Phase I Trial of Radiotherapy Combined With Durvalumab Alone Plus Either Monalizumab or Oleclumab in PD-L1 High Locally Advanced Non-Small Cell Lung Cancer (NSCLC) (ARCHON-1)
Phase: PHASE1
Conditions: Locally Advanced Lung Non-Small Cell Carcinoma, Locally Recurrent Lung Non-Small Cell Carcinoma, Stage II Lung Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Unresectable Lung Non-Small Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

NRG-LU004 
1                        Version Date:  November 3, 2021 
NRG ONCOLOGY  
NRG-LU004 
(ClinicalTrials.gov NCT #03801902) (23-JAN-2019) 
 
Phase I Trial of Accelerated or Conventionally Fractionated Radiotherapy Combined With 
MEDI4736 (durvalumab) in PD-L1 High Locally Advanced Non-Small Cell Lung Cancer 
(NSCLC) (ARCHON-1)  
 
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 (03-AUG-2020) 
Principal Investigator/Radiation Oncology 
Steven H. Lin, MD PhD 
The Univ of Texas MD Anderson Cancer Ctr 
1515 Holcombe Blvd., Unit 097 
Houston, Texas 77030 
713-563-8490/Fax: 713-563-2366 
shlin@mdanderson.org 
Medical Oncology Co-Chair 
Anne Tsao, MD 
The Univ of Texas M.D. Anderson Cancer Ctr 
1515 Holcombe Blvd. Unit 432 
Houston, TX 77030 
713-792-6363/Fax: 713-792-1220 
astsao@mdanderson.org 
 
 
Medical Oncology Co-Chair 
Martin Edelman, MD, FACP 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
215-728-5682/Fax: 215-728-5336 
Martin.Edelman@fccc.edu 
Medical Physics Co-Chair 
Anthony Doemer, MS, DABR 
Henry Ford Cancer Institute 
2799 W. Grand Blvd. 
Detroit, MI 48202 
313-916-0234/Fax: 313-916-3264   
adoemer1@hfhs.org 
 
 
Translational Co-Chair 
Charles B. Simone, II, MD 
Department of Radiation Oncology 
New York Proton Center 
225 East 126th Street 
New York, NY 10035 
646-968-9012 
csimone@nyproton.com 
Senior Statistician 
Stephanie Pugh, PhD 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0850/Fax: 215-928-0153 
pughs@nrgoncology.org 

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NRG ONCOLOGY  
NRG-LU004 
 
NRG Oncology Contact Information (03-NOV-2021) 
Data Management 
For questions concerning eligibility or 
data submission 
Matthew Novak, MS 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
412-965-2917 
NovakM@NRGOncology.org 
 
Tammy BausingerNRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA  19102 
215-574-3223BausingerT@NRGOncology.org 
RTQA 
For questions concerning RT data 
submission 
 
Jennifer Presley, B.S., R.T.(R)(M)(T) 
IROC Philadelphia – RT QA Center 
ACR Center for Research and Innovation 
50 South 16th Street, Suite 2800 
Philadelphia, PA  19102 
215-574-3153 
jpresley@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 
Fran Bradley 
NRG Oncology  
50 South 16th Street, Suite 2800  
Philadelphia, PA 19102 
215-940-8893/Fax: 215-928-0153 
BradleyF@NRGOncology.org 
Lung Cancer Committee Chair 
Jeffrey D. Bradley, MD  
Emory University School of Medicine 
Department of Radiation Oncology 
1364 Clifton Rd., NE, Ste. A1320 
Atlanta, GA 30322 
jeffrey.d.bradley@emory.edu 
 
 
 
 
 
NRG ONCOLOGY  
NRG-LU004 

NRG-LU004 
3                        Version Date:  November 3, 2021 
 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
MEDI4736 
(durvalumab) 
NCI/PMB 
778709 
 
DCTD 
 
 
Participating Sites 
 U.S. 
 Canada  
 Approved International Member Sites 
 
 
 
Document History 
 
Version Date 
Amendment 5 
November 3, 2021 
Amendment 4 
January 13, 2021 
Amendment 3 
August 3, 2020 
Amendment 2 
November 25, 2019 
Amendment 1 
January 23, 2019 
Initial 
December 4, 2018 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NRG ONCOLOGY 
NRG-LU004 (03-AUG-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. 

NRG-LU004 
4                        Version Date:  November 3, 2021 
 
CTSU CONTACT INFORMATION 
 
For regulatory 
requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
 
(Sign in at www.ctsu.org, 
and select the 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 for 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 CIRB supporting documents must be 
downloaded from the protocol-specific page located on the CTSU members’ website 
(https://www.ctsu.org). Access to the CTSU members’ website is managed through the Cancer 
Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration 
system and requires log-in with a CTEP-IAM username and password.  
 
Permission to view and download NRG-LU004 supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
 
Additional study related documents can be found on the protocol specific page of the NRG 
website. 
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI 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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NRG ONCOLOGY 
NRG-LU004 
 
TABLE OF CONTENTS 
1.0       OBJECTIVES ......................................................................................................................8 
1.1       Primary Objective ....................................................................................................8 
1.2       Secondary Objectives...............................................................................................8 
1.3       Exploratory Objectives ............................................................................................8 
2.0       BACKGROUND .................................................................................................................8 
2.1       Current Management Approach and Rationale for Study  .......................................8 
2.2       Clinical pharmacokinetics (PK) .............................................................................10 
3.0 
PATIENT ELIGIBILITY AND INELIGIBILITY CRITERIA ........................................18 
3.1 
Eligibility Criteria  .................................................................................................19 
3.2 
Ineligibility Criteria ...............................................................................................20 
4.0       REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........23 
5.         TREATMENT PLAN/REGIMEN DESCRIPTION..........................................................26 
5.1 
MEDI4736 (durvalumab).......................................................................................26 
5.2 
Radiation Therapy  .................................................................................................27 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................36 
5.4 
Duration of Therapy ...............................................................................................37 
6.  TREATMENT MODIFICATIONS/MANAGEMENT ............................................................38 
6.1      Toxicity Management Guidelines for Radiation-Related Immune-
Mediated, Infusion-Related, and Non-Immune Mediated Reactions for 
MEDI4736 (durvalumab).......................................................................................38 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................57 
7.1       Protocol Agents ......................................................................................................57 
7.2       Adverse Events and Serious Adverse Events ........................................................57 
7.3       Comprehensive Adverse Events and Potential Risks list (CAEPR) ......................57 
7.4       Expedited Reporting of Adverse Events  ...............................................................63 
            7.5       Pregnancy ...............................................................................................................65 
8.        REGISTRATION AND STUDY ENTRY PROCEDURES  .............................................65 
           8.1       Cancer Trials Support Unit Registration Procedures  .............................................67 
           8.2       RT-Specific Pre-Registration Requirements ...........................................................69 
           8.3       Digital RT Data Submission to NRG Using TRIAD  .............................................70 
           8.4       Patient Enrollment  .................................................................................................71 
9.0 
DRUG INFORMATION ...................................................................................................72 
9.1 
Investigational Study Agent – MEDI4736 (durvalumab)  .....................................72 
 

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10.       PATHOLOGY/BIOSPECIMENS .....................................................................................74 
10.1    Central Pathology Review ......................................................................................74 
10.2    Biospecimen Selection for Integral Biomarker Testing ..........................................74 
10.3    Biospecimen Selection for Integrated Biomarker Testing ......................................74    
10.4    Biospecimen Selection for Exploratory Biomarker Testing  ..................................75 
10.5    Mandatory Biospecimen Submissions  ...................................................................77 
10.6    Optional Specimen Submission  .............................................................................79 
11.      SPECIAL STUDIES (NON-TISSUE) ................................................................................80 
12.      MODALITY REVIEWS ....................................................................................................80 
12.1    Radiation Therapy Quality Assurance Reviews  ....................................................80 
12.2    Medical Oncology Modality Quality Assurance Reviews ......................................80 
13.      DATA AND RECORDS ....................................................................................................80 
13.1    Data Management/Collection  ................................................................................80 
13.2    Rave-CTEP-AERS Integration ...............................................................................81 
13.3    Data Quality Portal  ................................................................................................82 
13.4    Summary of Data Submission  ...............................................................................83 
14. 
STATISTICAL CONSIDERATIONS...............................................................................84 
14.1 
Study Design ..........................................................................................................84 
14.2 
Study Endpoints .....................................................................................................84 
14.3 
Primary Objectives Study Design ..........................................................................84 
14.4 
Study Monitoring of Primary Objectives ...............................................................85 
14.5 
Accrual/Study Duration Considerations ................................................................86 
14.6     Secondary Endpoints .............................................................................................86 
APPENDIX I:  RECIST CRITERIA .............................................................................................92 
APPENDIX II:  AJCC STAGING SYSTEM ................................................................................93 
APPENDIX III:  CTEP COLLABORATIVE AGREEMENTS LANGUAGE ............................95 
APPENDIX IV:  FORMULA TO ESTIMATE RENAL FUNCTION .........................................97 
APPENDIX V:  CLINICAL BLOOD SAMPLE SHIPMENT PREPARATION AND 
TRANSPORTATION FOR TELOMESCAN  ..................................................................99 
APPENDIX VI:  NRG BIOSPECIMEN BANK – SAN FRANCISCO ......................................105 
BIOSPECIMEN PROCEDURES  ...............................................................................................105 
APPENDIX VII:  NRG BIOSPECIMEN BANK-COLUMBUS ................................................109 
APPENDIX VIII:  CIMAC BIOMARKER TESTING  ..............................................................114 

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NRG-LU004 
SCHEMA (13-JAN-2021) 
 
 
Registration:  Institution-determined PD-L1 expression using Dako 22C3 IHC antibody 
platform or the Ventana SP263 assay.  The first 6 patients with PD-L1 expression of ≥50% will 
be registered to Cohort 1 and the following 6 patients with PD-L1 expression of ≥50% will be 
registered to Cohort 2. 
 
 
LEAD-IN SCHEMA (Initial Safety Schedules)  
 
Cohort 1, n=6 
MEDI4736 (durvalumab)†q4 weeks  (+/- 7 days) x 13 doses 
+ ACRT 60 Gy in 15 fractions x 3 weeks (weeks 1-3) 
 
Cohort 2, n=6 
MEDI4736 (durvalumab)† q4 weeks  (+/- 7 days) x 13 doses 
+ standard RT 60 Gy in 30 fractions x 6 weeks (weeks 1-6) 
† MEDI4736 (durvalumab) begins 2 weeks (Day -14) before RT (+/- 48 hours); see Section 5.1 
for dosing details 
 
EXPANSION COHORTS 
 
After completing one of the Initial Safety Schedules of concurrent RT+MEDI4736 
(durvalumab): 
• If Cohort 1 only is deemed safe, all patients will be registered to Cohort 3. 
• If Cohort 2 only is deemed safe, all patients will be registered to Cohort 4. 
• If both Cohorts 1 and 2 are deemed safe, patients will be randomized to either 
Cohort 3 or Cohort 4 with 1:1 randomization.   
 
 
RANDOMIZE 
 
 
Cohort 3, n=6 
 
MEDI4736 (durvalumab)†q4 weeks  (+/- 7 
days) x 13 doses  
+ ACRT 60 Gy in 15 fractions x 3 weeks 
(weeks 1-3) 
Cohort 4, n=6 
 
MEDI4736 (durvalumab)† q4 weeks (+/- 7 
days) x 13 doses 
+ standard RT 60 Gy in 30 fractions 
x 6 weeks (weeks 1-6) 
† MEDI4736 (durvalumab) begins 2 weeks (Day -14) before RT (+/- 48 hours); see Section 5.1 
for dosing details 

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8                        Version Date:  November 3, 2021 
1.0       OBJECTIVES 
1.1       Primary Objective  
1.1.1 To evaluate if the addition of MEDI4736 (durvalumab) to two schedules of radiation 
therapies (60 Gy in 30 fractions or 60 Gy in 15 fractions) is safe. 
 
1.2       Secondary Objectives 
1.2.1    To examine if the addition of MEDI4736 (durvalumab) to radiation therapy is feasible. 
1.2.2    To assess toxicities associated with the addition of MEDI4736 (durvalumab) to radiation 
therapy. 
1.2.3    To obtain preliminary estimates of progression-free survival (PFS), using RECIST 
guidelines, in patients who received MEDI4736 (durvalumab) added to radiation. 
Although the clinical benefit of MEDI4736 (durvalumab) in combination with 
radiotherapy has not yet been established, the intent of offering this treatment is to 
provide a possible therapeutic benefit, and thus the patient will be carefully monitored for 
tumor response.  
 
1.3       Exploratory Objectives 
1.3.1    To assess the impact the addition of MEDI4736 (durvalumab) has on progression-free 
survival, using irRC guidelines. 
1.3.2   To assess the changes in circulating tumor cells (CTCs) and various immune parameters 
during treatment with durvalumab and radiotherapy and changes after completion of 
treatment. 
 
2.0       BACKGROUND  
2.1       Current Management Approach and Rationale for Study (13-JAN-2021) 
Initially, the FDA approved the use of frontline pembrolizumab instead of chemotherapy 
in unresectable metastatic NSCLC patients with high PD-L1 IHC expression (defined as 
a Tumor Proportion Score (TPS) ≥ 50% using either the Dako 22C3 antibody or the 
Ventana SP263 antibody platforms) [Reck 2017] based on KEYNOTE-024, which 
demonstrated an improvement in median PFS (10.3 vs 6 months, p<0.01), and improved 
6-month overall survival (OS) (hazard ratio (HR) 0.6=0.005).  The updated survival 
results reported at the International Association for the Study of Lung Cancer (IASLC) 
2017 meeting demonstrated a HR of 0.63 [95% confidence interval (CI)], 0.47-0.86; P = 
.002) favoring pembrolizumab.  The median OS was 30.2 months for pembrolizumab 
compared to 14.2 months with chemotherapy.  It should be noted that these OS results 
held up in spite of significant cross-over in the second-line setting to checkpoint 
inhibitors in the patients who received chemotherapy.  Additionally, the overall response 
rate (ORR) was improved with pembrolizumab (44.8% vs 27.8%) with an increase in 
duration of response (not reached (NR) vs 6.3 months).  Quality of Life (QOL) analysis 
favored the pembrolizumab arm.  In this population of patients, PD-1/PD-L1 inhibitors 
are superior to systemic chemotherapy in metastatic NSCLC.   
 
The standard of care for local-regionally advanced NSCLC is concurrent chemoradiation.  
However, 5-year survival rates still hover around 20-25% for stage III NSCLC.  
Additional advances in treatment options are needed.  The results of the PACIFIC trial, a 

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phase III trial which adds consolidation MEDI4736 (durvalumab) to standard 
chemoradiation, demonstrated significant improvement in progression free survival (PFS) 
by 11 months (Antonia 2017).  There was not only a significantly longer time to distant 
metastatic disease or death (median 23.2 months vs. 14.6 months, HR 0.52 [(95% CI, 
0.39-0.69)] but there was also a significantly greater overall response rate [(28.4% vs 
16%, HR 1.78 (1.27-2.51)] and median duration of response [not reached vs. 13.8 
months, HR 0.43 (0.22-0.84)] in the primary disease after chemoradiation.  This suggests 
that immunotherapy alone can exert effects that can maintain local control of disease.  
This is seen even in patients without selection for PD-L1.  It is expected that the 
PACIFIC regimen will be a new standard of care for unresectable locally advanced 
NSCLC.  However, there is significant toxicity of concurrent chemoradiotherapy, which 
can significantly impact the patient’s quality of life and survival, especially in elderly 
patients (Stinchcombe 2017).  Since the median age of NSCLC is 70 years old, much 
work is needed for an effective and less toxic treatment regimen for patients.   
 
Conventional radiotherapy (RT) dose regimen of 60 Gy in 30 fractions is the current 
standard dosing (Perez 1980, Bradley 2015).  Accelerated hypofractionated RT (ACRT) 
increases the biologic equivalent dose and thereby improve disease control. There has 
been abundant clinical experience using ACRT without concurrent chemotherapy to 
achieve excellent local control for both early and locally advanced disease (Cheung et al, 
2014).  ACRT can also synergize with immunotherapy in many preclinical models, 
showing anti-PD-L1 antibody enhanced the efficacy of radiation through a CD8 T cell 
dependent mechanism (Deng, Weichselbaum 2014, Deng, Beckett 2014).  The anti-tumor 
effect was seen both locally in the primary tumor, and also contralateral, non-irradiated 
tumor, supporting the role of radiation inducing an immunologic “distant”, or abscopal, 
anti-tumor effect.  Even more important is the demonstration that it was the concomitant 
administration, and not the sequential administration, of anti-PD-L1 with radiation, that 
improved tumor control and survival in the mice (Dovedi et al, 2014).  
 
It is for these reasons that we believe that the systemic effects and local control effects of 
checkpoint inhibitors will even be greater in patients with high expression of PD-L1, as 
demonstrated in Keynote 024.  This is the primary rationale why we are selecting patients 
with PD-L1 high expressing tumors to replace concurrent chemotherapy for 
immunotherapy in combination with radiotherapy in our trial.  This benefit shouldn’t be 
confined to only the patients who are not eligible for chemotherapy, but all patients who 
are eligible for chemotherapy will likely benefit more from immunotherapy.   
 
However, ACRT with systemic therapy may cause concerning side effects that will be 
greater than just ACRT alone.  While this is not known if such side effects will be 
increased with immunotherapies, there is experience with platinum-based doublet 
chemotherapy that may raise similar concerns.  CALGB 31102 (Alliance) was a phase I 
study to escalate the dose per fraction while keeping the total dose at 60 Gy in order to 
define the maximally tolerated course of accelerated radiation therapy with concurrent 
chemotherapy.  With 21 evaluable patients, only modest hypofractionation was achieved, 
with the MTD defined in cohort 2 at 60 Gy in 2.5 Gy/fraction, with 2 patients in cohort 2 
sustained grade 5 toxicities (hemoptysis, pneumonitis)(Urbanic et al., 2018).  While the 

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current trial does not combine chemotherapy, which is known as a radiation sensitizer, 
there are potential hazards of combining with immunotherapy that will require very close 
monitoring of the potential additive or synergistic toxicities.  We are conducting the 
current study taking those safety concerns into consideration.   
 
