Conditions: Small-cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This study is for subjects with untreated Stage IV small cell lung cancer. Subjects will be given radiation therapy for five days, followed by standard of care chemo-immunotherapy (etoposide + carboplatin or cisplatin + durvalumab) for 4 cycles. Subjects may continue to receive durvalumab after 4 cycles have been completed until disease progression.

Detailed description:
This is a non-randomized, open-label, single-arm pilot phase II study of non-ablative stereotactic body radiotherapy (SBRT) in combination with standard-of-care chemo-immunotherapy in patients with untreated, extensive-stage (Stage IV) small cell lung cancer. Subjects will be treated with etoposide plus platinum (carboplatin or cisplatin) chemotherapy together with the PD-L1 checkpoint inhibitor durvalumab, which is a standard of care in this disease setting. Subjects will also receive a total of 6 Gy of radiotherapy X 5 fractions targeting multiple sites of intrathoracic disease when feasible and starting on the first day of the first cycle of chemo-immunotherapy; no further radiation will be planned after this. The hypothesis of this study is that the addition of sub-ablative doses of radiation to combination chemotherapy and immunotherapy will be safe and feasible and result in improved outcomes for patients with treatment-naive, extensive-stage small cell lung cancer.

Arms:
arm 1: None

Interventions: intervention 1: Carboplatin intervention 2: Cisplatin intervention 3: Etoposide intervention 4: Durvalumab intervention 5: Stereotactic Body Radiotherapy
Intervention descriptions: intervention 1: AUC = 5-6 mg/mL per min on Day 1 of each 21-day cycle, for 4 cycles intervention 2: 75-80 mg/m2 on Day 1 of each 21-day cycle, for 4 cycles intervention 3: 80-100 mg/m2 on Day 1, Day 2, and Day 3 of each 21-day cycle, for 4 cycles intervention 4: 1500 mg on Day 1 of each 21-day cycle, for 4 cycles. Following this, 1500 mg once every 4 weeks until disease progression intervention 5: 6 Gy of radiotherapy targeting multiple sites of intrathoracic disease on Days 1-5 of cycle 1.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 Phase II Trial of Platinum-Etoposide Chemotherapy and 
Durvalumab (MEDI4736) with Sub-Ablative Radiation in Patients 
with Newly Diagnosed Stage IV Small Cell Lung Cancer 
Protocol Version 3.5 dated 11/27/2021 
NCT04951115 


 
 
  
 
TITLE:  Phase II Trial of Platinum-Etoposide Chemotherapy and Durvalumab (MEDI4736) with Sub-Ablative 
Radiation in Patients with Newly Diagnosed Stage IV Small Cell Lung Cancer 
 
IRB Protocol #: 20-08022492 
IND/IDE #: 155205 
Version 3.5; Date: 11/27/21 
Funding Source(s): AstraZeneca 
 
Principal Investigators: 
 
Ashish Saxena, MD, PhD 
 
 
520 E 70th St, Starr 3rd Floor 
 
 
New York, NY 10021 
 
 
Phone: 646-962-2066 
 
 
Fax: 646-962-1603 
 
 
ahs9018@med.cornell.edu 
 
 
 
Encouse Golden, MD, PhD 
525 E 68th St|Stich Radiation Center 
New York, NY 10065 
Phone: 212-746-3600 
Fax: 212-746-8749 
eng2003@med.cornell.edu 
 
 
Co-Investigators: 
 
Silvia Formenti, MD 
 
 
525 East 68th Street | Stich Radiation Center 
 
 
New York, NY 10065 
 
 
Phone: 212-746-7277 
 
 
formenti@med.cornell.edu  
   
 
 
 
 
Giuseppe Giaccone, MD, PhD 
 
 
520 E 70th St, Starr 3rd Floor 
 
 
New York, NY 10021 
 
 
Phone:  
 
 
gig4001@med.cornell.edu  
 
 
 
 
Ronald Scheff, MD 
 
 
520 E 70th St, Starr 3rd Floor 
 
 
New York, NY 10021 
 
 
Phone: 646-962-2066 
 
 
rjs2002@med.cornell.edu  
 
        
 
 
Nicholas Sanfillipo, MD 
 
 
525 East 68th Street | Stich Radiation Center 
 
 
New York, NY 10065 
 
 
Phone: 212-746-3607 
 
 
nis9129@med.cornell.edu  
 


 
 
 
 
 
Sandra DeMaria, MD 
 
 
525 East 68th Street | Stich Radiation Center 
 
 
New York, NY 10065 
 
 
Phone: 212-746-6068 
 
 
szd3005@med.cornell.edu  
 
 
 
 
 
Olivier Elemento, PhD 
 
 
1305 York Avenue, Room Y-13.13 
 
 
New York, NY 10021 
 
 
 
 
Phone: 646-962-5726 
 
 
ole2001@med.cornell.edu  
 
 
 
 
M. Laura Martin, PhD 
 
 
1305 York Avenue 
 
 
New York, NY 10021 
 
 
Phone: 212 746 6359 
 
 
mlm4001@med.cornell.edu  
 
 
 
Paraskevi Giannakakou, PhD 
 
 
1300 York Ave. Box 65 
 
 
New York, NY 10065 
 
 
Phone: (212) 746-6565 
 
 
pag2015@med.cornell.edu  
 
 
 
 
Giuseppe Galletti, MD, PhD 
 
 
1300 York Ave. Box 65 
 
 
New York, NY 10065 
 
 
Phone: (212) 746-0293 
 
 
gig2002@med.cornell.edu  
 
 
 
Andy Huang, MD 
 
 
343 Fourth Ave 
 
 
Brooklyn, NY 11215 
 
 
Phone: 718-643-0483  
 
 
anh9107@nyp.org  
 
 
       Hani Ashamalla, MD 
 
       506 Sixth St 
 
       Brooklyn, NY 11215 
 
 
Phone: 718-780-3677 
 
 
haa9002@nyp.org  
 
 
       Gina Villani, MD 
 
 
56-45 Main St, West LL Suite 100 
 
 
Flushing, NY 11355 
 
 
Phone: 718-670-1180 
 
 
gmv9002@med.cornell.edu  


 
 
 
 
 
Lauren Elreda, MD 
 
 
56-45 Main Street, West LL Suite 100 
 
 
Flushing, NY 11355 
 
 
Phone: 718-670-1180 
 
 
 
 
lae2014@med.cornell.edu  
  
  
 
 
Research Nurse: Julia Hong, RN 
Research/Dara Coordinator: Genevieve Durso   
Program Manager: Alexandra Mavracick 
 
Statistician: 
 
Medical Monitor: 
Paul J Christos, DrPH 
Ana Molina, MD 
 
402 East 67th Street, Rm 241 
520 E 70th St, Starr 3rd Floor 
New York, NY 10065 
New York, NY 10021 
Phone: 646-962-8018 
Phone: 646-962-2066 
Fax:  
Fax: 646-962-2066 
pac2001@med.cornell.edu  
stt2007@med.cornell.edu  
 
 
Participating Sites:  
Weill Cornell Medicine 
 
 
Site PI: Ashish Saxena, MD, PhD 
 
 
520 E 70th St, Starr 3rd Floor 
 
 
New York, NY 10021 
 
 
 
Phone: 646-962-2066 
 
 
 
Fax: 646-962-1603 
 
 
 
ahs9018@med.cornell.edu  
 
 
  
 
NewYork Brooklyn Methodist Hospital 
506 Sixth St 
Brooklyn, NY 11215 
 
NYP Queens 
56-45 Main St, West LL Suite 100 
Flushing, NY 11355 
 
 
 
 
 
 
 
 
 


 
 
 
 
 


 
 
 
Table of Contents 
STATEMENT OF COMPLIANCE ........................................................................................... XVIII 
CONFIDENTIALITY STATEMENT ........................................................................................ XVIIII 
LIST OF ABBREVIATIONS ................................................................................................. XVIIIX 
1. PROTOCOL SUMMARY………………………………………………………………………………………………….…….1 
1.1 
Schema ...................................................................................................................... 4 
1.2 
Study Objectives ........................................................................................................ 4 
2. BACKGROUND………………………………………………………………………………………………………………………5 
2.1 
Small Cell Lung Cancer .............................................................................................. .5 
2.2 
Durvalumab……………………………………………………………………………………………………………….6 
2.3 
Radiation Therapy and Tumor Immunity…………………………………………………………………….7  
2.4 
Rationale ................................................................................................................... 8 
2.5 
Risk/Benefit Assessment ............................................................................................ 8 
2.6 
Correlative Studies Background ................................................................................ 10 
3. STUDY DESIGN ................................................................................................................. 15 
3.1 
Overall Design .......................................................................................................... 16 
3.2 
Scientific Rationale for Study Design ........................................................................ 17 
3.3 
Justification for Dose ............................................................................................... 17 
3.4 
End of Study Definition ............................................................................................ 18 
4. SUBJECT SELECTION ......................................................................................................... 18 
4.1 
Study Population ..................................................................................................... 18 
4.2 
Inclusion Criteria ...................................................................................................... 18 
4.3 
Exclusion Criteria ..................................................................................................... 20 
4.4 
Screen Failures ......................................................................................................... 21 
4.5 
Strategies for Recruitment and Retention ................................................................ 22 
5. REGISTRATION PROCEDURES ........................................................................................... 22 
5.1 
Subject Registration (WCM only) .............................................................................. 22 
6. STUDY PROCEDURES ........................................................................................................ 22 
6.1 
Schedule of Assessments ......................................................................................... 22 
7. STUDY INTERVENTION ................................................................................................... ..27 
    7.1     Chemotherapy………………………………………………………………………………………………………….27 
     7.2     Immunotherapy…………………………………………………………………………………………………….…28 
     7.3     Radiation Therapy……………………………………………………………………………………………………29 


 
 
7.4      Availability……………………………………………………………………………………………………………….40 
     7.5      Dosing Delays/Dose Modifications ........................................................................... 41 
7.6     General Concomitant Medication and Supportive Care Guidelines ............................ 41 
7.7    Duration of Therapy and Criteria for Removal from Study .......................................... 43 
7.8    Duration of Follow Up ................................................................................................ 44 
7.9    Study Intervention/Follow-up Compliance ................................................................. 44 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...................................................................................... 44 
8.1 
Discontinuation of Study Intervention ...................................................................... 44 
8.2 
Participant Discontinuation/Withdrawal from the Study .......................................... 45 
8.3 
Lost to Follow Up ..................................................................................................... 45 
9. CORRELATIVE/SPECIAL STUDIES ....................................................................................... 46 
9.1 
Tumor-immune microenvironment and the T-cell response . .................................... 46 
     9.2      Organoids from SCLC Tissue ..................................................................................... 47 
     9.3      Circulating Tumor Cells  ............................................................................................ 47 
10.  MEASUREMENT OF EFFECT ............................................................................................ 48 
10.1     Progression-Free Survival ........................................................................................ 48 
10.2     Overall Survival ....................................................................................................... 48 
10.3     Response Criteria .................................................................................................... 48 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ...................................................... 49 
11.1     Data Collection ....................................................................................................... 49 
11.2     Regulatory Considerations ...................................................................................... 49 
 
12. STATISTICAL CONSIDERATIONS………………………………………………………………………………………51 
12.1     Study Design/Endpoints .......................................................................................... 51 
12.2     Sample Size/Accrual Rate ........................................................................................ 51 
12.3     Stratification Factors ............................................................................................... 52 
12.4     Analysis of Endpoints .............................................................................................. 52 
12.5     Interim Analysis ...................................................................................................... 52 
12.6     Reporting and Exclusions ........................................................................................ 52 
13. ADVERSE EVENT REPORTING REQUIREMENTS……………………………………………………………….53 
13.1  Reporting…………………………………………………………………………………………………………………53 
13.2    Adverse Event Definition.......................................................................................... 55 
13.3 Definition of Adverse Events of Special Interest (AESI)……………………………………………..56 
13.4    Definition of SAE ...................................................................................................... 57 
13.5    AE/SAE Follow Up .................................................................................................... 59 
13.6    Time Period and Frequency for Event Assessment and Follow Up ............................. 59 
14. DATA AND SAFETY MONITORING PLAN (DSMP) .......................................................... ….60 


 
 
REFERENCES ........................................................................................................................ 62 
APPENDIX A: ADVERSE EVENTS REPORTED IN CASPIAN TRIAL .............................................. 68 
APPENDIX B: TOXICITY MANAGEMENT GUIDELINES - DURVALUMAB ................................... 75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Statement of Compliance 
 
The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards. The contents of this document shall not be disclosed to others without written 
authorization from WCM. 
 
 
 
 
 
 
 
 
 
 
 
Weill Cornell Medicine 
_________________________________________________________________ 
Institution Name 
 
 
 
 
 
Ashish Saxena 
______________________________     ______________________________     ____________________ 
Principal Investigator’s Name                 Principal Investigator’s Signature            Date 
 
 
 
 
 
 
 
 
 
 


 
 
List of Abbreviations 
 
 
3D-CRT 
AE 
AESI 
3D Conformal Radiation Therapy 
Adverse Event 
Adverse Events of Special Interest 
ALT  
AST  
CBC 
CI 
CFR 
Alanine Aminotransferase 
Aspartate aminotransferase 
Complete Blood Count 
Confidence Interval 
Code of Federal Regulations 
CRF 
CTCAE 
CT  
CTLA-4 
CTC 
Case Report Form 
Common Terminology Criteria for Adverse Events 
Computed Tomography 
Cytotoxic T-Lymphocyte-Associated protein 4 
Circulating Tumor Cell 
CTSC 
Clinical Translational Science Center  
D 
dL 
DSMB 
Day 
Deciliter 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
ECOG 
EIPM 
EOT 
EpCAM 
ES-SCLC 
FDA 
Eastern Cooperative Oncology Group 
Englander Institute for Precision Medicine 
End of Treatment 
Epithelial Cell Adhesion Molecule 
Extensive-Stage Small Cell Lung Cancer 
Food and Drug Administration 
g 
GCP 
Gram 
Good Clinical Practice 
HBV 
hCG  
HCV  
HIV 
Hepatitis B virus 
Human Chorionic Gonadotropin 
Hepatitis C Virus 
Human Immunodeficiency Virus 
ICB 
Immune Checkpoint Blockade 
ICF 
Informed Consent Form 
ImAE 
IMRT 
Immune-Mediated Adverse Event 
Intensity Modulated Radiation Therapy 


 
 
IO 
Immunotherapy  
IRB 
kg 
mAb 
mg 
min 
mL 
mm 
MRI 
NCI 
NSCLC 
ORR 
OS 
PBMC 
PCI 
PD-1 
PD-L1 
PD-L2 
PDTO 
PET 
PFS 
Institutional Review Board 
Kilogram 
Monoclonal Antibody 
Milligram 
Minute 
Milliliter 
Millimeter 
Magnetic Resonance Imaging 
National Cancer Institute 
Non-Small Cell Lung Cancer 
Overall Response Rate 
Overall Survival 
Peripheral Blood Mononuclear Cells 
Prophylactic Cranial Irradiation 
Programmed Cell Death-1 
Programmed Death-Ligand 1 
Programmed Death-Ligand 2 
Patient Derived Tumor Organoids 
Positron Emission Tomography 
Progression-Free Survival 
PI 
PS 
Principal Investigator 
Performance Status 
RANKL 
RECIST 
REDCap 
Receptor Activator of Nuclear Factor-κB Ligand 
Response Evaluation Criteria in Solid Tumors. 
Research Electronic Data Capture 
SAE 
SBRT 
SCLC 
SRS 
Serious Adverse Event 
Stereotactic Body Radiotherapy 
Small Cell Lung Cancer 
Stereotactic Radiosurgery 
TfR 
TNM 
Transferrin Receptor 
Tumor, Node, Metastasis 
TRT 
uL 
ULN 
VALCSG 
Thoracic Radiotherapy 
Microliter 
Upper Limit of Normal 
Veterans Administration Lung Cancer Study Group 
WBRT 
Whole Brain Radiation Therapy 


 
 
WCM 
WES 
Weill Cornell Medicine 
Whole-Exome Sequencing 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
1 (147) 
1. Protocol Summary 
 
Full Title: 
 
 
 
 
Phase II Trial of Platinum-Etoposide Chemotherapy and Durvalumab 
(MEDI4736) with Sub-Ablative Radiation in Patients with Newly 
Diagnosed Stage IV Small Cell Lung Cancer  
 
Short Title:  
 
 
 
Chemo-IO + RT in SCLC  
 
Clinical Phase:  
 
 
II 
 
Principal Investigators:  
 
Ashish Saxena, MD, PhD and Encouse Golden MD, PhD 
 
Study Description:  
 
This is a non-randomized, open-label, single-arm pilot phase II study of 
non-ablative radiotherapy in combination with standard-of-care chemo-
immunotherapy in patients with untreated, extensive-stage (Stage IV) 
small cell lung cancer. Subjects will be treated with etoposide plus 
platinum (carboplatin or cisplatin) chemotherapy together with the PD-
L1 checkpoint inhibitor durvalumab, which is a standard of care in this 
disease setting. Subjects will also receive a total of 6 Gy of radiotherapy 
X 5 fractions via 3D-CRT, IMRT, or SBRT and targeting multiple sites of 
intrathoracic disease when feasible and/or any site required for 
palliation of symptoms. Radiation will start prior to the completion of 
the second cycle of chemo-immunotherapy but will ideally begin on the 
first day of the first cycle; no further radiation will be planned after this. 
The hypothesis of this study is that the addition of sub-ablative doses of 
radiation to combination chemotherapy and immunotherapy will be 
safe and feasible and result in improved outcomes for patients with 
treatment-naive, extensive-stage small cell lung cancer. 
 
Sample Size: 
 
N= 42 
 
Enrollment: 
 
This study will plan to enroll 42 subjects to allow for 34 to be evaluable 
for the primary endpoints. 
 
Study Population: 
 
Adults aged 18 or older with untreated, extensive-stage small cell lung 
cancer. 
 
Enrollment Period: 
 
40 Months  
 
Study Design: 
 
This is a prospective, non-randomized, open-label, single-arm pilot 
phase II study of non-ablative radiotherapy in combination with 
standard-of-care chemo-immunotherapy in patients with untreated, 
extensive-stage (Stage IV) small cell lung cancer. This study will plan to 
enroll 42 subjects to allow for 34 to be evaluable for the primary 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
2 (147) 
endpoints. All subjects will be treated with etoposide plus platinum 
(carboplatin or cisplatin) chemotherapy together with the PD-L1 
checkpoint inhibitor durvalumab, which is a standard of care in this 
disease setting. All subjects will also receive a total of 6 Gy of 
radiotherapy X 5 fractions via 3D-CRT, IMRT, or SBRT and targeting 
multiple sites of intrathoracic disease when feasible and/or any site 
required for palliation of symptoms. Radiation will start prior to the 
completion of the second cycle of chemo-immunotherapy but will 
ideally begin on the first day of the first cycle; no further radiation will 
be planned after this. There will be a safety run-in period involving the 
first 10 subjects enrolled wherein if there is a 30% or greater incidence 
of grade 3 or higher toxicities with the proposed treatment regimen - 
specifically from radiation therapy (with focus on pneumonitis, 
pericarditis, esophagitis, rib fracture, or hemoptysis) or immune-
mediated adverse events (other than thyroid dysfunction) - then the 
radiation regimen will subsequently be switched to 5 Gy radiation per 
day for 5 fractions. 
 
 
Systemic therapy will be given as follows:  
 
 
- Carboplatin at AUC = 5-6 mg/mL per min or Cisplatin at 75-80mg/m2 
on Day 1 of each 21-day cycle, for 4 cycles 
 
 
- Etoposide at 80-100mg/m2 on Day 1, Day 2, and Day 3 of each 21-day 
cycle, for 4 cycles 
 
 
- Durvalumab at 1500mg on Day 1 of each 21-day cycle, for 4 cycles; 
following this, subjects will receive 1500mg Durvalumab once every 4 
weeks until disease progression.  
 
 
Prophylactic Cranial Irradiation (PCI) and consolidative Thoracic 
Radiotherapy (TRT) will not be given. 
 
Description of Sites/  
Facilities Enrolling 
Participants: 
 
This study will enroll subjects at NewYork Presbyterian Hospital-Weill 
Cornell Medicine. All sites are in the United States and within New York 
City. 
 
 
Study Duration: 
 
48 Months 
 
Participant Duration: 
 
12 months 
 
Study Agent/Device Name  
Intervention Description: 
- Carboplatin AUC = 5-6 mg/mL per min IV or Cisplatin 75-80mg/m2 IV 
on Day 1 of each 21-day cycle, for 4 cycles 
 
 
- Etoposide 80-100mg/m2 IV on Day 1, Day 2, and Day 3 of each 21-day 
cycle, for 4 cycles 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
3 (147) 
 
 
- Durvalumab 1500mg IV on Day 1 of each 21-day cycle, for 4 cycles; 
following this, subjects will receive 1500mg Durvalumab IV once every 4 
weeks until disease progression 
 
 
- A total dose of 6 Gy radiation per day for 5 fractions via 3D-CRT, IMRT, 
or SBRT and targeting multiple sites of intrathoracic disease when 
feasible and/or any site required for palliation of symptoms. Radiation 
will start prior to the completion of the second cycle of chemo-
immunotherapy but will ideally begin on the first day of the first cycle 
 
Primary Objective: 
 
To examine the safety and efficacy of adding multi-site, non-ablative 
radiation to standard systemic therapy with carboplatin or cisplatin and 
etoposide plus durvalumab for patients with extensive-stage small cell 
lung cancer. 
 
Exploratory Objectives:  
- To examine the tumor-immune microenvironment and the circulating 
immune cell and inflammatory protein composition in responders vs 
non-responders. 
 
 
- To grow tumor organoids from tissue samples collected 
 
 
- To isolate and characterize circulating tumor cells (CTCs) from 
peripheral blood 
 
 
 
 
 
Specifically, will examine: 
 
 
1.     Cytokine levels, including type I interferon (IFN-I) 
 
 
2.     Frequencies of immune cells among peripheral blood mononuclear 
cells (PBMCs): CD4+ T cells, CD8+ T cells, natural killer (NK) cells, myeloid-
derived suppressor cells (MDSCs), T regulatory cells (Tregs), 
macrophages, dendritic cells (DCs) 
3.     Frequencies of tumor-infiltrating lymphocytes (TILs) in tumor 
samples 
 
 
4.     T cell receptor (TCR) repertoire of CD8+ T cells from PBMCs and TILs 
 
 
5.     RNA sequencing profiles of tumors, tumor organoids, and CTCs 
 
 
6.     Mechanisms of resistance using tumor organoids 
 
Endpoints: 
 
Co-Primary Endpoints: 
- 
12-month Progression-Free Survival 
- 
Safety in terms of Incidence of ≥ Grade 3 Toxicities related to therapy given 
 
 
 
 
 
Secondary Endpoints: 
- 
12-month Overall Survival 
- 
Response Rate 
- 
Median Progression-Free Survival 
- 
Median Overall Survival 
- 
Pattern of Disease Progression 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
4 (147) 
 
1.1 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 Study Objectives 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
5 (147) 
1.2.1  Primary Objective 
To examine the safety and efficacy of adding multi-site, non-ablative radiation to standard 
systemic therapy with carboplatin or cisplatin and etoposide plus durvalumab for patients 
with extensive-stage small cell lung cancer. 
 
