marked with a biohazard label, and sent for 
destruction in accordance with institutional regulations on biohazardous waste management. 
 
Safety Guidelines for Clinical Study Patients and Caregivers 
• 
Avoid direct contact with body fluids of patients. 
• 
Immunocompromised individuals or pregnant women should not come into direct contact 
with body fluids of treated patients.  
 

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Safety Guidelines for Healthcare Staff when Handling OBP-301 
• 
Immunocompromised individuals or pregnant women should not prepare or administer OBP-
301 and should not come into direct contact with OBP-301 injection sites, dressings, or body 
fluids of treated patients.  
• 
Staff must follow Biosafety Level 2 guidelines by avoiding accidental exposure to OBP-301 
and follow the instructions for preparation, administration, and handling of OBP-301. 
• 
Staff must wear personal protective equipment (protective gown or laboratory coat, safety 
glasses or face shield, and gloves) while preparing or administering OBP-301. 
• 
Cover any exposed wounds before handling OBP-301. 
• 
In the event of an accidental occupational exposure (e.g., through a splash to the eyes or 
mucous membranes), flush with clean water for at least 15 minutes. 
• 
In the event of exposure to broken skin or needle stick, clean the affected area thoroughly 
with soap and water and/or a disinfectant.  
• 
Clean all surfaces that may have come in contact with OBP-301 and treat all spills with a 
virucidal agent such as 1% sodium hypochlorite or 70% isopropyl alcohol and blot using 
absorbent materials.  
• 
Dispose of all materials that may have come in contact with OBP-301 (e.g., vial, syringe, 
needle, cotton gauze, gloves, masks, or dressings) as biohazardous waste. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IV: Guidelines for Use and Completion of Clinical Trial Material (Drug) 
Destruction Certificate (11-JAN-2022) 
 
GENERAL 
After expenditure of each vial of OBP-301, the site must dispose of or destroy the vial in 
accordance with the existing disposal practices employed for biohazardous waste at your 
institution.  If unused clinical trial material expires or will not be used in this study, please contact 
the drug distributor, Catalent, for instructions on accountability and subsequent destruction (see 
Catalent contact information on the Clinical Trial Material Destruction Certificate on the NRG 
website). This form is for documentation of the destruction of unused vials. 
 
HEADER 
Protocol number: Enter the number of the study  
Clinical Trial Material: Enter the name of the study product OBP-301 (OBP-301) 
Principal Investigator: Enter the name of the Principal Investigator (PI). 
Site Number: Enter the number of the clinical site supplied by Sponsor. 
Site Name: Enter the name of Institution/Hospital and country 
 
TABLE 
Date of destruction: Enter the date that the vials were destroyed, in DD/MMM/YYYY format as 
shown: 10/Jun/2020. 
Lot Number:  Enter the lot number indicated on the OBP-301 label.   
Vial Status: Tick “Empty/Partially Used” and/or “Unopened”  
Number of Vials Destroyed:  Enter the number of the vials destroyed on the date given. 
Reason for Destruction: Tick one box only.  If destruction was requested or authorized by Sponsor, 
please attach the appropriate documentation.  If for another reason, please specify in the space 
provided.   
Initials of Person Destroying Material: Enter the name of the person responsible for destruction of 
the material.  This may be the PI or other personnel as designated by the Investigator. 
 
BOTTOM 
Name of Investigator or Designee: Please print.   
Signature of Investigator or Designee/date: Once a form is completed, please sign and date in 

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DD/MMM/YYYY format.   
 
 
 

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APPENDIX V: CARBOPLATIN DOSE CALCULATION INSTRUCTIONS (07-DEC-
2020) 
 
1) The Cockcroft-Gault formula will be used in NRG Oncology trials. 
 
Dosing of Carboplatin: 
1)  The carboplatin dose will be calculated to reach a target area under the curve (AUC) 
according to the Calvert formula using creatinine clearance (mL/min) from the Cockcroft-Gault 
formula. 
 
2)   In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dL.   
 
3)  The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity 
greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring 
dose modification, the dose of carboplatin will not need to be recalculated for subsequent cycles, 
but will be subject to dose modification for toxicity as noted in the protocol. 
 
4)  Carboplatin doses are required to be recalculated if the patient has a weight change of greater 
than or equal to 10%. Patients are permitted to have chemotherapy doses recalculated for < 10% 
weight changes. 
 
5)  At the time of dose modification, if the patient’s age had changed (the patient has had a 
birthday), the site can use the current age. 
 
CALVERT FORMULA: 
Carboplatin dose (mg) = target AUC x (GFR [or estimated CrCl] + 25) 
 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
 
The maximum allowed doses of carboplatin are: 
AUC 2 = 300 mg 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (mL/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
 
Creatinine Clearance (mL/min) =    [140-Age (years)] x actual body Weight* (kg)   {x 0.85 if female}  
                                                                
72 x serum creatinine (mg/dl)  
Notes: 
1) Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient.  
 
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25. 
 

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c. Adjusted weight should be used for estimation of GFR for patients with BMI of greater 
than or equal to 25  
 
d. Adjusted weight calculation: 
Ideal weight (kg) = ((Height (cm)/2.54) – 60) x 2.3) (+ 45.5 females) or (+ 50 for men)  
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
At the time of a dose modification for toxicity: 
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the time 
of a dose modification is higher than the creatinine used to calculate the previous dose, use 
the current (higher) creatinine. This will ensure that the patient is actually receiving a dose 
reduction. 
 
 
 
 
 

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APPENDIX VI: CORRELATIVE IMMUNE ASSSAYS 
 
Tumor and blood will be collected for the following correlative immune analyses:  
 
1. Immunoflourescence: 
Immunofluorescence (IF) is an emerging tissue-based methodology that allows for a single 
slide to be stained with multiple different antibodies conjugated to different fluorochromes. 
This permits for simultaneous semi-quantitative and qualitative characterization of multiple 
markers on one slide. Markers that will be analyzed include immune cell surface markers 
(CD3, CD4, CD8, FoxP3, CD68), pan-cytokeratin (for tumor cells) and Adhexon (for 
persistence of viral infection). Immunofluorescence will be performed in the laboratory of 
Dr. Prasad Adusumilli, MD at Memorial Sloan Kettering Cancer Center (MSKCC). 
 
2. Mulitparameter Flow Cytometry 
Multiparameter flow cytometry will be used to characterize the peripheral blood 
mononuclear cell phenotype at various time-points. Based on the time-intensive nature of 
these analyses, they may be restricted to patients with extreme outlier responses, e.g. 
complete vs. minimal pathologic response. The panel will include CD3, CD4, CD8, FoxP3, 
Ki67, ICOS, PD-1, LAG-3, TIM-3 and CTLA-4. Analyses will be performed in the Immune 
Monitoring Facility (IMF) at MSKCC. 
 
3. Cytokine Profiles: 
Cytokine profiles provide information about the status of immune activation and whether 
there is predominance of a Th1 or Th2 response. Th1 responses are associated with 
cytotoxic T cell responses and effective anti-tumor immunity, while Th2 responses are 
regarded as being anti-inflammatory and counteract Th1 responses. Cytokines can be 
measured using multiplexed ELISA kits, which can detect IL-1β, -2, -4, -6, -8, -10, -12p70, 
IL-13, tumor necrosis factor-α, interferon (IFN)-γ and others. Analyses will be performed in 
the IMF at MSKCC.