 
MEDI4736 (durvalumab)  
 
Mechanism of action 
MEDI4736 (durvalumab) is a human monoclonal antibody (mAb) of the immunoglobulin 
(Ig) G (IgG) 1 kappa subclass that blocks the interaction of programmed cell death ligand 
(PD-L) 1 (but not PD-L2) with PD-1 on T cells and cluster of differentiation (CD) 80 
(B7.1) on immune cells (IC). It is being developed by AstraZeneca/MedImmune for use 
in the treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document.).  
MEDI4736 (durvalumab) has been engineered to reduce antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity.  In vitro studies demonstrate that 
MEDI4736 (durvalumab) antagonizes the inhibitory effect of PD-L1 on primary human T 
cells, resulting in their restored proliferation and release of interferon gamma (IFNγ) 
(Stewart et al, 2015).  
2.2       Clinical pharmacokinetics (PK) 
As of October 24, 2016, PK data from study CD-ON-MEDI4736-1108 were available for 
993 patients following treatment with MEDI4736 (durvalumab) at 0.1 to 10 mg/kg every 
two weeks (Q2W) and 15 mg/kg every three weeks (Q3W) (dose-escalation), 10 mg/kg 
Q2W (dose-expansion), and 20 mg/kg every four weeks (Q4W) (dose-exploration), 
administered as an intravenous (IV) infusion over 60 minutes.  The maximum plasma 
concentration (Cmax) increased in an approximately dose-proportional manner over the 
dose range examined.  The area under the concentration-time curve from 0 to 14 days 
(AUC0-14) increased dose-proportionally at doses of 3 to 20 mg/kg and more than dose-
proportionally at doses of <3 mg/kg, likely due to saturable target-mediated clearance 
(CL).  The steady state was achieved at approximately Week 16.  Accumulation of 
MEDI4736 (durvalumab) was observed following repeated dosing.  Mean accumulation 
ratio (AR) ranged from 0.64 to 1.87 and 3.16 to 4.93 for Cmax and (trough plasma 
concentration (Ctrough), respectively.  Near complete target saturation (sPD-L1 and 
membrane bound) is expected with MEDI4736 (durvalumab) ≥3 mg/kg Q2W. 
 
Clinical safety summary 
As of July 12, 2017, MEDI4736 (durvalumab) 10 mg/kg Q2W has been given to more 
than 1800 patients from three MEDI4736 (durvalumab) monotherapy studies (CD-ON-
MEDI4736-1108, ATLANTIC and PACIFIC).  The majority of treatment-related AEs 
were manageable with dose delays, symptomatic treatment, and in the case of events 
suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity (see the Dosing Modification and Toxicity Management 
Guidelines in Section 6).  However, life-threatening and fatal events have been reported.   
 

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Adverse events (AEs) that were considered by the investigator as related to MEDI4736 
(durvalumab) in ≥5% of patients were fatigue (15.8%), diarrhea (8.1%), hypothyroidism 
(8.0%), nausea (7.2%), pruritus (6.9%), decreased appetite (6.4%), and rash (6.4%).  AEs 
of Grade 3 or higher considered related to MEDI4736 (durvalumab) were reported in 201 
patients (10.6%): 177 patients (9.4%) had events of Grade 3, 13 patients (0.7%) had 
events of Grade 4, and 11 patients (0.6%) had Grade 5 (fatal) events.  The only Grade 5 
event considered related to MEDI4736 (durvalumab) occurring in ≥2 patients was 
pneumonitis (5 patients [0.3%]).  A total of 108 patients (5.7%) had serious AEs (SAEs) 
that were considered by the investigator as related to MEDI4736 (durvalumab).   
 
AEs of special interest (AESI) 
The AESIs reported in AstraZeneca or MedImmune-sponsored MEDI4736 (durvalumab) 
studies are defined as AEs that include, but are not limited to, events with a potential 
inflammatory or immune-mediated mechanism that may require more frequent 
monitoring and/or interventions such as corticosteroids, immunosuppressants, and/or 
endocrine therapy.   
 
Early recognition of signs and symptoms potentially related to an inflammatory or 
immune-mediated mechanism is important for proper management of toxicities.  For 
guidance on identifying, evaluating, and treating AESIs/imAEs, see the Toxicity 
Management Guidelines.  
 
AESI/imAEs observed with anti PD-L1/PD-1 agents such as MEDI4736 (durvalumab) 
include pneumonitis, hepatitis, diarrhea/colitis and intestinal perforation, 
endocrinopathies (hypo- and hyper-thyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, rash/dermatitis, 
pancreatitis, myocarditis, myositis/polymyositis and rare/less frequent imAEs including 
neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. 
 
Other inflammatory responses that are rare with a potential immune-mediated etiology 
include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events involving 
the eye, skin, hematological and rheumatological events.  It is possible that events with 
an inflammatory or immune mediated mechanism could occur in nearly all organs. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs. 
 
The summary information for the AESIs below, unless stated otherwise, are based on the 
DCO of July 12, 2017. 
 
Pneumonitis 
Across the MEDI4736 (durvalumab) monotherapy pooled dataset pneumonitis events 
observed (pneumonitis, interstitial lung disease (ILD), acute interstitial pneumonitis and 
pulmonary fibrosis) were reported at a frequency rate of Common (98/1889; 5.2%).  
Most were Grade 1 or 2 in severity and most were reported as PT pneumonitis (88 
patients [4.7%]).  CTC Grade 3 pneumonitis (PT) was reported in 15 patients (0.8%); 

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CTC Grade 4 in 1 patient (<0.1%) and CTC Grade 5 pneumonitis in 5 patients (0.3%).  
CTC Grade 3 ILD (PT) has been reported from studies outside of the pooled dataset.  
There were no CTC Grade 4 or 5 events of ILD. 
 
Presentations of pneumonitis can range from asymptomatic lung infiltrates to those that 
mimic severe bacterial pneumonia (Teply and Lipson 2014).  Early consideration of 
pneumonitis should be realized when patients present with new onset or worsening of 
respiratory symptoms such as dyspnea or cough.  Prompt treatment with steroids is 
important as per current established Toxicity Management Guidelines. 
 
Hepatitis 
Immune-mediated hepatitis/hepatic toxicity is the inflammation of the liver.  Hepatic AEs 
induced by PD-1/PD-L1 inhibitors commonly present as asymptomatic increase of 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT), rarely total 
bilirubin.  A proportion of patients may be presenting with fatigue, fever and radiologic 
appearances including hepatomegaly, periportal lymphadenopathy and periportal edema 
(Zhang et al, 2016). 
 
As a grouped term, selected hepatic events including laboratory abnormalities were 
reportedly 12.0% (227 patients) across 1889 patients who have received MEDI4736 
(durvalumab) monotherapy 10 mg/kg Q2W.  Hepatitis events (autoimmune hepatitis, 
hepatitis toxic, hepatocellular injury, hepatotoxicity and hepatitis) were reported at a 
frequency rate of Uncommon (14 patients; 0.7%).  Seven of the 14 events of hepatitis 
were Grade 3.  There were no Grade 4 events with the exception of hepatitis acute (1 
patient) reported outside of the pooled dataset.  One patient experienced a CTC Grade 5 
event of autoimmune hepatitis.  Other AESIs such as hepatic failure (5 patients), jaundice 
(5 patients), hyperbilirubinemia (15 patients) and laboratory abnormality AESIs have 
been observed, 3 of which were CTC Grade 5 (hepatic failure, hyperbilirubinemia and 
transaminases increased).   
 
Monitoring liver function tests while receiving study medication is important as hepatitis 
often manifests as asymptomatic elevated levels of hepatic transaminases (ALT, AST, 
bilirubin; Kim et al, 2013).  Prompt treatment with steroids is important as per current 
established Toxicity Management Guidelines. 
 
Colitis 
Diarrhea is the most frequent AESI reported across the Phase I to Phase III clinical 
studies with MEDI4736 (durvalumab) monotherapy with a frequency of Very common 
(329/1889; 17.4%) in patients receiving 10 mg/kg MEDI4736 (durvalumab) IV Q2W.  
Most of these were Grade 1.  Treatment-emergent colitis-type AESIs were reported at a 
frequency of Common (21 of 1889 patients; 1.1%).  Most were Grade 2 or 3.  CTC Grade 
4 colitis was reported in 1 patient (rare; <0.1%). 
 
Patients should be monitored for signs and symptoms of colitis or diarrhea.  Investigators 
are instructed to begin diarrhea management early to minimize the risk of colitis (please 
refer to the Toxicity Management Guidelines).  Early initiation of diarrhea treatment 

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guidelines has been shown to reduce bowel perforation and colectomy rates, drug-related 
diarrhea, and serious gastrointestinal imAEs by up to 50% in patients treated with 
ipilimumab (Tarhini 2013). 
 
Intestinal perforation 
Full thickness injury of the bowel wall and subsequent perforation of the gastrointestinal 
tract can be due to a variety of etiologies, commonly instrumentation, surgery, bowel 
injury, bowel obstruction, neoplasms (particularly colon carcinoma) and concomitant 
medications such as prolonged use of non-steroidal inflammatory drugs (NSAIDs).  
Spontaneous perforation can be related to inflammatory changes or tissues weakened by 
medications or connective tissue disorders (Cahalane 2016).   
 
Across the MEDI4736 (durvalumab) monotherapy pool of studies, intestinal perforation 
was reported at a frequency rate of Uncommon (2/1889; 0.1%); Grades 2 and 4.  There 
were no Grade 5 events. 
 
Monitor for symptoms that may be related to bowel perforation such as sepsis, peritoneal 
signs, and ileus (refer to the Toxicity Management Guidelines for diarrhea/colitis).  
Investigators should adhere to the overall management for immune-mediated toxicities 
by performing a thorough evaluation to rule out alternative etiologies and by initiating 
prompt treatment including steroids. 
 
Endocrinopathies 
Immune-mediated endocrinopathy is the inflammation of any organ in the hypothalamic-
pituitary-adrenal axis, but is most typically reported to affect the pituitary, thyroid and/or 
adrenal glands, leading to hypophysitis/hypopituitarism, thyroid dysfunction, and/or 
adrenal insufficiency (Teply and Lipson 2014).  The clinical presentation of immune-
mediated endocrinopathies most often include hypothyroidism, hyperthyroidism, and 
nonspecific symptoms of headache and fatigue, but may also include myalgias, visual 
field defects, behavioral changes, electrolyte disturbances, loss of appetite and 
hypotension (Tarhini 2013).  Patients with endocrinopathies may present with abnormal 
endocrine laboratory test results including thyroid-stimulating hormone (TSH), free T4, 
total and free T3, cortisol, adrenocorticotrophic hormone, luteinizing hormone, follicle-
stimulating hormone, and testosterone. 
 
Frequencies for immune-mediated endocrinopathy, as grouped terms of AESIs including 
laboratory abnormality AEs, are indicated in the table below. 
 
Endocrinopathy AESIs 
 
Endocrinopathy 
MEDI4736 (durvalumab) 
monotherapy 
(10 mg/kg Q2W) 
(N=1889) 
MEDI4736 (durvalumab) + 
tremelimumab 
(20 mg/kg Q4W and 1 
mg/kg) 
(N=1088) 
Hypothyroidism a 
Very common 206 (10.9%) 
Very common 137 (12.6%) 

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Hyperthyroidism a 
Common 135 (7.1%) 
Common 78 (7.2%) 
Adrenal insufficiency a 
Uncommon 13 (0.7%) 
Common 21 (1.9%) 
Hypophysitis/Hypopituitarism 
a 
Rare 1 (<0.1%) 
Uncommon 24 (0.4%) 
Type 1 diabetes mellitus 
Rare 1 (<0.1%) 
0 (0.0%) 
aGrouped term based on a number of individual MedDRA PTs. 
AESI adverse event of special interest; MedDRA Medical Dictionary for Regulatory Activities; 
N total number of patients; PT preferred term; Q2W every 2 weeks; Q4W every 4 weeks. 
 
Most endocrinopathy events reported were Grade 1 or 2.  In the monotherapy pool, Grade 
3 events consisted of adrenal insufficiency (2 patients), hypophysitis/hypopituitarism (1 
patient), hyperthyroidism (1 patient) and hypothyroidism (2 patients).  There were no 
CTC Grade 4 or 5 events.  In the combination, AESIs for hypothyroidism and 
hyperthyroidism (including laboratory abnormalities) were the most frequently observed 
events with frequency rates of Very common (12.6%) and Common (7.2%), respectively.  
The severity of these events are predominantly Grades 1 and 2 with Grade 3 events 
observed with hyperthyroidism only (0.5%).  Adrenal insufficiency was reported as 
mostly Grades 2/3 with 1 Grade 4 event and no Grade 5 events.  Hypophysitis or 
hypopituitarism was reported as mostly Grade 3 with no Grade 4 or 5 events. 
 
Across the monotherapy pool of studies, 1 patient (<0.1%) experienced Grade 3 Type 1 
diabetes mellitus.  The patient, a 60 year old Caucasian male with NSCLC without a 
history of diabetes mellitus or hyperglycemia, developed severe autoimmune-mediated 
hyperglycemia (blood glucose 458 mg/dL) 43 days after starting MEDI4736 
(durvalumab), was tested positive for anti-GAD antibody 322 U/mL (reference range 0 
to 5 U/mL) and was negative for B-islet antibody.  He was diagnosed with Type 1 
diabetes mellitus and was treated with insulin; the DM resolved with sequelae (insulin 
dependency).   
 
Prompt recognition and management of endocrinopathies is important.  Refer to the 
endocrinology section of the Toxicity Management Guidelines. 
 
Nephritis 
The major clinical syndromes produced by immune-mediated renal injury include 
nephrotic syndrome, rapidly progressive glomerulonephritis, and acute renal failure 
(Cunard and Kelly 2003).  In association to immune-checkpoint inhibitors, two different 
forms of ipilimumab-induced renal damage are reported, acute kidney injury due to 
predominant acute granulomatous tubulointerstitial nephritis and nephrotic syndrome in 
lupus nephritis (Izzedine et al, 2014).  Signs and symptoms include increase in serum 
creatinine, decrease in urine output, peripheral edema, hematuria, loss of appetite.  
  
As a grouped term, selected renal events including laboratory abnormalities were 
reported at a frequency of 6.3% (119 patients) across the 1889 patients included in the 
MEDI4736 (durvalumab) monotherapy pool.  Blood creatinine was the most common 
event reported (4.0%), of which the majority were Grade 1 or 2 in severity.  Nephritis 
events were reported at a frequency rate of Uncommon (6 patients [0.3%]) with 1 event 

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each of Grade 2 autoimmune nephritis, glomerulonephritis, glomerulonephritis 
membranous, and nephritis and 2 tubulointerstitial nephritis (Grade 2 and 3).   
 
Patients should be monitored for changes in renal function (e.g., that manifest as elevated 
serum blood urea nitrogen and creatinine, decreased creatinine CL, electrolyte imbalance, 
decrease in urine output, or proteinuria and any other findings that may be indicative of 
nephritis) prior to and periodically during treatment.  Prompt treatment with steroids is 
important as per current established Toxicity Management Guidelines. 
 
Rash/dermatitis 
Immune-mediated dermatitis is generally mild and presents as mild local or diffuse 
maculo-papular, erythematous rash on the trunk or extremities, which may be 
accompanied by pruritus, alopecia, and vitiligo, suggestive of inflammatory response to 
melanocytes (Lacouture et al, 2014).  In rare cases, severe dermatitis has been reported to 
manifest as Stevens-Johnson syndrome, toxic epidermal necrolysis, or rashes complicated 
by dermal ulceration or necrotic, bullous, or hemorrhagic manifestations (Tarhini et al, 
2013, Kaehler et al, 2010).  
 
AESIs of rash (as a composite term) were reported as Very common in 283 (15.0%) 
patients receiving MEDI4736 (durvalumab) monotherapy and Very common in 256 
(23.5%) patients receiving the combination.  The majority of events were CTC Grade 1, 
with 11 and 7 patients, respectively, experiencing CTC Grade 3 events. 
 
AESIs falling under the grouped term of dermatitis include milder events such as pruritus, 
eczema and erythema to more specific or severe skin toxicities such as events of 
dermatitis bullous, dermatitis exfoliative or dermatitis psoriasiform.  Overall, these events 
have been reported as Very common (n=299; 15.8%) in monotherapy.  Most events were 
Grade 1, with 3 patients in the monotherapy group. 
 
Close monitoring, early detection and prompt treatment with steroids (topical or systemic 
based on severity) is important.  Refer to the Toxicity Management Guidelines. 
 
Myocarditis 
In the literature for other immune checkpoint inhibitors, a variety of clinical presentations, 
diagnostic evidence (laboratory, imaging, histopathology), and resulting diagnoses have 
been described in cases of myocarditis, including heart failure, brady- and 
tachyarrhythmias, and acute coronary syndrome-like presentations without evidence of 
ischemia.  Treatments are variable, and include immunosuppression and beta blockers, 
ACE inhibitors, and diuretics.  Outcomes can range from rapid response and resolution 
with immunosuppression to fulminant, fatal events.  
 
Across the MEDI4736 (durvalumab) monotherapy pool of studies, as of the DCO of July 
12, 2017, there has been 1 serious report of Grade 3 myocarditis and 2 additional cases 
(Grade 3 and Grade 4) outside of the pooled dataset.  In all cases the patients recovered or 
were improving with corticosteroid therapy. 
 

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Investigators should be aware of such rare, but severe immune-mediated adverse events 
including myocarditis with its presenting signs/symptoms (e.g., decreased ejection 
fraction, arrhythmias, in particular occurrences of atrioventricular block).   
 
For patients with suspected myocarditis, investigators should obtain a cardiology consult 
and institute full diagnostic work-up (that includes exclusion of other alternate causes 
such as infection) and the appropriate management that includes discontinuing drug 
(permanently if myocarditis is confirmed) and the prompt use of steroids or other 
immunsosuppressives.  Patients with pre-existing cardiac disorders should be closely 
monitored for deterioration in their cardiac condition, which could suggest new onset 
myocarditis. 
 
Myositis/polymyositis 
The diagnosis of myositis or polymyositis should be suspected in patients who present 
with proximal muscle weakness and the evaluation should include an examination of the 
skin, muscle enzyme measurement, antibody testing, any systemic disease manifestations 
and exclusion of other diseases including drug-induced myopathy.  Cases of myositis 
have been reported with myocarditis in which immune infiltration has been described in 
skeletal and cardiac muscle (Johnson et al, 2016). 
 
In the MEDI4736 (durvalumab) pool of studies as of the DCO, 3 patients (0.2%) 
reported the event of myositis, including 1 Grade 3 in severity.  Outside of the pooled 
dataset, there were 2 fatal events of polymyositis considered as treatment-related by the 
Investigator. 
 
Investigators should adhere to the Toxicity Management Guidelines by performing a 
thorough evaluation to rule out alternative etiologies and initiating prompt treatment with 
steroids and modification of study drug dose regimen depending on the severity of the 
event.  Refer to the Toxicity Management Guidelines. 
 
Pancreatitis  
Pancreatitis is an inflammatory condition of the pancreas that typically manifests initially 
as asymptomatic elevations of amylase and lipase in patients treated with immune 
checkpoint inhibitors.  Clinical presentation frequently includes low-grade abdominal 
pain with accompanying fever and malaise (Weber et al, 2012, Di Giacomo et al, 2010).  
Biopsies showed diffuse T-cell infiltrate consistent with immune-mediated pancreatitis 
(Weber et al, 2012). 
 
Across the 1889 patients in the monotherapy program, events of pancreatitis were 
Uncommon to Rare.  Four patients (0.2%) experienced pancreatitis (Grade 2, Grade 3 and 
Grade 4 in severity) and 1 patient (<0.1%) with Grade 3 acute pancreatitis.  Elevations in 
amylase and lipase were reported as Uncommon (0.6% and 0.5%, respectively).   
 
Patients should be monitored for signs and symptoms of pancreatitis including Grade 3 or 
4 elevations in lipase and/or amylase.  Close monitoring, early detection and prompt 
treatment of these events are important.  Refer to the Toxicity Management Guidelines. 