 
 
 
                       
Co-Primary Endpoints: 
- 
12-month Progression-Free Survival 
- 
Safety in terms of Incidence of ≥ Grade 3 Toxicities related to therapy given 
 
 
Secondary Endpoints: 
- 
12-month Overall Survival 
- 
Response Rate 
- 
Median Progression-Free Survival 
- 
Median Overall Survival 
- 
Pattern of Disease Progression 
 
1.2.2  Exploratory Objectives 
 
 
 
- To examine the tumor-immune microenvironment and the circulating immune cell and 
inflammatory protein composition in responding and resistant individuals. 
- To isolate and characterize circulating tumor cells (CTCs) from peripheral blood 
 
 
- To grow tumor organoids from tissue samples collected 
 
 
 
 
 
Specifically will examine: 
 
 
1.     Cytokine levels, including type I interferon (IFN-I) 
2.     Frequencies of immune cells among peripheral blood mononuclear cells (PBMCs): CD4+ 
T cells, CD8+ T cells, natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), T 
regulatory cells (Tregs), macrophages, dendritic cells (DCs) 
 
 
3.     Frequencies of tumor-infiltrating lymphocytes (TILs) in tumor samples 
 
 
4.     T cell receptor (TCR) repertoire of CD8+ T cells from PBMCs and TILs 
 
 
5.  RNA sequencing profiles of CTCs 
 
 
6.   Mechanisms of resistance using tumor organoids  
 
 
2. Background 
 
2.1  Small Cell Lung Cancer 
 
Lung Cancer is the leading cause of cancer death in the United States and is expected to account for 
roughly one-fourth of cancer deaths in this country in 20201. It has traditionally been divided into 
small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), based on tumor histology. SCLC 
represents approximately 10-15% of new lung carcinoma diagnoses, and this disease is 
characterized by a rapid doubling time and early development of lymph node and distant 
metastases, often already present at the time of diagnosis. The VALCSG system is the most 
commonly used staging system in clinical practice and divides small cell lung cancer into limited-
stage and extensive-stage disease. Limited-stage small cell lung cancer is defined as disease confined 
to one side of the chest as evidence by imaging and/or the ability of a radiation oncologist to 
encompass the disease in a “tolerable radiation field”.  Patients with limited-stage disease are 
typically treated with curative intent using concurrent chemotherapy and radiation therapy, with 5-


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
6 (147) 
year survival rates between 13% and 38%. Rarely, in cases of very limited disease, patients may 
undergo surgical resection followed by adjuvant chemotherapy and possibly adjuvant radiation. 
Patients who demonstrate SCLC beyond the limited-stage are classified as having extensive-stage 
SCLC (ES-SCLC). This includes those with malignant pleural effusion, contralateral lung nodules on 
both sides of the chest, distant metastases, and/or an overall disease burden that cannot be safely 
radiated within a “tolerable radiation field”2,3. ES-SCLC generally corresponds to Stage IV disease 
according to the TNM staging system4. 
 
About two-thirds of patients present with ES-SCLC, and although it is initially highly sensitive to 
chemotherapy with high response rates, most responses are not durable and the disease quickly 
progresses and becomes refractory to chemotherapy treatment. The median survival with standard 
platinum-etoposide chemotherapy is about 10 months, and this was the standard-of-care treatment 
for ES-SCLC for decades2,3. More recently, however, there have been multiple attempts to improve 
systemic therapy with the addition of immunotherapy. Among these efforts, IMPower133 was the 
first positive study, demonstrating that the addition of the anti-PD-L1 monoclonal antibody (mAb) 
atezolizumab to carboplatin and etoposide significantly improved progression-free survival (PFS) and 
overall survival (OS) compared to chemotherapy alone (median PFS = 5.2 months vs 4.3 months with 
hazard ratio for disease progression or death = 0.77 [95% Confidence Interval (CI)  = 0.62 to 0.96 
with p = 0.02]; median OS = 12.3 months vs 10.3 months with hazard ratio for death = 0.70 [95% CI = 
0.54 to 0.91 w/ p = 0.007] 5. The positive findings from IMPower133 established the combination of 
chemotherapy plus immune checkpoint blockade (ICB) as the new standard-of-care approach for ES-
SCLC. However, despite achieving statistical significance, the absolute improvement in median PFS 
or OS with the addition of atezolizumab was only 1-2 months beyond chemotherapy alone. 
Recently, planned interim analysis results from CASPIAN, a phase 3 trial using the anti-PD-L1 mAb 
durvalumab +/- the anti-CTLA-4 mAb tremelimumab in combination with platinum-etoposide 
chemotherapy for patients with ES-SCLC showed that the addition of durvalumab to chemotherapy 
also improved median OS compared to chemotherapy alone (median OS = 13.0 months vs 10.3 
months with hazard ratio of 0.73 [95% CI = 0.59 – 0.91 with p = 0.0047]). However the absolute 
improvement in median OS with the addition of durvalumab was again less than 3 months and the 
12-month PFS rate with combination chemotherapy-durvalumab was only 18%6.  
 
In light of the above, there remains a significant opportunity and an unmet need for novel 
therapeutic approaches for ES-SCLC to enhance the effectiveness of the combination of 
chemotherapy and ICB. Interestingly, consolidative thoracic radiotherapy was not permitted in 
either IMPower133 or CASPIAN. However, the CREST trial, which did not utilize any ICB therapy, 
showed a 10% 2-year survival rate benefit for patients with ES-SCLC receiving consolidative thoracic 
radiotherapy after any response to 4-6 cycles of standard platinum-based chemotherapy (13% 2-
year OS in the thoracic radiation group [CI = 9%–19%], vs 3% in the control group [CI = 2%–8%]; 
p=0·004)7. This has given rise to the speculation that radiotherapy may be contributing to more than 
local control within the irradiated field, including immune-mediated distant control of disease, and 
that radiation could be a formidable partner with immune checkpoint blockade8. 
 
2.2 Durvalumab 
 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass 
that inhibits binding of PD-L1 and is being developed by AstraZeneca for use in the treatment of 
cancer. The proposed mechanism of action (MOA) for durvalumab is interference in the interaction 
of PD-L1 with PD-1 and CD80 (B7.1).  Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases 
the inhibition of immune responses, including those that may result in tumor elimination.  In vitro 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
7 (147) 
studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human 
T cells resulting in the restored proliferation of IFN-γ9. In vivo studies have shown that durvalumab 
inhibits tumor growth in xenograft models via a T-cell-dependent mechanism9.  Based on these data, 
durvalumab is expected to stimulate the patient’s antitumor immune response by binding to PD-L1 
and shifting the balance toward an antitumor response. Durvalumab has been engineered to reduce 
antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.  
The non-clinical and clinical experience with Durvalumab is fully described in the most current 
version of the durvalumab Investigator’s Brochure. To date durvalumab has been given to more 
than 8000 patients as part of ongoing studies either as monotherapy or in combination with other 
anti-cancer agents.   
 
2.3 Radiation Therapy and Tumor Immunity 
 
Radiation therapy has generally had a limited role for the upfront management of ES-SCLC. 
Historically, this was based on the prevailing belief that radiation therapy, functioning primarily as a 
local modality, would have a very modest role once a cancer has metastasized. This was due to the 
expectation that radiation would have a limited effect on clinically meaningful endpoints in the 
setting of metastatic disease. However, this view of radiation therapy has gradually been 
superseded by a more nuanced perspective: The observation that radiation may occasionally induce 
anti-tumor effects on non-targeted lesions, termed the abscopal effect, has led to investigations 
that established the critical interplay between radiation therapy and tumor immunity10. 
Mechanistically, radiation therapy promotes immunogenic cell death in tumor cells, thereby 
recruiting elements of the innate and adaptive immune response and effectively converting an 
immunosuppressive tumor microenvironment into one that can generate and support tumor 
immunity. Multiple preclinical studies have demonstrated that the primary mediators of radiation-
induced immunity are CD8+ T cells11. In early-phase trials of patients with metastatic NSCLC, local 
sub-ablative stereotactic body radiation therapy (SBRT) to a metastatic lesion, in combination with 
immunotherapy (e.g., the anti-CTLA-4 mAb ipilimumab), has been shown to generate clinically 
significant tumor immunity, leading to a robust systemic response that appears to be an important 
contributor to the tumor response12. Additionally, in patients with non-resectable Stage III NSCLC, 
the robust overall survival benefit without undue toxicity reported with the addition of durvalumab 
in the PACIFIC trial was preceded by comprehensive concurrent chemoradiation targeting the 
primary tumor and loco-regional nodal metastases13. Thus, reduction in tumor burden and relief of 
immune suppression afforded by concurrent chemoradiation may potentially augment 
immunogenicity.  
 
Several lines of clinical evidence have recently suggested that local consolidation with radiotherapy 
in select subsets of patients with low metastatic disease burden can meaningfully extend survival14-
16. While confirmatory phase III studies are pending, the overall survival signal with multi-site SBRT 
observed in the SABR-COMET study of stereotactic ablative radiotherapy vs standard of care 
palliative treatment in patients with oligometastatic cancers is compelling and suggests that this 
approach is feasible and associated with an improved quality-of-life – although caution should be 
applied as treatment-related mortality did occur in the SBRT arm16,17. Gomez et al. found a median 
OS benefit for local consolidative radiotherapy (41.2 months [95% CI = 18.9 months to not reached]) 
versus maintenance therapy or observation (17.0 months [95% CI = 10.1 to 39.8 months] with p = 
.017 in NSCLC patients with oligometastatic disease (~2/3rds had only a single metastatic site). In 
addition, no additional grade 3 or greater toxicities were observed in the radiotherapy arm15. Given 
the early clinical promise of multi-site radiation, it is a rational extension to evaluate multi-site 
radiation in the context of immunotherapy. Luke et al. conducted a phase I trial of multi-site SBRT 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
8 (147) 
followed by pembrolizumab. While response rates were modest in a heterogeneous, heavily pre-
treated population, these investigators did observe upregulation of an IFN-ɣ-related RNA signature 
in non-irradiated lesions (prior to receipt of immunotherapy) providing evidence of systemic 
immunomodulation in response to multi-site SBRT18.  
 
The clinical benefit associated with multi-site radiation may simply be a reflection of improved 
outcomes due to cytoreduction and direct tumor cell kill. However, a reduction in systemic disease 
burden may also facilitate anti-tumor immunity. It is known that persistent antigenic stimulation, as 
occurs in the context of established tumors (that have escaped immune surveillance) and chronic 
viral infection, may lead to impaired cytotoxic T-cell function and an exhausted T-cell phenotype19. 
As such, a high tumor burden state may be conceptualized as a state of immune dysfunction due to 
excessive and persistent antigen. Huang et al. eloquently demonstrated that pre-treatment tumor 
burden is a major determinant of outcome among melanoma patients treated with anti-PD-1 
immunotherapy and provided mechanistic evidence that CD8+ T-cell reinvigoration (Ki-67+ PD-1+) 
alone may not be sufficient to yield a clinical response in the context of high tumor burden20. 
Indeed, an elevated “reinvigoration-to-tumor burden” ratio was positively associated with objective 
response rate and overall survival. As such, a reduction in tumor burden and consequently antigen 
load may in part explain how cytoreductive therapies such as multi-site SBRT can facilitate responses 
to immunotherapy. In support of this concept, preclinical models have demonstrated that the 
cytoreductive effects of cisplatin can further augment abscopal responses in mice treated with 
radiation and anti-PD-1 therapy. The addition of cisplatin to the radio-immunotherapy doublet led 
to enhanced T-cell trafficking and antigen-specific T-cell infiltration into non-irradiated tumors, 
which extended survival relative to any other combination regimen21. 
 
The aforementioned translational studies and proof-of-principle trials have paved the way for 
ongoing studies combining radiation with ICB in metastatic NSCLC. However, there are a paucity of 
similar studies in ES-SCLC, particularly in the front-line setting. A small (17 subject) randomized 
phase II study of tremelimumab and durvalumab with or without SBRT (at 9Gy X 3 fractions to one 
selected tumor site) for patients with relapsed ES-SCLC who had received 1-2 lines of prior therapy 
failed to show sufficient signals for efficacy with ICB therapy with or without SBRT, though there was 
a trend toward improved PFS and OS with the addition of radiation22. 
 
2.4 Rationale 
 
As detailed above, survival for patients with ES-SCLC is generally poor, with median overall survival 
only around 12-13 months even with initial treatment involving combination chemotherapy and 
immunotherapy5,6. Subsequent treatments for this study population usually involve single-agent 
chemotherapies, which then show median survivals of only 3-6 months3. Thus, new strategies are 
still needed to improve outcomes in this patient population. The addition of sub-ablative and 
possibly multi-site intrathoracic radiation to standard chemo-immunotherapy may enhance the 
tumor immune response and lead to better survival outcomes for this patient population. 
 
2.5  Risk/Benefit Assessment  
 
 
2.5.1 
Known Potential Risks 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents 
are thought to be due to the effects of inflammatory cells on specific tissues. These risks 
are generally events with a potential inflammatory or immune mediated mechanism, 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
9 (147) 
and which may require more frequent monitoring and/or unique interventions such as 
immunosuppressants and/or endocrine therapy. These immune mediated effects can 
occur in nearly any organ system, and are most commonly seen as gastrointestinal AEs 
such as colitis and diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such 
as hepatitis and liver enzyme elevations, skin events such as rash and dermatitis, and 
endocrinopathies including hypo- and hyper-thyroidism. 
Risks with durvalumab include, but are not limited to, diarrhea/colitis, 
pneumonitis/interstitial lung disease (ILD), endocrinopathies (ie, events of 
hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and hypothyroidism, type I 
diabetes mellitus (which may present with diabetic ketoacidosis), and diabetes 
insipidus), hepatitis/increases in transaminases, nephritis/increases in creatinine, 
rash/dermatitis (including pemphigoid), myocarditis, myositis/polymyositis, immune 
thrombocytopenia, infusion related reactions, hypersensitivity reactions, pancreatitis, 
encephalitis, serious infections, subcutaneous injection site reaction, and other rare or 
less frequent inflammatory events including neuromuscular toxicities (eg, Guillain-Barré 
syndrome, myasthenia gravis) 
For information on all identified and potential risks with durvalumab please always refer 
to the current version of the durvalumab IB. 
The potential adverse effects (AEs) of the systemic therapy regimen of cisplatin or 
carboplatin plus etoposide together with durvalumab were reported in the results of the 
CASPIAN study (see Appendix A). Specifically, AEs of any cause and grade occurred in 
98% of subjects treated with durvalumab plus platinum-etoposide, while 62% of those 
in this study arm developed any grade 3 or 4 AE, the most common of which were 
neutropenia and anemia. Only 9% of subjects developed an AE that lead to 
discontinuation of therapy, however. Deaths due to AE of any cause occurred in 5% of 
subjects, similar to that in the standard platinum-etoposide group. Immune-mediated 
AEs (ImAEs) occurred in 20% of subjects treated with durvalumab plus platinum-
etoposide, with only 5% being grade 3 or 4. The most common ImAEs were hypo- and 
hyperthyroidism. Death due to ImAE occurred in <1% of subjects (1 subject – due to 
hepatotoxicity)6. 
A primary objective of this study is to evaluate the risks of adding non-ablative radiation 
to the above treatment regimen. Potential risks which the study will focus on will be an 
increase in ImAEs (other than thyroid dysfunction, which is generally easily managed), 
and an increase in radiation-related AEs, specifically pneumonitis, pericarditis, 
esophagitis, rib fracture, and hemoptysis. The reported rates of pneumonitis after SBRT 
requiring intervention range from 0-29%, with an uncommon occurrence of severe (≥ 
grade 3) pneumonitis23-26.  Reported cardiac events associated with SBRT occur in 0-
7.9% of treated patients23,27-29. Chest wall related toxicities after SBRT include skin 
toxicity (1.2-14%)30,31, rib fracture (5%) and chronic chest wall pain (5-25%) and are 
usually associated with peripherally located lung tumors32,33. Esophageal injury ranging 
from mild esophagitis to stricture, perforation, and/or fistula formation has been 
reported to occur in 12% of patients treated with SBRT34,35. Finally, with standard 
fractionation schemes fatal hemoptysis secondary to aortic damage, rupture, aneurysm, 
or aortic dissection may occur in up to 5.7% of patients, particular for those that receive 
a maximum composite dose to 1cm3 of the aorta ≥ 120Gy (25% rate of grade 5 toxicity) 
versus < 120Gy (0% rate of grade 5 toxicity)36. Similar cases have been reported with 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
10 (147) 
SBRT37. Currently, 50Gy delivered over five fractions has been a widely adopted SBRT 
regimen for treatment of centrally located tumors and tumors close to the chest 
wall38,39. Less intensive SBRT fractionation schemes or risk-adapted approaches further 
limits toxicities and provides for a safer approach26,40-42. For this study, we have chosen a 
conservative regimen of 25-30Gy delivered over five fractions (less than the commonly 
used 50Gy delivered over five fractions regimen). While this radiation will be delivered 
via SBRT whenever feasible, radiation via 3D-CRT and IMRT will also be permitted..  
 
2.5.2 
Known Potential Benefits  
 
 The potential benefit of the systemic therapy regimen of cisplatin or carboplatin plus 
etoposide together with durvalumab were reported in the results of the CASPIAN study 
and are outlined in the background section of this protocol.6 We hypothesize that the 
addition of radiation to one or more sites of disease will enhance the efficacy of 
systemic chemotherapy plus immunotherapy, improving 12-month progression free 
survival and possibly also response rates and median progression-free and overall 
survival. This hypothesis is based on data outlined in the background section which have 
shown that radiation in dosages similar to those used in this protocol can augment 
checkpoint-inhibitor-induced, immune-mediated killing of non-small cell lung cancer. 
This includes unpublished preliminary data from our clinical trial of neoadjuvant 
durvalumab with or without non-ablative SBRT for the pre-operative treatment of stage 
I, II, and IIIA NSCLC (https://clinicaltrials.gov/ct2/show/NCT02904954) and our clinical 
trial of ipilimumab plus nivolumab with non-ablative SBRT for stage IV NSCLC 
(https://clinicaltrials.gov/ct2/show/NCT03168464). 
 
2.5.3 
Assessment of Potential Risks and Benefits 
Given known safety profiles of systemic therapy with platinum-etoposide plus 
durvalumab systemic therapy, as well as those of non-ablative radiation, we believe that 
the combination of these two approaches will be safe and feasible in this study 
population of patients with treatment-naïve ES-SCLC. As safety will be a primary 
objective of this study, the subjects will be monitored closely for adverse events, which 
will be a primary endpoint of the trial. The study includes a safety run-in period 
involving the first 10 subjects enrolled wherein if there is a 30% or greater incidence of 
grade 3 or higher toxicities with the radiation regimen of 6 Gy per day for 5 fractions - 
specifically from radiation therapy or ImAEs (other than thyroid dysfunction) - then the 
radiation regimen will subsequently be switched to 5 Gy radiation per day for 5 
fractions. If there is still a 30% or greater incidence of grade 3 or higher toxicities from 
radiation therapy or ImAEs adverse events among the subsequent 10 subjects, then the 
study will be terminated.  
We therefore believe that the potential value of the information gained from this trial 
and the potential for improvement in outcomes will likely outweigh the possible 
increased risk to participants. 
 
2.6 Correlative Studies Background 
 
 
 
2.6.1 Tumor-Immune Microenvironment and Circulating Immune Cells/Inflammatory Proteins 
An anti-tumor immune response is dependent on the appropriate balance of activities 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
11 (147) 
from effector cells and suppressor cells in the tumor-immune microenvironment43. ICB 
therapies can alter the compositions of circulating and tumor-infiltrating immune cells 
and these compositions can correlate with treatment response44-46. Additionally, 
radiation therapy to tumors causes accumulation of DNA in the cytoplasm of irradiated 
cells which in turn leads to the activation of the cyclic GMP-AMP synthase 
(cGAS)/stimulator of interferon genes (STING) pathway, with the resultant production of 
type 1 interferon (IFN) and other pro-inflammatory cytokines. These cytokines also play 
a role in tumor-immune response.47 Other cytokines and soluble factors that can be 
increased by radiation therapy may be associated with immune suppression (e.g., 
soluble MICA/B, soluble CD73)48. 
 
We therefore will plan to examine the tumor-immune microenvironment and the 
circulating immune cell and inflammatory protein composition in the study subjects, as 
correlative studies. Specifically, we will isolate peripheral blood mononuclear cells 
(PBMCs) and examine them for frequencies of CD4+ T cells, CD8+ T cells, natural killer 
(NK) cells, myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), 
macrophages, and dendritic cells (DCs). We will specifically examine Ki67+PD-1+ CD8 T 
cells with an effector-like phenotype (HLA-DR+CD38+Bcl-1low) since they have been 
shown to be predictive of response In lung cancer patients treated with anti-PD-1 when 
increased within 4 weeks of treatment start from baseline by two to seven-fold 49. We 
will also quantify cytokine levels in the peripheral blood of subjects, particularly type-1 
IFN. Additionally, if we are able to obtain sufficient tissue from biopsy samples, we will 
examine the frequencies of tumor-infiltrating lymphocytes (TILs) in these samples, as 
well as the T cell receptor (TCR) repertoire of the CD8+ T cells from the TILs and the 
PBMCs. These studies may provide insight into the mechanisms of immune response 
and resistance to the treatment modalities used in this study. 
 
 
 
2.6.2 Tumor Organoids 
As part of the Englander Institute for Precision (EIPM) at Weill Cornell Medicine, the 
Tumor Organoid Platform is an active program focused on development of 3D patient 
derived tumor organoids (PDTO) from metastatic and primary anatomic sites, obtained 
through biopsies, surgical resections and rapid autopsy procedures. The fresh tissue is 
obtained through our IRB-approved precision medicine clinical trial where full patient 
consent is obtained for both organoid and xenograft development. Standard operation 
procedures are in place for all aspects of tissue processing and culture maintenance. In 
this setting, we are able to extend our personalized medicine program to include high 
throughput and/or targeted drug screening which can be validated through histologic 
examination and genomic sequencing, and both in vivo and in vitro models. To date, we 
have established in our biobank, more than a 100 3D PDTOs, spanning a range of 13 
primary tumor types that can be used for a variety of experiments and co-clinical trials 
(Figure 1).  
 
In our recent publications, PDTO samples have demonstrated high purity as well as ploidy 
and genomic burden profiles that matched patient tumor data. Allele-specific copy-
number analysis of 1,062 putative cancer genes showed a median of 86% concordance 
when comparing PDTOs to the native tumor tissues. Minor differences observed are 
either due to subclonality in the native tumor (subclones not represented in the PDTO) or 
due to the progression of the PDTO/PDX. Similarly, SNV analysis showed excellent 
concordance between native tumors and matching PDTOs. We have demonstrated that 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
12 (147) 
these specimens can be successfully thawed and reestablished in culture for use in 
scientific research. Organoid technologies are developed in a dedicated space which is 
comprised of 3 four-foot biosafety cabinets, 6 Panasonic incubators, a Beckman Coulter 
centrifuge, an Olympus inverted microscope (CKX53), Olympus DP73 camera and Cell 
Sense Imaging Software, VWR water bath and a Thermo Scientific, MaxQ 4450 incubated 
shaker. 
 
The EIPM’s new high throughput drug screening platform is an integrative robotics system 
that connects some of the most coveted laboratory equipment on the market into a fully 
modular, HEPA filtered unit. With capabilities such as high content imaging, endpoint 
reads using a variety of PMT channels, in house static and dynamic incubator systems, a 
centrifuge and a state of the art liquid handler connected by two robotic arms and a 
powerful scheduling software, fully customized experiments can be run in their entirety 
in a sterile environment. Instrument software is scheduled to be 21CFR.11 compliant by 
the end of 2021 and it is our goal to develop our platform into a CLIA certified testing 
facility. 
 
The Operetta CLS high content imaging system enables live cell experiments, 3D imaging, 
and high resolution and fast read times. Associated with Harmony software which is 
specifically designed for 3D cell models, the Operetta is capable of sensitive and 
quantitative measurements that can be used as a stand-alone reader or incorporated into 
our high throughput automation system. Spinning disk confocal optics and synchronized 
LED illumination provide stable excitation and minimize phototoxicity and bleaching for 
meaningful live-cell assays. A large format sCMOS camera with water-immersion 
objectives provides high resolution, while the software addresses the imaging and 
analysis challenges presented by complex cellular models.  
 
Over the last few months we have been optimizing and validating image-based cell 
viability measurements using our previously biobanked organoids. The validation was 
done against an endpoint metabolic measure of ATP production. For this, one of our 
established colorectal lines, PM1230, which was shown to have a mutation in KRAS was 
treated with the MEK inhibitor Trametinib. A dose response curve starting at 3µM with 
an 8-point dilution of 1:3 was compared to an untreated control (DMSO). Duplicate 
experiments were run in parallel; one for the purpose of imaging and the other for cell 
titer glo measurement of cell metabolism. After 4 days of treatment, NucBlue and Cell 
Mask were added to the plates slotted for image analysis, after which they were 
incubated for 1 hour at 37°C. A pre-scan analysis was performed at a magnification of 5X 
(air) to pre-select an unbiased population of organoids utilizing instrument based 
software features. Selected organoids were then re-scanned at 63X (water-immersion), 
using z-stack analysis tools in order to perform 3D image analysis. As shown in Figure 2, 
both methods exhibit the same drug response. Although further optimization is required 
to reach the full potential of this platform, these results are a promising use of high 
content imaging as a complement to the indirect measure of viability using Cell Titer Glo. 
 
As proof-of-concept, we have already generated and banked 15 lung PDTOs from 
treatment naïve Non-Small Cell Lung Cancer patients. Targeted sequencing of the initial 
lung PDTOs lines showed they contain cancer driver mutations (KRAS, EGFR and P53), 
confirming that our growth conditions are optimized for lung cancer organoids (Figure 3). 
In this study we will focus on growing organoids from Small Cell Lung Cancer patients. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
13 (147) 
 
 
 
 
 
 
3.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breast
5%
Cervix
2%
Uterus
9%
Ovary
4%
Colorectal
28%
Stomach
8%
Esophagus/GE 
junction…
Bile duct…
Pancreas
5%
Kidney
2%
Prostate
5%
Bladder
9%
Lung 
13%
Melanoma
1%
Non-tumor 
organoids
5%
Unkown primary
2%
Peritoneal carcinomatosis
2%
Figure 1. Patient-derived tumor organoid biobank at Englander Institute for Precision Medicine 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
14 (147) 
 
 
 
 
Figure 2. Optimization of the high throughput imaging platform. (A) Representative brightfield (upper panel) and NucBlue 
(lower panel) pictures of a colorectal organoid line (PM1230) treated with a dose response of Trametinib, a K-Ras inhibitor 
(starting at 3µM with a 3-dilution factor). The pictures were taken with a 5X air objective (B) Quantification of organoid 
volume (µm3) using our high content system Operetta in combination with Harmony Software based on 3D imagining of 
NucBlue. (C) Viability measurement of organoid line PM1230 in a parallel experiment to (A) using Cell Titer Glo 3D, which 
measures ATP production. Data was normalized to control (untreated) and represents meanSEM. (D) Representative 
pictures of PM1230 colorectal organoids at 63X magnification stained with NUcBlue (Blue) and CellMask (Red).  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
15 (147) 
 
 
 
 
 
 
 
 
 
2.6.3 Circulating Tumor Cells 
A technical limitation of studies aimed to understand molecular determinants of 
therapeutic response in cancer cells is the availability of tumor tissue. First, the invasive 
nature of biopsies often prevents longitudinal analysis of the dynamic response of 
cancer and immune cells to the treatment. Second, tissue derived from the biopsy of a 
single tumor site may not recapitulate the entire tumor biology. This lack of tumor 
material, together with the inability to perform serial tumor biopsies, limits extensive 
and longitudinal investigation of the molecular determinants of tumor response to 
treatment and disease progression. 
 
To overcome these limitations, we will utilize circulating tumor cells (CTCs) as a source 
of tumor material to investigate the molecular response of tumor cells to the proposed 
treatment. To date, most CTC enrichment methodologies (including the only FDA-
cleared method, CellSearch), utilize the Epithelial Cell Adhesion Molecule (EpCAM) as a 
positive selection CTC marker. Several studies reported that CellSearch successfully 
identifies CTCs in SCLC patients and that EpCAM-based CTC enumeration yields 
prognostic significance50. EpCAM+-CTCs have been previously utilized to interrogate the 
molecular characteristics of SCLC as they can recapitulate clinical response to 
chemotherapy in patients51. However, EpCAM expression is significantly reduced or 
even lost during the epithelial-mesenchymal transition (EMT), a key process in cancer 
progression during which metastatic capability is acquired52. Therefore, the population 
of EpCAM+-CTCs represents only a subpopulation of CTCs, limiting their biological 
relevance and clinical use. To help overcome this limitation in NSCLC patients, Dr. 
Paraskevi Giannakakou’s lab identified Transferrin Receptor (TfR) as an alternative cell-
surface antigen that can be used to capture CTCs across the EMT gradient. TfR is a cell 
surface protein that mediates intracellular iron uptake by binding to the iron carrier 
transferrin. This protein is expressed at low levels in many normal tissues but it is 
significantly over-expressed in cancer cells, including NSCLC cells53. However, it is 
unclear if this protein is overexpressed in SCLC tumors and CTCs, though we are 
currently assessing this in the lab. 
 
As a correlative study of this trial, we will prospectively and longitudinally isolate and 
molecularly analyze CTCs and matching peripheral blood mononuclear cells (PBMCs) 
from subjects receiving the combination of chemo-immunotherapy and non-ablative 
radiation. The goal of our analysis is to identify genes/pathways associated with clinical 
response/resistance to this treatment by performing untargeted RNA sequencing of 
patient-derived-CTCs (tumor compartment) with matching PBMCs (immune 
compartment). 
 
To overcome the limitations intrinsic to an EpCAM-based positive selection, we will 
enrich CTCs by using the antigen-agnostic RosetteSep™ Circulating Epithelial Tumor Cells 
Figure 3 Representative brightfield picture of 
Non-Small Cell Lung tumor organoids cultured 
in matrigel.  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
16 (147) 
enrichment assay (STEMCELL™ Technologies); this approach utilizes anti-
CD45/antiglycophorin A antibody complexes that crosslinks red blood cells (glycophorin 
A+) and white blood cells (CD45+), which are subsequently eliminated by gradient-based 
separation. Such antigen agnostic approach allows the enrichment of a pool of 
heterogeneous subpopulation of CTCs compared to traditional approaches that rely on 
positive selection of epithelial markers (i.e. EpCAM). Additionally, if work in the lab 
shows that SCLC CTCs express TfR (as NSCLC CTCs do), then we will also attempt to use 
this marker to help isolate CTCs from the subjects in this study. 
 
Gene set enrichment analysis of differentially expressed genes between baseline, on-
treatment, and relapse CTCs will be performed to identify pathways associated with 
onset of resistance to the treatment. To assess immune cell activation induced by 
treatment, matched PBMCs will be isolated from the above and gene expression 
analysis will be performed. Gene set enrichment analysis of differentially expressed 
genes between baseline and on treatment will reveal immune signatures characterizing 
host immune activation as a consequence of the treatment and will identify immune 
components that discriminate responders from non-responder patients.  
 
 
3. Study Design 
 
3.1 Overall Design 
 
This is a prospective, non-randomized, open-label, single-arm pilot phase II study of non-ablative 
radiation in combination with standard-of-care chemo-immunotherapy in patients with untreated, 
extensive-stage small cell lung cancer. The hypothesis of this study is that the addition of sub-
ablative doses of radiation to combination chemotherapy and immunotherapy will be safe and 
feasible and result in improved outcomes for patients with treatment-naive, extensive-stage small 
cell lung cancer. 
 
The study will plan to enroll 42 subjects across 3 sites to allow for 34 subjects to be evaluable for the 
primary endpoints. All subjects will be treated with etoposide plus platinum (carboplatin or 
cisplatin) chemotherapy together with the PD-L1 checkpoint inhibitor durvalumab, which is a 
standard of care in this disease setting. All subjects will also receive a total of 6 Gy of radiotherapy 
per day for 5 fractions. Radiation will start prior to the completion of the second cycle of chemo-
immunotherapy but will ideally begin on the first day of the first cycle; no further radiation will be 
planned after this.  
 
There will be a safety run-in period involving the first 10 subjects enrolled wherein if there is a 30% 
or greater incidence of grade 3 or higher toxicities with the proposed treatment regimen - 
specifically from radiation therapy (with focus on pneumonitis, pericarditis, esophagitis, rib fracture, 
or hemoptysis) or immune-mediated adverse events (other than thyroid dysfunction) - then the 
radiation regimen will subsequently be switched to 5 Gy radiation per day for 5 fractions. If there is 
still a 30% or greater incidence of grade 3 or higher toxicities from radiation therapy or immune-
mediated adverse events among the subsequent 10 subjects, then the study will be terminated. If 
this does not occur, then accrual will continue until 34 total subjects are evaluable.   
 
Systemic therapy will be given as follows:  
- Carboplatin at AUC = 5-6 mg/mL per min or Cisplatin at 75-80mg/m2 on Day 1 of each 
21-day cycle, for 4 cycles 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
17 (147) 
- Etoposide at 80-100mg/m2 on Day 1, Day 2, and Day 3 of each 21-day cycle, for 4 
cycles 
- Durvalumab at 1500mg on Day 1 of each 21-day cycle, for 4 cycles; following this, 
subjects will receive 1500mg Durvalumab once every 4 weeks until disease progression.  
 
Treatment will continue until disease progression, intolerability due to toxicity, or withdrawal of 
consent. Prophylactic Cranial Irradiation (PCI) and consolidative Thoracic Radiotherapy (TRT) will not 
be given. 
 
This study will enroll subjects at NewYork Presbyterian Hospital-Weill Cornell Medicine. 
 
 
3.2 Scientific Rationale for Study Design 
        
This is a pilot study to examine the feasibility and preliminary safety and efficacy results of 
combining chemotherapy and IO therapy with non-ablative radiation in ES-SCLC patients. Given the 
incidence of SCLC encountered at the involved study sites, a single-arm trial was determined to be 
more feasible in terms of accrual needed to achieve a statistically significant outcome. The goal of 
the current trial is to show proof of concept for the therapeutic approach of combining 
chemotherapy and IO therapy with non-ablative radiation and to provide data that would support a 
larger, randomized-controlled trial. 
 
As chemotherapy plus IO therapy is already the standard of care treatment for ES-SCLC, the addition 
of radiation to this approach will be the variable being tested. We will use the results of the CASPIAN 
study6 as a historical control for comparison. As such, the study interventions in this trial were 
chosen to mirror those of the experimental arm (platinum + etoposide + durvalumab) of the 
CASPIAN trial. As in that trial, PCI and TRT will not be given following completion of chemotherapy 
and immunotherapy. The endpoints being evaluated in this trial have also been reported for the 
experimental arm of the CASPIAN study. 
 
3.3 Justification for Dose  
 
Carboplatin, Cisplatin, Etoposide, and Durvalumab will be given at their FDA-approved dosages and 
in concordance with the treatment regimen administered in the CASPIAN study.  
      
Durvalumab will be given at a fixed dose in this trial, as was done in the CASPIAN study. A population 
PK model was developed for durvalumab using monotherapy data from a Phase I study (study 1108; 
N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). Population PK analysis 
indicated only minor impact of body weight (WT) on the PK of durvalumab (coefficient of ≤0.5). The 
impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab was 
evaluated by comparing predicted steady state PK concentrations (5th, median and 95th 
percentiles) using the population PK model. A fixed dose of 750 mg was selected to approximate 10 
mg/kg (based on median body WT of ~75 kg). A total of 1000 patients were simulated using body 
WT distribution of 40–120 kg. Simulation results demonstrate that body WT-based and fixed dosing 
regimens yield similar median steady state PK concentrations with slightly less overall between-
patient variability with fixed dosing regimen.  
Similar findings have been reported by others54-57. Wang and colleagues investigated 12 monoclonal 
antibodies and found that fixed and body size-based dosing perform similarly, with fixed dosing 
being better for 7 of 12 antibodies55. In addition, they investigated 18 therapeutic proteins and 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
18 (147) 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in pharmacokinetic/pharmacodynamics parameters56.  
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors. Given expectation of similar pharmacokinetic exposure and variability, AstraZeneca 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed 
dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the current study. 
 
Non-ablative radiation will be given at a dose of 6 Gy X 5 fractions, ideally starting on the first day of 
the first cycle of the systemic therapy regimen. We have previously shown that this dose and 
fractionation scheme is safe to deliver, while inducing responses to the immune checkpoint inhibitor 
Ipilimumab in non-small cell lung cancer patients12,58. We will allow subjects in this current trial to 
start radiation after the first cycle of systemic therapy, but not after the second cycle. 
 
3.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Assessments 
(SoA), Section 6.1. The end of the study is defined as completion of the last visit or procedure shown 
in the SoA in the trial. 
 
 
4. Subject Selection 
 
4.1 Study Population 
 
Subjects with a diagnosis of untreated extensive-stage small cell lung cancer who meet the inclusion 
and exclusion criteria will be eligible for participation in this study. 
 
4.2 Inclusion Criteria 
1. Adults ≥ 18 years old  
2. Written informed consent from subject or from Health Care Proxy prior to performing any 
protocol-related procedures, including screening evaluations. 
3. Pathological diagnosis of SCLC from biopsy (core biopsy or fine needle aspiration); mixed-
histology (NSCLC and SCLC) allowed 
4. ES-SCLC (American Joint Committee on Cancer, 8th edition, stage IV [T any, N any, M1a or M1b], 
or T3–4 due to multiple lung nodules that are too extensive or tumor or nodal volume that is too 
large to be encompassed in a tolerable radiation plan) 
5. Brain metastases allowed, but must be asymptomatic without the need for systemic steroids at 
doses more than 10 mg/day of prednisone or its equivalent, or treated with Whole Brain 
Radiation Therapy (WBRT) or Stereotactic Radiosurgery (SRS) 
6. Body weight > 30kg 
7. ECOG Performance Status (PS) 0-1 at enrollment. ECOG PS 2 allowed if PS decline considered by 
treating study investigator to be secondary to SCLC  
8. At least 1 lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
(except lymph nodes, which must have a short axis ≥15 mm) with CT, PET-CT, or MRI and that is 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
19 (147) 
suitable for accurate repeated measurements as per Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 guidelines. 
9. No prior exposure to IO therapy including, but not limited to, anti-CTLA-4, anti-PD-1, antiPD-L1, 
and anti-PD-L2 antibodies 
10. No prior radiation therapy in the past 3 years prior to study enrollment. Radiation treatment of 
brain metastases from small cell lung cancer will be permitted, as per inclusion criteria 5 above. 
Other specific radiotherapy treatments occurring within the past 3 years, such as electron beam 
therapy for skin cancers, pterygium irradiation with Sr-90 or SRS for non-malignant disease, or 
prior I-131 for hyperthyroidism, may not be an absolute contraindication, and will be considered 
on a case by case basis. 
11. Life expectancy of at least 12 weeks from the start of therapy 
12. Adequate baseline organ functions as defined below 
a.  Hemoglobin ≥8.0 g/dL. 
b. Absolute neutrophil count ≥1.5 × 103/uL (use of granulocyte colony-stimulating factor is 
not permitted at screening). 
c. Platelet count ≥75 × 103/uL. 
d. Serum bilirubin ≤1.5 × the ULN. This will not apply to patients with confirmed Gilbert’s 
syndrome, who will be allowed in consultation with their physician. 
e. In patients without hepatic metastasis: ALT and AST ≤2.5 × ULN; for patients with 
hepatic metastases, ALT and AST ≤5 × ULN. 
f. Measured or calculated creatinine clearance: >60 mL/min for patients on cisplatin and 
>45 mL/min for patients on carboplatin, as determined by Cockcroft‒Gault (using actual 
body weight). 
i. Males: 
Creatinine clearance (mL/min) = [Weight (kg) × (140 − Age)]/[72 × serum 
creatinine (mg/dL)] 
ii. Females: 
Creatinine clearance (mL/min) = [Weight (kg) × (140 − Age)]/ [72 × serum 
creatinine (mg/dL)] × 0.85 
13. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-
menopausal patients. Women will be considered post-menopausal if they have been 
amenorrhoeic for 12 months without an alternative medical cause. The following age-specific 
requirements apply: 
a. Women <50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle stimulating hormone levels 
in the post-menopausal range for the institution or underwent surgical sterilization 
(bilateral oophorectomy or hysterectomy). 
b. Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic 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). 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
20 (147) 
4.3 Exclusion Criteria  
1. 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. 
2. Concurrent enrollment in another clinical study, unless it is an observational (non-
interventional) clinical study or the follow-up period of an interventional study. 
3. Participation in another clinical study with a therapeutic investigational product during the last 4 
weeks. 
4. Contraindications to platinum-based chemotherapy 
5. Contraindications to radiation therapy 
6. Prior radiation therapy to same site as proposed sub-ablative radiation site 
7. Cannot tolerate radiation treatment position or immobilization 
8. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer 
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., 
hormone replacement therapy) is acceptable, as is use of bisphosphonate or RANKL inhibitor 
therapy for prevention of skeletal-related events from bone metastases. 
9. History of another primary malignancy except for: 
a. Malignancy treated with curative intent and with no known active disease ≥3 years 
before the first dose of the investigational product and of low potential risk for 
recurrence. 
b. Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of 
disease. 
c. Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer 
in situ). 
10. History Limited-Stage SCLC treated with concurrent chemo-radiation 
11. History of allogenic organ transplantation. 
12. Major surgical procedure (as defined by the investigator) within 28 days prior to Cycle 1 Day 1 of 
systemic therapy. Local surgery of isolated lesions for palliative intent is acceptable. 
13. Paraneoplastic syndrome of autoimmune nature, requiring systemic treatment (systemic 
steroids or immunosuppressive agents) 
14. Documented, active, and uncontrolled autoimmune or inflammatory disorders (including 
inflammatory bowel disease, diverticulitis with the exception of diverticulosis, systemic lupus 
erythematosus, sarcoidosis syndrome, Wegener syndrome (granulomatosis with polyangiitis), 
Graves’ disease, rheumatoid arthritis, hypophysitis, and uveitis, etc.). The following are 
exceptions to this criterion: 
a. Patients with vitiligo or alopecia. 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone 
replacement 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
21 (147) 
c. Any chronic skin condition that does not require systemic therapy. 
d. Patients with celiac disease controlled by diet alone. 
e. Patients without active disease in the last 5 years may be included but only after 
consultation with the medical monitor and with appropriate subspecialty consultation 
(e.g. with endocrinology, gastroenterology, rheumatology, etc.) 
f. Patients whose autoimmune or inflammatory disorder is controlled with medication 
may be included but only after consultation with the medical monitor and with 
appropriate subspecialty consultation (e.g. with endocrinology, gastroenterology, 
rheumatology, etc.) 
15. Uncontrolled intercurrent illness, including but not limited to, uncontrolled ongoing or active 
infection, interstitial lung disease, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that 
would limit compliance with study requirement, substantially increase risk of incurring adverse 
events, or compromise the ability of the patient to give written informed consent. 
16. Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and tuberculosis testing in line with local practice), HBV 
(known positive HBV surface antigen result), HCV, or HIV (positive HIV 1/2 antibodies). Patients 
with a past or resolved HBV infection (defined as the presence of HBV core antibody and 
absence of HBV surface antigen) are eligible, as are patients with HBV infection controlled by 
antiviral medication (defined as undetectable viral load). Patients positive for HCV antibody are 
eligible only if polymerase chain reaction is negative for HCV ribonucleic acid. 
17. 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). 
Premedication with steroids for chemotherapy is acceptable. 
18. History of active primary immunodeficiency. 
19. Receipt of live, attenuated vaccine within 30 days prior to the first dose of durvalumab 
20. Female patients who are pregnant or breast-feeding or male or female patients of reproductive 
potential who are not willing to employ effective birth control from screening to 90 days after 
the last dose of durvalumab monotherapy. 
21. Known allergy or hypersensitivity to durvalumab, etoposide, carboplatin, cisplatin, or any of 
their excipients. 
4.4 Screen Failures  
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
22 (147) 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
absence of a measurable lesion, ECOG performance status, life expectancy, laboratory parameters, 
being on systemic corticosteroid therapy, inability to tolerate radiation treatment position or 
immobilization, or uncontrolled intercurrent illness or active infection may be rescreened. 
Rescreened participants should be assigned the same participant number as for the initial screening. 
 
4.5 Strategies for Recruitment and Retention 
 
To increase recruitment for this study, we will receive referrals from 4 sites within the NewYork-
Presbyterian hospital system – NewYork Presbyterian Hospital-Weill Cornell Medicine, NewYork 
Presbyterian Lower Manhattan Hospital, NewYork-Presbyterian Brooklyn Methodist, and NewYork-
Presbyterian Queens. Not only will this help recruitment in terms of number of subjects but, due to 
the differing patient demographics in the areas served by each site, we should also be able to enroll 
subjects of different races and ethnicities. In the near future we hope to open this study at the 
Brooklyn and Queens affiliate sites, once the logistics of transporting study drug have been resolved. 
 
This study will plan to enroll 42 subjects to allow for 34 to be evaluable for the primary endpoints. 
We anticipate accruing roughly 1 subject per month. 
Subjects will be identified and approached by treating medical oncologists or radiation oncologists in 
the outpatient clinics of any of the sites involved in the trial. The trial may also be discussed with 
patients who are admitted to the hospital at any of the enrolling sites. 
 
The trial will be listed on the Joint Clinical Trials Office (JCTO) public website and will also be 
discussed at local professional meetings such as the NY Lung Cancer Learning Center conferences, in 
order to help generate referrals. 
 
Subjects will not be compensated for taking part in this trial. 
 
  
 
5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure for 
Subject Registration. 
6. Study Procedures 
 
6.1 Schedule of Assessments 
 
 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
23 (147) 
Table 1. Schedule of trial events 
 
 
   
Screening 
D -28 to 
D-1 
Cycle 1 
Cycles 2 - 4 
C5D1+ 
(D85+) 
EOT 
D1 
D2 
D3 
D4 
D5 
D1 
D2 
D3 
 
 
 
Carboplatin/Cisplatin 
 
X 
 
 
 
 
X 
 
 
 
 
Etoposide 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
Durvalumab 
 
X 
 
 
 
 
X 
 
 
Xa 
 
 
Radiationb 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
Radiation Simulation 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
X 
 
 
Xa 
X 
 
Physical exam 
X 
X 
 
 
 
 
X 
 
 
Xa 
X 
Concurrent 
Medications 
X 
X 
 
 
 
 
X 
 
 
Xa 
X 
 
Vital signs including 
Height and Weight 
X 
X 
 
 
 
 
X 
 
 
Xa 
X 
CT or PET-CTc 
X 
 
 
 
 
 
Xd 
 
 
Xd,e 
 
MRI Brainf 
X 
 
 
 
 
 
Xd,g 
 
 
Xd,e,g 
 
CBC w/diff 
X 
X 
 
 
 
 
X 
 
 
Xa 
X 
 
Serum chemistry with 
LFTs 
X 
X 
 
 
 
 
X 
 
 
Xa 
X 
 
Amylase and/or Lipase 
X 
X 
 
 
 
 
X 
 
 
Xa 
X 
Thyroid Function 
Panel 
X 
X 
 
 
 
 
X 
 
 
Xa 
X 
Hepatitis A, B, C 
Profile 
X 
 
 
 
 
 
 
 
 
 
 
 
Beta-hCGh 
X 
X 
 
 
 
 
X 
 
 
X 
X 
Adverse event 
Capture 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for correlative 
studies 
 
X 
 
 
 
 
X 
 
 
Xi 
X 
 
Research biopsy 
(Optional) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Xj 
X 
Continuous Assessment 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
24 (147) 
a After D85, repeat every 28 days (+/- 7 days) until disease progression 
b Exact radiation schedule to be determined by treating Radiation Oncologist; all five fractions of radiation should 
be completed within 2 weeks of first radiation dose (>3 weeks is an acceptable variation); SBRT is preferred but 
3D-CRT and IMRT are permitted. 
c CT scans of the Chest and Abdomen/Pelvis with or without Contrast; PET-CT Skull Base to Thigh 
d Imaging can be done +/- 7 days 
e After D85, repeat every 8 weeks +/- 7 days until disease progression 
f MRI Brain with and without Contrast 
g MRI Brain only needs to be done at this time point if subject was found to have brain metastases at baseline 
assessment; otherwise MRI Brain can be done as clinically indicated 
h For pre-menopausal females of childbearing potential 
i After D85, repeat every 8 weeks (+/- 7 days) until D365 
j Optional Research Biopsy can be done +/- 21 days 
 
Abbreviations: C = Cycle; D = Day; diff = differential; LFTs = Liver Function Tests; EOT = End of Treatment  
 
6.1.1 
Screening Visit (-28 to -1 Days before start of treatment) 
  
• 
Informed consent 
• 
Inclusion/Exclusion Criteria Review 
• 
Medical History 
• 
Medication History/Concurrent Medications 
• 
Vital signs including Height and Weight 
• 
Physical Exam 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; 
Amylase and/or Lipase; Thyroid Function Panel; Hepatitis A, B, and C profile; 
Beta-hCG (for pre-menopausal females) 
• 
CT Chest and Abdomen/Pelvis with or without Contrast or PET-CT Skull Base to 
Thigh 
• 
MRI Brain with and without Contrast 
• 
Optional Research Biopsy 
• 
Radiation Simulation and Treatment Planning 
 
 
 
 
6.1.2 
Treatment Phase 
 
 
 
 
 
 
 
 
 
 6.1.2.1 Cycle 1 Day 1 (Day 1)  
• 
Interval Medical History 
• 
Concurrent Medications 
• 
Vital signs including Height and Weight 
• 
Physical Exam 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; 
Amylase and/or Lipase; Thyroid Function Panel; beta-hCG (for pre-
menopausal females) 
• 
Blood for Correlative Studies 
• 
Fraction 1 (6 Gy) of radiation (when feasible) – repeat 6 Gy for total of 5 
fractions; fractions do not need to be given on consecutive days but all 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
25 (147) 
attempts should be made to do so. When feasible, radiation should be given 
before chemo-immunotherapy on any given day. Radiation may start after 
Cycle 1 Day 1 but not after Cycle 2 Day 3 
• 
Carboplatin AUC = 5-6 mg/mL per min IV or Cisplatin 75-80mg/m2 IV on D1 
• 
Etoposide 80-100mg/m2 IV on D1, D2, and D3  
• 
 Durvalumab 1500mg IV on D1  
 