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Other rare or less frequent AESIs and immune-mediated adverse events  
Events with an inflammatory or immune mediated mechanism could occur in nearly all 
organs.  ImAEs that are less frequent with a potential immune-mediated etiology include, 
but are not limited to:  pericarditis, sarcoidosis, uveitis, and other events involving the eye 
(e.g., keratitis and optic neuritis), skin (e.g., scleroderma and vitiligo), hematological 
(e.g., hemolytic anemia and, immune thrombocytopenic purpura) and rheumatological 
events (polymyalgia rheumatic and autoimmune arthritis).  
 
Neuropathy/neuromuscular toxicities such as Guillain-Barre Syndrome and myasthenia 
gravis have also been observed.  One patient receiving MEDI4736 (durvalumab) 
monotherapy outside of the pooled dataset experienced Grade 4 myasthenia gravis 
 
Prompt treatment of these conditions as per current Toxicity Management Guidelines is 
required. 
 
Infusion-related reactions, anaphylaxis and allergic reactions 
Adverse reactions that occur during or shortly after infusion may include fever, chills, 
hypotension, dyspnea, tachycardia, cyanosis, respiratory failure, urticarial and pruritus, 
angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, 
headache, hypertension rash, headache, flushing, sweating, myalgia, nausea, vomiting, 
unresponsiveness, and hemodynamic instability.  The typical onset can be within 30 
minutes to 2 hours after the initiation of drug infusion, although symptoms may be 
delayed for up to 24 hours.  The majority of reactions occur after the first or second 
exposure to the agent, but between 10% and 30% occur during subsequent treatments 
(Lenz 2007). 
 
Anaphylaxis is a systemic, immediate hypersensitivity reaction that is mediated by 
interactions between factors released from IgE and mast cells; these interactions result in 
an antigen-antibody reaction.  Clinical manifestations of acute allergic reactions may 
range from localized skin reactions at the injection site to AEs, which can include, but are 
not limited to, those events similar to infusion-related reactions to severe reactions 
including anaphylaxis and drug hypersensitivity syndromes.  These reactions may be 
more common with higher rates of infusion, and in patients with a history of allergies. 
 
Patients participating in MEDI4736 (durvalumab) clinical studies should be closely 
monitored during and after infusions.  Severe hypersensitivity reactions should be 
managed according to standard clinical practice, and medical equipment and staff trained 
to treat acute anaphylactic reactions must be immediately available at all sites that 
perform mAb infusions.  
 
Cytokine release syndrome 
Certain mAb therapeutics have been shown to induce a range of acute infusion reactions 
including cytokine-release syndrome that can lead to AEs in patients.  As of the DCO 
date, there have been no reported events of cytokine release syndrome in the ongoing 
MEDI4736 (durvalumab) studies. 

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Immune-complex disease 
The potential risk of immune complex disease for MEDI4736 (durvalumab) is theoretical 
based on the known risk associated with mAbs and other proteins.  The incidence of 
MEDI4736 (durvalumab) ADA-positive patients in clinical studies is low, and hence the 
risk of immune complex disease is likely to be low.  Specifically, of 1124 patients treated 
with MEDI4736 (durvalumab) 10 mg/kg Q2W and evaluable for the presence of ADAs, 
3.3% of patients tested positive for treatment-emergent ADAs.  Neutralizing antibodies 
against MEDI4736 (durvalumab) were detected in 0.3% of patients.  The presence of 
ADAs did not have a clinically relevant effect on PK.  There have been no reported events 
of immune complex reactions in patients receiving MEDI4736 (durvalumab). 
 
 
For guidance on identifying, evaluating, and treating an imAE please see the Toxicity 
Management Guidelines. 
 
2.2.2    Infections 
In addition to infections determined as ADRs, other infections are considered as potential 
risks based on the potential mechanism of action of checkpoint inhibitors. 
 
Serious and/or ≥Grade 3 infections requiring hospitalization including, but not limited to, 
sepsis, pneumonia, lung infections, have been reported in clinical studies with 
MEDI4736 (durvalumab), but are often confounded by underlying disease and use of 
concomitant medications (e.g., steroids and other immunosuppressives).  As of the DCO, 
events from the MedDRA Infections and Infestations SOC, events with a severity ≥Grade 
3 and frequency of ≥1% in the monotherapy pool included lung infection (n=19; 1%), 
pneumonia (n=51; 2.7%), sepsis (n=35; 1.9%) and urinary tract infection (n=21; 1.1%).  
Overall, CTC Grade 3 events were reported in 143 patients (7.6%), CTC Grade 4 events 
were reported in 36 patients (1.9%) and CTC Grade 5 infection events in 18 patients 
(1.0%).   
 
Non-serious infections have been reported in clinical studies with MEDI4736 
(durvalumab).  Of the ADRs under the MedDRA Infections and Infestations SOC, events 
reported as non-serious only and with a frequency of >1% included nasopharyngitis 
(n=92; 4.9%), oral candidiasis (n=49; 2.6%), pharyngitis (n=20; 1.1%) and rhinitis (n=39; 
2.1%).   
 
3.0  PATIENT 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).  
 
 

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3.1 
Eligibility Criteria (13-JAN-2021) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.1.1 Pathologic (cytological or histological) proof of diagnosis of stage II-III (AJCC 8th ed.) 
unresectable or inoperable, non-metastatic NSCLC within 60 days prior to registration, 
with no liver or renal end organ damage, as determined by normal laboratory values 
noted below.  Locally recurrent, N1-N3 disease following surgery without prior radiation 
therapy is eligible.  Patients with N1 to N3 and undetectable primary lung tumors (T0) 
are eligible. 
3.1.2 Pathological diagnosis of PD-L1 high expressing tumors (≥50%) within 60 days prior to 
registration (using Dako 22C3 IHC antibody or the Ventana SP263 antibody 
platforms) performed at a CLIA-certified lab. 
3.1.3 Appropriate stage for study entry based on the following diagnostic workup: 
• History/physical examination within 30 days prior to registration; 
• PET/CT scan for staging within 30 days prior to registration (note: if CT portion of 
PET/CT scan is not of diagnostic quality, then a separate CT scan with contrast is 
required); 
• MRI scan of the brain with contrast; if medically contraindicated, then CT scan of the 
brain with contrast (unless medically contraindicated) is acceptable, within 30 days 
prior to registration;  
• Sufficient lung function with FEV1 ≥ 0.8 Liter or ≥ 35% predicted and DLCO ≥ 40% 
with or without bronchodilator within 30 days prior to registration; 
• Patients who meet the criterion above without O2, but who need acute (started within 
10 days prior to registration) supplemental oxygen due to tumor-caused 
obstruction/hypoxia are eligible, provided the amount of the O2 needed has been 
stable.  
3.1.4    Age ≥ 18;  
3.1.5    Body weight > 30 kg; 
3.1.6 ECOG Performance Status of 0-2 within 30 days prior to registration; 
3.1.7 Adequate hematologic function within 30 days prior to registration defined as follows: 
• ANC ≥ 1500 cells/mm³; 
• Lymphocyte count ≥ 500 cells/mm³; 
• Platelet count ≥ 100,000 cells/mm³;  
• Hemoglobin ≥ 9.0 g/dL (Note: The use of transfusion or other intervention to achieve 
Hgb ≥ 9.0 g/dl is acceptable). 
3.1.8 Adequate renal function within 30 days prior to registration defined as follows: 
Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2 (See Appendix IV for eGFR 
calculations). 
3.1.9 Adequate hepatic function within 30 days prior to registration defined as follows: 
• Total bilirubin ≤ 1.5 x ULN with the following exception: 
o Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x 
ULN may be enrolled; 
• AST and ALT ≤ 2.5 x ULN. 
 3.1.10  Evidence of post-menopausal status or negative urinary or serum pregnancy test for  
female pre-menopausal patients, obtained within 14 days prior to registration. Women 

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will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:  
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy). 
3.1.11  Patients who are human immunodeficiency virus (HIV) positive may participate IF they 
meet the following eligibility requirements: 
• They must be stable on their anti-retroviral regimen, and they must be healthy from 
an HIV perspective.  
• They must have a CD4 count of greater than 250 cells/mcL.  
• They must not be receiving prophylactic therapy for an opportunistic infection. 
3.1.12  The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry. 
 
3.2 
Ineligibility Criteria (25-NOV-2019) 
Patients with any of the following conditions are NOT eligible for this study. 
3.2.1 Definitive clinical or radiologic evidence of metastatic disease. 
3.2.2 Prior invasive malignancy (except those with a negligible risk of metastasis or death and 
with expected curative outcome [such as adequately treated carcinoma in situ of the 
cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically 
with curative intent, or ductal carcinoma in situ treated surgically with curative intent] or 
undergoing active surveillance per standard-of-care management [e.g., CLL Rai Stage 0, 
prostate cancer with Gleason score ≤ 6, and PSA ≤ 10 mg/mL]) unless disease free for a 
minimum of 3 years;   
3.2.3 Prior chemotherapy or systemic therapy for the study cancer; note that prior 
chemotherapy for a different cancer is allowable;  
3.2.4 Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields so that cumulative composite dose combining previous plan and 
current plan to be within 80 Gy to the trachea, major blood vessels, esophagus, and heart, 
and 55 Gy to the spinal cord (if such patients are being considered, this will need to be 
centrally reviewed). Prior chest radiation without overlap is permissible; 
3.2.5 History of autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.  
Patients with a history of treated autoimmune thyroid disease requiring thyroid 
replacement but not immunosuppressives, as well as type 1 diabetes, are permitted.  

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Patients with vitiligo, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
3.2.6 History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on chest PET/CT or CT scan; 
3.2.7 Severe, active co-morbidity defined as follows: 
• Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, fatty liver, and inherited liver disease; 
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation 
of the results or render the patient at high risk from treatment complications; 
• Active tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and TB testing in line with local practice); 
• Active hepatitis B (chronic or acute) or hepatitis C infection.  Patients with past or 
resolved hepatitis B infection (defined as having a negative hepatitis B surface 
antigen (HBsAg) test, a positive anti-HBc [antibody to hepatitis B core antigen], and 
a negative viral DNA test (only obtained if HBsAg is found positive) are eligible.  
Patients positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV RNA. 
3.2.8 Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception during treatment and for 
3 months after the last dose of MEDI4736 (durvalumab); this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic. Women 
who are breastfeeding are also excluded. 
3.2.9 Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with 
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion 
criteria:  
a. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 
b. Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with the Study 
Physician.  
3.2.10  Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 
3.2.11  History of allogenic organ transplantation. 
3.2.12  History of leptomeningeal carcinomatosis 
3.2.13  History of active primary immunodeficiency  
3.2.14  Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab. The following are exceptions to this criterion: 
a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection); 
b. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of 
prednisone or its equivalent; 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 

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3.2.15  Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:  
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days 
after the last dose of IP. 
3.2.16  Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 

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4.0  REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
PRE-TREATMENT ASSESSMENTS (23-JAN-2019) 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to Treatment 
(calendar days) 
Pathologic proof of NSCLC 
60 
 
History, physical 
examination, performance 
status, vital signs* 
30 
 
PD-L1 level 
60 
 
PET/CT for staging 
(including tumor 
measurements †) 
30 
 
Brain MRI with contrast or 
brain CT with contrast if there 
is contraindication for MRI 
30 
 
Pulmonary Function Tests 
(FEV1 and DLCO) 
30 
 
Urine or serum pregnancy test 
(women of childbearing 
potential) 
14 
 
CMP (Complete Metabolic 
Panel) and CBC with 
differential** 
30 
 
TSH*** 
 
As clinically indicated 
ECG, Troponin**** 
 
As clinically indicated 
Biospecimen Collection: 
tissue and blood for integrated 
CTC and immune biomarker 
analyses – see Section 10 and 
Appendices V to VIII for 
details 
 
 Once prior to receipt of 
durvalumab 
 
* 
Vital signs to include heart rate and blood pressure, additional baseline cardiac 
monitoring (e.g. ECG, troponin, BNP) as clinically indicated 
** 
CMP to include creatinine, total bilirubin, AST and ALT, electrolytes (potassium, 
sodium, and chloride).  CBC with differential to include absolute neutrophil count, 
WBC, lymphocyte count, platelet count, and hemoglobin. 
*** 
TSH with reflex to T4, then T3 if clinically indicated  
**** 
Cardiac monitoring as clinically indicated based upon relevant past medical history and 
signs/symptoms 
† 
Radiographic tumor measurements should be obtained via Chest CT.  See RECIST 1.1 
(Appendix I) for allowable imaging modalities used to assess disease at baseline and 
subsequent visits. 

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ASSESSMENTS DURING TREATMENT (23-JAN-2019) 
Assessments 
During Radiation 
Therapy/MEDI4736 
(durvalumab) Treatment 
During Post-Radiation 
Therapy/MEDI4736 
(durvalumab) Treatment 
History and Physical Exam, 
Vital Signs*, Performance 
Status and Concurrent 
Medications 
Weekly 
Every cycle 
Toxicity Assessment Graded 
per NCI CTCAE, v 5.0 
Weekly 
Every cycle 
TSH** 
As clinically indicated 
Every 3 cycles unless 
clinically indicated 
CMP and CBC with 
differential 
Weekly 
Every cycle 
CT scan chest (through 
adrenals) with contrast 
(unless contraindicated) 
 
4-6 weeks after conclusion 
of RT and then every 3 
months 
Biospecimen Collection: 
tissue and blood for 
integrated CTC and immune 
biomarker analyses – see 
Section 10 and Appendices 
V to VIII for details 
On Day 15 from start of 
radiation and Day 30 from start 
of radiation 
At 3 months from start of 
durvalumab (i.e. cycle 4) 
Biospecimen Collection of 
CTC only 
None 
At 6 months and 12 months 
from start of durvalumab 
(i.e. cycles 7 and 13) 
*  Vital signs to include heart rate and blood pressure, additional cardiac monitoring (e.g. ECG, 
troponin, BNP) as clinically indicated; see Section 5.1 for VS assessment during MEDI4736 
(durvalumab) infusion 
**TSH with reflex to T4, then T3 if clinically indicated 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ASSESSMENTS IN FOLLOW UP 
Assessments 
 q3 months for year 1 from end of 
MEDI4736 (durvalumab), q4 months for 
year 2 from end of MEDI4736 
(durvalumab) 
As clinically 
indicated 
Performance Status 
X 
 
History and Physical 
Examination 
X 
 
Toxicity Assessment Graded 
per NCI CTCAE, v 5.0 
X 
 
 
TSH* 
X 
(Until return to normal limits and then as 
clinically indicated) 
 
CT scan of chest (through 
adrenals) 
X 
(Or to progression, whichever occurs first) 
 
MRI Brain or CT scan with 
contrast  
 
X 
*TSH with reflex to T4, then T3 if clinically indicated 
 

 
NRG-LU004 
26                        Version Date:  November 3, 2021 
Definition of Disease Assessments 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eisenhauer 2009] which will be site-reported.  Immune-Related Response Criteria 
(irRC) guidelines for treatment response (ESMO guidelines, Haanen 2017) will also be 
calculated by NRG Oncology using site-reported tumor measurements.  See Appendix I for 
details. 
5. TREATMENT PLAN/REGIMEN DESCRIPTION 
Systemic therapy protocol treatment with MEDI4736 (durvalumab) must start within 2 weeks of 
trial registration and 2 weeks (Day -14) prior (+/- 48 hours) to the start of RT.   
5.1 
MEDI4736 (durvalumab)   
NOTE:  Please refer to the Investigator Brochure for complete details on safety and 
treatment information.  [See Section 9.1 for instructions about how to obtain the IB and 
preparation of MEDI4736 (durvalumab).] 
 
MEDI4736 (durvalumab) will be administered intravenously as a 1500 mg fixed dose over 60 
minutes starting 2 weeks (Day -14 +/- 48 hours) prior to starting radiation therapy, for 13 cycles 
(1 cycle = 4 weeks), until disease progression or toxicity or death, whichever comes first (see 
Section 5.2.6).  Patients must be monitored before and after the infusion with assessment of vital 
signs at the times specified in Section 4 and as clinically indicated. During the infusion period, 
patients must be monitored (pulse rate, blood pressure) every 30 minutes (including times where 
infusion rate is slowed or temporarily stopped). 
 
If RT is held or discontinued, MEDI4736 (durvalumab) may be continued as scheduled.  In 
patients who require dose delays, MEDI4736 (durvalumab) will be continued as soon as the 
patient meets retreatment criteria, and the full dose of 1500 mg will be administered. If the 
patient does not meet retreatment criteria before the next scheduled dose, if/when the toxicity 
resolves to the point where treatment is possible, the doses of MEDI4736 (durvalumab) are 
applied off schedule q 4 weeks.  The missing doses will not be made up.  
 
Cohort 1 & Expansion Cohort 3 
Week 
Days 
ACRT (4 Gy/fractions) 
MEDI4736 (durvalumab) 1500 mg IV 
-2 
-14 to -8 
 
Day -14 
-1 
-7 to -1 
 
 
1 
1 to 7 
Day 1 to 5 
 
2 
8 to 14 
Day 8 to 12 
 
3 
15 to 21 
Day 15 to 19 
Day 15 
4 
22 to 28 
 
 
5 
29 to 35 
 
 
6 
36 to 42 
 
 
7-47 
43 to 329 
 
q 4 weeks X 11 cycles: Days 43, 71, 99, 
127, 155, 183, 211, 239, 267, 295, 323 
 

 
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Cohort 2 & Expansion Cohort 4 
Week 
Days 
Standard RT (2 
Gy/fractions) 
MEDI4736 (durvalumab) 1500 mg IV 
-2 
-14 to -8 
 
Day -14 
-1 
-7 to -1 
 
 
1 
1 to 7 
Day 1 to 5 
 
2 
8 to 14 
Day 8 to 12 
 
3 
15 to 21 
Day 15 to 19 
Day 15 
4 
22 to 28 
Day 22 to 26 
 
5 
29 to 35 
Day 29 to 33 
 
6 
36 to 42 
Day 36 to 40 
 
7-47 
43 to 329 
 
q 4 weeks X 11 cycles: Days 43, 71, 99, 
127, 155, 183, 211, 239, 267, 295, 323 
5.2 
Radiation Therapy (25-NOV-2019) 
Radiation therapy protocol treatment must begin within 2 weeks (Day -14 +/- 48 hours) after 
start of MEDI4736 (durvalumab) administration.  Pre-treatment review is required for each 
treatment plan prior to the start of RT.   Three (3) business days are required for the pre-
treatment review once all required data is received in completion.  Refer to Section 12.1 for 
submission details.  Daily IGRT will be used for all patients. 
 
5.2.1 Treatment Technology 
Three-dimensional conformal radiation therapy (3D-CRT) or Intensity Modulated Radiation 
Therapy (IMRT) is allowed.  Proton Beam Therapy is not allowed.  IMRT delivered from units 
with capabilities including Tomotherapy, ViewRay and VMAT are permitted.  For photons, 
beam energy of 6-10 MV will be used.  Daily image guided radiation therapy (IGRT) using 
orthogonal X-ray, cone beam CT, CT on rails, or MR guidance must be used for all patients, 
regardless of radiation techniques.  Multi-leaf collimation (MLC) will be used to spare normal 
tissues outside of the target volume. 
 
5.2.2 Immobilization and Simulation  
Immobilization 
Proper immobilization is critical for this protocol.  Patient setup reproducibility must be achieved 
using appropriate clinical devices.  Alpha cradles or Vac-Lok devices are used for shoulder 
immobilization.  Arms are abducted bilaterally with hands above the head (preferably in all cases 
unless patients are incapable of doing so but setup must be reproducible daily and treatment 
planning will accommodate for the deviation). 
 
Simulation Imaging  
Simulation CTs should be CT slices of 3 mm slice thickness starting from the level of the cricoid 
cartilage and extending inferiorly through the entire liver volume.  Administration of intravenous 
(I.V.) contrast during simulation CT is optional provided a diagnostic CT with contrast has been 
done to help delineate the major blood vessels.  If such diagnostic CT is not available, I.V. 
contrast should be given during the treatment planning CT.  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. 

 
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Motion Management Technique 
The use of four-dimensional radiation treatment planning is highly encouraged to account for 
respiratory motion in the treatment planning process.  Other methods permitted are active breath 
hold, gated treatment and abdominal compression.   
 
5.2.3 Imaging for Structure Definition and Image Registration 
A volumetric treatment planning CT study will be required to define gross tumor volume (GTV), 
clinical target volume (CTV), and planning target volume (PTV)(see definitions below).  
Contiguous CT slices, having no more than 3 mm thickness through the regions harboring gross 
tumor and grossly enlarged lymph nodes and no more than 10 mm thickness of the remaining 
regions are to be obtained starting from the level of the cricoid cartilage and extending inferiorly 
through the entire liver volume.  The GTV, CTV, and PTV and critical structures will be 
outlined on all appropriate CT slices.  A treatment planning FDG PET/CT scan (or FDG-PET 
alone) 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, the CT from this study may be used as 
the planning CT scan.  Otherwise, a diagnostic PET/CT used for staging could be used for target 
delineation with image co-registration with the planning CT.   
 
5.2.4 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 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. 
 
There are two tables below. The first table (Table A) applies to patients being treated using the 
non-preferred motion management method.  The second table (Table B) applies only to patients 
being planned with 4DCT with maximum intensity projection of the tumor volume based on the 
entire tumor motion.   
 
Contouring of the ITV_6000 is necessary only when the ITV approach is used.  
 
TABLE A: FREE BREATHING / ABDOMINAL COMPRESSION / ACTIVE BREATH 
HOLD / GATING MOTION MANAGEMENT TECHNIQUES 
DICOM Standard Name  
Description  
Detailed Specification  
GTV_6000   
   
GTV to receive 60 Gy   
 
 
Required for free 
breathing, active breath 
hold or gating motion 
management techniques   
 
CTV_6000   
 
CTV to receive 60 Gy  
 
Required 
PTV_6000 
PTV to receive 60 Gy 
Required 

 
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29                        Version Date:  November 3, 2021 
TABLE B: 4D VOLUME TECHNIQUE 
DICOM Standard Name  
Description  
Detailed Specification  
IGTV_6000   
   
Defined as the enveloping 
GTV motion over the 
course of the entire 
respiratory cycle  
 
Required when a 4DCT is 
used to encapsulate entire 
breathing cycle volume 
 
ITV_6000   
 
ITV to receive 60 Gy    
 
Required when IGTV is 
drawn  
PTV_6000 
PTV to receive 60 Gy 
Required 
 
Detailed Specifications  
Target volumes: The definitions of volumes will be in accordance with the ICRU 50 (1999) for 
3D and ICRU 83 (2010) for IMRT. 
 
Accounting for Tumor Motion Approaches and Internal and Setup Margins 
Internal margin (IM): The IM used will be dictated by the motion management decision made at 
time of simulation.   
1. 
If the simulation is done with a free-breathing CT only, the IM will be 1 cm in the 
superior-inferior direction and 0.5 cm in the axial direction.   
2. 
If simulation is done with abdominal compression, the IM will be 0.8 cm in the superior-
inferior direction and 0.5 cm in the axial direction.   
3. 
If simulation is done using an active breath-hold or gated breathing technique, the IM 
will be 0.5 cm in all directions.   
4. 
If simulation is done using a 4DCT to develop a maximum intensity projection of the 
tumor volume, no IM is needed.   
 
Setup margin (SM):  Daily IGRT is a requirement for this trial; therefore, the SM will be 0.5 cm 
in all directions. 
GTV_6000:  The primary tumor and clinically positive lymph nodes seen either on the planning 
CT 
(> 1cm short axis diameter) or pre-treatment PET scan (SUV > 3) will constitute the GTV.  This 
volume(s) may be disjointed.  In the event of a collapsed lobe or lung segment, the use of PET to 
distinguish tumor from fluid/atelectasis is encouraged.  
CTV_6000:  The CTV is defined to be the GTV plus a 0.5cm to 1cm margin as appropriate to 
account for microscopic tumor extension.  If an IGTV is used then a 0.5cm to 1cm margin is 
added to the IGTV to form a CTV.  The CTV should be adjusted to not expand into other organs 
such as esophagus, major blood vessels, or bone. 
IGTV_6000: The primary tumor and clinically positive lymph nodes seen on the planning CT (> 
1 cm short axis diameter) and pre-treatment PET scan (SUV > 3) over the course of a respiratory 
cycle. This volume(s) may be disjointed. In the event of a collapsed lobe or lung segment, the 
use of PET to distinguish tumor from fluid/atelectasis is encouraged.  Maximum intensity 
projection image may be used for contouring, with verification against all breathing phases. 

 
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30                        Version Date:  November 3, 2021 
ITV_6000: The ITV will be equal to the IGTV plus a 0.5 cm clinical margin as appropriate to 
account for microscopic tumor extension. 
PTV_6000:  The PTV will be equal to the ITV+IM+SM.  SM is defined in Detailed 
Specifications paragraph above.  In cases in which the PTV expansion extends outside of the 
skin, towards the spinal cord or into the spinal canal, it can be assumed that tumor motion will 
not occur in this direction, and the PTV margin in this direction can be limited.  PTV margin can 
be limited up to 0.5cm towards this particular dimension (skin or spinal canal). 
 
5.2.5 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 
SpinalCord 
Spinal Cord 
 
Required 
Lungs-GTV 
Combined lungs minus 
GTV 
Required 
SpinalCord_PRV03 
PRV 3 mm expansion 
to the spinal cord  
Required 
Esophagus 
Esophagus 
Required 
Heart 
Heart 
Required 
BrachialPlexus 
Brachial Plexus 
Required for upper lobe 
tumors or high mediastinal 
nodal involvement 
Trachea 
Trachea 
Required 
GreatVes 
Major blood vessels 
(aorta, pulmonary 
trunk) 
Required 
 
Detailed Specifications 
 
SpinalCord: Boundaries: Cranial: 1st slice of CT; Caudal: last slice of CT 
SpinalCord_PRV03: Boundaries: Uniform 3 mm expansion in all directions 
 
Esophagus: Boundaries: Cranial: Bottom of cricoid; Caudal: GE junction 

 
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Lungs-GTV:  Boundaries:  Cranial: From apex bilaterally; Caudal: to bottom of L2; 
                        Right + Left Lung Combined but excluding GTV  
  
Heart:  Boundaries:  Base: Bottom of the aortic arch; Inferior: Apical most of the ventricle 
 
BrachialPlexus:  C5, C6, C7, C8, T1 nerve roots and cord extensions 
 
Trachea:  Bottom of cricoid to mainstem bronchi 
 
GreatVes:  Arch of aorta, pulmonary vessels  
 
5.2.6 Dose Prescription  
Radiation Therapy in the form of Accelerated Hypofractionated Radiation Therapy 
(ACRT) (Cohort 1 and Expansion Cohort 3): 
ACRT is to be carried out using hypofractionated radiotherapy in 4 Gy per fraction for a total 
dose of 60 Gy in 15 fractions.  Radiation treatment will be administered 5 days per week, 1 
fraction per day.  It is recommended that radiation treatment begin on a Monday, Tuesday, or 
Wednesday.  Treatment may begin on Thursday though not preferred.  There are no field 
reductions.  All fields must be treated daily and the entire PTV must be treated daily. 
 
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. 
 
Radiation Therapy in the form of conventionally fractionated radiation therapy (Cohort 2 
and Expansion Cohort 4):   
Photon radiation should be carried out using standard fractionated radiation therapy in 2 Gy per 
fraction for a total dose of 60 Gy in 30 fractions.  Radiation treatment will be administered 5 
days per week, 1 fraction per day.  It is recommended that radiation treatment begin on a 
Monday, Tuesday, or Wednesday.  Treatment may begin on Thursday though not preferred.  
There are no field reductions.  All fields must be treated daily and the entire PTV must be treated 
daily.   
 
Accelerated Hypofractionated RT (ACRT): 4 Gy x 15 fractions =  
60 Gy (Cohort 1 & Expansion Cohort 3) 
Target 
Standard Name 
Dose (Gy) Fraction 
Size (Gy) 
# of 
fractions  
Frequency 
Dose specification technique 
 
PTV_6000    
 
60 
 
4.0 
 
15 
Daily 
1 fraction 
per day 
Covering up to 95% of PTV 
but at minimum of 95% of 
PTV should get at least 45 Gy 
depending on proximity of 
adjacent normal structures 
according to dose avoidance 

 
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rules given in Sec. 5.2.7 below. 
 
 
Standard RT: 2 Gy x 30 fractions = 60 Gy (Cohort 2 & Expansion Cohort 4) 
Target 
Standard Name 
Dose (Gy) Fraction 
Size (Gy) 
# of 
fractions  
Frequency 
Dose specification technique 
 
PTV_6000   
 
 
60 
 
2.0 
 
30 
Daily 
1 fraction 
per day 
Covering 95% of PTV 
 
5.2.7 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_6000 volume 
receives prescription dose of 60 Gy. 
 
Accelerated Hypofractionated RT (ACRT) Compliance Criteria (Cohort 1 & Expansion 
Cohort 3) 
 
ACRT Target Volume Constraints and Compliance Criteria (Cohort 1 & Expansion 
Cohort 3) 
Accelerated Hypofractionated RT (ACRT): 4 Gy x 15 Fractions = 60 Gy 
Name of 
Structure 
Dosimetric  
Parameter 
Per  
Protocol 
Variation  
Acceptable 
PTV_6000 
D95%[Gy] 
60 
50 to 61.2 
 
D99%[Gy] 
>= 52.5 
>= 45 
 
D0.03cc[Gy] 
<= 66 
<= 69 
 
Per Protocol range is excluded from Variation Acceptable range. 
Note: 45 Gy in 15 fractions is the minimal PTV dose depending on adjacent normal tissue 
constraints 
 
ACRT Normal Structure Constraints and Compliance Criteria (Cohort 1 & Expansion 
Cohort 3) 
Accelerated Hypofractionated RT (ACRT): 4 Gy x 15 Fractions = 60 Gy 
Name of Structure 
Dosimetric 
Parameter 
Per  
Protocol 
Variation 
Acceptable 
a/b 
Lungs-GTV 
V5 [%] 
<=65 
<=70 
2.5 

 
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33                        Version Date:  November 3, 2021 
V16.5  [%] 
<=37 
<=40 
2.5 
 
Mean[Gy] 
<=16.5  
<=18.5  
2.5 
SpinalCord 
D0.03cc[Gy] 
<=36.5   
<=40.2     
2.5 
SpinalCord_PRV03  
D0.03cc[Gy] 
<=40.2   
<=43.9   
2.5 
Esophagus 
D0.03cc[Gy] 
<=58.9    
<=61.3   
10 
 
Mean[Gy] 
<=31   
<=32   
10 
BrachialPlexus 
D0.03cc[Gy] 
<= 49.8   
<=52   
2.5 
Heart 
D0.03cc[Gy] 
<= 49.8   
<=52  
2.5 
 
Mean [Gy] 
<=16.5   
<= 18.5   
2.5 
Trachea  
D0.03cc[Gy] 
<=52   
<=53.5   
2.5 
GreatVes  
D0.03cc[Gy] 
<=53.5   
<=55   
2.5 
Note: It is recommended that the esophagus not be circumferentially irradiated with >53.1 Gy 
(i.e., the 53.1 Gy isodose line should not encompass the entire axial cross-section of the 
esophagus at any level). 
Per Protocol range is excluded from Variation Acceptable range. 
 
ACRT Delivery Compliance Criteria (Cohort 1 & Expansion Cohort 3) 
 
Per Protocol 
Variation 
Acceptable 
Start Date  
 
Monday, Tuesday, or 
Wednesday  
Thursday  
Overall Treatment Time  
<26 days 
26-33 days 
Interruptions (other than 
holidays) 
0-3 days 
4-7 days 
 
Standard RT Compliance Criteria (Cohort 2 & Expansion Cohort 4) 
 
Standard RT Target Volume Constraints and Compliance Criteria (Cohort 2 & Expansion 
Cohort 4) 
Name of Structure 
Standard RT: 2 Gy x 30 Fractions = 60 Gy 
 
PTV_6000 
Dosimetric  
Parameter 
Per  
Protocol 
Variation  
Acceptable 
 
D95%[Gy] 
60 
58.8 to 61.2   
 
D99%[Gy] 
>= 54 
>=51 
 
D0.03cc[Gy] 
<= 66 
<= 69 
Per Protocol range is excluded from Variation Acceptable range. 
 
 
Normal Structure Constraints and Compliance Criteria (Cohort 2 & Expansion Cohort 4) 

 
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34                        Version Date:  November 3, 2021 
Standard RT: 2 Gy x 30 Fractions = 60 Gy 
Name of Structure 
Dosimetric 
Parameter 
Per  
Protocol  
Variation 
Acceptable 
a/b 
Lungs-GTV    
V5[%] 
<=65   
<= 70   
2.5 
 
V20[%] 
<=37  
<=40 
2.5 
 
Mean[Gy] 
<=20 
<=22 
2.5 
SpinalCord 
D0.03cc[Gy] 
<=45 
<=50   
2.5 
SpinalCord_PRV03 
D0.03cc[Gy] 
<=50 
<=55 
2.5 
Esophagus 
D0.03cc[Gy] 
<=67 
<=70 
10 
 
Mean[Gy] 
<=34 
<=35 
10 
BrachialPlexus 
D0.03cc[Gy] 
<=63   
<=66  
2.5 
Heart 
D0.03cc[Gy]  
<=63  
<=66 
2.5 
 
Mean[Gy] 
<=20  
<=22 
2.5 
Trachea 
D0.03cc[Gy] 
<=66 
<=68 
2.5 
 
GreatVes 
D0.03cc[Gy] 
<=68 
<=70 
2.5 
Note: It is recommended that the esophagus not be circumferentially irradiated with >60 
Gy (i.e., the 60 Gy isodose line should not encompass the entire axial cross-section of the 
esophagus at any level). 
Per Protocol range is excluded from Variation Acceptable range. 
 
Standard RT Delivery Compliance Criteria (Cohort 2 & Expansion Cohort 4) 
 
 
 
 
 
 
 
 
 
 
5.2.8   Treatment Planning Priorities and Instructions 
 
Critical Structure and Target priorities must be listed in order of decreasing importance 
1. 
SpinalCord 
2. 
Lungs-GTV 
3. 
Esophagus 
 
Per Protocol 
Variation 
Acceptable 
Start Date  
 
Monday, Tuesday, or 
Wednesday 
Thursday  
Overall Treatment Time (30 
fractions) 
<47 days 
47-53 days 
Interruptions (other than 
holidays) 
0-3 Days 
4-7 days 

 
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35                        Version Date:  November 3, 2021 
4. 
BrachialPlexus 
5. 
Heart 
6. 
Trachea 
7. 
PTV  
8. 
GreatVes 
9. 
ChestWall 
10. 
Skin 
 
Dose Calculations 
Acceptable choices of algorithm are listed at http://irochouston.mdanderson.org.  Any algorithm 
used for this study must be credentialed by IROC Houston. 
 
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. These principles hold for Pencil Beam type 
algorithms and for homogeneous dose calculations when allowed for a clinical trial (e.g., conical 
collimators in stereotactic radiosurgery). 
 
Primary dataset for dose calculation 
The primary dataset for dose calculation must be a free-breathing CT that was acquired along 
with 4DCT, an average intensity pixel CT (AveIP) generated from the 4DCT, 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. 
Dose matrix resolution 
Dose grid size should be <= 3 mm in all directions. 
 
5.2.9     Patient specific QA 
Any patient-specific QA that needs to be acquired should follow institutional guidelines and 
AAPM task group report recommendations. 
 
For IMRT/VMAT plans, patient specific QA is highly recommended. The recommended patient 
specific QA criterion is for 90% of the comparison points to pass a ±3%/3mm Gamma Index 
analysis. 
 
5.2.10   Daily Treatment Localization/IGRT 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate accuracy 
and precision throughout its entire process from target and normal tissue delineation, to radiation 
delivery, to adaptation of therapy to anatomic and biological changes over time in individual 
patients. 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. 
 

 
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Daily image guidance that allows for 3D shifts is the minimum requirement for this trial.  Most 
advanced imaging techniques can be utilized, as long as they also allow for 3D shifts.  The setup 
margin in this trial is tied to the use of daily image guidance.  When able to localize using soft 
tissue, the target will be most effective for localization.  Other soft tissues in the lung such as the 
carina can help for mediastinal alignment.  Fiducial markers can be used for localization as 
needed.  Bony alignment as a surrogate is also acceptable.  Any linear shifts seen that are ≥2 mm 
should be applied prior to treatment.   
 
-Minimal IGRT requirements 
Location 
No Fiducials 
With Fiducials** 
Lung* 
Imaging that allows for 3D 
shifts 
Imaging that allows for 3D 
shifts 
*Registration using a soft tissue surrogate for the tumor is recommended.  Free-breathing CTs 
are not to be used as reference images for 4D CBCT IGRT process 
**Clearly visible anatomical markers are acceptable as fiducials, e.g. inserted radio opaque 
markers. 
 