 
6.1.2.2 Cycle 2 Day 1 (Day 22) (± 7 days) 
• 
 Interval Medical History 
• 
Concurrent Medications 
• 
Vital signs including Height and Weight 
• 
Physical Exam 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; 
Amylase and/or Lipase; Thyroid Function Panel; beta-hCG (for pre-
menopausal females) 
• 
Adverse Event Evaluation 
• 
Carboplatin AUC = 5-6 mg/mL per min IV or Cisplatin 75-80mg/m2 IV on D22 
• 
Etoposide 80-100mg/m2 IV on D22, D23, and D24  
• 
 Durvalumab 1500mg IV on D22  
 
 
 
 
 
6.1.2.3 Cycle 3 Day 1 (Day 43) (± 7 days) 
• 
CT Chest and Abdomen/Pelvis with or without Contrast or PET-CT Skull Base 
to Thigh – should ideally be done with results obtained prior to D43 
• 
MRI Brain with and without Contrast if indicated – should ideally be done 
with results obtained prior to D43 
• 
Interval Medical History 
• 
Concurrent Medications 
• 
Vital signs including Height and Weight 
• 
Physical Exam 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; 
Amylase and/or Lipase; Thyroid Function Panel; beta-hCG (for pre-
menopausal females) 
• 
Adverse Event Evaluation 
• 
Blood for Correlative Studies 
• 
Carboplatin AUC = 5-6 mg/mL per min IV or Cisplatin 75-80mg/m2 IV on D43 
• 
Etoposide 80-100mg/m2 IV on D43, D44, and D45  
• 
Durvalumab 1500mg IV on D43 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
26 (147) 
 
6.1.2.4 Cycle 4 Day 1 (Day 64) (± 7 days) 
• 
 Interval Medical History 
• 
Concurrent Medications 
• 
Vital signs including Height and Weight 
• 
Physical Exam 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; 
Amylase and/or Lipase; Thyroid Function Panel; beta-hCG (for pre-
menopausal females) 
• 
Adverse Event Evaluation 
• 
Carboplatin AUC = 5-6 mg/mL per min IV or Cisplatin 75-80mg/m2 IV on D64 
• 
Etoposide 80-100mg/m2 IV on D64, D65, and D66  
• 
Durvalumab 1500mg IV on D64 
 
 
6.1.2.5 Cycle 5 Day 1 (Day 85) (± 7 days) and Beyond until Disease Progression 
• 
CT Chest and Abdomen/Pelvis with or without Contrast or PET-CT Skull Base 
to Thigh – should ideally be done with results obtained prior to D85 
o Repeat every 8 weeks (± 7 days) until disease progression 
• 
MRI Brain with and without Contrast if indicated – should ideally be done 
with results obtained prior to D85 
o Repeat every 8 weeks (± 7 days) if indicated until disease 
progression 
• 
Interval Medical History 
o Repeat every 28 days (± 7 days) until disease progression 
• 
Concurrent Medications 
o Repeat every 28 days (± 7 days) until disease progression 
• 
Vital signs including Height and Weight 
o Repeat every 28 days (± 7 days) until disease progression 
• 
Physical Exam 
o Repeat every 28 days (± 7 days) until disease progression 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; 
Amylase and/or Lipase; Thyroid Function Panel; beta-hCG (for pre-
menopausal females) 
o Repeat every 28 days (± 7 days) until disease progression 
• 
Adverse Event Evaluation 
o Repeat every 28 days (± 7 days) until disease progression 
• 
Blood for Correlative Studies 
o Repeat every 8 weeks (± 7 days) until D365 
• 
Durvalumab 1500mg IV on D85 
o Repeat every 28 days (± 7 days) until disease progression 
• 
Optional Research Biopsy (± 21 days) 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
27 (147) 
 
 
6.1.2.6 End of Treatment Visit – To Occur at Radiographic or Clinical Disease 
Progression (± 28 days) 
• 
 Interval Medical History 
• 
Concurrent Medications 
• 
Vital signs including Height and Weight 
• 
Physical Exam 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; 
Amylase and/or Lipase; Thyroid Function Panel; beta-hCG (for pre-
menopausal females) 
• 
Adverse Event Evaluation 
• 
Blood for Correlative Studies 
• 
Optional Research Biopsy 
 
6.1.3 
Follow-up Phase: From Time of Progression to Withdrawal from Study or Death 
• 
Interval Medical History 
o Every 28 days (± 7 days) for the first 84 days; then every 84 days (± 7 
days) 
• 
Concurrent Medications 
o Every 28 days (± 7 days) for the first 84 days; then every 84 days (± 7 
days) 
• 
Vital signs including Height and Weight 
o Every 28 days (± 7 days) for 84 days 
• 
Physical Exam 
o Every 28 days (± 7 days) for 84 days 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; 
Thyroid Function Panel 
o Every 28 days (± 7 days) for 84 days 
• 
Adverse Event Evaluation 
o Every 28 days (± 7 days) for the first 84 days; then every 84 days (± 7 
days) 
 
 
7. Study Intervention   
 
7.1 Chemotherapy  
 
Carboplatin, Cisplatin, and Etoposide will be used in the FDA-approved manner for ES-SCLC and 
infused via IV using standard institutional guidelines. Carboplatin will be given at an area under the 
curve (AUC) of 5-6 mg/mL per min; alternatively, Cisplatin will be given at 75-80mg/m2 on Day 1 of a 
21-day cycle. The choice of Carboplatin vs Cisplatin and the exact dosing of each drug will be 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
28 (147) 
determined by the treating medical oncologist. Switching from Cisplatin-based to Carboplatin-based 
therapy will be permitted if this is done due to adverse effects from Cisplatin or to otherwise 
improve tolerability of the chemotherapy regimen. In general, Carboplatin will be infused over 1 
hour and Cisplatin over 2 hours.  
 
Etoposide will be given at 80-100mg/m2 on Day 1, Day 2, and Day 3 of a 21-day cycle, with the exact 
dosage again determined by the treating medical oncologist. In general, Etoposide will be infused 
over 1 hour. 
 
Pre-medications given to prevent and treat chemotherapy-induced nausea and vomiting as well as 
chemotherapy-induced infusion reactions will be given as per institutional guidelines and at the 
discretion of the treating medical oncologist.  
 
7.2 Immunotherapy 
 
7.2.1 Supply of Durvalumab 
 
Durvalumab will be supplied by AstraZeneca as a 500 mg vial concentrate for solution for infusion.  
The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine hydrochloride, 275 mM 
trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0 and density 
of 1.054 g/mL.  The nominal volume is 10 mL.  
 
Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution, free from visible 
particles. 
 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Investigational product must be kept in original packaging until use to prevent prolonged light 
exposure. 
 
7.2.2 Preparation and Administration of Durvalumab Doses with an IV Bag 
 
During the first 4 cycles of treatment, durvalumab will be administered prior to chemotherapy 
drugs.  
 
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the durvalumab 
vial to the start of administration must not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
If the final product is stored at both refrigerated and ambient temperatures, the total time must 
not exceed 24 hrs. 
 
A dose of 1500 mg (for patients >30 kg) will be administered using an IV bag containing 0.9% (w/v) 
saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter.  Add 30 mL (i.e. 1500 mg) of 
durvalumab  to the IV bag. The IV bag size should be selected such that the final concentration is 
within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
 
If patient weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered using an IV 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
29 (147) 
bag size selected such that the final concentration is within 1 to 15 mg/mL. 
     
Standard infusion time is 1 hour, however if there are interruptions, the total allowed time must not 
exceed 8 hours at room temperature.  
 
Do not co-administer other drugs through the same infusion line. 
 
The IV line will be flushed according to local practices to ensure the full dose is administered.  
Infusion time does not include the final flush time. 
 
If either preparation time or infusion time exceeds the time limits a new dose must be prepared 
from new vials.  Durvalumab does not contain preservatives, and any unused portion must be 
discarded.  
 
 
7.2.3 Monitoring of Dose Administration 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% 
of the initial rate until completion of the infusion. For patients with a ≤Grade 2 infusion related 
reaction, subsequent infusions may be administered at 50% of the initial rate. Acetaminophen 
and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per institutional 
standard may be administered at the discretion of the investigator. If the infusion related reaction is 
Grade 3 or higher in severity, study drug will be discontinued. Standard infusion time is one hour, 
however if there are interruptions, the total allowed time must not exceed 8 hours at room 
temperature (otherwise requires new infusion preparation). For management of patients who 
experience an infusion reaction, please refer to the toxicity and management guidelines in Appendix 
B. 
 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs and 
medical equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognize and treat anaphylaxis. The study site must have immediate 
access to emergency resuscitation teams and equipment in addition to the ability to admit patients 
to an intensive care unit if necessary. 
 
7.3 Radiation Therapy 
 
7.3.1 Localization, Simulation, and Immobilization 
 
Simulation for multi-site radiation requires the presence of the following: the treating physician (or a 
designee with knowledge of the patient and multi-site radiation procedures), a physicist dedicated 
to doing multi-site radiation, and the simulation therapists trained in the setup of patients 
undergoing multi-site radiation. Radiation will be performed by SBRT whenever feasible, though 3D-
CRT and IMRT are also permitted. The simulation will be scheduled in ARIA (or an alternate 
scheduling system such as MOSAIQ) and assigned to the appropriate staff. The team will discuss all 
treatment sites during the “time-out” procedure and prior to performing the simulation. Every 
effort should be made to have the treating physician present at the simulation and on the first day 
of treatment. 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
30 (147) 
Patients will be positioned in a stable pose conducive to allowing accurate reproducibility of the 
target position throughout treatment. All patients will undergo CT-based treatment planning in 
custom made immobilization devices. An adequate immobilization device for radiation is required. 
At WCM-New York Presbyterian the FREEDOMXTM SBRT module by CDR systems will be used for 
patient immobilization whenever possible. Respiratory motion management is required for SBRT. 
The FREEDOM™ pneumatic abdominal compression belt or the abdominal compression paddle 
(used in conjunction with the FREEDOMXTM SBRT module) is preferred for managing respiratory 
and tumor motion while maintaining maximum patient comfort. The patient will be coached into 
the shallow breathing technique prior to and during the time of simulation and for each SBRT 
session. The compression belt (if used) will be tested for leaks before simulation and treatment and 
the pressure will be monitored throughout (≤ 3-4 mmHg variation is allowed). The simulation 
therapists will document localization setup on the CDR setup sheet and upload into ARIA. CT scan 
range must allow simultaneous view of the patient’s anatomy adequately to ensure contouring of all 
targeted lesions, as well as necessary organs at risk (OAR). High resolution CT scans should be 
obtained with uniform slice thickness of ≤ 3 mm (≤ 2mm slice thickness through the area of interest 
is preferred) throughout.  
 
 
7.3.2 Use of Contrast Agents 
 
The use of IV contrast is recommended (not required for peripheral lung lesions). A complete 
metabolic panel to acquire an estimated glomerular filtration rate (eGFR) should be obtained ≤ 30 
days prior to the date of CT simulation. If recent labs are not available, new labs are recommended 
to be drawn at the time of consultation or ≥ 24hrs prior to the date of CT simulation to allow 
adequate time for acquisition of final laboratory results. A questionnaire of allergies (including 
IV/oral contrast) will be filled out by the patient and reviewed by the nurse and physician prior to 
simulation. If the patient requires steroids due to a history of an allergic reaction to IV/oral 
contrast, CT simulation without contrast should be given due consideration. Every attempt should 
be made to have the treating MD present at the time of CT simulation. For additional information, 
see the NYP-Weill Cornell Radiation Oncology Department Policy and Procedure for IV contrast 
administration for CT-Simulation (T127) and the Department of Radiology Protocols at 
http://radiqal.nyp.org/pronto/login_web. 
 
 
7.3.3 Respiratory Motion Assessment and Management 
 
Lesions with potential for respiratory motion (for example thoracic targets) should be evaluated by 
appropriate means including 4D CT scan, implanted fiducial marker, or fluoroscopy at the time of 
simulation. Respiratory motion management including abdominal compression, active breathing 
control, breath hold, end expiratory gating, or fiducial marker tracking is recommended for any 
lesion to be treated with expected motion > 5mm; therefore, thoracic lesions should be planned 
with some sort of respiratory control. A recommended approach would be to use an ITV technique 
for motion < 1cm, but for motion > 1cm (typically too large for a free breathing ITV) motion 
management including but not limited to abdominal compression, active-breathing control (ABC), 
gating, breath hold, etc. should be used. The FREEDOM™ pneumatic abdominal compression belt 
(used in conjunction with the FREEDOMXTM SBRT module) or the abdominal compression paddle 
are preferred for managing respiratory and tumor motion while maintaining maximum patient 
comfort. For patients that will be treated on the MRIdian LINAC, the breath hold and automated 
beam-gating technique will be used.  
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
31 (147) 
7.3.4 Localization Using Daily IGRT 
 
This study requires the use of image guided radiation treatment (IGRT). IGRT as defined by NRG 
Oncology is a computer assisted process that uses imaging devices that generate a series of 
coordinates for shifting the patient support system in three orthogonal directions (sometimes also 
including rotational changes) to position the treatment beams relative to target regions. The 
allowed technologies are as follows: cone-beam CT (CBCT) using either a specially mounted kV 
imaging head or the MV treatment beam with an opposed electronic imaging panel, dual fixed-
position in-room kV imaging systems that are orthogonal or near orthogonal, an in-room standard 
diagnostic CT scanner that is geometrically linked to the treatment unit, and the Tomotherapy® 
approach. Simple portal imaging approaches that do not use computer assistance are not 
considered suitable for this study.  
 
 
7.3.5 IGRT requirements 
 
The minimum IGRT requirement for thoracic lesions is listed below. Volumetric imaging refers to 3D 
modalities (e.g. kV cone-beam, MV cone-beam, CT on rails), while orthogonal imaging refers to 2D 
modalities (e.g., kV OBI, ExacTrac). When fiducials are used a CBCT needs to be used to document 
not only the accuracy of the target but also the relationship of the target with the OAR – this cannot 
be adequately assessed with orthogonal films alone. 
 
Table 2 
Location 
Minimum IGRT Requirement 
 
No Fiducials 
With Fiducials 
Lung 
Volumetric (3D) 
Volumetric (3D) + 
Orthogonal kV (2D) 
Mediastinal/Cervical LN 
Volumetric (3D) 
N/A 
 
 
 
7.3.6 Target Volumes 
 
 
7.3.6.1 Thoracic lesions 
 
Thoracic lesions to be treated will be dictated by the ability to meet pre-specified dose constraints 
for adjacent organs at risk (OARs). 
 
Lung Central: GTV within 2 cm of proximal bronchial tree (carina, right and left main bronchi, right 
and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus, 
right and left lower lobe bronchi) as described in RTOG 0813/0915. Tumors that are immediately 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
32 (147) 
adjacent to mediastinal or pericardial pleura (PTV touching the pleura) also are considered central 
tumors. 
 
Lung Peripheral: lesions within the 
lung parenchyma with GTV outside of 
the proximal bronchial tree.  
 
Mediastinal/Cervical LN: Mediastinal: 
GTV arising within the anatomic space 
between the lungs, above the 
diaphragm, and below the thoracic 
inlet at the level of the top of the 
sternal notch. Cervical Lymph Nodes: 
GTV occurring within cervical lymph 
nodes Levels I-VI and/or 
retropharyngeal spaces.  
 
  7.3.7 Target Volume Definition 
Based on Location 
 
Specific radiation planning parameters depend on the location of the treated lesion as well as 
mechanism used for motion management/evaluation. The table below defines appropriate planning 
CT window/leveling, recommended additional modality scans to be fused, as well as how to define 
the GTV, ITV, CTV, and PTV for intrathoracic disease. Only rigid registration will be permitted for 
multi-modality fusion. In general, the GTV is defined as the entirety of the lesion as seen on planning 
CT scan aided by additional diagnostic imaging studies (i.e., PET/CT or MRI). Use of additional 
diagnostic studies is left to the discretion of the treating physician. The CTV = GTV; there is no 
margin added for microscopic extension. In general, either a helical CT or 4DCT will be used for 
defining the GTV/ITV depending upon the tumor motion encountered, although both scans may be 
acquired at the time of simulation. Typically, the ITV is generated using either expiratory/inspiratory 
phase scans or from reconstructed maximum intensity projection (MIP) scans. Maximum/minimum 
intensity projections (MIP/MinIP) should be used with caution because the MIP reconstruction for 
lung or MinIP reconstruction for liver may erroneously define an ITV in cases of significant irregular 
breathing or when tumors abut soft tissue structures (e.g., the diaphragm for MIP) or fat (for the 
MinIP). 
 
The approach for target volume delineation for extrathoracic sites of disease will follow the example 
of intrathoracic disease as outlined in section 7.3. For any site of disease, the constraints for the 
organs at risk per the modified TG101 constraints in section 7.3 will be maintained. 
 
Table 3 
Planning Parameter 
Location 
Lung Central 
Lung Peripheral 
Mediastinal/Cervical LNs 
CT window/level 
Pulmonary/Mediastinal 
Pulmonary/Mediastinal 
Pulmonary/Mediastinal 
Additional Studies 
PET/CT 
PET/CT 
PET/CT 
GTV definition 
Lesion 
Lesion 
Lesion 
CTV definition 
GTV/ITV 
GTV/ITV 
GTIV/ITV 
PTV expansion 
CTV + 3-5mm 
CTV + 3-5mm 
CTV + 3-5mm 
Note: A GTV to ITV expansion of greater than 1cm in any one direction is strongly discouraged and 
alternative respiratory management technique is suggested. Mediastinal lymph nodes should 
undergo motion assessment and an ITV should be generated to account for motion.  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
33 (147) 
 
7.3.8 Treatment Planning 
 
General Considerations: A variety of planning techniques can be used to deliver radiation. General 
guidelines include the following: 
• 
Multiple coplanar or non-coplanar beam arrangements are acceptable.  
• 
Typically, 7-13 static radiation beams with equal weighting are used. It is recommended that at 
least 10 beams be used when possible.  
• 
A minimum field dimension of 3 cm should be observed while treating small lesions with 3D-CRT.  
• 
Dynamic conformal arcs are acceptable. It is recommended that arcs span a total for all beams of 
340 degrees. 
• 
For non-IMRT or dose painting techniques, the conformal field aperture size and shape should 
correspond nearly identically to the projection of the PTV along a beam’s eye view (i.e., no 
additional “margin” for dose buildup at the edges of the blocks or MLC jaws beyond the PTV). The 
only exception will be when observing the minimum field dimension of 3 cm when treating small 
lesions.  
• 
The prescription isodose line covering 95% the PTV will generally be 80-90% but may range from 
60-90% where the maximum dose is 100%. As a result, a “hotspot” will exist within the PTV that 
is equal to the prescription dose divided by the prescription isodose line (i.e., 45 Gy/0.6 = 75 Gy 
when 45 Gy is prescribed to the 60% isodose).  
• 
Doses higher than the prescription isodose (i.e., hotspots) should be manipulated to occur within 
the target. 
• 
For 3D conformal plans, the goal of covering 95% of the PTV with the prescription isodose line will 
be maintained with the hotspots inside of the target. Organ at risk dose constraints will need to 
be maintained and take precedent to minimize risk of toxicities. 
• 
Hotspot location should be reviewed by the treating radiation oncologist. Every effort should be 
made to plan for the hotspots to be within the target while the constraints for the organs at risk 
are maintained for both 3D and IMRT. The DMax for 3D plans should be no more than 115% of 
the prescription dose. 
 
Dose calculations: All dose distributions shall include corrections for heterogeneities. All doses 
should be reported in terms of dose-to-water and not in terms of dose-to-medium. Successful 
treatment planning will require accomplishment of all the following criteria: 
1. Normalization: The treatment plan should be initially normalized such that 100% corresponds 
to the maximum dose within the PTV (MAXPTV). While this point will typically correspond to 
the PTV center of mass, it can be located elsewhere within the PTV.  
2. Prescription Isodose Surface Coverage: The prescription isodose surface will be chosen such 
that 95% of the target volume (PTV) is conformally covered by the prescription isodose 
surface. Doses less than 95% of the prescription dose are restricted to the outside edges of 
the PTV. The prescription isodose surface selected MUST be ≥ 60% and ≤ 90% of the dose 
maximum within the PTV (MAXPTV). The MAXPTV corresponds to the normalization point 
(100%) of the plan as noted in number 1 above.  
3. Target Dose Heterogeneity: Rather than prioritizing target dose homogeneity, SBRT 
treatment planning prioritizes adequate minimum target coverage and rapid dose fall-off 
gradients outside of the target. Hot spots within targets are generally accepted without 
consequence since targets are mostly tumor. The only exception is when the hotspot within 
the PTV also intersects an OAR.  
4. Critical Organ Doses: Respect all critical organ dose-volume limits.  
5. High-Dose Spillage:  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
34 (147) 
a. Location: Any dose > 105% of the prescription dose should occur within the PTV and not 
within the normal tissues outside the PTV.  
b. Volume: Acceptable isodose distributions should be as conformal as possible. To this end, the 
ratio of prescription isodose volume to PTV should be as small as possible.  
i. The ratio of the prescription isodose volume to the PTV volume should be < 1.2. Acceptable 
variations include a ratio of 1.2-1.5. Ratios above 1.5 will be considered unacceptable 
variations. The prescription line for each lesion will be contoured for calculation of this ratio. 
The prescription line will be labelled as V_5000 with the 5000 changing to reflect the 
prescription dose in cGy.  
ii. Guidelines for the ratio of the 50% prescription isodose volume to the PTV volume (R50%) 
and for the maximum dose at 2cm (D2cm) from the PTV are given in table below.  
iii. Given that conformal tumor coverage is often more difficult to achieve in lung than in more 
homogeneous organs, these ratios should serve as a guide for liver, abdominal-pelvic, 
mediastinal/cervical lesions as well.  
iv. Elliptically shaped lesions as well as extremity lesions may not meet these guidelines. This 
is acceptable if normal tissue constraints are respected. These criteria will not be required 
in treating very small tumors (< 2.5 cm axial GTV dimension or < 1.5 cm craniocaudal GTV 
dimension) in which the required minimum field size of 3 cm results in the inability to meet 
a conformity ratio of 1:5. 
 
     Table 4 
PTV Volume (cc) 
Ratio of 50% Prescription Isodose 
Volume to PTV Volume, R50% 
Maximum Dose at 2cm (D2cm) 
from PTV in any direction as % 
of Prescribed Dose 
1.8 
< 7.5 
< 57 
3.8 
< 6.5 
< 57 
7.4 
< 6 
< 58 
13.2 
< 5.8 
< 58 
22 
< 5.5 
< 63 
34 
< 5.3 
< 68 
50 
< 5 
< 77 
70 
< 4.8 
< 86 
95 
< 4.4 
< 89 
126 
< 4 
< 91 
163 
< 3.7 
< 94 
Note: For values of PTV dimension or volume not specified, linear interpolation between table 
entries is required. For tumors within 2 cm of the skin, it may be difficult to meet the values for 
D2cm and R50%. In these cases, these criteria will not be used. 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
35 (147) 
7.3.9 Planning Priorities  
 
Every attempt should be made to successfully satisfy all of the 
planning goals and OAR criteria. In some circumstances, it may 
not be possible to meet all the ideal criteria, leading to plans in 
the Variation Acceptable range. Thus, suggested priority of 
planning goals in order of importance is as follows:  
1. 
Respect spinal cord, cauda equina, sacral plexus and 
brachial plexus dose constraints.  
2. 
Meet dose “compactness” constraints including the 
prescription isodose surface coverage, high-dose spillage 
(location and volume), and intermediate dose spillage (D2cm, 
and R50%) as these define the aim in using SBRT. Dose 
compactness should be assessed for plans based on treatment 
dose for a single lesion at a time.  
3. Meet critical structure constraints other than those listed in 1. OAR dose constraints 
should be met based on composite dose planning. Unacceptable deviations should 
be avoided in all cases.  
4. In cases where PTV coverage cannot be achieved while avoiding unacceptable 
deviations to OAR, coverage of a section of PTV including or immediately adjacent 
to the OAR may be as low as 70% of the prescription dose ONLY in this situation. 
 
7.3.10 Critical structures 
 
The following table outlines the naming of the various normal and critical structures. If multiple 
lesions named PTV_5000 exist, each should be labelled according to numerical order of the 
anatomical sites listed below (e.g., “PTV_5000_1” is a peripheral lung lesion while “PTV_5000_4” is a 
liver lesion). If multiple lesions exist within a single anatomical site, each lesion can be distinguished 
by adding a letter to the end of the PTV name (“PTV_5000_1a” and “PTV_5000_1b”). 
 