5.2.11 Case Review  
Pre-treatment reviews are required for all cases.  See Sections 8.3 and 12.1 for specifics on 
submission process and requirements.  RT may not begin until approval is received.  Three (3) 
business days are required for the pre-treatment review once all required data is received in 
completion.    
5.3 
General Concomitant Medication and Supportive Care Guidelines 
5.3.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
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.    
▪ Anticonvulsants 
▪ Antiemetics 
▪ Anticoagulants 
▪ Antidiarrheals 
▪ Analgesics 
▪ Hematopoietic Growth Factors 
▪ Nutritional supplementation 
▪ Highly active antiretroviral therapy (HAART) 
▪ Megastrol administered as appetite stimulant is acceptable while the patient is 
enrolled in the study   
▪ Premedication may be administered at the discretion of the treating physician. 
▪ The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
5.3.2 Therapies Not Permitted: 
 
▪ Traditional herbal medicines should not be administered because the ingredients of 
many herbal medicines are not fully studied and their use may result in unanticipated 
drug interactions that may cause, or confound assessment of, toxicity; 
▪ Patients are not allowed to receive immunostimulatory agents, including but not 

 
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limited to IFN-α, IFN-γ, or IL-2, during the entire study.  These agents, in 
combination with MEDI4736 (durvalumab), could potentially increase the risk for 
autoimmune conditions. 
▪ Patients should also not be receiving immunosuppressive medications, including but 
not limited to cyclophosphamide, azathioprine, methotrexate, or thalidomide.  These 
agents could potentially alter the activity and the safety of MEDI4736 (durvalumab).  
Systemic corticosteroids may be administered at the discretion of the treating 
physician.  If feasible, alternatives should be considered.   
▪ Patients who donate blood while participating in this study, or:  1) for at least 90 days 
following the last infusion of durvalumab; or 2) 90 days after receipt of the final dose 
of durvalumab; or 3) until after 4-5X the half-life of durvalumab or until the time 
specified in the prescribing information of durvalumab, whichever occurs longest. 
▪ Colony stimulating factors, including G-CSF, pegylated G-CSF are not permitted at 
any time.  Erythropoietin analogs are not recommended, but may be used in 
accordance with ASCO guidelines. 
▪ Immunotherapy, chemotherapy or radiation therapy not specified in this protocol 
▪ Investigational agents other than MEDI4736 (durvalumab). 
▪ Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine.  Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
▪ Glucocorticoids for any purpose other than the following two clinical situations: 
o To control radiation-related nausea, if viewed as absolutely necessary for 
symptom control by the radiation oncologist.  Every effort should be made to 
minimize glucocorticoid administration, e.g. utilization of appropriate 
alternative medications including 5HT3, NK-1 antagonists, olanzapine etc. 
(note:  no more than 4 mg decadron or 10 mg prednisone daily). 
o To modulate symptoms from an adverse event of suspected immunologic 
etiology.  Note: The use of physiologic doses of corticosteroids (e.g. ≤ 10 mg 
per day of prednisone or equivalent) may be approved after consultation with 
the Principal Investigator. 
o Patients who, in the assessment of the treating investigator, require the use of 
any of the aforementioned treatments for clinical management should be 
removed from protocol treatment.  Patients may receive other medications that 
the investigator deems to be medically necessary. 
 
5.3.3 Participation in Other Trials  
• Patients are not to participate in other therapeutic trials.  However, trials that do not 
add experimental agents are allowed (e.g. imaging trials, quality of life, etc). 
5.4     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 

 
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applies: 
▪ 
Completion of all 13 cycles of MEDI4736 (durvalumab), 
▪ 
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. 
 
*At time of disease progression, patients will be managed per the discretion of the treating 
physician and will continue to be followed per the follow-up assessments in Section 4 of the 
protocol.   
6.  TREATMENT MODIFICATIONS/MANAGEMENT (13-JAN-2021) 
6.1      Toxicity Management Guidelines for Radiation-Related, Immune-Mediated, 
Infusion-Related, and Non-Immune Mediated Reactions for MEDI4736 
(durvalumab) 
Radiation-Related Toxicities: 
Severe adverse events that may be related to radiation therapy during the course of radiation such 
as any grade 3-4 cardiopulmonary SAEs (congestive heart failure, pneumonitis, arrhythmias, 
myocardial infarction), grade 4 esophagitis, or any AEs that lead to hospitalization that could be 
attributed to radiation therapy to make continued therapy infeasible should lead to the radiation 
therapy to be held.  RT could be resumed if AEs return to grade 2 or less, but if the AEs do not 
return to grade 2 or less within 14 days, RT will be permanently discontinued.   
 
MEDI4736 (Durvalumab) Related-Toxicities: 
For MEDI4736 (durvalumab), there will not be any dose escalation or de-escalation.  If the 
MEDI4736 (durvalumab) dose is held or interrupted it will not be made up.  If RT is held or 
discontinued, MEDI4736 (durvalumab) may be continued as scheduled.  If the patient meets 
retreatment criteria, the full dose of 1500 mg will be administered. If the patient does not meet 
retreatment criteria before the next scheduled dose, if/when the toxicity resolves to the point 
where treatment is possible, the doses of MEDI4736 (durvalumab) are applied off schedule every 
4 weeks.  
 
Adverse events (both non-serious and serious) associated with MEDI4736 (durvalumab) 
exposure may represent an immunologic etiology. These adverse events may occur shortly after 
the first dose or several months after the last dose of treatment. MEDI4736 (durvalumab) must 
be withheld for drug-related toxicities and severe or life-threatening AEs as per the table below. 
 
All toxicities are per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 
Guidelines for the management and dosing modifications for immune-mediated reactions, infusion-related reactions, 
and non-immune-mediated reactions for MEDI4736 (durvalumab) monotherapy are provided in the subsections 
below as follows: 
• 
General guidelines for toxicity management and dosing modifications (Table 5a) 
• 
Toxicity management and dosing modifications guidelines for specific immune-related adverse events 
(irAEs)/immune-mediated AEs (imAEs) and other irAEs/imAEs not specified (Table 5b)  

 
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Note:  As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal 
to Grade 2, please discuss with Study Physician.” 
 
7.   ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1   Protocol Agents 
 
 
Investigational Agents 
The investigational agent administered in NRG-LU004, MEDI4736 (durvalumab) (NSC 
#778709), is being made available under an IND sponsored by CTEP. 
Refer to the MEDI4736 (durvalumab) investigator brochure (IB) for detailed 
pharmacologic and safety information.  
For MEDI4736 (durvalumab), determination of whether an adverse event meets 
expedited reporting criteria, see the reporting table in section 7.4 of the protocol. 
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 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 
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       Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MEDI4736 (durvalumab, NSC 778709) (25-NOV-2019) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 

 
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Adverse events reported on MEDI4736 (durvalumab) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that MEDI4736 
(durvalumab) caused the adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Disseminated intravascular 
coagulation 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (coronary 
artery disease); Pericardial effusion; Pericardial tamponade; Restrictive cardiomyopathy; Right 
ventricular dysfunction; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Eye disorders - Other (choroidal effusion with shut down of ciliary body) 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dental caries; Gastrointestinal 
disorders - Other (gastrointestinal hemorrhage); Mucositis oral; Proctitis; Small intestinal 
obstruction; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; 
Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic hemorrhage 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (drug-induced liver 
injury); Serum sickness 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Wound complication 
INVESTIGATIONS - Blood bilirubin increased; CPK increased; Electrocardiogram T wave 
abnormal; GGT increased; Lipase increased; Lymphocyte count decreased; Neutrophil count 
decreased; Platelet count decreased; Serum amylase increased; Weight loss; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hypermagnesemia; Hypoalbuminemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back 
pain; Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (brain 
metastasis swelling); Neoplasms benign, malignant and unspecified (incl cysts and polyps) - 
Other (lung cyst); Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(tumor flare, tumor inflammation); Treatment related secondary malignancy; Tumor 
hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Dizziness; Edema cerebral; Headache; Nervous 
system disorders - Other (axonal neuropathy); Nervous system disorders - Other (hemiparesis); 
Paresthesia; Seizure 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Hypoxia; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin 
VASCULAR DISORDERS - Hypertension 
 

 
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Note: MEDI4736 (durvalumab) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
7.4     Expedited Reporting of Adverse Events (25-NOV-2019) 
All adverse events (AEs) are submitted for expedited reporting protocol-specific rules evaluation 
using the Medidata Rave data management system. All AEs will be evaluated by the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) to determine 
whether expedited reporting is recommended based on a set of programmed expedited reporting 
rules. AEs identified as meeting the programmed expedited reporting requirements can then be 
submitted in CTEP-AERS. A deep link in Rave will take the user directly to CTEP-AERS where 
the expedited report may be completed and submitted via CTEP-AERS. 
 
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 link in RAVE.  CTEP-AERS is also accessed via the CTEP web site, but all expedited 
reports must be initiated in RAVE (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.   
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-
only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
CTEP as the IND sponsor for this study by telephone at 301-897-7497 and 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. 
 
7.4.1 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 5 
days.  
• Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Supporting source documentation should include the protocol 
number, patient ID number, and CTEP-AERS ticket number on each page, and fax 
supporting documentation to CTEP at 301-897-7404 and contact NRG Oncology at 
1-215-574-3191 for source document submission assistance. 
• In the event of site assessment disagreement with a CTEP-AERS rules assessment of 
an expedited report “NOT recommended”, based upon the protocol-specific reporting 
requirements and criteria outlined in the AE Reporting Tables, sites may bypass the 
“NOT recommended” assessment; the CTEP-AERS allows submission of all reports 
regardless of the results of the assessment.  

 
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65                        Version Date:  November 3, 2021 
Not applicable. 
 
7.4.3 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. 
 
7.4.4 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.  
 
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. 
7.5       Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be 
completed and submitted to CTEP.  Any pregnancy occurring in a patient or patient’s 
partner from the time of consent to 3 months after the last dose of study drug must be 
reported and then followed for outcome.  Newborn infants should be followed until 30 
days old.  Please see the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on 
how to report pregnancy and its outcome to CTEP.  
 
8.0       REGISTRATION AND STUDY ENTRY PROCEDURES (03-AUG-2020) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and 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).  In addition, persons with a registration type of 

 
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67                        Version Date:  November 3, 2021 
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.  
 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>.  For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov.  
 
8.1      Cancer Trials Support Unit Registration Procedures (13-JAN-2021) 
            This study is supported by the NCI Cancer Trials Support Unit (CTSU).   
 
8.1.1     IRB Approval  
             For CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research Program 
(NCORP) Research Bases after March 1, 2019, all U.S.-based sites must be members of 
the NCI Central Institutional Review Board (NCI CIRB). 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.  
 
 Sites 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.  Site registration forms may be downloaded from the protocol specific 
page on the NRG 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. 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• Compliance with all protocol-specific requirements (PSRs). 
• IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC to 
begin the modality credentialing process.   

 
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In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the  
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• Holds the appropriate CTEP registration type for the protocol; 
• Rostered at the site on the IRB/REB approval and on at least one participating 
roster; 
• Rostered on the NCI CIRB Signatory record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and  
• Holds an active CTEP status. 
 
8.1.2    Downloading Site Registration Documents:   
Site registration forms may be downloaded from the protocol-specific page on the NRG 
website. 
 
CIRB-approved protocol documents are located on the CTSU member’s website. 
Permission to view and download this protocol and its supporting CIRB documents is 
restricted based on person and site roster assignment. To participate, the institution and 
its associated investigators and staff must be associated with the LPO or a Protocol 
Organization (PO) on the protocol.  One way to search for a protocol is listed below. 
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 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 
Oncology and protocol number NRG-LU004; 
• Click on Documents, select Site Registration, and download the protocol.   
 
8.1.3    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 in order to 
receive further instruction and support. 

 
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8.1.4    Checking Site’s Registration Status:   
            Site registration status may be verified on the CTSU members’ website.   
• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• Enter the site’s 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 given 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 NCI or their affiliated networks. 
8.2      RT-Specific Pre-Registration Requirements (25-NOV-2019) 
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.  This document must be uploaded by the 
site to the CTSU Regulatory Submission Portal for RSS to be updated.   
 
RT   
Credentialing 
Requirements 
Web Link for Credentialing Procedures and Instructions 
http://irochouston.mdanderson.org 
Treatment 
Modality 
 
Photon 
Key Information 
Credentialing 
Status 
Inquiry Form 
x 
 
To determine if your institution has 
completed the requirements above, please 
complete a “Credentialing Status Inquiry 
Form” found under Credentialing on the 
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. 

 
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70                        Version Date:  November 3, 2021 
Phantom 
Irradiation 
x 
 
 
 
A 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 Notification 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 Oncology 
Headquarters that all desired credentialing 
requirements have been met. 
8.3 
Digital RT Data Submission to NRG Using TRIAD (13-JAN-2021) 
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 
DICOM images as they are transferred. 
 
8.3.1    TRIAD Access Requirements:   
• A valid CTEP IAM account. 
• Registration type of:  Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR).  Please refer to the CTEP 
Registration Procedures section for instructions on how to request a CTEP-IAM 
account and complete registration in RCR.  
• TRIAD Site User role on an NCTN or ETCTN 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. 
 
8.3.2    TRIAD Installations:  
To submit images, the individual holding the TRIAD Site User role will ned to 
install the TRIAD application on his/her 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 at TRIAD-
Support@acr.org or 1-703-390-9858. 

 
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71                        Version Date:  November 3, 2021 
8.4       Patient Enrollment (13-JAN-2021) 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
 
8.4.1 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 or the Theradex Interactive Web 
Response System (IWRS) 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:   
• A valid CTEP-IAM account; 
• 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; and 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR 
only), or investigator receiving 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. 
• 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 CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
To receive site reimbursement for specific tests and/or biospecimen submissions, 
completion dates must be entered in the OPEN Funding screen post registration. Please 
refer to the protocol specific funding page on the CTSU members’ website for additional 
information. Timely entry of completion dates is recommended as this will trigger site 
reimbursement. 
 

 
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9.0       DRUG INFORMATION  
9.1 
Investigational Study Agent – MEDI4736 (durvalumab) (NSC #778709, IND 
#
 (03-NOV-2021) 
9.1.1    Supply 
This study will be conducted under IND# 
 to be held by NCI and will require 
FDA submission and approval as part of the IND. MEDI4736 (durvalumab) is provided 
by AstraZeneca and distributed by the DCTD/NCI. MEDI4736 (durvalumab) will be 
supplied to patients on study free of charge.  
 
           Agent Ordering and Agent Accountability 
           NCI-supplied agent may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), 
NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead investigator at that 
institution. 
 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password. For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time. Refer to the PMB’s website for 
specific policies and guidelines related to agent management. 
 
Agent Inventory Records  
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
            Investigator Brochure Availability 
The current version of the IB will be accessible to site investigators and research staff 
through the PMB OAOP application. Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” 
password, and active person registration status. Questions about IB access may be 
directed to the PMB IB Coordinator via email. 

 
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Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/  
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/  
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator: IBCoordinator@mail.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov  
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
9.1.2   Agent-Specific Information 
             
             
Other Names: IMFINZI™ 
 
Classification: Anti-PD-L1 MAb 
 
Molecular Weight: ~ 149 kDa 
 
Mode of Action: Durvalumab (MEDI4736) inhibits binding of programmed cell death 
ligand 1 (PD-L1) to PD-1 and CD80.  In-vitro studies demonstrate that durvalumab 
(MEDI4736) relieves PD-L1-mediated suppression of human T-cell activation.  
Durvalumab (MEDI4736) does not trigger antibody-dependent cellular cytotoxicity or 
complement-dependent cytotoxicity in cell-based functional assays. 
 
Description: Durvalumab (MEDI4736) is a human immunoglobulin G1 kappa (IgG1κ) 
monoclonal antibody. 
 
How Supplied: Durvalumab (MEDI4736) is supplied by AstraZeneca, and distributed by 
the Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Durvalumab (MEDI4736) 
injection is a clear to slightly opalescent, colorless to slightly yellow solution for 
intravenous use.  Each vial contains 500 mg of durvalumab (MEDI4736) in 10 mL of 
solution.  Each 1 mL of solution contains 50 mg of durvalumab (MEDI4736) and is 
formulated in: L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-
trehalose dihydrate (104 mg), polysorbate 80 (0.2 mg), and Water for Injection, USP. 
 
Preparation: Durvalumab (MEDI4736) solution for infusion must be diluted prior to 
administration.  To prepare the infusion solution add the dose volume of durvalumab 
(MEDI4736) to an infusion bag containing 0.9% Sodium Chloride Injection or Dextrose 

 
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5% in Water Injection, USP and mix by gentle inversion to ensure homogeneity of the 
dose in the bag.  The final concentration must be between 1 mg/mL to 15 mg/mL. 
 
Infusion bags must be latex-free and can be made of polypropylene, polyethylene, 
polyolefin copolymers, or polyvinyl chloride. 
 
Storage: Store intact vials between 2-8°C (36-46°F).  Do not freeze.  Protect from light by 
storing in the original box.   
 
If a storage temperature excursion is identified, promptly return durvalumab 
(MEDI4736) to between 2-8°C and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature monitoring and 
duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability. 
 
Stability: Refer to the package label for expiration. 
 
Total in-use storage time from needle puncture of durvalumab (MEDI4736) vial to start 
of administration should not exceed 8 hours at room temperature or 24 hours at 2-8°C 
(36-46°F).  Prior to the start of the infusion, ensure that the bag contents are at room 
temperature (approximately 25°C) to avoid an infusion reaction due to the administration 
of the solution at low temperatures.   
 
Route of Administration: IV infusion 
 
Method of Administration: Infuse over approximately 60 minutes using an infusion set 
containing a 0.22 or 0.2 μm in-line filter.  No incompatibilities between durvalumab 
(MEDI4736) and polyethylene, polypropylene, polyvinylchloride, or polyolefin 
copolymers have been observed.  Flush the IV line with a volume of IV bag diluent equal 
to the priming volume of the infusion set used at the completion of infusion.  Do not co-
administer other drugs through the same infusion line. 
 
Patient Care Implications: Refer to the protocol for information on evaluation and 
management of potential immune-related adverse events. 
 
10.       PATHOLOGY/BIOSPECIMENS 
  
10.1 
Central Pathology Review 
Not applicable 
 
10.2 
Biospecimen Selection for Integral Biomarker Testing 
Not applicable 
 
10.3 
Biospecimen Selection for Integrated Biomarker Testing 
Not applicable. 
 

 
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• Mandatory IHC Staining:  PD-L1 Staining ≥50% positive, performed at 
participating sites’ CLIA-certified labs using Dako 22C3 IHC antibody or the 
Ventana SP263 testing platforms, then values submitted to NRG Oncology via patient 
OPEN Eligibility Checklist.   
 
The PD-L1 protein is expressed on the plasma membrane of a range of hematopoietic 
and solid tissue cells interacting with the PD-1 receptor present on the surface of T- 
and B-lymphocytes and some myeloid cells. PD-L1/PD-1 binding triggers signal 
transduction cascades that results in self-tolerance and immune system suppression 
normally acting as an immune checkpoint that prevents overstimulation and 
autoimmunity. Upregulation of PD-1 expression is often present on tumor infiltrating 
lymphocytes and correspondingly, enhanced PD-L1 expression can be found on many 
tumor cells. Blockade of PD-L1 stimulation of PD-1 impedes immune inhibition and 
allows for recognition of tumor as non-self, resulting in tumor cytotoxicity. Several 
clinical trials have demonstrated that PD-L1 status may be predictive of benefit from 
treatment with checkpoint inhibitors. Durvalumab is a humanized monoclonal 
antibody targeting PD-1 with increased PD-L1 expression.  Tumors with high 
expression of PD-L1 show increased objective response rate and improved 
progression free and overall survival compared to low expressors. PD-L1 IHC 22C3 
is a qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, 
Clone 22C3 intended for use in the detection of PD-L1 protein in formalin-fixed, 
paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue and gastric or 
gastroesophageal junction adenocarcinoma using EnVision FLEX visualization and 
performed on Autostainer Link 48. PD-L1 IHC 22C3 is indicated as an aid in 
identifying NSCLC patients for treatment with pembrolizumab.  PD-L1 protein 
expression in NSCLC is determined by using Tumor Proportion Score (TPS), which 
is the percentage of viable tumor cells showing partial or complete membrane 
staining at any intensity. The specimen is considered to have PD-L1 expression if 
TPS ≥ 1% and high PD-L1 expression if TPS ≥ 50%. 
 
• Mandatory Circulating Tumor Cell (CTC) at Liquid Biotech:  Blood will be 
shipped directly to Liquid Biotech USA for testing. See Appendix V for details. 
 
• Mandatory Time of Flight Mass Cytometry (CyTOF):  CIMAC; assessed at 
baseline (pre-treatment), days 15 and 30, and 3 months 
 
• Mandatory T Cell Receptor (TCR) Sequencing:  ImmunoSeq at CIMAC-
designated lab; assessed at baseline (pre-treatment), days 15 and 30, and 3 months 
 
• Mandatory Cytokine Analysis:  Multiplex Immunoassay using OLink Technology; 
assessed at baseline (pre-treatment), days 15 and 30, and 3 months 
 
• Mandatory ELISA/Grand Serology:  CIMAC 
 
• Mandatory Circulating Tumor DNA (ctDNA):  DNA Profiling by Deep 
Sequencing:  CIMAC-designated laboratory 

 
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• Optional SP263 Assay (PD-L1) – In tumors where only the Dako 22C3 testing was 
done, a qualitative immunohistochemical assay can be performed using rabbit 
monoclonal anti-PD-L1 clone SP263 intended for use in the assessment of the PD-L1 
protein in formalin-fixed, paraffin-embedded (FFPE):  CIMAC or other CIMAC-
designated laboratory 
o (NOTE:  This will be done as an exploratory special study on the unstained 
sections (if available). 
 
See Mandatory Biospecimen Submission Tables (Section 10.5) and CIMAC Biomarker 
Testing Appendix (Appendix VIII) for further details. 
 
10.5 
Mandatory Biospecimen Submissions (25-NOV-2019) 
The patient must give permission to participate in this mandatory study component. 
Participating sites are required to submit the patient’s biospecimens as outlined below.  
10.5.1  Mandatory Biospecimen Submission Table for CTC Analysis 
See table below and Appendix V for further details. 
 
Mandatory Specimen Collection #1:  Blood for CTC analysis 
Why specimen is being collected:  Integrated marker for predicting response to treatment. 
Follow blood collection instructions in Appendix V. 
 
Kits and Shipping costs:  All necessary materials for shipping (including blood collection tubes 
and prepaid FedEx labels) may be obtained from Liquid Biotech USA. Please contact Liquid 
Biotech USA at support@liquidbiotechusa.com (tel: 267-225-7361) to arrange for delivery of 
materials. 
 
Ship samples (per instructions in Appendix V below) to:   
Liquid Biotech USA 
@ Princeton Innovation Center BioLabs 
303A College Rd. E. 
Princeton, NJ 08540 
 
Questions:  contact Liquid Biotech at the email above. 
 
Specimen 
Type  
Collection Time Points 
 
Collection Information 
and Requirements/ 
Instructions for Site 
Shipping  
 

 
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1 A specimen transmittal form and copy of the corresponding pathology report must be shipped 
with all tissue biospecimens sent to the NRG BB-San Francisco.  The pathology report must 
have specimen obtained date and pathology accession number visible on the report; all other PHI 
must be redacted. 
 
2 The NRGBB-SF can embed the punches for sites without the facilities to embed punches into 
blocks.  If a block or punch absolutely cannot be submitted, sites may submit fresh-cut, air dry 
and ship two 5 micron unstained sections on supercharged/positive charged (Plus) glass 
microscope slides (Leica Bond Plus slides if available).  The tissue sections should be centered 
on the slide (12mm (left label), 3mm (top-bottom), and 7mm (right).  Unstained slides must be 
labeled with Study, Case#, accession number, block number and date the slide was cut.  Sections 
must be shipped within 48 hours of sectioning. 
 
3 NRG Oncology BB-San Francisco / Protocol NRG-LU004, University of California San 
Francisco, 2340 Sutter Street, Room S341, San Francisco, CA 94115, Phone:  (415) 476-7864; 
FAX:  (415) 476-5271, Email:  NRGBB@ucsf.edu. 
 
11.      SPECIAL STUDIES (NON-TISSUE) 
           Not applicable to this study. 
12.      MODALITY REVIEWS 
12.1    Radiation Therapy Quality Assurance Reviews (03-AUG-2020) 
The Radiation Oncology Study Chair, Dr. Lin, or one of the radiation oncologist co-
chairs, will perform a pre-treatment RT Quality Assurance Review for each case enrolled 
after NRG Headquarters has received complete data. 
12.2    Medical Oncology Modality Quality Assurance Reviews 
The Medical Oncology Study Chair, Dr. Tsao, will perform a systemic therapy Assurance 
Review of all patients.  The goal of the review is to evaluate protocol compliance.  The 
review process is contingent on timely submission of treatment data as specified in 
Section 12.2. The scoring mechanism is: 1) Per Protocol, 2) Acceptable Variation, 3) 
Unacceptable Deviation, and 4) Not Evaluable.   
 
Dr. Tsao will perform a Quality Assurance Review after NRG Headquarters has received 
complete data for the first 6 cases enrolled. The final cases will be reviewed within 3 
months after this study has reached the target accrual or as soon as NRG Headquarters has 
received complete data for all cases enrolled, whichever occurs first. 
 
13.      DATA AND RECORDS 
13.1    Data Management/Collection (03-AUG-2020) 
   
Medidata Rave is a 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: 

 
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• A valid CTEP-IAM account; and  
• 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: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must hold an Associates (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 RSS, 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 into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, 
and click on the “accept” link in the upper right-corner of the iMedidata page. Please note, 
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 will be listed 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 that have not previously activated their iMedidata/Rave accounts at the time of 
initial site registration approval for the study in RSS 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 website under the Rave tab at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
13.2    Rave-CTEP-AERS Integration (03-AUG-2020) 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline Adverse Events (AE) entered in 
Rave to determine whether they require expedited reporting, and facilitates entry in 
CTEP-AERS for those AEs requiring expedited reporting.    
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to collect 
AEs that start during the period or persist from the previous reporting period. CRA will 
enter AEs that occur prior to the start of treatment on a baseline form that is not included 
in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must begin and 

 
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end on the baseline Adverse Events form and should not be included on the standard 
Adverse Events form that is available at treatment unless there has been an increase in 
grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query free. 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements. The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare occurrence, that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
• 
Study specific documents: Protocols > Documents> Education and Promotion; and   
• 
Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information> User Guides & Help Topics. 
 
          NCI requirements for SAE reporting are available on the CTEP website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available 
at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ 
aeguidelines.pdf. 
13.3   Data Quality Portal (03-AUG-2020) 
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 and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 

 
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The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave   
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 
DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   
13.4    Summary of Data Submission (25-NOV-2019) 
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 Section 7.4 for information about expedited and routine 
reporting.   
 
Summary of All Data Submission: Refer to the protocol specific page on the NRG 
website (www.nrgoncology.org). 
 
See Section 8.3 for TRIAD account access and installation instructions.  See data 
submission table for TRIAD below. 
 
DICOM Items 
Planning CT PET (if used for 
contour delineation) 
Must be submitted and 
approval received prior to 
start of RT 
RT Structure 
 
RT Digital Plan 
 
RT Dose 
 
 
RT Plan 
 
All required structures must be labeled per the tables in Sections 
5.2.4 
 
5.2.5 
 
 
 
Upon submission of the digital data via TRIAD, complete an online 
 
Digital Data Submission Information Form (DDSI): 
https://www.irocqa.org/Resources/TRIAD 
 
 

 
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NOTE: ALL SIMULATION AND PORTAL IMAGES WILL BE 
KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED. 
 
14.       STATISTICAL CONSIDERATIONS 
14.1 
Study Design 
This is a phase I trial to assess the safety and feasibility of MEDI4736 (durvalumab) and 
RT that is split into 2 parts.  In the initial safety part, 6 patients will enroll to the ACRT + 
MEDI4736 (durvalumab) arm, with a mandatory toxicity evaluation period of 90 days 
from the start of radiation therapy.  After the first 6 patients are enrolled onto the ACRT, 
6 patients will be enrolled to the standard radiation + MEDI4736 (durvalumab) arm with 
a mandatory toxicity evaluation of 8 weeks from the start of radiation therapy.  Once all 
patients have been assessed for toxicity, the expansion part of this study will enroll 6 
patients each to the arm(s) that is/are deemed safe.  If both arms are deemed safe, then a 
total of 12 patients will be randomized to receive ACRT + MEDI4736 (durvalumab) or 
standard radiation + MEDI4736 (durvalumab).   If only one of the two arms is deemed 
safe, then only that arm will enroll 6 additional patients.  If neither arm is deemed safe, 
then the study will not continue onto the expansion part. 
 
14.2 
Study Endpoints 
14.2.1 Primary endpoint: Safety of MEDI4736 (durvalumab) in combination with RT  
14.2.2  Secondary endpoints 
• Feasibility of MEDI4736 (durvalumab) in combination with RT 
• Adverse events, as measured by CTCAE v 5.0 
• Progression free survival, according to RECIST guidelines 
14.2.3  Exploratory endpoints 
• Progression free survival, according to irRC guidelines 
• CTC and immune parameter changes during treatment  
 
14.3 
Primary Objectives Study Design (03-AUG-2020) 
14.3.1 Primary Hypothesis and Endpoints 
 
The primary hypothesis is that MEDI4736 (durvalumab) in combination with two 
schedules of radiation therapies (60 Gy in 30 fractions or 60 Gy in 15 fractions) is safe. 
14.3.2 How Primary Endpoints Will Be Analyzed  
The tolerability of this regimen is defined as having one or no safety events defined as:  
1) grade 4-5 non-hematologic serious adverse events (SAEs) as defined in Section 7.4.2 
possibly, probably or definitely related to protocol treatment by 90 days from the start of 
concurrent therapy (start of RT) for the ACRT + MEDI4736 (durvalumab) arm and 8 
weeks from the start of concurrent therapy (start of RT) for the standard radiation + 
MEDI4736 (durvalumab) arm;  
2) any adverse events possibly, probably or definitely related to protocol treatment that 
lead to prolonged dose delays (defined as skipping at least 2 doses of MEDI4736 
(durvalumab) during the same monitoring period for each arm);  
3) permanent discontinuation of MEDI4736 (durvalumab) due to toxicity possibly, 
probably or definitely related to protocol treatment within the first 30 days of starting 
MEDI4736 (durvalumab); or  

 
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4) SAEs possibly, probably or definitely related to RT (including grade 3-4 congestive 
heart failure, pneumonitis, arrhythmias, and myocardial infarction, grade 4 esophagitis, 
and any AEs that lead to hospitalization) that causes either an interruption or early 
termination of RT as specified in Section 6.1.   
 
The proportion of patients who have tolerated the treatment will be provided.  All adverse 
events will be graded according to CTCAE v 5.0.  All DLTs will be adjudicated by the 
study PI and either the disease site chair or a study chair in terms of attribution to 
protocol treatment and whether the event meets the definition of a DLT.  If the 
adjudicators are not in agreement, a third adjudicator will be brought in to review the 
DLT.   
 
14.3.3 Sample Size and Power Calculations 
Evaluable patients must be eligible at the time of study registration and have started 
protocol treatment.  If a patient dies or withdraws consent from the study within the 
safety monitoring period without experiencing a safety event that patient will be replaced.  
Each arm will enroll a maximum of 12 evaluable patients for assessment of tolerability.  
In the first part of the study for either arm, if 0-1 of 6 evaluable patients develop any of 
the safety events after completing RT, then the regimen will be deemed safe and that arm 
will continue to the second part of the study and enroll 6 additional evaluable patients.  
However, if 2 or more of 6 evaluable patients develop any safety events, that arm is 
considered not safe and will not be pursued in the second part.  With a cohort of 6 
patients, the probability of the treatment being judged to be too toxic when the true 
toxicity rate is 40% or higher is at least 77%. If the true toxicity rate is 18% or lower, the 
probability that the treatment will be deemed to be safe is at least 70%.   
 
If 4 or more of the 12 evaluable patients on an arm experience a safety event, the 
treatment will be considered not tolerable.  If 4 patients experience a safety event prior to 
reaching the target sample size of 12 patients, accrual to that cohort will be closed.  If 3 
patients experience a safety event once 9 patients have been enrolled but prior to reaching 
12 patients, accrual will be suspended to monitor the remaining patients still in the safety 
assessment window for whom a safety event has not been reported.  Accrual to that 
cohort will only be reopened if no additional patients have experienced a safety event.   
 
The other cohort will remain open to accrual, if applicable, during this time.  If fewer  
than 4 of the 12 evaluable patients on an arm experience a safety event, then the 
treatment will be considered tolerable.  With a cohort of 12 patients, the probability of the 
treatment being judged to be too toxic when the true toxicity rate is 40% or higher is at 
least 78%. If the true toxicity rate is 18% or lower, the probability that the treatment will 
be deemed to be safe is 85%.  In order to proceed to a phase II trial, the treatment(s) must 
be considered both safe (as defined above) and feasible (as defined in Section 14.6.2). 
 
14.4 
Study Monitoring of Primary Objectives 
Interim Analysis to Monitor Study Progress 
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 

 
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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.  
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, 
July 31, and October 31.  Instructions for submitting data using the CDUS can be found 
on the CTEP website  
(http://ctep.cancer.gov/reporting/cdus.html). 
 
After the start of the accrual, the study team, including the study chairs, study 
statisticians, data managers and protocol administrator, and a representative from each 
participating site will hold at least monthly conference calls to review the overall conduct 
of the study lead by the study statistician. Data on treatment dose delivery, adverse events 
reported, patient demographics and eligibility will be assembled and reviewed.  At each 
meeting, consideration is also given to the rate of accrual. Brief minutes of each meeting 
will be written by the study chairs to document the review of information and any 
decision made. The meeting minutes will be submitted to the NRG early phase protocol 
monitoring oversight committee for review. 
 
If one or both arms are to move forward to the expansion cohort based on the criteria 
stated in Section 14.3.3, a review of the data with the study team and CTEP will take 
place. 
 
14.5 
Accrual/Study Duration Considerations 
Accrual is expected to be 4 patients/month after a 3 month initial ramp-up period.  Initial 
Safety Schedules (enrollment of 6 patients/arm) is expected to close after 6 months.  
Expansion Cohorts will open, assuming ACRT + MEDI4736 (durvalumab) is shown to 
be safe and feasible, approximately 4-6 months after closing Initial Safety Schedules (to 
allow for 8-16 weeks of follow-up to assess prolonged dose delays as well as time for 
data collection and analysis).  It is projected to take 4 months to accrue to Randomization 
stage (1 month ramp-up period and 3 months accruing 4 patients/month).  This stage will 
similarly require 8-16 weeks of follow-up to assess prolonged dose delays.  The primary 
analysis is projected to occur approximately 20 months from study activation. 
 
14.6     Secondary Endpoints  
14.6.1 Secondary Hypotheses and Endpoints:  
• MEDI4736 (durvalumab) in combination with RT is feasible 
• Adverse events, as measured by CTCAE v 5.0 
• Progression free survival 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Feasibility 
Feasibility is based on an evaluation of the percentage of patients who received at least 
80% of the planned dose of MEDI4736 (durvalumab) therapy during the first 8 weeks 
following initial dose of MEDI4736 (durvalumab). Feasibility will only be assessed for 

 
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the treatment cohort(s) that moves to the expansion phase. The observation of at least 
80% (10/12 per arm) of patients who received at least 80% of the planned dose is 
considered to be evidence that this regimen is feasible in this setting.   
 
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. 
 
Progression Free Survival 
Tumor response will be assessed by the RECIST guidelines (as reported by the sites) as 
defined in Section 4.  Progression free survival (PFS), defined as the time from 
registration to progressive disease or death, whichever occurs first, will be estimated 
using the Kaplan Meier method.  Plots and descriptive statistics will be provided for both 
treatment arms but no formal testing performed due to lack of statistical power.   
 
14.6.3 Exploratory Hypotheses and Endpoints 
Progression Free Survival 
Tumor measurements will be collected at baseline, the end of treatment and throughout 
follow-up in order to determine response using the irRC guidelines.  Progression free 
survival (PFS), defined as the time from registration to progressive disease or death, 
whichever occurs first, will be estimated using the Kaplan Meier method.  Plots and 
descriptive statistics will be provided for both treatment arms but no formal testing 
performed due to lack of statistical power.   
 
 
Biomarker Analysis 
 
Biomarker analyses will be conducted for feasibility purposes.  There is not sufficient 
power to detect differences between arms or any prognostic ability of the biomarkers 
described.  Therefore all biomarker analyses, including the immune parameters described 
in Section 10.4.1, will focus on descriptive statistics and change from baseline to 
subsequent collection times.  Circulating tumor cells will be collected and analyzed at the 
time of progression.  It is hypothesized that progressed patients will have a value of green 
fluorescent proton-expressing cells per ML > 1.3 (Frick 2018, Dorsey 2015).  Therefore, 
at 2 years, an analysis will be conducted to determine if every progressed patient has a 
value > 1.3.    
  
14.6.4 Gender/Ethnicity/Race Distribution 
There will not be sufficient sample sizes to conduct any subgroup analyses based on race, 
ethnicity, and/or gender. 
 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Hispanic or Latino 
 

 
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REFERENCES (25-NOV-2019) 
 
Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-
Small-Cell Lung Cancer.  N Eng J Med, September 8, 2017; 377:1919-1929. 
 
Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after 
Chemoradiotherapy in Stage III NSCLC. N Eng J Med, 2018;379:2342-50. 
 
Bradley JD, Paulus R, Komaki R, et al. Standard dose versus high dose conformal radiotherapy 
with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for 
patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomized, two-by-
two factorial phase 3 study.  Lancet Oncol 2015:16(2):187-199. 
 
Büttner R, Gosney JR, Skov BG, et al.  Programmed Death-Ligand 1 Immunohistochemistry 
Testing: A Review of Analytical Assays and Clinical Implementation in Non-Small-Cell Lung 
Cancer.  J Clin Oncol. 2017 Dec 1;35(34):3867-3876. 
 
Cahalane MJ.  Overview of gastrointestinal tract perforation. UpToDate, November 29, 2017.  
https://www.uptodate.com/contents/overview-of-gastrointestinal-tract-perforation 
 
Chaudhuri AA, Chabon JJ, Lovejoy AF, et al.  Early Detection of Molecular Residual Disease in 
Localized Lung Cancer by Circulating Tumor DNA Profiling. Cancer Discov, 2017 Dec; 
7(12):1394-1403. 
 
Cheung P, Faria S, Ahmed S, et al. Phase II study of accelerated hypofractionated three-
dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC 
CTG BR.25. J Natl Cancer Inst Jul 29; 106(8), 2014. 
 
Cunard R, Kelly CJ.  Immune-mediated renal disease.  J Allergy Clin Immunol. 2003 Feb; 111(2 
Suppl):S637-44. 
 
Deng L, Liang H, Burnette B, et al.  Radiation-induced equilibrium is a balance between tumor 
cell proliferation and T cell-mediated killing. J Clin Invest. 2014: 124(2):687-95. 
 