Table 5 
Standard Name 
Description 
Group 1: Lung – Peripheral 
 
PTV_3000_1 
For peripheral lung tumors 
GTV_3000_1 
For peripheral lung tumors 
PTV_20_1 
PTV with 2cm expansion 
NonPTV_1 
External minus PTV 
NonPTV_20_1 
External minus PTV_20 (PTV with a 2 cm 
expansion) 
Spinal Cord 
Spinal Cord 
Brachial Plexus 
Brachial Plexus 
BrachialPlexus_L 
Left Brachial Plexus 
BrachialPlexus_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, right 
and left upper lobe bronchi, intermedius 
bronchus, right middle lobe bronchus, 
lingular bronchus right and left lower lobe 
bronchi 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
36 (147) 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
Proximal bronchial tree expanded by 2cm 
Larynx 
Larynx 
ChestWall 
Chest wall  
Rib 
Ribs within 5 cm of the PTV should be 
contoured 
Heart 
Heart 
External 
Body surface 
SkinOAR 
Skin will be defined as the outer 0.5 cm of 
the body surface 
Lungs 
Combined Left and Right Lungs - GTV 
Lung_R 
Right Lung- GTV 
Lung_L 
LEFT Lung- GTV 
Trachea 
Trachea 
Stomach 
Stomach 
Liver 
Liver 
BileDuct 
Bile duct 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Group 2: Lung – Central 
Description 
PTV_3000_2 
For central lung tumors 
GTV_3000_2 
For central lung tumors 
PTV_20_2 
PTV with 2cm expansion 
NonPTV_2 
External minus PTV 
NonPTV_20_2 
External minus PTV_20 (PTV with a 2 cm 
expansion) 
SpinalCord 
Spinal Cord 
BrachialPlexus 
Brachial Plexus 
BrachialPlexus_L 
Left Brachial Plexus 
BrachialPlexus_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, right 
and left upper lobe bronchi, intermedius 
bronchus, right middle lobe bronchus, 
lingular bronchus right and left lower lobe 
bronchi 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
Proximal bronchial tree expanded by 2cm 
Larynx 
Larynx 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should be 
contoured 
Heart 
Heart 
External 
Body surface 
SkinOAR 
Skin will be defined as the outer 0.5 cm of 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
37 (147) 
the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung -  GTV 
Lung_L 
Left lung - GTV 
Trachea 
Trachea 
Stomach 
Stomach 
Liver 
Liver 
BileDuct 
Bile duct 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 3 Mediastinal/Cervical Lymph Node 
Description 
PTV_3000_3 
For central lung tumors 
GTV_3000_3 
For central lung tumors 
PTV_20_3 
PTV with 2cm expansion 
NonPTV_3 
External minus PTV 
NonPTV_20_3 
External minus PTV_20 (PTV with a 2 cm 
expansion) 
SpinalCord 
Spinal Cord 
BrachialPlexus 
Brachial Plexus 
BrachialPlexus_L 
Left Brachial Plexus 
BrachialPlexus_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, right 
and left upper lobe bronchi, intermedius 
bronchus, right middle lobe bronchus, 
lingular bronchus right and left lower lobe 
bronchi 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
Proximal bronchial tree expanded by 2cm 
Larynx 
Larynx 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should be 
contoured 
Heart 
Heart 
External 
Body surface 
SkinOAR 
Skin will be defined as the outer 0.5 cm of 
the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left lung 
Trachea 
Trachea 
Stomach 
Stomach 
Liver 
Liver  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
38 (147) 
BileDuct 
Bile duct 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
 
7.3.11 Organs at risk 
 
All lesion-specific organs at risk (OAR) must be contoured. The specific OAR to be contoured will 
depend on the location of lesion to be treated. The contour of structures that have a lumen 
(bronchus, trachea, esophagus, etc.) will include both the “wall” and the “lumen” to result in a 
cylindrical structure. In general, OAR within 5 cm of any lesion should be contoured. To identify 
these OARs, all PTVs will be expanded by 5 cm and any OAR that overlaps with PTV + 5 cm must be 
contoured. 
 
7.3.12 Critical Organ Dose-Volume Limits  
 
Dose distributions of organs at risk are critical to understand toxicity following SBRT. To facilitate 
planning, dose should be calculated on a single CT scan simultaneously with in-plane resolution of at 
least 2 x 2 x 3mm. Dose-volume histograms will be generated to evaluate dose to critical organs at 
risk. 
 
7.3.13 Planning priorities for Organs at Risk  
 
The spinal cord doses are absolute limits. Some OARs (i.e., the esophagus, trachea, bronchi and 
heart within the lung) may be situated adjacent to the treated GTV/PTV. As such, there is no 
specified limit as tumors that are immediately adjacent to that organ will not be able to be treated 
to the prescription doses without irradiating a small volume of that organ to the prescribed dose. In 
such a case, the planning must be accomplished so that there is no hot spot within that organ, even 
if that organ is part of the GTV/PTV, i.e., that no part of any serial OAR receives more than 105% of 
the prescribed dose. In addition, the volume of the OAR in question needs to be minimized, both in 
length and in the width (i.e., circumference), with efforts made to reduce the dose to the 
contralateral wall of the organ. For parallel OAR, exceeding the doses by more than 110% of the 
prescribed dose will be considered unacceptable. For non-spinal cord OAR with known sensitivity to 
high doses of radiation (including the bowel, esophagus, and stomach) included within a PTV or 
immediately adjacent to PTVs, a prescription dose at the lower end of acceptable variation should 
be used. Additionally, every effort should be made to cover the GTV with the prescription dose 
while ensuring rapid fall off to the organ at risk. Coverage of a section of PTV including or 
immediately adjacent to the OAR may be as low as 70% of the prescription dose ONLY in this 
situation. Every effort should be made to cover 100% of the GTV by the prescription dose at the 
lower end of acceptable variation. For tumors that are not immediately adjacent to any OAR, 
centers are encouraged to observe prudent treatment planning principles in avoiding unnecessary 
radiation exposure to critical normal structures; we expect that the OAR doses will be as low as 
achievable (ideally, < 6 Gy/fraction).  
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
39 (147) 
 
Table 6: Modified AAPM Task Group 101 dose constraints for 5 fractions59 
Serial Organ 
Volume 
Volume Dose (Gy) 
Avoidance Endpoint 
(≥ Grade 3) 
Spinal Cord 
0.03 cc 
30 
Myelitis 
0.35 cc 
23 
1.2 cc 
14.5 
Ipsilateral Brachial 
Plexus 
0.03 cc 
30.5 
Brachial Plexopathy 
3 cc 
27 
Cauda Equina 
0.03 cc 
32 
Neuritis 
5 cc 
30 
Sacral Plexus 
0.03 cc 
32 
Neuropathy 
5 cc 
30 
Neuritis 
Trachea and 
Ipsilateral 
Bronchus 
0.03 cc 
40 
Stenosis/Fistula 
4 cc 
16.5 
Esophagus 
0.03 cc 
35 
Stenosis/Fistula 
5 cc 
19.5 
Heart/Pericardium 
0.03 cc 
38 
Pericarditis 
15 cc 
32 
Great vessels 
0.03 cc 
53 
Aneurysm 
10 cc 
47 
Skin 
0.03cc 
39.5 
Ulceration 
10 cc 
36.5 
Stomach 
0.03 cc 
32 
Ulceration/Fistula 
10 cc 
18 
Duodenum 
0.03 cc 
32 
Ulceration 
5 cc 
18 
10 cc 
12.5 
Jejunum/Ileum 
0.03 cc 
35 
Enteritis/obstruction 
5 cc 
19.5 
Colon 
0.03  cc 
38 
Colitis/Fistula 
20 cc 
25 
Rectum 
0.03 cc 
38 
Proctitis/Fistula 
 
20 
25 
Bladder 
0.03 cc 
38 
Cystitis/Fistula 
15 cc 
18.3 
Ureter 
0.03 cc 
45 
Stenosis 
Femoral head 
10 cc 
30 
Necrosis 
Bile Duct 
0.03 cc 
41 
Stenosis 
Renal 
hilum/Vascular 
Trunk 
< 2/3 volume 
23 
Malignant 
Hypertension 
Chest Wall 
1 cc 
5 cc 
45 
40 
Pain/Necrosis  
Rib 
0.03 cc 
43 
Pain or Fracture 
1 cc 
35 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
40 (147) 
Parallel Organ* 
Volume 
Volume Dose (Gy) 
Avoidance Endpoint 
Lung (total) 
< 37% lung volume 
13.5 
Pneumonitis 
<1500 cc 
12.5 
Basic Lung Function 
<1000 cc 
13.5 
Pneumonitis 
Renal cortex 
< 200 cc 
17.5 
Basic Renal Function 
Liver 
<700 cc 
15 
Basic Liver Function 
 Note: Every effort should be made to avoid circumferential irradiation. Doses to serial OAR up to 
and including 105% of the dose prescribed to the PTV will be an acceptable variation. Doses to 
parallel OAR up to 110% of the values listed in the table will be an acceptable variation. 
*ClearCheck: For parallel organs dose constraints shall include the Minimal Volume Spared (MVS); 
for example, MVS1350cGy ≥ 1000cc for Lung (total). 
 
7.3.14 Documentation requirements 
 
In general, treatment interruptions should be avoided by preventative medical measures and 
supportive therapies. Treatment breaks, including indications, must be clearly documented in the 
treatment record. 
 
7.3.15 Compliance Criteria 
 
7.3.15.1 Treatment Duration 
 
Treatment duration will be defined per lesion. Per Protocol, all five fractions of radiation should be 
completed within 2-3 weeks of first radiation dose (>3 weeks is an unacceptable variation). 
 
7.3.15.2 PTV Dosimetry Compliance  
 
Acceptable variations in the protocol prescription dose (dose covering 95% of the PTV) should be 
evaluated for each lesion. Prescription doses outside of the variation acceptable range will be scored 
as Deviation Unacceptable. Scoring of PTV coverage will be: acceptable if ≥ 95%, variation 
acceptable if 70-95%, deviation unacceptable if < 70%.  
 
7.3.15.3 Organ at Risk Dosimetry Compliance  
 
Critical structure doses should be based on composite dose distribution when more than one met is 
treated. Respect spinal cord, cauda equina, sacral plexus and brachial plexus dose constraints. Any 
dose to spinal cord, cauda equina, sacral plexus above that listed in the above Tables will be 
considered an unacceptable deviation. For all other OAR, when OAR dose criteria cannot be 
accomplished by following planning priorities, doses to serial OAR of more than 105% of the dose 
prescribed to the PTV will be Unacceptable Deviations. Doses to parallel OAR exceeding 110% of the 
dose prescribed to the PTV will be scored as unacceptable deviations. Doses in the range between 
the numbers in the tables and unacceptable deviation will be considered acceptable variations. 
 
 
7.4 Availability 
 
As the systemic chemotherapy agents (Carboplatin, Cisplatin, and Etoposide) employed in this study 
will be used according to their FDA-approved indications, they will be obtained through the various 
institutions taking part in this trial and billed to the subjects’ insurance. Durvalumab will be supplied 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
41 (147) 
by AstraZeneca. Radiation treatment will be delivered at the appropriate facilities within each 
participating institution.  
 
7.5 Dosing Delays/Dose Modifications 
 
 
Dose-reductions up to Carboplatin AUC = 2.5, Cisplatin = 35mg/m2, and/or Etoposide = 50mg/m2 
will be permitted during treatment at the discretion of the treating medical oncologist. There will be 
no dose-reductions for Durvalumab. Infusion times for chemotherapy and Durvalumab may be 
adjusted to improve tolerability, as per the treating medical oncologist. 
 
Each 21-day cycle of Carboplatin/Cisplatin + Etoposide + Durvalumab may be delayed up to 4 weeks. 
Each 28-day cycle of single-agent Durvalumab may be delayed up to 6 weeks. 
 
Every effort should be made to limit dose-reductions and delays in chemotherapy and 
immunotherapy. 
 
All five fractions of radiation should be completed within 2-3 weeks of first radiation dose. Greater 
than 3 weeks is an unacceptable variation. 
 
7.6  General Concomitant Medication and Supportive Care Guidelines 
 
All concomitant medications will be recorded and/or updated on subject medication log throughout 
the course of the study and saved in subject binder, if applicable. 
 
 
7.6.1 Prohibited Medications 
 
- Any investigational anticancer therapy other than those under investigation in this study. 
- Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic or hormonal therapy for 
cancer treatment other than those under investigation in this study. 
- EGFR TKIs 
- Live attenuated vaccines 
- Herbal and natural remedies which may have immune-modulating effects 
- Immunosuppressive medications including, but not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and tumor necrosis 
factor-α blockers 
 
The following are allowed exceptions: 
• 
Use of immunosuppressive medications for the management of IP-related AEs,  
• 
Short-term premedication for patients receiving chemotherapy where the prescribing 
information for the agent requires the use of steroids for documented hypersensitivity reactions  
• 
Use in patients with contrast allergies.  
• 
In addition, use of inhaled, topical, and intranasal corticosteroids is permitted. 
  
In addition, a temporary period of steroids will be allowed if clinically indicated and considered to be 
essential for the management of non-immunotherapy related events experienced by the patient 
(e.g., chronic obstructive pulmonary disease, radiation, nausea, etc.). 
 
 
7.6.2 Contraception 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
42 (147) 
The following restrictions apply while the patient is receiving study treatment and for the specified 
times before and after: 
1. Female patient of child-bearing potential 
Female patients of childbearing potential who are not abstinent and intend to be sexually active 
with a non-sterilized male partner must use at least 1 highly effective method of contraception 
(Table 7) from the time of screening throughout the total duration of the drug treatment and the 
drug washout period (90 days after the last dose of durvalumab monotherapy). Non-sterilized male 
partners of a female patient of childbearing potential must use male condom plus spermicide 
throughout this period. Cessation of birth control after this point should be discussed with a 
responsible physician.  Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control.  Female patients should also refrain from breastfeeding 
throughout this period.  
2. Male patients with a female partner of childbearing potential 
Non-sterilized male patients who are not abstinent and intend to be sexually active with a female 
partner of childbearing potential must use a male condom plus spermicide from the time of 
screening throughout the total duration of the drug treatment and the drug washout period (90 
days after the last dose of durvalumab monotherapy). However, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception.  Male patients 
should refrain from sperm donation throughout this period. 
Female partners (of childbearing potential) of male patients must also use a highly effective method 
of contraception throughout this period (Table 7).   
 
Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral 
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.   
Women will be considered post-menopausal if they have been amenorrheic for 12 months without 
an alternative medical cause.  The following age-specific requirements apply:  
• 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. 
• 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. 
 
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, 
less than 1% per year) when used consistently and correctly are described in Table 7.  Note that 
some contraception methods are not considered highly effective (e.g. male or female condom 
with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-
copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills 
where inhibition of ovulation is not the primary mode of action [excluding Cerazette/ 
desogestrel which is considered highly effective]; and triphasic combined oral contraceptive 
pills). 
 
 
7.6.3 Blood Donation 
 
Patients should not donate blood while participating in this study, or for at least 90 days following 
the last infusion of durvalumab. 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
43 (147) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 7: Highly Effective Methods of Contraception (<1% Failure Rate) 
• Barrier/Intrauterine methods 
• Hormonal Methods 
• Copper T intrauterine device 
• Levonorgestrel-releasing intrauterine 
system (e.g., Mirena®)a 
 
• Implants: Etonogestrel-releasing 
implants: e.g. Implanon® or 
Norplant®  
• Intravaginal: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices: e.g. NuvaRing®  
• Injection: Medroxyprogesterone 
injection: e.g. Depo-Provera®  
• Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• Patch: 
Norelgestromin/ethinylestradiol-
releasing transdermal system: e.g. 
Ortho Evra®  
• Minipillc: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only 
highly effective progesterone-based  
a This is also considered a hormonal method 
 
7.7  Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays, chemotherapy plus Durvalumab will continue for 4 cycles with 
subsequent single-agent Durvalumab continuing indefinitely, or until one of the following criteria 
applies: 
 
o 
Disease progression 
o 
Intercurrent illness that prevents further administration of treatment, 
o 
Unacceptable adverse event(s), 
o 
Subject decides to withdraw from the study, or 
o General or specific changes in the subject’s condition render the subject unacceptable for 
further treatment in the judgment of the investigator. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
44 (147) 
 
Subjects may continue on single-agent Durvalumab after disease progression by RECIST criteria 
if this is felt to be beneficial by the treating medical oncologist. RECIST progression should be 
confirmed on 2 imaging scans at least 4 weeks apart, though this is not required. 
 
7.8    Duration of Follow Up 
 
Subjects will be followed for 2 years after removal from study or until death, whichever occurs first.  
Subjects removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  
 
7.9 Study Intervention/Follow-up Compliance 
 
The study will be conducted as described in the final IRB-approved protocol. Adherence to the 
protocol will be assessed and verified by the research study team, the DSMB, and, if needed, by the 
medical monitor. Repeated attempts will be made to get subjects to return for study follow-up 
appointments; however, after 3 months subjects will be considered “lost to follow-up” and no 
longer participating in the study. 
 
 
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
8.1 Discontinuation of Study Intervention 
 
An individual subject who is discontinued from the study will not receive any further investigational 
product. An investigator may discontinue a participant from the study for the following reasons:  
1. If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
2. Disease progression which requires discontinuation of the study intervention 
3. If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation because continuing investigational 
therapy might constitute a safety risk 
4. Participant unable to receive radiation, chemotherapy, or ICB therapy for 12 weeks. 
5. Withdrawal of consent or participant lost to follow-up after several attempts to contact subject 
to schedule study visit. 
6. Adverse event related to radiation or chemotherapy that, in the opinion of the investigator or 
the sponsor, contraindicates further treatment with these modalities 
7. Pregnancy or intent to become pregnant  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
45 (147) 
8. Adverse event related to durvalumab that is Grade ≥ 3, with the exception of toxicities that do 
not meet criteria for discontinuation as per guidelines in Appendix B or per NCCN Clinical 
Practice Guidelines in Oncology Management of Immunotherapy-Related Toxicities60. 
9. Grade ≥ 3 infusion reaction  
10. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
discontinuation, such as refusal to adhere to scheduled visits or initiation of alternative 
anticancer therapy including another investigational agent  
 
Discontinuation from study intervention does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to, changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event 
(AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Interval Medical History 
• 
Concurrent Medications 
• 
Vital signs including Height and Weight 
• 
Physical Exam 
• 
Labwork: CBC with differential; Serum Chemistry with Liver Function Tests; Thyroid Function 
Panel 
• 
Adverse Event Evaluation 
 
8.2 Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study, will not 
be replaced. 
8.3 Lost to Follow Up 
 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits for 3 
months and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
46 (147) 
• 
The site will attempt to contact the participant and reschedule the missed visit within 14 days 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
9. Correlative/Special Studies  
 
9.1 Tumor-immune microenvironment and the T-cell response  
These studies will be done in the laboratory of Dr. Sandra DeMaria, MD at WCM. 
 
 
A comprehensive approach is proposed to analyze immunological changes that reflect both local 
and systemic responses, and general immune activation as well as tumor antigen-specific T cell 
responses. To this end, serial blood samples (50-ml) will be collected for serum and peripheral blood 
mononuclear cells (PBMC): at baseline, day 43, day 85 (at response evaluation) and thereafter every 
8 weeks and at progression. Small aliquots of PBMC will be used ex vivo for preparation of DNA and 
RNA, and the remainder preserved frozen until evaluation by flow cytometry and/or by functional 
assays. Tumor tissue will be obtained at baseline, at day 85 and at progression from patients who 
consent to optional biopsies. Three 18G cores will be allocated for the following: DNA and RNA 
isolation (snap frozen), histology and multiplex imaging (fixed in formalin), and for generation of 
organoids by the EIPM Ex-vivo Lab (see section 9.2.1).  
 
Flow cytometry analysis of circulating PBMC: Cryo-preserved PBMC isolated from serially collected 
blood following standardized SOPs, will be analyzed by multi-parameter flow cytometry. Specifically, 
levels of regulatory T cells (Tregs), will be monitored, and T cells (CD3+CD4+ and CD3+CD8+) 
analyzed for markers of naïve, effector and central memory phenotype (CD45RA/CCR7), 
proliferation (Ki67), and activation/exhaustion (CD25, CD137, PD-1, Tim-3, CTLA-4, and LAG3). 
Myeloid cells will be investigated for the expression of granulocytic and monocytic MDSC markers, 
and for the expression levels of MHC-I and MHC-II molecules, costimulatory and co-inhibitory 
molecules, including PD-L1.  We will measure Ki67+PD-1+ CD8 T cells with an effector-like phenotype 
(HLA-DR+CD38+Bcl-1low) since they have been shown to be predictive of response In lung cancer 
patients treated with anti-PD-1 when increased within 4 weeks of treatment start from baseline by 
two to seven-fold 49. 
 
Soluble markers: Serum/plasma levels of multiple chemokines and cytokines reflecting inflammatory 
and immune responses (IL-6, IL-10, IL-2, IFN-γ, CXCL10/11, TNFα, CCL2, CCL5, etc.) will be measured 
using the human cytokine array (R&D Systems). We will also use a sensitive ELISA assay (Cat 41415-
1, PBL assay Science) to measure the levels of serum IFNb since this cytokine is mechanistically 
relevant to the immunogenicity of SBRT 12.  In addition, other cytokines and soluble factors that can 
be increased by RT may be associated with immune suppression (e.g., soluble MICA/B, soluble 
CD73) 48.  
 
Whole Exome Sequencing (WES) and Neoantigen prediction will be performed as we have 
previously described 12. Briefly, DNA isolated from tumor and from PBMC (normal tissue control) will 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
47 (147) 
be used for WES performed by the genomics core at WCM. Baseline tumor and PBMC WES data will 
be used in VarScan2 to detect somatic variants. Variants with somatic p-value (SPV) < 0.05 are 
considered statistically significant. Optitype algorithm will be used for HLA genotyping 61. The VCF 
files containing somatic mutations will be subjected to standard VEP, Downstream, and Wildtype 
annotations, and filtered for frameshift and missense mutations 62. Additionally, variant allele 
frequency (VAF) data will be generated using bamreadcount. The NetMHC and NetMHCpan 
algorithms will be used to predict patient-specific MHC-I binding for all possible 8-11 amino-acid 
long variant and corresponding wildtype peptide chains spanning the mutation using the pVAC-seq 
pipeline 63-65. Candidate neoepitopes will be synthesized and tested in vitro for recognition by the 
patients’ T cells isolated from blood in ELISPOT assays.  
 
TCRB CDR3 sequencing and repertoire analysis. Amplification and sequencing of TCRB CDR3 regions 
will be performed using the Adaptive Biotechnologies ImmunoSEQ platform 66. We have experience 
using this platform to analyze the expansion of TCR repertoire induced by treatment with RT and 
anti-CTLA-4 in mice 67 and in patients 12.  
 
Multiplex imaging by mass cytometry using the Hyperion Imaging System: The Hyperion™ Imaging 
System brings together imaging capability with proven CyTOF® technology to facilitate Imaging Mass 
Cytometry™ applications. This allows highly multiplexed IHC enabling the simultaneous analysis of 
up to 37 protein markers 68. Over 60 metal-labeled antibodies are currently commercially available 
(Fluidigm) and have been optimized to detect markers in immuno-oncology pathways and cancer. 
Fluidigm also provides metal-labeling kits to prepare additional custom antibodies. We will use the 
Maxpar® Complete Human T Cell Immuno-oncology Panel Set to characterize infiltrating T cells. This 
panel has been validated and provides information about naïve, central memory, effector memory 
and effector CD4 and CD8 T cells, naïve and memory Tregs, Th1 and Th2 T cells, activation and 
homing status, and checkpoint expression. Additional panels will be used to characterize myeloid 
populations 69, and B cells, depending on the initial findings. Data deconvolution will be performed 
by Dr. Elemento, a co-investigator in this protocol.   
 
9.2 Organoids from SCLC Tissue 
Tissue from standard of care or research biopsies will be brought to the EIPM via standard operating 
procedures in place here at WCM. Organoid specimens are biobanked when the culture has 
demonstrated that it can be successfully expanded beyond its initial plating. We define successful 
establishment of PDTO cultures as when they contain viable cells that form spheroid-like structures 
and can be propagated after the initial processing for at least five passages. Tumor verification 
assays involve histologic examination to ensure that the tissue initially submitted is tumor70, and 
that the growing organoids are tumoral as well71. The specimens are then characterized, stored in 
our living biobank, and used for functional studies. Once they are considered successfully 
established, they are subjected to Whole-Exome Sequencing (WES) to test concordance at base-pair 
resolution with the native tumor72,73. We evaluate tumor purity and ploidy using the CLONET 
computational framework (CLONality Estimate in Tumors)74. 
 