Deng L, Liang H, Burnette B, et al.  Radiation and anti-PD-L1 antibody combinatorial therapy 
induces T cell-mediated depletion of myeloid-derived suppressor cells and tumor regression. 
Oncoimmunology 2014:3:e28499. 
 
Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 
antibodies across clinical indications.  Semin Oncol 2010; 37:499-507. 
 
Dorsey JF, Kao GD, MacArthur KM, Ju M, Steinmetz D, Wileyto EP, Simone CB 2nd, Hahn 
SM. Tracking viable circulating tumor cells (CTCs) in the peripheral blood 
of non-small cell lung cancer (NSCLC) patients undergoing definitive radiation therapy: pilot 
study results. Cancer. 2015 Jan 1; 121(1):139-49. 
 

 
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Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated 
radiotherapy can be overcome by concurrent PD-L1 blockade.  Cancer Res 2014:74(19):5458-
68.  
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1).  Eur J Ca, 2009 Jan; 45:228-247, 2009. 
 
Frick MA, Kao GD, Aguarin L, Chinniah C, Swisher-McClure S, Berman AT, Levin WP, 
Cengel KA, DeCesaris C, Hahn SM, Dorsey JF, Simone CB 2nd. Circulating Tumor Cell 
Assessment in Presumed Early Stage Non-small Cell Lung Cancer Patients Treated with 
Stereotactic Body Radiation Therapy: A Prospective Pilot Study. Int J Radiat Oncol Biol Phys. 
2018; in press. 10.1016/j.ijrobp.2018.06.041. 
 
Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.  Ann Oncol 
2017:28(4):119-142. 
 
Izzedine H, Gueutin V, Gharbi C, et al. Kidney injuries related to ipilimumab. Invest New 
Drugs.  2014; 32:769-773. 
 
Johnson, DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune 
Checkpoint Blockade.  N Engl J Med 2016; 375:1749-1755. 
 
Kaehler, KC, Piel S, Livingstone E, et al. Update on immunologic therapy with anti-CTLA-4 
antibodies in melanoma: identification of clinical and biological response patterns, immune-
related adverse events, and their management.  Semin Oncol 2010; 37:485-498. 
 
Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated hepatitis: imaging and 
clinicopathologic findings.  Invest New Drugs. 2013; 31:1071-1077. 
 
Lacouture, ME, Wolchok, JD, Yosipovitch G, et al. Ipilimumab in patients with cancer and the 
management of dermatologic adverse events.  J Am Acad Dermatol. 2014; 71:161-169. 
 
Lenz HU.  Management and preparedness for infusion and hypersensitivity reactions.  
Oncologist; 2007 May; 12(5):601-9. 
 
Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating 
tumor DNA with broad patient coverage. Nat Med 2014 May; 20(5):548-54. 
 
Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved 
detection of circulating tumor DNA. Nat Biotechnol 2016 May; 34(5):547-555. 
 
Perez CA, Stanley K, Rubin P, et al.  A Prospective Randomized Study of Various Irradiation 
Doses and Fractionation Schedules in the Treatment of Inoperable Non-Oat-Cell Carcinoma of 
the Lung.  Preliminary Report by the Radiation Therapy Oncology Group.  Cancer 45(11):2744-
53, 1980.   

 
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Reck M, Brahmer JR. Pembrolizumab in Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 
376(10):997. 
 
Stewart R., Morrow M, Hammond SA, et al.  (2015). Identification and Characterization of 
MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody.  Cancer Immunol Res.  3:1052-
1062. 
 
Stinchcombe TE, Zhang Y, Vokes EE, et al.  Pooled Analysis of Individual Patient Data on 
Concurrent Chemoradiotherapy for Stage III Non-Small-Cell Lung Cancer in Elderly Patients 
Compared With Younger Patients Who Participated in US National Cancer Institute Cooperative 
Group Studies.  J Clin Oncol 35(25):2885-2891, 2017. 
 
Sughayer MA, Alnaimy F, Alsughayer AM, Qamhia N1.  Comparison of 22C3 PharmDx and 
SP263 Assays to Test PD-L1 Expression in NSCLC.  Appl Immunohistochem Mol Morphol. 
2019 Oct;27(9):663-666. 
 
Tarhini A. Immune-mediated adverse events associated with ipilimumab ctla-4 blockade 
therapy: the underlying mechanisms and clinical management.  Scientifica (Cairo).  
2013:857519. 
 
Teply BA, Lipson EJ. Identification and management of toxicities from immune checkpoint-
blocking drugs. Oncology 2014:  Nov 28 Suppl 3:30-8. 
 
Urbanic JJ, Wang X, Bogart JA, et al. Phase 1 Study of Accelerated Hypofractionated Radiation 
Therapy with Concurrent Chemotherapy for Stage III Non-Small Cell Lung Cancer: CALGB 
31102 (Alliance). Int J Radiation Oncol Biol Phys 2019; 101(1):177-185. 
 
Weber, JS, Kahler KC, Hauschild A. Management of immune-related adverse events and 
kinetics of response with ipilimumab.  J Clin Oncol 2012; 30:2691-2697. 
 
Zhang X, Ran Y, Wang K, et al. Incidence and risk of hepatic toxicities with PD-1 inhibitors in 
cancer patients: a meta-analysis. Drug Des Devel Ther (2016); 10:3153-3161.

 
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APPENDIX I:  RECIST CRITERIA 
 
RECIST 1.1 
irRECIST 
Target and non-target lesions 
Sum of the longest diameters of 
target lesions (uni-dimensional) 
Measurable lesions are ≥10 mm 
in diameter (≥15 mm for nodal 
lesions) 
Maximum of five lesions (two 
per organ) 
Same 
New lesion 
Represents PD 
Does not correspond to a 
formal progression 
The longest diameter will be 
added to the total measured 
tumor burden of all target 
lesions at baseline 
CR 
Disappearance of all target and 
non-target lesions 
Nodal short axis diameter < 10 
mm 
No new lesions 
Same 
PR 
Decrease of 30% in tumour 
burden relative to baseline Non-
unequivocal progression of non-
target lesions No new lesions 
Same 
SD 
Neither PR or PD 
Same 
PD 
Increase ≥20% of the sum of LD 
compared with nadir (minimum 5 
mm) or progression of non-target 
lesions or new lesion 
irPD Increase ≥20% (minimum 
5 mm) in TMTB compared 
with nadir or progression of 
non-target lesions or new lesion 
 
Confirmation of progression 
recommended minimum 4 
weeks after the first irPD 
assessment 
Confirmed PD 
Not required 
New unequivocal progression 
or worsened progression from 
initial PD visit  
Appearance of another new 
lesion 
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; TMTB, total measured 
tumour burden. 

APPENDIX III:  CTEP COLLABORATIVE AGREEMENTS LANGUAGE 
 
Protocols that involve agent(s) covered by a collaborative agreement with a biotech/pharma 
company(ies) must incorporate the NCI/ DCTD Collaborative Agreement Language shown 
below. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to 
the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as “Collaborator(s)”) and the 
NCI Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the “Intellectual Property 
Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators. The 
protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a 
copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in 
combination with (an)other Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a.   NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b.   Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c.   Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 

 
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3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings. Press releases and other media 
presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email : ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 

 
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3. Estimated creatinine clearance (ClCr) by the Cockcroft-Gault (C-G) equation 
(Cockcroft and Gault, 1976). 
 
 
 
References 
1. Levey, AS, Stevens LA, Schmid CH, et al (2009). A new equation to estimate glomerular 
filtration rate.  Ann Inter Med.  150:604-612. 
2. Levey, AS, Coresh J, Greene T, et al (2006). Using standardized serum creatinine values in 
the modification of diet in renal disease study equation for estimating glomerular filtration 
rate.  Ann Intern Med.  145:247-254. 
3. Cockcroft, DW and Gault MH (1976). Prediction of creatinine clearance from serum 
creatinine.  Nephron.  16:31-41. 

APPENDIX V:  CLINICAL BLOOD SAMPLE SHIPMENT PREPARATION AND 
TRANSPORTATION FOR TELOMESCAN (25-NOV-2019) 
 
I. RATIONALE 
The purpose of this document is to describe the procedure for handling, packaging, and shipping 
blood samples from study participants, by ensuring safe and timely delivery to Liquid Biotech 
USA. 
 
1. Circulating Tumor Cell (CTC)  
A. Overview 
Currently, there is little known about the numbers, time course, and effect of therapy on 
Circulating Tumor Cells (CTCs) in NSCLC patients. The biospecimens collected in this 
study will allow for an assessment of (1) CTC changes during treatment with durvalumab 
and radiotherapy and after completion of treatment, and (2) the relationship between CTC 
changes during and following treatment with radiographic tumor response and disease 
recurrence.  CTCs will be enriched from whole blood and treated with TelomeScan 
(OBP-401). TelomeScan is a genetically engineered adenovirus that replicates and 
produces GFP (Green Fluorescent Protein) specifically in live, cancerous cells with high 
TERT expression. GFP expressing cells will be imaged and enumerated. The 
disappearance of CTCs / mL is an indication of disease clearance, and the reappearance 
of CTCs / mL is an indication of progressive disease or recurrence. 
B. Laboratory Testing Procedures 
Blood specimens are required for this analysis. The procedure of blood collection for 
each patient will be as follows: Blood will be drawn into a waste tube (to avoid collecting 
skin material and potential contaminating skin stem cells). The waste tube will either be 
discarded or used to investigate other laboratory methods involving CTC virus 
transduction. Subsequently, blood will be collected in ACD-A tubes at ambient 
temperature and placed in an insulated tube box inside a biohazard plastic bag and 
transported to the laboratory for processing.   
 
II. MATERIALS 
No. 
Product 
Quantity 
1 
TelomeScan corrugated shipping box 
1 
2 
Biohazard Specimen Transport Bag 
1 
3 
Absorbent pad 
1 
4 
Gel pack (Phase 22™ Cryopak) 
2 
5 
List of contents card 
1 
6 
Barcoded BD Vacutainer™ Blood 
Collection Tube with ACD-A (8.5mL) 
3 
7 
Insulated tube holder box 
1 
8 
Commercial Grade Packaging tape 
1 (supplied as 
needed per site) 
 
III. PROCEDURE 
 SHIPMENT PREPARATION INSTRUCTIONS 

 
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1. All necessary materials for shipping (including blood collection tubes and 2 gel packs for 
internal temperature control) may be obtained from Liquid Biotech USA. Please contact 
Liquid Biotech USA at support@liquidbiotechusa.com (tel: 267-225-7361) to arrange for 
delivery of materials. Prior to blood collection, it is recommended for patient visit dates 
to be logged by going to www.liquidbiotechusa.com and clicking the “Schedule” button 
on the main page. 
 
 
 
2. Using the barcoded blood collection tubes with Acid-Citrate-Dextrose Solution A (ACD-
A), completely collect whole blood. It is critical that tubes are inverted 8-10 times 
immediately following collection of each tube.  The first 5 mL of the blood draw should 
be drawn in a discard tube to avoid skin cell contamination. Extra ACD-A tubes are 
supplied which may be used for the initial 5mL discard. Only 1 completely filled tube is 
required for testing. Each tube should be filled with 8.5mL of blood to completely fill the 
tube. It is necessary to ship samples on the same day as the blood draw. Samples should 
be stored at ambient temperature until shipped.  
NOTE: Liquid Biotech USA is NOT able to accept deliveries on a weekend or major US 
holiday. Please do NOT draw blood on a Friday or the 2 days prior to a major US 
holiday, as the sample will not be received in a timely manner. If the patient can only be 
seen on one of these days, please coordinate special transportation needs with Liquid 
Biotech USA. 
 
3. Barcoded tubes should be clearly labeled to include date and time of blood draw. NOTE: 
Sites may include a unique identifier number documentation purposes.  
 
4. Place filled tube(s) in the insulated tube holder and place inside a Biohazard Specimen 
Transport Bag with absorbent material. 
 

 
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5. Place the tube holder in bag between the 2 gel packs that are supplied with the kit. These 
gel packs change phase between solid and liquid at 72°F. When shipping during the 
colder seasons (external low temperature <32°F), it is recommended to ship packs in the 
liquid state. When shipping during the warmer seasons (external high temperature >86°F) 
it is recommended to ship packs in the solid state. 
 
 
6. Fill out the itemized list of contents card and place on top of the Styrofoam box. The card 
should have checked Diagnostic Specimens, Glass and/or Plastic tubes, Tube Separator 
Bag(s), Secondary Container/Canister, and Absorbent Pad(s). Optionally, the 
“Requisition” and “Instruction Sheet” should be checked if included.  
 
 
 
 
 
 
 
 
 
7.  Seal the corrugated box with packaging tape across the front flap.  
 

 
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8. Samples should be shipped at ambient temperature the same day they are collected.  
 
9. Kits are pre-labeled with FedEx shipping information. Ship the package at ambient 
temperature by contacting FedEx for pick-up at 1-800-463-3339.  
 
 
NOTE: It is critical that samples are shipped the same day as blood collection (using 
FedEx overnight), so that they may be processed within approximately 24 hours of the 
blood draw. Samples that are not received by Liquid Biotech USA on the day following 
blood collection will not be processed.  
 
IV. HEALTH AND SAFETY 
1. Standard safety precautions are to be followed. Always wear gloves when handling blood 
samples.  
2. Refer to the risk assessment, hazard data sheets, and Departmental policy at your location 
for additional safety information. 
 
V. PERSONNEL  
Appropriate staff for sample packaging preparation and shipment may include all trusted 
and responsible institution lab personnel qualified to handle blood samples.  
 
VI. Packaging and shipment checklist of clinical specimens 
Check 
or 
Initial 
Item/Activity 
 
All primary receptacles (i.e., specimen collection containers) have positive closures, 
such as conventional caps. 
 
Each primary receptacle is labeled with the date/time the sample was collected, and 
optionally a unique identifier. 
 
For liquid specimens, the primary receptacle is leak-proof and contains a maximum 
of 10 ml. 
 
When shipped by air, the primary or secondary containers are able to withstand, 
without leakage, an internal pressure producing a pressure differential of not less than 
95kPa (14 psi) in the range of -40°C to 55°C (-40°F to 130°F). 
 
The primary receptacles are individually wrapped or separated and placed inside a 

 
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APPENDIX VI:  NRG BIOSPECIMEN BANK – SAN FRANCISCO 
BIOSPECIMEN PROCEDURES (25-NOV-2019) 
A. Shipping instructions for Banking Samples 
B. FFPE Specimen Plug Kit Collection 
 
A.  Shipping Instructions for Banking FFPE: 
 
US Postal Service Mailing Address: 
Use only for non-urgent ambient specimens- 
FFPEs, slides, blocks: 
Courier Address (FedEx, UPS, etc.): 
For Frozen, Urgent or Trackable Specimens: 
 
NRG Oncology Biospecimen Bank – San 
Francisco 
UCSF – Box 1800 
2340 Sutter St., Room S341 
San Francisco, CA 94143 
 
 
NRG Oncology Biospecimen Bank – San 
Francisco  
University of California San Francisco 
2340 Sutter St., Room S341 
San Francisco, CA 94115 
415-476-7864 
 
 
1. Include all required specimen paperwork in pocket of biohazard bag. 
 
2. Check that the Specimen Transmittal (ST) Form has been completely filled out. Use NRG 
labels for the top box (Study & Case). 
 
3. Only send samples that have a case # assigned. If the patient does not have a case number it 
means they are not registered yet. Contact NRG Oncology data managers with questions 
regarding registration. 
 
4. Check that all samples are labeled with the NRG Study, case number, and date of procedure. 
 
5. FFPE Specimens for Banking:  
• 
H&E Slide of primary tumor (can be duplicate cut slide, does not have to be diagnostic 
slide).  
• 
FFPE Tissue Block of primary tumor (must be same block as H&E slide being 
submitted). If an FNA was done we cannot accept FNA slides unless there is an FFPE 
cell block with tumor cells available. Sites are to submit one FNA H&E and matching 
FNA FFPE cell block if sufficient tumor cells are available. If there are insufficient cells 
then note this on the ST form with the H&E being submitted. 
• 
For sites unable to submit the complete tumor tissue block then then the following 
alternative is acceptable: Either:  
o Two unstained slides with date cut on the slides.  
o OR Two 2mm (or 3mm) punches (tumor size dependent) embedded in paraffin 
with a corresponding H&E. (Punch kits available from NRGBB-SF upon request). 
If sites are unable to embed the punches they may send the punches to the 
biobank to be embedded.  

 
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o If sites are unable to provide punches due to limited amounts of tissue, then TWO 
freshly cut 5 micron unstained slides are an acceptable alternative in such cases. 
Sites must label the unstained slides with Study, Case#, accession number, block 
number and date the slides were cut. Slides must be shipped to NRGBB-SF within 
2 business days from when they were cut.  
 
Please make sure all FFPE specimens are labeled with Study#, Case#, Specimen accession 
number and block ID. Redact or cover up the patient name if present. Do not add paper sticky 
labels over this information. It is the Biospecimen Banks SOP to remove all sticky labels on 
slides before adding an NRGBB label.  
 
All FFPE submission must include the H&E slide that matches the samples. We cannot accept 
FFPE submissions without the H&E slide. If submitting embedded punches, an H&E from the 
punch block must be included along with the original block H&E with the area punched marked 
on the original H&E.  
 
If patients consent to banking DO NOT ship us FFPE specimens with a return request. We 
cannot accept or bank samples that we cannot keep. Always send what can be banked 
(duplicate H&Es, Blocks or punches). We can punch and return blocks if noted in the protocol. 
You may indicate that you want us to punch and return the block on the ST form and you can 
include a return request form and return airbill with the submission. Punch kits can be 
requested from us by email (NRGBB@ucsf.edu) if sites wish to punch the block themselves. 
 
Slides should be shipped in plastic slide holder/slide box. Place a small wad of padding in top 
of the container. If you can hear slides shaking it is likely that they will break during shipping. 
 
DO NOT ship slides in cardboard slide flats or single unit plastic slide holders. 
 
FFPE Blocks can be shipped in a plastic block holder or wrapped with paper or placed in a 
paper envelope, and placed in a cardboard box with padding. Do not wrap blocks with bubble 
wrap or gauze. Place padding in top of container so that if you shake the container the blocks 
are not shaking. If you can hear blocks shaking they may break during shipping. During warm 
weather months the use of cold packs is highly recommended to prevent wax from melting. 
 
Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States 
Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address 
(94115). Do NOT ship on Dry Ice. Do not ship in a flat or padded envelope without a protective 
box/container inside, they can be crushed, even if in a plastic slide holder. 
 
Urgent overnight shipments (central review) should always be sent by Courier. Do not send by 
First overnight or Saturday delivery as our building is not open before 8am or on weekends. 
 
✓ For Questions regarding collection/shipping please contact the NRG Oncology 
Biospecimen Bank- San Francisco by e-mail: NRGBB@ucsf.edu or phone: 415-476-
7864 or Fax: 415-476-5271. 
 