Our plan is to optimize and use the Operetta system (see background section 2.5.3) to run the high 
throughput drug screening planned in the current study. Drug screenings performed in our high 
throughput platform would have two readouts: a primary readout of organoid growth/death as 
determined by imaging over time and a secondary endpoint readout of cell metabolism as an indirect 
measure of cell viability. 3D analysis includes parameters such as intensity, position, morphology (such 
as solid vs. hollow sphere, cell shape, etc.) and texture. Following 3D analysis, a final endpoint 
luminescence measurement using Cell titer Glo will be taken to measure cell viability on our high 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
48 (147) 
throughput drug screening robot’s Biotek Synergy Neo plate reader. Each compound will be tested in 
a dose-response manner and hits will be determined based on two primary criteria, efficacy of each 
compound relative to the rest of the compounds in the screen (AUC), and impact of each compound 
on that specific organoid relative to the rest of the organoids that have been tested (Z-score).  
 
9.3 Circulating Tumor Cells 
These studies will be done in the laboratory of Dr. Paraskevi Giannakakou, PhD at WCM. 
 
All subjects in this study will get blood samples drawn for circulating tumor cell (CTC) enrichment. 
CTCs and PBMCs will be collected before the initiation of therapy (baseline), during the course of the 
treatment (on-treatment) and at the moment of disease progression (relapse). 
 
Twenty mL of peripheral whole blood will be collected at each time point in two 10 mL EDTA tubes 
(purple top) by standard venous phlebotomy. Gently invert the tubes 8-10 times after blood 
collection. Tubes will be stored at ambient temperature until brought to the Giannakakou lab at 
Weill Cornell Medicine. Do not freeze the tubes. The tubes must be received by the Giannakakou lab 
within 24 hours of collection. Ensure that the EDTA tubes are transported at ambient temperature. 
If collected samples cannot be transported on the same day of collection (e.g. Friday-Saturday or 
Holiday collections), please contact the Giannakakou lab at 212 746-0293 for further instruction at 
least 24 hours prior to anticipated collection. 
 
CTC enrichment will be performed at the Giannakakou lab and CTCs will be analyzed for 
transcriptomic studies. Briefly, CTCs will be enriched by negative depletion using the RosetteSep 
Human CD45 depletion cocktail (STEMCELL technologies). If SCLC CTCs are found to express TfR, 
then this protein will also be used as a positive selection marker. At each time point, 1 mL of the 
blood collected will be used to isolate peripheral blood mononuclear cells (PBMCs), using density 
centrifugation (Ficoll). 
 
RNA will be extracted from CTCs and PBMCs and gene expression will be analyzed by RNA-
sequencing. Differentially expressed genes in the enriched CTCs and matching PBMCs between C1D1 
and subsequent time points will be identified, and gene set enrichment analysis of differentially 
expressed genes between C1D1 and the on-treatment and relapse time points will be performed to 
identify specific pathways and biological functions associated with sensitivity or resistance to the 
treatment. 
 
 
10.  Measurement of Effect 
 
10.1 Progression-Free Survival  
 
PFS will be defined as the time from first study treatment to the point of either radiographic 
progression of malignancy by RECIST 1.1 criteria or death. Death will be considered clinical 
progression if the cause of death is felt to be due to the underlying malignancy (vs due to toxicity or 
a non-malignancy related cause such as accident). Median PFS will be estimated using the Kaplan-
Meier method. 
The proportion of subjects without progression (as defined above) at 12-months after start of study 
treatment will constitute the 12-month PFS rate, which is the primary endpoint of this study. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
49 (147) 
 
10.2 Overall Survival 
 
OS will be defined as the time from first study treatment to the time of death from any cause. 
Median OS will be estimated using the Kaplan-Meier method. 
The proportion of subjects still alive at 12-months after start of study treatment will constitute the 
12-month OS rate. 
 
10.3 Response Criteria 
 
Response will be assessed based on imaging as per RECIST 1.1 criteria. The Overall Response Rate 
(ORR) will be calculated by the proportion of subjects achieving a RECISTv1.1 complete or partial 
response. 
 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, efficacy, and 
adverse event data for all enrolled subjects.  
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system 
that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for the 
creation of customized, secure data management systems that include Web-based data-
entry forms, reporting tools, and a full array of security features including user and 
group based privileges, authentication using institution LDAP system, with a full audit 
trail of data manipulation and export procedures.  REDCap is maintained on CTSC-
owned servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported through a 
multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 
submitted to the appropriate Ethics Committee. Written approval of the study and all 
relevant study information must be obtained before the study center can be initiated or 
the IP is released to the Investigator. Any necessary extensions or renewals of IRB 
approval must be obtained for changes to the study, such as amendments to the protocol, 
the ICF, or other study documentation. The written approval of the IRB together with the 
approved ICF must be filed in the study files.  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
50 (147) 
The Investigator will report promptly to the IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit 
written summaries of the study status to the IRB as required. On completion of the study, 
the IRB will be notified that the study has ended.  
 
All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 
amendments will be submitted to the relevant institutional IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this 
case, the necessary action will be taken first, with the relevant protocol amendment 
following shortly thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead 
site, Weill Cornell Medicine, updated documents will be provided to participating sites, 
as applicable. Weill Cornell Medicine must approve all consent form changes prior to local 
IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities 
will be notified that the study has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the 
ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines and the 
applicable national and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable 
ethics committees and investigations will be undertaken by scientifically and medically 
qualified persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-
GCP and local regulations, as applicable, from each potential subject or each subject’s 
legally authorized representative prior to participating in the research study. Subjects 
who agree to participate will sign the approved informed consent form and will be 
provided a copy of the signed document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided 
to the subject must approved by IRB prior to use. The ICF will adhere to IRB requirements, 
applicable laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of 
the trial is solely responsible for determining whether the trial and its results are subject 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
51 (147) 
to the requirements for submission to http://www.clinicaltrials.gov. Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information. 
 
11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit evaluation 
of the study and quality of the data produced.  After completion of the study, all documents 
and data relating to the study will be kept in an orderly manner by the Investigator in a secure 
study file.  Essential documents should be retained for 2 years after the final marketing 
approval in an ICH region or for at least 2 years since the discontinuation of clinical 
development of the IP. In addition, all subjects medical records and other source 
documentation will be kept for the maximum time permitted by the hospital, institution, or 
medical practice.   
 
 
12. Statistical Considerations 
 
12.1 Study Design/Endpoints 
 
One primary aim of this study is to demonstrate that the addition of radiation to chemotherapy 
and immunotherapy is associated with an improvement in 12-month PFS from 18% historical 
control to approximately 38% with the addition of radiation. With a sample size of 34 patients 
receiving chemotherapy/immunotherapy plus radiation, a one-group chi-square test will have 
80% power to detect the difference between a null hypothesis 12-month PFS proportion of 18% 
(i.e., historical control) and an alternative hypothesis 12-month PFS proportion of 38% (i.e., 
chemotherapy + immunotherapy + radiation), with a 0.05 two-sided significance level. As well, a 
sample size of 34 patients will allow a two-sided 95% confidence interval for the expected 12-
month PFS proportion (38%) to be constructed to be within ± 16.3% of the observed 12-month 
PFS proportion. 
 
The second primary aim of this study is to evaluate the safety of combining carboplatin + 
etoposide chemotherapy, durvalumab immunotherapy, and non-ablative radiation to one or 
more sites of disease. Due to this, we propose a safety run-in for the first 10 subjects. If there is 
a 30% or greater incidence of grade 3 or higher toxicities with the proposed treatment regimen, 
specifically from radiation therapy (with focus on pneumonitis, pericarditis, esophagitis, rib 
fracture, or hemoptysis) or immune-mediated adverse events (other than thyroid dysfunction), 
then the radiation regimen will be switched to 5 Gy radiation per day for 5 days. If there is still a 
30% or greater incidence of grade 3 or higher toxicities from radiation therapy or immune-
mediated adverse events among the subsequent 10 subjects, then the study will be terminated. 
If this does not occur, then accrual will continue until 34 total subjects are evaluable. 
 
12.2 Sample Size/Accrual Rate 
 
This study will plan to enroll 42 subjects to allow for 34 to be evaluable for the primary 
endpoints.  
 
 
We plan to accrue roughly 1 subject per month. 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
52 (147) 
12.3 Stratification Factors  
 
 
As this is a pilot study with a relatively small number of patients, no stratification is planned. 
However, sub-group analysis of patients with ECOG PS 2 vs PS 0-1 will be performed for the 
primary endpoint of the study. 
 
 12.4 Analysis of Endpoints 
 
All analyses will be performed in SAS Version 9.4 (SAS Institute, Inc., Cary, North Carolina).  
 
12.4.1 Analysis of Primary Endpoints 
 
The primary endpoint of the 12-month PFS proportion will be calculated and a 95% 
confidence interval will be estimated via binomial proportions. A one-group chi-square 
test will be used to compare the 12-month PFS proportion with a historical 12-month 
PFS proportion of 18%. PFS will also be estimated using the Kaplan-Meier method, and 
95% confidence intervals for PFS estimates (including median PFS) will be calculated 
using Greenwood's formula. 
 
The primary endpoint of safety will be described by the incidence of ≥ Grade 3 toxicities 
definitely or probably related to the treatments given (i.e. radiation, immunotherapy, 
and/or chemotherapy), as reported and graded by NCI CTCAE version 5.0. 
Full descriptive analysis of safety will also be conducted (e.g. AEs considered causally 
related to treatment regimen, serious AEs, AEs leading to discontinuation). 
 
12.4.2 Analysis of Secondary Endpoints 
 
Secondary endpoints of the objective response proportion and 12-month overall 
survival (OS) will be calculated and 95% confidence intervals will be estimated via 
binomial proportions.  
 
OS will also be estimated using the Kaplan-Meier method, and 95% confidence intervals 
for OS estimates (including median OS) will be calculated using Greenwood's formula.  
 
 
Pattern of disease progression will focus on the rates of progression in the radiated 
lesions vs non-radiated lesions and rates of new lesions. 
 
12.5 Interim Analysis 
 
No interim analysis for efficacy is planned. Interim analyses for safety will be performed as 
outlined in Section 12.1.  
 
12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of Toxicity 
 
All subjects will be evaluable for toxicity from the time of their first treatment with 
carboplatin or cisplatin with etoposide and durvalumab or their first radiation fraction. 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
53 (147) 
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × 
ULN may need to be reported as SAEs. Please refer to Appendix B, the Toxicity 
Management Guidelines, for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law. 
 
12.6.2 Evaluation of Response 
 
All subjects included in the study will be assessed for response to treatment if they have 
received at least 1 cycle of platinum plus etoposide chemotherapy with durvalumab and 
completed radiation.  
 
 
13. Adverse Event Reporting Requirements  
 
13.1 Reporting 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by subjects or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
 
 
 
13.1.1 Reporting of Deaths to AstraZeneca 
 
All deaths must be recorded and reported as outlined in Section 13.2.2 and 13.4.3.  In 
addition, all SAEs resulting in death or death of unknown cause must be reported to 
AstraZeneca via AEMailboxClinicalTrialTCS@astrazeneca.com within 7 calendar days of 
awareness or sooner when required 
 
 
 
13.1.2 Overdose 
 
An overdose is defined as a patient receiving a dose of durvalumab in excess of that 
specified in the Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study patient with durvalumab, with or without associated AEs/SAEs, 
is required to be reported within 24 hours of knowledge of the event to the sponsor. 
The sponsor must report these to AstraZeneca/MedImmune Patient Safety or designee 
using the designated Safety e-mailbox (see Section 13.4.3 for contact information) 
within 7 calendar days or sooner when required. If the overdose results in an AE, the AE 
must also be recorded as an AE. Overdose does not automatically make an AE serious, 
but if the consequences of the overdose are serious, for example death or 
hospitalization, the event is serious and must be recorded and reported as an SAE (see 
Section 13.4.3). There is currently no specific treatment in the event of an overdose of 
durvalumab. 
 
 
 
13.1.3 Hepatic Function Abnormality 
 
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
54 (147) 
case in a study patient, with or without associated clinical manifestations, is required to 
be reported as “hepatic function abnormal” within 24 hours of knowledge of the event 
to the sponsor. The Sponsor must report these events to AstraZeneca Patient Safety 
using the designated Safety e-mailbox (see Section 13.4.3 for contact information) 
within 7 calendar days or sooner when required, unless a definitive underlying diagnosis 
for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed. The criteria for a potential Hy’s Law case is 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline 
Phosphatase (ALP). 
 
• 
If the definitive underlying diagnosis for the abnormality has been established 
and is unrelated to investigational product, the decision to continue dosing of the study 
patient will be based on the clinical judgment of the investigator. 
 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of 
the study patient must be interrupted immediately. Follow-up investigations and 
inquiries must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator 
and evaluated by the sponsor and AstraZeneca/MedImmune.  
 
 
 
13.1.4 Pregnancy 
 
 
 
 
 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs should be 
discontinued immediately.  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under 
study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities or birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) should be 
followed up and documented even if the patient was discontinued from the study.  
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform the sponsor within 1 day, i.e., immediately, but no later than 
24 hours of when he or she becomes aware of it.  
The sponsor will work with the Investigator to ensure that all relevant information is 
provided within 1 to 5 calendar days.  The Sponsor must report to AstraZeneca Patient 
Safety using the designated Safety e-mailbox (see Section 13.4.3 for contact 
information) within 7 calendar days or sooner when required for pregnancies with SAEs 
and within 30 days for all other pregnancies.  
 
 
 
The same timelines apply when outcome information is available.  
 
 
 
 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study 
and for 180 days after the last dose of durvalumab + any drug combination therapy or 
90 days after the last dose of durvalumab monotherapy, whichever is the longer time 
period.  
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
55 (147) 
normal birth, or congenital abnormality) occurring from the date of the first dose until 
180 days after the last dose of durvalumab + any drug combination therapy or 90 days 
after the last dose of durvalumab monotherapy, whichever is the longer time period 
should, if possible, be followed up and documented.  
Where a report of pregnancy is received, prior to obtaining information about the 
pregnancy, the Investigator must obtain the consent of the patient’s partner. Therefore, 
the local study team should adopt the generic ICF template in line with local procedures 
and submit it to the relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) 
prior to use. 
 
13.2 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug and does not imply any judgment about causality. An adverse 
event can arise with any use of the drug (e.g., off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose.  
 
 
 
13.2.1   Disease Progression 
 
Disease progression can be considered as a worsening of a patient’s condition 
attributable to the disease for which the IP is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. 
The development of new or progression of existing metastasis to the primary cancer 
under study should be considered as disease progression and not an AE. Events that are 
unequivocally due to disease progression should not be reported as an AE during the 
study. 
 
13.2.2   Deaths 
 
 
 
All deaths that occur during the study treatment period, or within the protocol-defined 
follow-up period after the administration of the last dose of study drug, must be 
reported as follows: 
• 
Death clearly resulting from disease progression should be reported and 
documented in the CRF, in the Statement of Death page. It should 
not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the 
disease under study, the AE causing the death must be reported. 
• 
The report should contain a comment regarding the co-involvement of 
disease progression, if appropriate, and should assign main and 
contributory causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE. It 
should also be documented in the Statement of Death page in the 
CRF. 
 
 
13.2.3 Investigational Agent or Device Risks (Expected Adverse Events) 
 
As the combination of platinum + etoposide chemotherapy and Durvalumab 
immunotherapy is now FDA-approved for patients with ES-SCLC, the “investigational 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
56 (147) 
agent” in this study will be the sub-ablative radiation. Mild to moderate (grade <3) 
adverse events from thoracic radiation include the following: esophagitis, dermatitis, 
radiation recall reaction, pleural effusion, pericardial effusion, pleuritic pain, non-cardiac 
chest pain, chest wall pain, pneumonitis, atelectasis, cough, dyspnea, pulmonary 
fibrosis, generalized muscle weakness, fatigue, photosensitivity, telangiectasias, FEV 
decrease, WBC decrease, lymphocyte count decrease, and neutrophil count decrease. 
Severe adverse events (grade ≥3) from radiation may also include the above mentioned 
plus those listed in Table 6. 
 
  13.2.4  Adverse Event Characteristics and Related Attributions 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found in the   
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov). 
 
• 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
  13.2.5  Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be 
maintained by the research staff and kept in the subject’s research chart.     
 
   13.2.6  Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_
Policy.pdf.  
 
      13.3 Definition of Adverse Events of Special Interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest 
specific to understanding of the Investigational Product and may require close 
monitoring. An AESI may be serious or non-serious.  
If the Investigator has any questions in regards to an event being an ImAE, the 
Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
• 
Diarrhea / Colitis and intestinal perforation 
• 
Pneumonitis / ILD 
• 
Hepatitis / transaminase increases 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
57 (147) 
• 
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal 
insufficiency, hyper- and hypothyroidism and type I diabetes mellitus) 
 
• 
Rash / Dermatitis 
o Nephritis / Blood creatinine increases 
• 
Pancreatitis / serum lipase and amylase increases   
• 
Myocarditis 
• 
Myositis / Polymyositis 
• 
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and 
myasthenia gravis) 
• 
Intestinal Perforations 
Other inflammatory responses that are rare/less frequent with a potential immune-
mediated etiology include, but are not limited to: 
• 
Pericarditis 
• 
Sarcoidosis 
• 
Uveitis 
• 
Other events involving the eye and skin 
• 
Hematological events 
• 
Rheumatological events 
• 
Vasculitis 
• 
Non-infectious meningitis 
• 
Non-infectious encephalitis.  
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. 
Further information on these risks (e.g. presenting symptoms) can be found in the 
current version of the durvalumab Investigator’s Brochure. More specific guidelines for 
their evaluation and treatment are described in detail in the Dosing Modification and 
Toxicity Management Guidelines (please see Appendix B). These guidelines have been 
prepared by the Sponsor to assist the Investigator in the exercise of his/her clinical 
judgment in treating these types of toxicities.  These guidelines apply to AEs considered 
causally related to the study drug/study regimen by the reporting investigator. 
 
      13.4 Definition of SAE 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
58 (147) 
 
SAEs include death, life threatening adverse experiences, hospitalization or prolongation of 
hospitalization, disability or incapacitation, overdose, congenital anomalies and any other 
serious events that may jeopardize the subject or require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Medical or scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in this latter situation. 
Examples of medically important events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalizations; or development of drug dependency or drug abuse. 
 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP and have been identified after 
the patient’s inclusion in this study.  
 
Adverse Events (AEs) for malignant tumors reported during a study should generally be assessed 
as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 
should be used. In certain situations, however, medical judgement on an individual event basis 
should be applied to clarify that the malignant tumor event should be assessed and reported as 
a Non-Serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is 
being treated by the IP under study and is not the development of new or progression of 
existing metastasis to the tumor under study). Malignant tumors that – as part of normal, if rare, 
progression – undergo transformation (e.g., Richter's transformation of B cell chronic 
lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumor. 
 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca. 
 
 
13.4.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB 
policy, which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate
_Reporting_Policy.pdf.  
 
 
13.4.2 Reporting of SAE to FDA 
 
SAEs will be reported to the FDA as per FDA reporting guidelines by the IND 
application sponsor. IND application sponsor must report any suspected adverse 
reaction or adverse reaction to study treatment that is both serious and 
unexpected. Unexpected fatal or life-threatening suspected adverse reactions 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
59 (147) 
represent especially important safety information and must be reported to FDA as 
soon as possible but no later than 7 calendar days following the sponsor’s initial 
receipt of the information. SA 
i. death, 
ii. a life-threatening adverse event,   
iii. in-patient hospitalization or prolongation of existing hospitalization, 
iv. a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or   
v. a congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or research subject and may 
require medical or surgical intervention to prevent one of the outcomes listed as 
serious. 
 
CDER INDs:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Biological Products  
5901-B Ammendale Road  
Beltsville, MD 20705-1266   
 
 
13.4.3 Reporting of SAE to AstraZeneca 
 
Institution will send AstraZeneca copies of any and all serious adverse event 
reports filed with the FDA or other applicable regulatory authorities, as well as 
copies of any correspondence with the FDA or other applicable regulatory 
authorities, regarding any and all serious adverse events, irrespective of association 
with the Study Drug(s) in the course of the Clinical Trial. SAE reports (individual 
case reports and line listings) and accompanying cover page will be sent to 
AstraZeneca via Email: AEmailboxclinicaltrialTCS@astrazeneca.com  
 
 
13.5 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This 
requirement indicates that follow-up may be required for some events after the subject 
discontinues participation from the study.  
 
13.6 Time Period and Frequency for Event Assessment and Follow Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
60 (147) 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The study team will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 90 days (for SAEs) after the last day 
of study participation.  At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until resolution or 
stabilization.] 
 
 
14. Data and Safety Monitoring Plan (DSMP) 
 
This study will utilize the Weill Cornell Medicine (WCM) Institutional Data Safety Monitoring Board 
(DSMB) and follow its policies and procedures for monitoring the study for safety concerns. The WCM 
DSMB is comprised of medical specialists and advisors on human rights issues in human subjects 
research. The WCM DSMB will review the IRB approved protocol, the data and safety monitoring plan, 
and any stopping guidelines during protocol initiation. During the course of the study, the DSMB will 
review cumulative study data at a specified interval to evaluate safety, risk-benefit ratio, study 
conduct, and scientific validity and integrity of the trial. The WCM DSMB may also convene as needed 
if stopping criteria are met or other safety issues arise that the Principal Investigator and/or IRB would 
like the WCM DSMB to address. Ultimately, the DSMB validates the continuation of the trial or 
determines if a study needs modification or termination. After each evaluation, the DSMB will provide 
the principle investigator with recommendations for protocol modification, continuation, or 
termination. 
  
For this study, a report will be submitted to the DSMB every 6 months. A report will also be submitted 
if it is determined that the radiation fractionation schedule needs to be adjusted as per the study 
protocol. If the study stopping rule below is met, then a report will also be submitted to the DSMB at 
that time. 
 
 
 
 
14.1 Stopping Rule 
 
 
 
 
 If there is a 30% or greater incidence of grade 3 or higher toxicities with the proposed 
treatment regimen in the first 10 subjects, specifically from radiation therapy (with focus 
on pneumonitis, pericarditis, esophagitis, rib fracture, or hemoptysis) or immune-
mediated adverse events (other than thyroid dysfunction), then the radiation regimen 
will be switched to 5 Gy radiation per day for 5 days. If there is still a 30% or greater 
incidence of grade 3 or higher toxicities from radiation therapy or immune-mediated 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
61 (147) 
adverse events among the subsequent 10 subjects, then the study will be terminated. If 
this does not occur, then accrual will continue until 34 total subjects are evaluable. 
 
 If safety concerns arise, the DSMB will identify these concerns and recommend 
modification or termination of the clinical trial.   
  
14.2 Study Monitoring 
  
 
The study will be monitored by the WCM DSMB as described in the DSMP.   
 
The study team (consisting of the PI, Research Nurse, and Data Manager at a minimum) 
will review monthly AE reports to ensure there are no unexpected or unacceptable safety 
concerns. 
 