 
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✓ For forms and additional information please visit our website:  
http://NRGBB.UCSF.EDU 
 
B.    NRG FFPE SPECIMEN PLUG KIT INSTRUCTIONS: 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen 
Bank- San Francisco. The plug kit contains a shipping tube and a punch tool. 
 
  
 
 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank- San Francisco and we will sample a 
plug from the block and return the remaining block to your facility.  Please indicate on the ST form 
the request to perform the plug procedure and return of the block. Include a return request form with 
a return airbill. 
  
Ship specimen plug kit, specimen in punch tool, or block and all paperwork to the address below. For 
Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the 
Step 2 
Label the punch tool with the proper specimen ID 
and Block ID.  DON’T remove specimen from the 
punch if punch is not being embedded by the site. 
 
Use a separate punch tool for every specimen. Call 
or e-mail us if you have any questions or need 
additional specimen plug kits. 
Site that have the capacity to embed the blocks may 
do so. They should submit a fresh H&E from the 
punch block.  
Step 3 (for non-embedded samples) 
Once punch tool is labeled, place in shipping 
tube and mail to address below. Please do not 
mix specimens in the same tube.    
 
The bank will remove core specimen from the 
punch, embed in a paraffin block, and label with 
specimen ID. 
 
Step 1 
If the block is stored cold, allow it to equilibrate for 
30 minutes at room temperature. Place the punch 
tool on the paraffin block over the selected tumor 
area. (Ask a pathologist to select area with tumor.) 
Push the punch into the paraffin block. Twist the 
punch tool once around to separate the plug from 
the block. Then pull the punch tool out of the 
block. The punch should be filled with tissue 
sample. 

 
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NRG Oncology Biospecimen Bank- San Francisco by e-mail: NRGBB@ucsf.edu or call 415-476-
7864/Fax 415-476-5271. 
 
 
US Postal Service Mailing Address:  
Use only for non-urgent ambient specimens- 
FFPEs, slides, blocks: 
 
Courier Address (FedEx, UPS, etc.):  
For Frozen, Urgent or Trackable Specimens: 
NRG Oncology Biospecimen Bank-  
San Francisco 
UCSF-  Box 1800 
2340 Sutter St, room S341 
 San Francisco, CA 94143 
NRG Oncology Biospecimen Bank- San 
Francisco 
University of California San Francisco 
2340 Sutter St, room S341 
San Francisco, CA 94115 
415-476-7864 

APPENDIX VII:  NRG BIOSPECIMEN BANK-COLUMBUS 
BIOSPECIMEN PROCEDURES (25-NOV-2019) 
 
1. Obtaining a Bank ID for Biospecimens 
One Bank ID (N # # # # # # # # #) is assigned per patient per study. All biospecimens and 
accompanying paperwork must be labeled with this coded patient number.  
 
A Bank ID is automatically assigned once a subject has been enrolled and appears in 
Rave.  The Bank ID will appear in the header at the top of the subject’s main page in 
Rave.  
 
Please contact User Support if you need assistance (support@nrgoncology.org). 
 
2. Requesting Biospecimen Kits 
Upon request, a biospecimen kit including a Streck tube and ambient shipper will be 
provided for the collection and shipment of cfDNA whole blood biospecimens. A 
separate kit is needed for each cfDNA whole blood biospecimen. 
 
Sites can order online via the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement). If you are new to Kit 
Management, you must register for an account prior to ordering NRG-LU004 kits. Each 
site may order two NRG-LU004 kits per day. 
Supplies will not be provided for the collection or shipment of whole blood collected 
in sodium heparin (NaHep) or EDTA tubes. 
 
Please contact the NRG BB-Columbus if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits 
should arrive within 3-5 business days. 
 
3. Whole Blood Biospecimens Shipped to the NRG BB-Columbus 
 
Labeling Whole Blood 
A waterproof permanent marker or printed label should be used to label each blood 
biospecimen with: 
 
Bank ID (N # # # # # # # # #)* 
Patient ID (e.g., AB # # # - LU004 - # # # # #) 
specimen code (see protocol section 10.5.3) 
collection date (mm/dd/yyyy) 
 
* Leading zeros may be omitted when labeling biospecimens with the Bank ID.  For 
example, N000000010 may be written as N10. 
 

 
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Required Documentation 
All blood biospecimens should be submitted with the following documentation: 
• Blood Biospecimen Submission Form 
 
All blood biospecimens will be processed as per the current CIMAC Umbrella. 
 
3.1 T Cell Whole Blood 
3.1.1 
Collection Time Points 
T cell whole blood should be collected as per section 10.5.2. 
3.1.2 
Collecting T Cell Whole Blood 
1.  Label the green top sodium heparin (NaHep) collection tube(s) as described 
above. Multiple tubes may be used to collect the required amount. Do not use 
glass blood collection tubes. 
2. Draw 30mL of blood into the labeled green top tube(s). 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the 
blood and sodium heparin. 
4. Whole blood specimens should be kept at room temperature until the 
specimens can be shipped. Whole blood must be shipped to the NRG BB-
Columbus the day the specimen is collected. If the specimen cannot be 
shipped the day it is collected, it should be discarded. 
 
3.2 T Cell Repertoire (TCR) Whole Blood 
3.2.1 
Collection Time Points 
T cell repertoire (TCR) whole blood should be collected as per section 10.5.2. 
3.2.2 
Collecting T Cell Repertoire (TCR) Whole Blood 
1.  Label the lavender/purple top (EDTA) collection tube as described above. Do 
not use glass blood collection tubes. 
2. Draw 2mL of blood into the labeled lavender/purple top tube. 
3.  Immediately after collection, gently invert the tube 5-10 times to mix the 
blood and EDTA. 
4. Whole blood specimens should be kept at room temperature until the 
specimens can be shipped. Whole blood must be shipped to the NRG BB-
Columbus the day the specimen is collected. If the specimen cannot be 
shipped the day it is collected, it should be discarded. 
 
 
3.3 Cell-Free DNA (cfDNA) Whole Blood 
3.3.1 
Collection Time Points 
Cell-free DNA (cfDNA) whole blood should be collected as per section 10.5.2. 
3.3.2 
Special Notes Regarding the Collection of Blood in Streck (cf DNA) Tubes 
• Heparin should be avoided in pre-collection flush procedures. 
• All other blood biospecimens should be drawn before the Streck (cell-free 
DNA) tube when multiple blood biospecimens are collected on the same day. 
• Over or under filling a Streck (cell-free DNA) tube will result in an incorrect 
blood-to-additive ratio. 
• No other tube may be substituted for a Streck (cell-free DNA) tube. 
 

 
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3.3.3 Collecting Streck (Cell-Free DNA) Whole Blood 
1.  Label the Streck (cell-free DNA) collection tube as described below. 
2. 
Draw 10mL of blood into the labeled tube. 
3.  Immediately after collection, gently invert the tube 5-10 times. 
4. 
Ship whole blood to the NRG BB-Columbus the day the biospecimen is 
collected. If the whole blood absolutely cannot be shipped the day it is 
collected, the tube must remain at room temperature until shipment.  
 
4.  Shipping Whole Blood Biospecimens to the NRG BB-Columbus 
• Biospecimens should not be shipped until after patient registration. 
• The required documentation must be included for each biospecimen.  
• All biospecimens should be shipped to: 
NRG BB-Columbus / Protocol NRG LU004 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: 614-722-2865 
FAX: 614-722-2897 
Email: BPCBank@nationwidechildrens.org 
 
• Whole blood biospecimens can be shipped to the NRG BB-Columbus Monday through 
Friday for Tuesday through Saturday delivery. Do not ship whole blood the day 
before a holiday. Ship biospecimens via FedEx priority overnight. 
• When shipping whole blood biospecimens, your site must comply with IATA 
standards (www.iata.org). If you have questions regarding your shipment, contact the 
NRG BB-Columbus at BPCBank@nationwidechildrens.org or by phoning 866-464-
2262.  
 
4.1 Whole Blood Collected in Sodium Heparin (NaHep) and EDTA Tubes 
To ship whole blood collected in Sodium Heparin (NaHep) and EDTA tubes you will 
need (1) a sturdy shipping container (e.g., a cardboard or styrofoam box), (2) a leak 
proof biohazard envelope with absorbent material*, (3) a puncture and pressure 
resistant envelope (e.g. Tyvek envelope), (4) an Exempt Human Specimen sticker, 
and (5) a pre-paid FedEx air bill. 
*If you will be shipping both whole blood collected in sodium heparin (NaHep) and 
EDTA, please put each biospecimen in a separate plastic zip-lock bag before placing 
the biospecimens in the shipping bag.  
 
If you do not have these materials available at your site, you may order them from 
any supplier (e.g., Saf-T-Pak; Phone: 800-814-7484; Website: www.saftpak.com). 
 
4.1.1  Shipping Whole Blood in Sodium Heparin (NaHep) and EDTA Tubes 
Note: Sodium heparin (NaHep) whole blood must be processed immediately 
upon receipt at the NRG BB-Columbus. To ensure this processing, please note 
the special instructions in #7 below. 

 
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112                        Version Date:  November 3, 2021 
1. 
Ship whole blood collected in sodium heparin (NaHep) or EDTA tubes using 
your own shipping container and supplies. 
2. 
Place the whole blood biospecimens in a biohazard envelope containing 
absorbent material. Expel as much air as possible before sealing the bag. 
3. 
Wrap the biohazard envelope in bubble wrap or another padded material. 
4. 
Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible 
before sealing the envelope. 
5. 
Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx 
box). 
6. 
Insert a copy of the Blood Biospecimen Submission Form for each 
biospecimen.  
7. 
Attach an Exempt Human Specimen sticker to the outside of the shipping 
container. A neon- or brightly-colored sticker that states “CIMAC Blood,” as 
well as the blood collection date and time (e.g., 1/2/2019, 12:32pm), must also 
be attached to the shipping container. 
8. 
Print a pre-paid FedEx air bill using the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement/) and attach to the 
top of the shipping container. 
9. 
Make arrangements for FedEx pick-up through your site’s usual procedure or 
by calling 800-238-5355. 
 
4.2 Whole Blood Collected in Streck Tubes 
To ship whole blood collected in Streck tubes you will a Streck Cell-Free DNA 
Ambient Shipper. Refer to Section 2 for details. 
 
4.2.1 Shipping Whole Blood Using a Streck Cell-Free DNA Ambient Shipper 
1. Before packaging cfDNA whole blood biospecimens, verify that each 
biospecimen is labeled according to the instructions above.   
2. Prepare the SAF-T-TEMP Gel Pak for shipment. Note: If contents of the Pak are 
crunchy, place Pak in a warm water bath until gel is smooth. Do not refrigerate, 
freeze, or microwave.  
3. Place the SAF-T-TEMP Pak in bottom of insulated chest. Note: The insulated 
chest must be shipped inside the provided cardboard box.  
4. Place the blood collection tube in zip-lock bags.   
5. Next, place zip-lock bag into a biohazard envelope with absorbent material. Expel 
as much air as possible and seal the envelope securely.  
6. Place the biohazard envelope into a Tyvek envelope. Expel as much air as 
possible and seal securely. 
7. Place packaged Streck blood collection tube and a completed copy of the Blood 
Biospecimen Submission Form on top of SAF-T-TEMP Gel Pak.  
8.  Place the lid on the insulated chest.  
9. Close the outer flaps of the shipping box and tape shut. 
10. Print a pre-paid FedEx air bill using the Kit Management link 
(https://ricapps.nationwidechildrens.org/KitManagement/) and attach to the top of 
the shipping container. 
 

 
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113                        Version Date:  November 3, 2021 
11. Attach an Exempt Human Specimen sticker to the side of the box. 
12. Make arrangements for FedEx pick-up through your site’s usual procedure or by 
calling 800-238-5355. 

APPENDIX VIII:  CANCER IMMUNE MONITORING AND ANALYSIS CENTER 
(CIMAC) BIOMARKER TESTING (03-NOV-2021) 
 
1.   CyTOF  
A. Overview 
Assessment of changes in immune cell diversity over time is required to quantify the 
immune cell subsets in circulation, with each subset given in percentages rather than 
absolute amount or levels. The dynamic changes in immune cell subsets throughout 
therapy may tell us whether specific subsets of T cells are being expanded, such as 
memory T cells or activated T cells. We hypothesize that expansion of specific subsets of 
cells will correlate most strongly with the disease outcomes of patients. The immune cell 
subsets that change with the different radiation schedules with immunotherapy could also 
relate to enhanced toxicities, which will be monitored very closely as the primary 
endpoint of this phase I study. 
B. Laboratory Testing Procedures 
Assessing multiple cell types simultaneously in a high dimensional manner requires 
multiparametric technology that could simultaneously assess all of the parameters on a 
single cell. Using Time of Flight Mass Cytometry (CyTOF), antibodies conjugated with 
rare transition element isotopes that differ by one atomic number could be quantified and 
distinguished using a TOF mass cytometer. The theoretical maximum of parameters is 
100, but the most common uses have only interrogated up to 34 surface or intracellular 
proteins. This already greatly exceeds the capability of standard fluorescence-based flow 
cytometry. Using MatLab analysis, one can resolve cell identify (e.g., CD8, CD4, Treg, 
MDSC, NK, B cells) and expression levels of various activating, inhibitory, or signaling 
molecules on these cells. 
 
2.   TCR Sequencing  
A. Overview 
 Lymphocyte maturation is a process marked by immunophenotypic changes, as well as 
discrete and regulated molecular events. The first event in the process of antitumor 
cytotoxic T-cell response is antigen capture by antigen-presenting cells (APCs). The 
antigens are processed and subsequently presented on HLA class I molecules to CD8+ T 
cells to activate the T-cell response against these specific antigens. Following activation, 
effector CD8+ T cells infiltrate into tumor tissues, releasing cytotoxic agent upon 
recognition of cancer cells through the interaction between TCR and its cognate antigen 
bound to HLA class I.  
 
The diversity of T cells is determined by their TCR. The complimentary determining 
region 3 (CDR3) of the TCR chain is the most variable portion of the TCR and is critical 
for MHC–peptide complex recognition. The range of individual TCR-bearing T-cell 
clones that comprises the repertoire specific for a particular antigenic MHC–peptide com-
plex varies substantially in terms of TCR frequency and diversity. A consequence of this 
specificity is that the TCR CDR3 sequence can be used as a "molecular tag" to identify 
each T-cell clone. Recently presented data have indicated that that large clonal T-cell 
expansions were associated with inferior PFS and OS in B-cell lymphoma. 

 
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B. Laboratory Testing Procedures 
CIMAC will designate a laboratory to perform TCR sequencing.* 
*Note:  at CIMAC discretion, if sufficient material is available. 
 
3.   Cytokine Analysis  
A. Overview 
This exploratory analysis will identify the quantity and types of cytokines released in the 
blood during and after therapy. Cytokines and chemokines mediate the cross talk between 
cells of the immune system, both locally and systemically. Certain inflammatory 
mediators such as interferons act as surrogates of the activation of the immune system, 
and also signal the effectiveness of cancer therapy. Certain markers are also 
immunosuppressive (e.g., TGFbeta), so the effectiveness of the immune system response 
is a balance of immunostimulating and immunosuppressive cytokines. Radiation therapy 
could also illicit profound cytokine release and the amount could have relationship to 
both the radiation dose and fractionation schemes, and the synergistic interaction with 
immunotherapy. We hypothesize that proinflammatory cytokines could be release 
differentially depending on the radiation schedule, which could further be accentuated by 
immunotherapy. Inflammatory mediators could also contribute to immune related adverse 
events that may be exacerbated by radiation therapy. Therefore, we may also see early 
surrogates of toxicity by monitoring dynamic alterations of cytokine levels. 
B. Laboratory Testing Procedures 
Multiplex Immunoassay using the OLink Technology. Plasma (prepared from blood 
collected in green-top sodium-heparin tubes) will be collected and sent to the NRGBB-
Columbus for processing, then sent to the CIMAC laboratory at the Icahn School of 
Medicine at Mount Sinai in New York to conduct the OLink assay. Samples will be 
collected at baseline, Day 15 and 30 post treatment, and at 3 months from the start of 
durvalumab (i.e. cycle 4).  Olink assay has large dynamic range and each assay has 
internal controls that will ensure the robustness of the test. 
 
4.   ELISA/Grand Serology 
A. Overview 
B. One approach to test whether tumors become more immunogenic as a result of 
immunotherapy is to measure naturally occurring antibodies in patient serum or plasma. 
Autologous serotyping has resulted in a growing list of immunogenic human cancer 
antigens1, including mutational, overexpressed, oncogenic viral, differentiation, and 
cancer-testis antigens. These antigens, though usually intracellular, reflect the immune 
system’s capacity to detect abnormalities associated with neoplasia. The presence of 
antibodies to tumor antigens can be used as a marker of tumor presence or progression, 
but may also help generate T cell responses via immune complexes with cognate antigen. 
In some cases, such as the cancer/testis antigen NY-ESO-1, serum antibodies are 
associated with spontaneous T cell responses in peripheral blood. We propose to test the 
hypotheses that immunotherapy leads to induction or increase in immunity to locally 
expressed antigens by assessing serological changes pre-post treatment, and that the 
serological repertoire in patients may be useful as a prognostic or predictive tool. 
Laboratory Testing Procedures 

 
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Using serological markers as a surrogate for presence of antitumor immunity is proposed 
as a quick and affordable way to assess tumor immunocompetence and response. A series 
of known tumor antigens will be assessed in a hypothesis-driven manner for their 
capacity to elicit autoantibodies in treated patients. Using ELISA, we will test a set of 25 
tumor antigens, including mutational, stem-cell, and cancer-testis antigens such as TP53, 
NY-ESO-1, SOX2, PRAME, WT1, MAGE-A3, SSX2, etc., most of which already have 
demonstrated immunogenicity in various solid and hematologic tumors. Grand Serology 
is also ideally suited to test for potential for antigen spreading, i.e., development of 
seroreactivity to antigens unrelated to immunogenes, which is a useful measurement to 
assess in immunotherapy. 
 
5.   Circulating Tumor DNA (ctDNA) 
A. Overview 
The detectability of any strand of DNA bearing cancer specific mutations can be 
quantified as well as the number of molecules per mL of blood. Any molecule of cancer 
specific DNA (or ctDNA) can be determined as minimal residual disease, and the 
disappearance of the ctDNA in the blood is an indication of disease clearance. The level 
may also indicate disease burden as well. 
B. Laboratory Testing Procedures 
Ultradeep allelic sequencing of ctDNA – to be performed by the appropriate CIMAC 
laboratory. 
 
6. PD-L1 (SP263) Immunohistochemistry (IHC) 
a. Overview 
PD-L1 is an informative immunotherapy biomarker: Aberrant expression of PD-L1 on 
tumor and immune cells in the tumor microenvironment impedes anti-tumor immunity, 
allowing tumors to grow and metastasize.  SP263 tumor cell staining quickly calculates 
PD-L1 positivity for user-defined regions of interest. 
b. Laboratory Testing Procedures 
PD-L1 (SP263) IHC will be done using optional tissue biospecimens for cases that were 
stained using the Dako 22C3 (the Dako 22C3 will be used in case(s) without the PD-L1 
22C3 assay already performed, Multiplex IHC, and if sufficient tissue/DNA from tissue 
remains – TCRseq).