 
Dr. Ana Molina, M.D. will serve in the capacity of Independent Medical Monitor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
62 (147) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
References 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 
2020;70(1):7-30. 
2. 
Schneider BJ, Saxena A, Downey RJ. Surgery for early-stage small cell lung 
cancer. Journal of the National Comprehensive Cancer Network : JNCCN. 
2011;9(10):1132-1139. 
3. 
Levy B, Saxena A, Schneider BJ. Systemic therapy for small cell lung cancer. 
Journal of the National Comprehensive Cancer Network : JNCCN. 
2013;11(7):780-787. 
4. 
Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging 
Project: Proposals for Revision of the TNM Stage Groupings in the 
Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J 
Thorac Oncol. 2016;11(1):39-51. 
5. 
Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus 
Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 
2018;379(23):2220-2229. 
6. 
Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide 
versus platinum-etoposide in first-line treatment of extensive-stage small-
cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 
trial. Lancet. 2019. 
7. 
Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for 
extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. 
Lancet. 2015;385(9962):36-42. 
8. 
Golden EB, Shin SM, Schiff PB, Formenti SC. Radiotherapy for extensive stage 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
63 (147) 
small-cell lung cancer. Lancet. 2015;385(9975):1290-1291. 
9. 
Stewart R, Morrow M, Hammond SA, et al. Identification and 
Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal 
Antibody. Cancer Immunol Res. 2015;3(9):1052-1062. 
10. 
Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant 
untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol 
Biol Phys. 2004;58(3):862-870. 
11. 
Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 
2009;10(7):718-726. 
12. 
Formenti SC, Rudqvist NP, Golden E, et al. Radiotherapy induces responses 
of lung cancer to CTLA-4 blockade. Nat Med. 2018;24(12):1845-1851. 
13. 
Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after 
Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379(24):2342-
2350. 
14. 
Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour 
for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised 
controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366. 
15. 
Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. 
Maintenance Therapy or Observation for Patients With Oligometastatic Non-
Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, 
Randomized Study. J Clin Oncol. 2019;37(18):1558-1565. 
16. 
Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus 
standard of care palliative treatment in patients with oligometastatic 
cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 
2019;393(10185):2051-2058. 
17. 
Olson R, Senan S, Harrow S, et al. Quality of Life Outcomes After Stereotactic 
Ablative Radiation Therapy (SABR) Versus Standard of Care Treatments in 
the Oligometastatic Setting: A Secondary Analysis of the SABR-COMET 
Randomized Trial. Int J Radiat Oncol Biol Phys. 2019;105(5):943-947. 
18. 
Luke JJ, Lemons JM, Karrison TG, et al. Safety and Clinical Activity of 
Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients 
With Advanced Solid Tumors. J Clin Oncol. 2018;36(16):1611-1618. 
19. 
Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral 
persistence alters CD8 T-cell immunodominance and tissue distribution and 
results in distinct stages of functional impairment. J Virol. 2003;77(8):4911-
4927. 
20. 
Huang AC, Postow MA, Orlowski RJ, et al. T-cell invigoration to tumour 
burden ratio associated with anti-PD-1 response. Nature. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
64 (147) 
2017;545(7652):60-65. 
21. 
Luo R, Firat E, Gaedicke S, Guffart E, Watanabe T, Niedermann G. Cisplatin 
Facilitates Radiation-Induced Abscopal Effects in Conjunction with PD-1 
Checkpoint Blockade Through CXCR3/CXCL10-Mediated T-cell Recruitment. 
Clin Cancer Res. 2019;25(23):7243-7255. 
22. 
Owonikoko TK, Higgins KA, Chen Z, et al. A randomized phase II study of 
tremelimumab and durvalumab with or without radiation for patients with 
relapsed small cell lung cancer (SCLC). J Clin Oncol. 2019;37((suppl; abstr 
8515)). 
23. 
Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic 
ablative radiotherapy for centrally located early-stage lung cancer. J Thorac 
Oncol. 2011;6(12):2036-2043. 
24. 
Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study 
of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung 
cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys. 
2005;63(5):1427-1431. 
25. 
Yamashita H, Nakagawa K, Nakamura N, et al. Exceptionally high incidence of 
symptomatic grade 2-5 radiation pneumonitis after stereotactic radiation 
therapy for lung tumors. Radiat Oncol. 2007;2:21. 
26. 
Guckenberger M, Baier K, Polat B, et al. Dose-response relationship for 
radiation-induced pneumonitis after pulmonary stereotactic body 
radiotherapy. Radiother Oncol. 2010;97(1):65-70. 
27. 
Milano MT, Chen Y, Katz AW, Philip A, Schell MC, Okunieff P. Central thoracic 
lesions treated with hypofractionated stereotactic body radiotherapy. 
Radiother Oncol. 2009;91(3):301-306. 
28. 
Nishimura S, Takeda A, Sanuki N, et al. Toxicities of organs at risk in the 
mediastinal and hilar regions following stereotactic body radiotherapy for 
centrally located lung tumors. J Thorac Oncol. 2014;9(9):1370-1376. 
29. 
Modh A, Rimner A, Williams E, et al. Local control and toxicity in a large 
cohort of central lung tumors treated with stereotactic body radiation 
therapy. Int J Radiat Oncol Biol Phys. 2014;90(5):1168-1176. 
30. 
Hoppe BS, Laser B, Kowalski AV, et al. Acute skin toxicity following 
stereotactic body radiation therapy for stage I non-small-cell lung cancer: 
who's at risk? Int J Radiat Oncol Biol Phys. 2008;72(5):1283-1286. 
31. 
Lo SS, Sahgal A, Chang EL, et al. Serious complications associated with 
stereotactic ablative radiotherapy and strategies to mitigate the risk. Clin 
Oncol (R Coll Radiol). 2013;25(6):378-387. 
32. 
Stephans KL, Djemil T, Tendulkar RD, Robinson CG, Reddy CA, Videtic GM. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
65 (147) 
Prediction of chest wall toxicity from lung stereotactic body radiotherapy 
(SBRT). Int J Radiat Oncol Biol Phys. 2012;82(2):974-980. 
33. 
Voroney JP, Hope A, Dahele MR, et al. Chest wall pain and rib fracture after 
stereotactic radiotherapy for peripheral non-small cell lung cancer. J Thorac 
Oncol. 2009;4(8):1035-1037. 
34. 
Wu AJ, Williams E, Modh A, et al. Dosimetric predictors of esophageal 
toxicity after stereotactic body radiotherapy for central lung tumors. 
Radiother Oncol. 2014;112(2):267-271. 
35. 
Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic 
radioablation: results of a phase I study in medically inoperable stage I non-
small cell lung cancer. Chest. 2003;124(5):1946-1955. 
36. 
Evans JD, Gomez DR, Amini A, et al. Aortic dose constraints when 
reirradiating thoracic tumors. Radiother Oncol. 2013;106(3):327-332. 
37. 
Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when 
treating central tumors in a phase II study of stereotactic body radiation 
therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 
2006;24(30):4833-4839. 
38. 
Corradetti MN, Haas AR, Rengan R. Central-airway necrosis after stereotactic 
body-radiation therapy. N Engl J Med. 2012;366(24):2327-2329. 
39. 
Olsen JR, Robinson CG, El Naqa I, et al. Dose-response for stereotactic body 
radiotherapy in early-stage non-small-cell lung cancer. Int J Radiat Oncol Biol 
Phys. 2011;81(4):e299-303. 
40. 
Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of risk-
adapted fractionated stereotactic radiotherapy for stage I non-small-cell 
lung cancer. Int J Radiat Oncol Biol Phys. 2008;70(3):685-692. 
41. 
Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy in 
centrally and superiorly located stage I or isolated recurrent non-small-cell 
lung cancer. Int J Radiat Oncol Biol Phys. 2008;72(4):967-971. 
42. 
Senan S, Haasbeek NJ, Smit EF, Lagerwaard FJ. Stereotactic radiotherapy for 
centrally located early-stage lung tumors. J Clin Oncol. 2007;25(4):464; 
author reply 465. 
43. 
Altorki NK, Markowitz GJ, Gao D, et al. The lung microenvironment: an 
important regulator of tumour growth and metastasis. Nat Rev Cancer. 
2019;19(1):9-31. 
44. 
Hegde PS, Karanikas V, Evers S. The Where, the When, and the How of 
Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint 
Inhibition. Clin Cancer Res. 2016;22(8):1865-1874. 
45. 
Manjarrez-Orduño N, Menard LC, Kansal S, et al. Circulating T Cell 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
66 (147) 
Subpopulations Correlate With Immune Responses at the Tumor Site and 
Clinical Response to PD1 Inhibition in Non-Small Cell Lung Cancer. Front 
Immunol. 2018;9:1613. 
46. 
Anagnostou V, Forde PM, White JR, et al. Dynamics of Tumor and Immune 
Responses during Immune Checkpoint Blockade in Non-Small Cell Lung 
Cancer. Cancer Res. 2019;79(6):1214-1225. 
47. 
Lhuillier C, Rudqvist NP, Elemento O, Formenti SC, Demaria S. Radiation 
therapy and anti-tumor immunity: exposing immunogenic mutations to the 
immune system. Genome Med. 2019;11(1):40. 
48. 
Wennerberg E, Spada S, Rudqvist NP, et al. CD73 Blockade Promotes 
Dendritic Cell Infiltration of Irradiated Tumors and Tumor Rejection. Cancer 
Immunol Res. 2020;8(4):465-478. 
49. 
Kamphorst AO, Pillai RN, Yang S, et al. Proliferation of PD-1+ CD8 T cells in 
peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc 
Natl Acad Sci U S A. 2017;114(19):4993-4998. 
50. 
Hou JM, Krebs MG, Lancashire L, et al. Clinical significance and molecular 
characteristics of circulating tumor cells and circulating tumor microemboli 
in patients with small-cell lung cancer. J Clin Oncol. 2012;30(5):525-532. 
51. 
Hodgkinson CL, Morrow CJ, Li Y, et al. Tumorigenicity and genetic profiling of 
circulating tumor cells in small-cell lung cancer. Nat Med. 2014;20(8):897-
903. 
52. 
Hyun KA, Koo GB, Han H, et al. Epithelial-to-mesenchymal transition leads to 
loss of EpCAM and different physical properties in circulating tumor cells 
from metastatic breast cancer. Oncotarget. 2016;7(17):24677-24687. 
53. 
Daniels TR, Bernabeu E, Rodríguez JA, et al. The transferrin receptor and the 
targeted delivery of therapeutic agents against cancer. Biochim Biophys 
Acta. 2012;1820(3):291-317. 
54. 
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of 
pertuzumab in cancer patients based on population pharmacokinetic 
analysis. Pharm Res. 2006;23(6):1275-1284. 
55. 
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-
based dosing of monoclonal antibodies in adult clinical trials. J Clin 
Pharmacol. 2009;49(9):1012-1024. 
56. 
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based 
dosing of therapeutic peptides and proteins in adults. J Clin Pharmacol. 
2012;52(1):18-28. 
57. 
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of 
sifalimumab, an investigational anti-interferon-α monoclonal antibody, in 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
67 (147) 
systemic lupus erythematosus. Clin Pharmacokinet. 2013;52(11):1017-1027. 
58. 
Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal 
response to radiation and ipilimumab in a patient with metastatic non-small 
cell lung cancer. Cancer Immunol Res. 2013;1(6):365-372. 
59. 
Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation 
therapy: the report of AAPM Task Group 101. Med Phys. 2010;37(8):4078-
4101. 
60. 
NCCN. National Comprehensive Cancer Network Clinical Practice Guidelines 
in Oncology.  Management of Immunotherapy-Related 
Toxicities. https://www.nccn.org/professionals/physician_gls/pdf/immunoth
erapy.pdf.  Published 2020. Accessed 28 May, 2020. 
61. 
Szolek A, Schubert B, Mohr C, Sturm M, Feldhahn M, Kohlbacher O. 
OptiType: precision HLA typing from next-generation sequencing data. 
Bioinformatics. 2014;30(23):3310-3316. 
62. 
McLaren W, Gil L, Hunt SE, et al. The Ensembl Variant Effect Predictor. 
Genome Biol. 2016;17(1):122. 
63. 
Hundal J, Carreno BM, Petti AA, et al. pVAC-Seq: A genome-guided in silico 
approach to identifying tumor neoantigens. Genome Med. 2016;8(1):11. 
64. 
Nielsen M, Lundegaard C, Worning P, et al. Reliable prediction of T-cell 
epitopes using neural networks with novel sequence representations. 
Protein Sci. 2003;12(5):1007-1017. 
65. 
Andreatta M, Nielsen M. Gapped sequence alignment using artificial neural 
networks: application to the MHC class I system. Bioinformatics. 
2016;32(4):511-517. 
66. 
Carlson CS, Emerson RO, Sherwood AM, et al. Using synthetic templates to 
design an unbiased multiplex PCR assay. Nat Commun. 2013;4:2680. 
67. 
Rudqvist NP, Pilones KA, Lhuillier C, et al. Radiotherapy and CTLA-4 Blockade 
Shape the TCR Repertoire of Tumor-Infiltrating T Cells. Cancer Immunol Res. 
2018;6(2):139-150. 
68. 
Giesen C, Wang HA, Schapiro D, et al. Highly multiplexed imaging of tumor 
tissues with subcellular resolution by mass cytometry. Nat Methods. 
2014;11(4):417-422. 
69. 
Lavin Y, Kobayashi S, Leader A, et al. Innate Immune Landscape in Early Lung 
Adenocarcinoma by Paired Single-Cell Analyses. Cell. 2017;169(4):750-765 
e717. 
70. 
Sailer V, Pauli C, Merzier EC, et al. On-site Cytology for Development of 
Patient-Derived Three-dimensional Organoid Cultures - A Pilot Study. 
Anticancer Res. 2017;37(4):1569-1573. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
68 (147) 
71. 
Pauli C, Puca L, Mosquera JM, et al. An emerging role for cytopathology in 
precision oncology. Cancer Cytopathol. 2016;124(3):167-173. 
72. 
Pauli C, Hopkins BD, Prandi D, et al. Personalized. Cancer Discov. 
2017;7(5):462-477. 
73. 
Puca L, Bareja R, Prandi D, et al. Patient derived organoids to model rare 
prostate cancer phenotypes. Nat Commun. 2018;9(1):2404. 
74. 
Prandi D, Baca SC, Romanel A, et al. Unraveling the clonal hierarchy of 
somatic genomic aberrations. Genome Biol. 2014;15(8):439. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
69 (147) 
Appendix A 
Adverse Events Reported in CASPIAN Trial of Platinum-Etoposide vs Durvalumab plus Platinum - 
Etoposide. Tables 4 and S5-S8 from Publication of Trial6 
  
 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
70 (147) 
 
 
Data cutoff date: March 11, 2019. Listed are all adverse events assessed by the investigator as possibly related to 
any study treatment that occurred during the treatment period and up to 90 days after the last dose of 
durvalumab or EP or up to the start of any subsequent therapy (whichever occurred first). *Includes patients who 
permanently discontinued at least one study drug. †Treatment-related adverse events leading to death in the 
durvalumab plus EP arm were cardiac arrest, dehydration, hepatotoxicity, pancytopenia, and sepsis in one patient 
each. Treatment-related adverse events leading to death in the EP arm were pancytopenia and 
thrombocytopenia/haemorrhage in one patient each. ‡The events are listed in descending order of frequency 
across both treatment arms. EP=platinum-etoposide. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
71 (147) 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
72 (147) 
 
Data cutoff date: March 11, 2019. Listed are all serious adverse events that occurred during the treatment period and 
up to 90 days after the last dose of durvalumab or EP or up to the start of any subsequent therapy (whichever 
occurred first). *The events are listed in descending order of frequency across both treatment arms. EP=platinum-
etoposide. 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
73 (147) 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
74 (147) 
 
 
Data cutoff date: March 11, 2019. Listed are all adverse events leading to discontinuation that occurred during the 
treatment period and up to 90 days after the last dose of durvalumab or EP or up to the start of any subsequent 
therapy (whichever occurred first). *Includes patients who permanently discontinued at least one study drug. †The 
events are listed in descending order of frequency across both treatment arms. EP=platinum-etoposide. 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
75 (147) 
 
Data cutoff date: 11 March 2019. Listed are all immune-mediated adverse events that occurred during the 
treatment period and up to 90 days after the last dose of durvalumab or EP or up to the start of any subsequent 
therapy (whichever occurred first). *Grade 5 immune-mediated adverse events occurred in one patient receiving 
durvalumab plus EP (hepatotoxicity) and one patient receiving EP (pneumonitis). †An immune-mediated adverse 
event is defined as an event that is associated with drug exposure and 21 consistent with an immune-mediated 
mechanism of action, where there is no clear alternate etiology and the event required treatment with systemic 
corticosteroids or other immunosuppressants and/or, for specific endocrine events, endocrine therapy. ‡The 
events are listed in descending order of frequency across both treatment arms. §The events in the ‘other 
rare/miscellaneous’ category were both arthritis.  
EP=platinum-etoposide. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
76 (147) 
 
Appendix B 
 
Toxicity Management Guidelines (TMGs) 
Drug Substance 
Durvalumab and 
Tremelimumab 
 
TMG Version 
28 October 2021 
 
ANNEX TO PROTOCOL 
 
Dosing Modification and Toxicity Management Guidelines (TMGs) for   
Durvalumab Monotherapy, Durvalumab in Combination with other 
Products, or Tremelimumab Monotherapy 
 
Note: Annex is to be used in any clinical trial protocol within which patients are treated 
with  
Durvalumab Monotherapy, Durvalumab in Combination with other Products, or  
Tremelimumab Monotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table of Contents 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
77 (147) 
General Considerations Regarding immune mediated adverse events 
(imAEs)…………………………….. 
4 
Relevant Society Guidelines for Management of 
imAEs…………………………………………………… 
4 
Pediatric Considerations Regarding 
imAEs………………………………………………………………… 
5 
Specific imAEs 
Pneumonitis/Interstitial Lung 
Disease…………………………………………………………………. 
6 
Diarrhea/Colitis……………………………………………………………………………………
…… 
8 
Hepatitis (elevated LFTs) 
……………………………………………………………………………... 
10 
Hepatitis (elevated LFTs) in Patients With Hepatocellular Cancer 
(HCC)…………………………… 
12 
Nephritis or Renal Dysfunction (elevated serum 
creatinine)………………………………………….. 
14 
Rash or Dermatitis (including 
Pemphigoid)…………………………………………………………… 
16 
Endocrinopathy (hyperthyroidism, thyroiditis, hypothyroidism, type 1 diabetes mellitus,  
17 
hypophysitis, hypopituitarism, adrenal 
insufficiency)………………………………………………… 
Amylase/Lipase 
Increased…………………………………………………………………………….. 
19 
Acute 
Pancreatitis……………………………………………………………………………………… 20 
Neurotoxicity (non-infectious meningitis, non-infectious encephalitis, autonomic 
neuropathy)……... 
20 
Peripheral Neuromotor Syndromes (Guillain-Barre, myasthenia 
gravis)……………………………... 
22 
Myocarditis…………………………………………………………………………………………
….. 
25 
Myositis/Polymyositis……………………………………………………………………………


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
78 (147) 
……. 
26 
Other Immune-mediated 
Reactions………………………………………………………………………….. 
30 
Infusion-Related 
Reactions………………………………………………………………………………….. 
31 
Non-Immune Mediated 
Reactions…………………………………………………………………………… 
32 
List of 
Abbreviations………………………………………………………………………………………
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
33 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
79 (147) 
1. VERSION HISTORY 
28 October 2021 
 
The Toxicity Management Guidelines (TMGs) have been developed to assist investigators with 
the recognition and management of toxicities associated with use of the immune-checkpoint 
inhibitors durvalumab [MEDI4736] (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor). 
Given the similar underlying mechanism of toxicities observed with these two compounds, 
these TMGs are applicable to the management of patients receiving either drug as monotherapy 
or both drugs in combination. Additionally, these guidelines are applicable when either drug is 
used alone or both drugs are used in combination and, also, other anti-cancer drugs (i.e., 
antineoplastic chemotherapy, targeted agents) are administered concurrently or sequentially as 
part of a protocol-specific treatment regimen.  The TMGs provide information for the 
management of immune-mediated reactions, infusion-related reactions, and non-immune-
mediated reactions that may be observed with monotherapy or combination checkpoint inhibitor 
regimens, with specific instructions for checkpoint inhibitor-specific dose modifications 
(including discontinuation) and treatment interventions.  Investigators are advised however to 
use local practice guidelines and consult local references for the management of toxicities 
observed with other anti-cancer treatment. 
Dosing modification and toxicity management for immune-mediated, infusion-related, and 
nonimmune–mediated reactions associated with the use of a checkpoint inhibitor or checkpoint 
inhibitors in this protocol – whether that is durvalumab alone, tremelimumab alone, or 
durvalumab + tremelimumab in combination, or durvalumab +/- tremelimumab in combination 
with other anti-cancer drugs (i.e., antineoplastic chemotherapy, targeted agents) administered 
concurrently or sequentially – should therefore be performed in accordance with this Annex to 
Protocol, which for the purposes of submission and approval of substantial updates is 
maintained as a standalone document. TMG updates are iterated by date, and should be used in 
accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 
specified in the clinical study protocol.  
Although the TMG versioning is independent of the protocol, the TMG Annex to Protocol 
should be read in conjunction with the Clinical Study Protocol, where if applicable additional 
references for the management of toxicities observed with other anti-cancer treatment are 
included in the specific section of the Clinical Study Protocol.  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
80 (147) 
Dosing Modification and Toxicity Management Guidelines (TMGs) for Durvalumab Monotherapy, Durvalumab 
in Combination with other Products, or Tremelimumab Monotherapy – 28 October 2021 
 
1.1. General Considerations Regarding Immune-Mediated Reactions 
 
These guidelines are provided as a recommendation to support investigators in the management of potential immune-
mediated adverse events (imAEs).  
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible 
immune-mediated reactions. Investigators are advised to take into consideration the appropriate practice guidelines and other 
society guidelines (e.g., National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO)) in 
the management of these events. Refer to the section of the table titled “Other -Immune-Mediated Reactions” for general guidance 
on imAEs not noted in the “Specific Immune-Mediated Reactions” section. 
Early identification and management of imAEs is essential to ensure safe use of the study drug.  Monitor patients closely for 
symptoms and signs that may be clinical manifestations of underlying imAEs. Patients with suspected imAEs  should be 
thoroughly evaluated to rule out any alternative etiologies (e.g., disease progression, concomitant medications, infections). In the 
absence of a clear alternative etiology, all such events should be managed as if they were immune-mediated.  Institute medical 
management promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen for severe 
(Grade 3) imAEs. Permanently discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe 
(Grade 3) imAEs that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.  
Based on the severity of the imAE, durvalumab and/or tremelimumab should be withheld and corticosteroids administered. Upon 
improvement to Grade ≤ 1, corticosteroid should be tapered over ≥ 28 days.  More potent immunosuppressive agents should be 
considered for events not responding to systemic steroids. Alternative immunosuppressive agents not listed in this guideline may 
be considered at the discretion of the investigator based on clinical practice and relevant guidelines. With longterm steroid and 
other immunosuppressive use, consider need for Pneumocystis jirovecii pneumonia (PJP) prophylaxis, gastrointestinal protection, 
and glucose monitoring. Dose modifications of study drug/study regimen should be based on severity of treatment-emergent 
toxicities graded per NCI CTCAE version in the applicable study protocol. 
 
1.2. Relevant Society Guidelines for Management of imAEs 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
81 (147) 
These society guidelines are provided as references to serve in support of best clinical practice and the TMGs. Please note, 
these were the current versions of these guidelines at the time of updating TMGs. Please refer to the most up to date version of 
these guidelines. 
1. 
Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint 
inhibitor-related adverse events. J Immunother Cancer 2021;9:e002435 
2. 
Brahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor 
therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36(17):1714-1768. 
3. 
Haanen JBAG, et al. Management of toxicities for immunotherapy: European Society for Medical Oncology (ESMO) 
clinical practice guidelines for diagnosis, treatment, and follow-up. Annals Oncol 2017;28(Suppl4):i119-i1142. 
4. 
Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J 
Hepatol 2020;72(2):320-341. 
5. 
Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related 
toxicities version 3.2021. Published May 14, 2021. 
Pediatric Considerations Regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study 
drug/study regimen based on CTCAE grade/severity is the 
same for pediatric patients as it is for adult patients, as well 
as to permanently discontinue study drug/study regimen if 
unable to reduce corticosteroid ≤ a dose equivalent to that 
required for corticosteroid replacement therapy within 12 
weeks of initiating corticosteroids. 
− 
− 
− 
All recommendations for specialist consultation should 
occur with a pediatric specialist in the specialty 
recommended. 
The recommendations for steroid dosing (i.e., 
mg/kg/day) provided for adult patients should also be 
used for pediatric patients. 
The recommendations for intravenous immunoglobulin 
(IVIG) and plasmapheresis use provided for adult 
patients may be considered for pediatric patients. 
− The infliximab 5 mg/kg IV one time dose recommended 
for adults is the same as recommended for pediatric 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
82 (147) 
patients ≥ 6 years old. For subsequent dosing and dosing 
in children < 6 years old, consult a pediatric specialist. 
− For pediatric dosing of mycophenolate mofetil, consult a 
pediatric specialist. 
− With long-term steroid and other immunosuppressive 
use, consider need for PJP prophylaxis, gastrointestinal 
protection, and glucose monitoring. 
 
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
83 (147) 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the  
Event  
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial  
Lung Disease (ILD) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for  
defining the 
CTCAE 
grade/severity) 
General Guidance 
- 
− 
For Any Grade 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g. 
infection, progressive disease) 
Monitor patients for signs and 
symptoms of pneumonitis or 
ILD (new onset or worsening 
shortness of breath or cough). 
Evaluate patients with imaging 
and pulmonary function tests, 
including other diagnostic 
procedures as described below.  
− Suspected pneumonitis should 
be confirmed with radiographic 
imaging and other infectious 
and disease-related aetiologies 
excluded, and managed as 
described below. 
− Initial work-up may include 
clinical evaluation, monitoring 
of oxygenation via pulse 
oximetry (resting and exertion), 
laboratory work-up, and high- 


 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
8 4  (1 4 7 ) 
r es ol uti o n c o m p ut e d 
t o m o gr a p h y ( C T) sc a n. 
 
 
 
− C o nsi d er P ul m o n ar y a n d 
I nf ecti o us Dis e as es c o ns ults. 
Gr a de 1  
N o d os e m o dific ati o ns r e q uir e d. H o w e v er, 
c o nsi d er h ol di n g st u d y dr u g/st u d y r e gi m e n 
d os e as cli nic all y a p pr o pri at e a n d d uri n g 
di a g n ostic w or k -u p f or ot h er eti ol o gi es.  
 
− 
F or Gr a de 1  
M o nit or a n d cl os el y f oll o w u p 
i n 2 t o 4 d a ys f or cli nic al 
s y m pt o ms, p uls e oxi m etr y 
(r esti n g a n d ex erti o n), a n d 
l a b or at or y w or k u p, a n d t h e n as 
cli nic all y i n dic at e d. 
Gr a de 2  
H ol d st u d y dr u g/st u d y r e gi m e n d os e u ntil Gr a d e 
2 r es ol uti o n t o Gr a d e ≤1.  
 If t oxicit y i m pr o v es t o Gr a d e ≤1, t h e n t h e 
d ecisi o n t o r ei niti at e st u d y dr u g/st u d y 
r e gi m e n will b e b as e d u p o n tr e ati n g 
p h ysici a n’s cli nic al j u d g m e nt a n d aft er 
c o m pl eti o n of st er oi d t a p er (< 1 0 m g 
pr e d nis o n e or e q ui v al e nt).  
− 
− 
F or Gr a de 2  
M o nit or s y m pt o ms d ail y a n d 
c o nsi d er h os pit aliz ati o n. 
O bt ai n P ul m o n ar y a n d 
I nf ecti o us Dis e as es C o ns ults; 
c o nsi d er disc ussi n g wit h Cli nic al 
St u d y L e a d, as n e e d e d.  
 
 
 
− Pr o m ptl y st art s yst e mic st er oi ds 
( e. g., pr e d nis o n e 1 t o 2 
m g/ k g/ d a y P O or I V e q uiv al e nt).  
 
 
− R ei m a g e as cli nic all y i n dic at e d, 
c o nsi d er c h est C T wit h c o ntr ast 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
85 (147) 
and repeat in 3-4 weeks. 
− If no improvement within 2 to 3 
days, additional workup should 
be considered and prompt 
treatment with IV 
methylprednisolone 2 to 4 
mg/kg/day started. 
Grade 3 or 4 
− If no improvement within 2 to 3 
days despite IV 
methylprednisolone at 2 to 4 
mg/kg/day, promptly start 
immunosuppressive therapy. 
such as tumor necrosis factor 
(TNF) inhibitors (e.g., infliximab 
at 5 mg/kg IV once, may be 
repeated at 2 and 6 weeks after 
initial dose at the discretion of 
the treating provider or relevant 
practice guidelines). Caution: It is 
important to rule out sepsis and 
refer to infliximab label for 
general guidance before using 
infliximab. Consider, as 
necessary, discussing with Clinical 
Study Lead. 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
86 (147) 
− Promptly initiate empiric IV 
methylprednisolone 1 to 4 
mg/kg/day or equivalent. 
− Obtain Pulmonary and Infectious 
Diseases Consults; consider 
discussing with Clinical Study 
Lead, as needed. 
− Hospitalize the patient. 
− Supportive care (e.g., oxygen). 
− If no improvement within 2 days, 
additional workup should be 
considered and prompt 
treatment with additional 
immunosuppressive therapy such 
as TNF inhibitors (e.g., infliximab 
at 5 mg/kg IV, may be repeated 
at 2 and 6 weeks after initial dose 
at the discretion of the treating 
provider or relevant practice 
guidelines). Caution:  
 
Diarrhea/Colitis 
rule out sepsis and refer to 
infliximab label for general 
guidance before using infliximab. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
87 (147) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for  
defining the 
CTCAE 
grade/severity) 
General Guidance 
− 
− 
For Any Grade 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, other medications, 
or infections), including testing 
for Clostridium difficile toxin, 
etc. 
Monitor for symptoms that may 
be related to 
diarrhea/enterocolitis 
(abdominal pain, cramping, or 
changes in bowel habits such as 
increased frequency over 
baseline or blood in stool) or 
related to bowel perforation  
(such as sepsis, peritoneal signs, 
and ileus). 
− WHEN 
SYMPTOMS 
OR 
EVALUATION  
INDICATE AN INTESTINAL  
PERFORATION IS 
SUSPECTED,  
CONSULT A SURGEON  
EXPERIENCED IN 
ABDOMINAL SURGERY 
IMMEDIATELY WITHOUT 
ANY DELAY.  
− PERMANENTLY 
DISCONTINUE STUDY 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
88 (147) 
DRUG FOR ANY GRADE OF 
INTESTINAL 
PERFORATION. 
− Steroids should be considered in 
the absence of clear alternative 
etiology, even for lowgrade 
events, in order to prevent 
potential progression to higher 
grade events, including intestinal 
perforation.  
− Use analgesics carefully; they can 
mask symptoms of perforation 
and peritonitis. 
Grade 1 
No dose modifications. 
For Grade 1 
− Monitor closely for worsening 
symptoms. 
− Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes 
(e.g., American Dietetic 
Association  
colitis diet), loperamide, and 
other supportive care measures.  
− If symptoms persist, consider 
checking lactoferrin; if positive, 
treat as Grade 2  
 


 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
8 9  (1 4 7 ) 
Gr a de 2  
 
 
b el o w. If n e g ati v e a n d n o 
i nf ecti o n, c o nti n u e Gr a d e 1 
m a n a g e m e nt.  
 d st u d y dr u g/st u d y r e gi m e n u ntil r es ol uti o n t o 
d e ≤1  
If t oxicit y i m pr o v es t o Gr a d e ≤1, t h e n st u d y 
dr u g/st u d y r e gi m e n c a n b e r es u m e d aft er 
c o m pl eti o n of st er oi d t a p er ( < 1 0 m g 
pr e d nis o n e, or e q ui v al e nt).  
− 
F or Gr a de 2  
C o nsi d er s y m pt o m atic tr e at m e nt, 
i ncl u di n g h y dr ati o n, el ectr ol yt e 
r e pl ac e m e nt, di et ar y c h a n g es 
( e. g., A m eric a n Di et etic 
Ass oci ati o n c olitis di et), a n d 
l o p er a mi d e a n d/ or b u d es o ni d e. 
 
 
 
− Pr o m ptl y st art pr e d nis o n e 1 t o 2 
m g/ k g/ d a y P O or I V e q uiv al e nt.  
 
 
 
− If e v e nt is n ot r es p o nsi v e wit hi n 2 
t o 3 d a ys or w ors e ns d es pit e 
pr e d nis o n e at 1 t o 2 m g/k g/ d a y 
P O or I V e q ui v al e nt, c o ns ult a 
g astr oi nt esti n al ( GI) s p eci alist f or 
c o nsi d er ati o n of f urt h er w or k u p, 
s uc h as i m a gi n g a n d/ or 
c ol o n osc o p y, t o c o nfir m c olitis 
a n d r ul e o ut p erf or ati o n.  


 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
9 0  (1 4 7 ) 
 
 
 
− If still n o i m pr o v e m e nt wit hi n 2 
t o 3 d a ys d es pit e 1 t o 2 m g/ k g I V 
m et h yl pr e d nis ol o n e, pr o m ptl y 
st art a d diti o n al 
i m m u n os u p pr ess a nt a g e nt s uc h 
as i nflixi m a b at 5 m g/ k g I V, m a y 
b e r e p e at e d at 2 a n d 6 w e e ks 
aft er i niti al d os e at t h e discr eti o n 
of t h e tr e ati n g  pr o vi d er or 
r el e v a nt pr actic e g ui d eli n es. 
C a uti o n: it is i m p ort a nt t o r ul e 
o ut b o w el p erf or ati o n a n d r ef er 
t o i nflixi m a b l a b el f or g e n er al 
g ui d a nc e b ef or e usi n g i nflixi m a b.  
 
 
 
− If perf or ati o n is s us pecte d, 
c o ns ult a s ur ge o n e x perie nce d 
i n a b d o mi n al s ur ger y 
i m me di atel y wit h o ut a n y del a y. 
Gr a de 3 or 4   
 
− C o nsi d er, as n ec ess ar y, disc ussi n g 
wit h Cli nic al St u d y L e a d if n o 
r es ol uti o n t o Gr a d e  
≤1 i n 3 t o 4 d a ys.  
 
Gr a de 3  
 F or p ati e nts tr e at e d wit h d ur v al u m a b 
m o n ot h er a p y, h ol d st u dy dr u g/st u d y 
r e gi m e n u ntil r es ol uti o n t o Gr a d e ≤1; 
st u d y dr u g/st u d y r e gi m e n c a n b e 
r es u m e d  
− 
− 
F or Gr a de 3 or 4  
Pr o m ptl y i niti at e e m piric I V 
m et h yl pr e d nis ol o n e 1 t o 2 
m g/ k g/ d a y or e q ui v al e nt.  
M o nit or st o ol fr e q u e ncy a n d 
v ol u m e a n d m ai nt ai n h y dr ati o n.  


 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
9 1  (1 4 7 ) 
 
 
 
 
P er m 
st u d 
aft er c o m pl eti o n of st er oi d t a p er ( < 1 0 m g 
pr e d nis o n e p er d a y, or e q ui v al e nt).  
F or p ati e nts tr e at e d wit h d ur v al u m a b i n 
c o m bi n ati o n wit h ot h er pr o d ucts ( n ot 
tr e m eli m u m a b), d ecisi o n t o b e m a d e at 
t h e discr eti o n of t h e st u d y i n v esti g at or, 
i n disc ussi o n wit h Astr a Z e n ec a Cli nic al 
St u d y L e a d.  
F or p ati e nts tr e at e d wit h d ur v al u m a b i n 
c o m bi n ati o n wit h tr e m eli m u m a b or 
tr e m eli m u m a b m o n ot h er a p y, 
P er m a n e ntl y disc o nti n u e s t u d y dr u g f or 
1) Gr a d e 3 di arr h e a c olitis or 2) A n y 
gr a d e of i nt esti n al p erf or ati o n i n a n y 
p ati e nt tr e at e d wit h i m m u n e c h ec k p oi nt 
i n hi bit or (I CI).   
Gr a de 4 
a n e ntl y 
disc o nti n u e y 
dr u g/st u d y 
r e gi m e n. 
− 
− 
− 
Ur g e nt  GI  c o ns ult  a n d  i m a gi n g  
a n d/ or 
c ol o n osc o py
 as
 
a p pr o pri at e.  
If still n o i m pr o v e m e nt wit hi n 2 
d a ys, c o nti n u e st er oi ds a n d 
pr o m ptl y a d d f urt h er 
i m m u n os u p pr ess a nts. ( e. g., 
i nflixi m a b at 5 m g/ k g I V, m a y b e 
r e p e at e d at 2 a n d 6 w e eks aft er 
i niti al d os e at t h e discr eti o n of 
t h e tr e ati n g pr o vi d er or r el e v a nt 
pr actic e g ui d eli n es). C a uti o n : 
E ns ur e GI c o ns ult t o r ul e o ut 
b o w el p erf or ati o n a n d r ef er t o 
i nflixi m a b l a b el f or g e n er al 
g ui d a nc e b ef or e usi n g i nflixi m a b.  
If perf or ati o n is s us pecte d, 
c o ns ult a s ur ge o n e x perie nce d 
i n a b d o mi n al s ur ger y 
i m me di atel y wit h o ut a n y 
del a y.  


 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
9 2  (1 4 7 ) 
He p atitis  
(ele v at e d li ver 
f u ncti o n tests 
( L F Ts)) 
A n y Gr a de  
( R ef er t o N CI C T C A E 
a p plic a bl e v ersi o n 
i n st u d y pr ot oc ol 
f or  
d efi ni n g t h e C T C A E 
gr a d e/s e v erit y)  
 
Ge ner al G ui d a nce  
− 
− 
F or A n y Gr a de  
P ati e nts s h o ul d b e t h or o u g hl y 
e v al u at e d t o r ul e o ut a n y 
alt er n ati v e eti ol o g y ( e. g., vir al 
h e p atitis, dis e as e pr o gr essi o n, 
c o nc o mit a nt m e dic ati o ns).  
M o nit or  a n d  e v al u at e  L F Ts:  
as p art at e
 a mi n otr a nsf er as e
 
( A S T),
 al a ni n e
 
a mi n otr a nsf er as e
 ( AL T),
 
al k ali n e  p h os p h at as e  ( AL P),  
a n d t o t al bilir u bi n ( T. bili.). 
 
Gr a de 1  
 
 
N o d  
If it  
os e m o dific ati o ns.  
w ors e ns, t h e n c o nsi d er h ol di n g t h er a p y.  
− 
F or Gr a de 1  
C o nti n u e L F T m o nit ori n g p er 
pr ot oc ol.  
 
Gr a de 2  
 
 
H ol d 
r es ol 
If t ox 
st u d y dr u g/st u d y r e gi m e n d os e u ntil Gr a d e 2  
uti o n t o Gr a d e ≤1.  
icit y i m pr o v es t o Gr a d e ≤1 or b as eli n e a n d 
t h er e w er e  
 el e v ati o ns i n bilir u bi n, r es u m e st u d y 
g/st u d y  
− 
F or Gr a de 2  
R e g ul ar a n d fr e q u e nt c h ec ki n g of 
L F Ts ( e. g., e v er y 1 t o 2 d a ys) u ntil 
L F T el e v ati o ns i m pr o v e or 
r es ol v e. 
 
I nfli xi m a b s h o ul d n ot  
re gi me n aft er c o m pleti o n of ster oi d ta per ( < 1 0 m g   −  
If n o res ol uti o n t o Gra d e 
≤1 i n 1 t o 2 da ys, pre d nis o ne or e q ui vale nt).  c o nsi der disc ussi n g wit h Cli nical St u d y  
 
be use d f or  
Lea d, as n ee de d.  
 
Per ma ne ntl y disc o nti n ue st u d y dr u g/st u d y re gi me n f or a n y  
m a n a ge m e nt of  
− If e v e nt is persiste nt ( > 2 t o 3 da ys) or cas e meeti n g H y’s la w criteri a ( A S T a n d/ or A L T > 3 × w orse ns, 
pr o m ptl y start pre d nis o ne 1 t o i m m u ne-rel ate d  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
93 (147) 
ULN + bilirubin >2 × ULN without initial findings of  
2 mg/kg/day PO or IV 
equivalent. hepatitis. 
cholestasis (i.e., elevatedALP) and in the absence 
of any alternative cause. 
 
1.2.1. Grade 3 or 4 For Grade 3 
• Hold study drug/study regimen For 
elevations in transaminases ≤8 × ULN 
(and no elevations in bilirubin), or 
elevations in bilirubin ≤5 × ULN until 
resolution to  
completion of steroid taper (<10 mg 
prednisone, or equivalent). 
• If in combination with tremelimumab, do 
not restart tremelimumab. 
Permanently discontinue study drug/study 
regimen for elevations in transaminases >8 × 
ULN or any elevations in bilirubin >5 × ULN 
1.2.2. 
For Grade 4 
Permanently discontinue study drug/study 
regimen. 
1.2.3. 
For Grade 3 or 4 
− Promptly initiate empiric IV 
methylprednisolone at 1 to 2 
mg/kg/day or equivalent. 
PLEASE SEE  
shaded area 
immediately 
below this 
section to find 
guidance for 
management 
of 
“Hepatitis 
(elevated 
LFTS)” in 
hepatocellular 
carcinoma 
(HCC) 
patients 


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
94 (147) 
− If still no improvement within 2 
to 3 days despite 1 to 2 
mg/kg/day methylprednisolone 
IV or equivalent, promptly start 
treatment with an additional 
immunosuppressant.(e.g., 
mycophenolate mofetil 0.5 – 1 g 
every 12 hours then taper in 
consultation with hepatology 
consult or relevant practice 
guidelines). Discuss with Clinical 
Study Lead if mycophenolate is 
not available.  
Infliximab should NOT be used. 
− Perform 
Hepatology 
Consult, 
abdominal workup, and imaging 
as appropriate. 
 


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
95 (147) 
Hepatitis  
(elevated LFTs) 
Infliximab should 
not be used for  
management of  
THIS shaded 
area is 
guidance only 
for 
management 
of  
“Hepatitis 
(elevated 
LFTs)” in 
HCC patients 
immune-related 
hepatitis. 
See instructions 
at bottom of 
shaded area if 
transaminase rise 
is  
not isolated but 
(at any time) 
Any Elevations 
of  
AST, ALT, or 
T. Bili as 
Described 
Below 
General Guidance 
− 
− 
− 
− 
− 
− 
− 
For Any Elevations Described 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., viral 
hepatitis, disease progression, 
concomitant medications, 
worsening of liver cirrhosis [e.g., 
portal vein thrombosis]). 
Monitor and evaluate liver 
function test: AST, ALT, ALP, and 
T. Bili. 
For hepatitis B (HBV) + patients: 
evaluate quantitative HBV viral 
load, quantitative Hepatitis B 
surface antigen (HBsAg), or 
Hepatitis B envelope antigen 
(HBeAg). 
For hepatitis C (HCV) + patients: 
evaluate quantitative HCV viral 
load. 
Consider consulting Hepatology 
or Infectious Diseases specialists 
regarding changing or starting 
antiviral HBV medications if HBV 
viral load is >2000 IU/ml. 
Consider consulting Hepatology 
or Infectious Diseases specialists 
regarding changing or starting 
antiviral HCV medications if HCV 
viral load has increased by ≥2-


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
96 (147) 
occurs in setting 
of either 
increasing  
bilirubin or signs 
of  
DILI/liver 
decompensation 
fold. 
For HCV+ with Hepatitis B core 
antibody (HBcAb) +: Evaluate for 
both HBV and HCV as above. 


C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
9 7  (1 4 7 ) 
Is ol at e d A S T or 
AL T  
> UL N a n d  
≤5. 0 × UL N, 
w h et h er n or m al 
or el e v at e d at  
b as eli n e  
 
 
 
N o d os e m o dific ati o ns.  
If AL T/ A S T el e v ati o ns r e pr es e nts si g nific a nt 
w ors e ni n g b as e d o n i n v esti g at or 
ass ess m e nt, t h e n tr e at as  d escri b e d f or 
el e v ati o ns i n t h e r o w b el o w.  
F or all  tr a ns a mi n as e el ev ati o ns , s e e 
i nstr ucti o ns at b ott o m of s h a d e d ar e a if 
tr a ns a mi n as e ris e is n ot is ol at e d b ut ( at a n y 
ti m e) occ urs i n s etti n g of eit h er i ncre asi n g 
bilir u bi n or si g ns of DI LI/li ver 
dec o m pe ns ati o n  
 
 
 


C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
9 8  (1 4 7 ) 
Is ol at e d A S T or AL T  
> 5. 0 × UL N a n d  
≤8. 0 × UL N, if 
n or m al at 
b as eli n e  
Is ol at e d A S T or AL T  
> 2. 0 × b as eli n e a n d  
≤1 2. 5 × UL N, if 
el e v at e d > UL N at 
b as eli n e  
 
 
 
H ol d st u d y dr u g/st u d y r e gi m e n d os e u ntil  
r es ol uti o n t o A S T or AL T ≤5. 0 × UL N . 
If t oxicit y w ors e ns, t h e n tr e at as  d escri b e d 
f or el e v ati o ns i n t h e r o ws b el o w.If t oxicit y 
i m pr o v es t o  A S T or AL T ≤5. 0 × UL N , r es u m e 
st u d y dr u g/st u d y r e gi m e n aft er c o m pl eti o n 
of st er oi d t a p er ( < 1 0 m g pr e d nis o n e, or 
e q ui v al e nt).  
P er m a n e ntl y disc o nti n u e st u d y dr u g/st u d y  
r e gi m e n f or a n y c as e m e eti n g Hy’s l a w crit eri a, 
i n t h e a bs e nc e of a n y alt er n ati v e c a us e.b 
− 
− 
− 
− 
R e g ul ar a n d fr e q u e nt c h ec ki n g of 
L F Ts ( e. g., e v er y 1 t o 3 d a ys) u ntil 
el e v ati o ns of t h es e ar e i m pr o vi n g 
or r es ol v e d.  
R ec o m m e n d c o ns ult 
h e p at ol o gist; c o nsi d er  a b d o mi n al 
ultr as o u n d, i ncl u di n g D o p pl er 
ass ess m e nt of li v er p erf usi o n.  
C o nsi d er, as n ec ess ar y, disc ussi n g 
wit h Cli nic al St u d y L e a d.  
If e v e nt is p ersist e nt ( > 2 t o 3 
d a ys) or w ors e ns, a n d 
i n v esti g at or s us p ects t oxicit y t o 
b e a n i m A E, st art pr e d nis o n e 1 t o 
2 m g/ k g/ d a y P O or I V e q ui v al e nt.  
If still n o i m pr o v e m e nt wit hi n 2 
t o 3 d a ys d es pit e 1 t o 2 
m g/ k g/ d a y of pr e d nis o n e P O or 
I V e q ui v al e nt, c o nsi d er a d diti o n al 
w or k u p. If still n o i m pr o v e m e nt 
wit hi n 2 t o  
3 d a ys d es pit e 2 m g/ k g/ d a y of I V 
m et h yl p r e d nis ol o n e, c o nsi d er 
a d diti o n al a b d o mi n al w or k u p 
(i ncl u di n g li v er bi o ps y) a n d 
i m a gi n g (i. e., li v er ultr as o u n d), 
a n d c o nsi d er st arti n g a d diti o n al  
i m m u n os u p pr ess a nts. ( e. g., 
m yc o p h e n ol at e m of etil 0. 5 – 1 g 
e v er y 1 2 h o urs t h e n t a p er i n 


C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
9 9  (1 4 7 ) 
c o ns ult ati o n wit h h e pat ol o g y 
c o ns ult or r el e v a nt pr actic e 
g ui d eli n es). Disc uss Cli nic al St u d y 
L e a d if m yc o p h e n ol at e m of etil is 
n ot a v ail a bl e. I nfli xi m a b s h o ul d 
N O T be use d.  
 
Is ol at e d A S T or 
AL T  
> 8. 0 × UL N a n d  
≤2 0. 0 × UL N, if 
n or m al at 
b as eli n e  
 
 
H ol d st u d y dr u g/st u d y r e gi m e n d os e u ntil 
r es ol uti o n t o   
A S T or AL T ≤5. 0 × UL N R es u m e st u d y 
dr u g/st u d y r e gi m e n if el e v ati o ns d o w n gr a d e 
t o  A S T or AL T ≤5. 0 × UL N  a n d aft er 
c o m pl eti o n of st er oi d t a p er ( < 1 0 m g 
pr e d nis o n e, or e q ui v al e nt).  
P er m a n e ntl y disc o nti n u e st u d y dr u g/st u d y 
− 
− 
− 
− 
R e g ul ar a n d fr e q u e nt c h ec ki n g of 
L F Ts ( e. g., e v er y 1-2 d a ys) u ntil 
el e v ati o ns of t h es e ar e i m pr o vi n g 
or r es ol v e d.  
C o ns ult h e p at ol o gist ( u nl ess 
i n v esti g at or is h e p at ol o gist); 
o bt ai n a b d o mi n al ultr as o u n d, 
i ncl u di n g D o p pl er ass ess m e nt of 
li v er p erf usi o n; a n d c o nsi d er li v er 


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
100 (147) 
Isolated AST or 
ALT  
>12.5×ULN and  
≤20.0×ULN, if   
regimen if the elevations do not downgrade to  
AST or ALT ≤5.0×ULN within 14 days 
biopsy. 
Consider discussing with Clinical 
Study Lead, as needed. 
If investigator suspects toxicity to 
be immune-mediated, promptly 
initiate empiric  
 
elevated >ULN at  
IV methylprednisolone at 1 to 2 
mg/kg/day or equivalent. 
baseline 
− If no improvement within 2 to 3 
days despite 1 to 2 mg/kg/day 
methylprednisolone 
IV 
or 
equivalent, obtain liver biopsy (if 
it has not been done already) and 
promptly start treatment with an 
additional immunosuppressant. 
(e.g.,., mycophenolate mofetil 
0.5 – 1 g every 12 hours then 
taper in consultation with a 
hepatologist or relevant practice 
guidelines). Discuss with Stucy 
Clinical Lead if mycophenolate is 
not available. Infliximab should 
NOT be used. 


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
101 (147) 
 
Isolated AST or ALT Permanently discontinue study drug/study regimen. 
>20×ULN,  whether  
Same as above  
normal or elevated at  
(except recommend obtaining liver biopsy early) 
baseline 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if 
normal at baseline; or 2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase rise 
- 
For example, manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if 
normal at baseline, or AST or ALT  
>2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., 
AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if  
elevated >ULN at baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
Nephritis or 
renal 
dysfunctio
n 
(elevated 
serum 
creatinine) 
Any Grade 
(Refer to NCI CTCAE 
applicable version in study 
protocol for  
defining the CTCAE grade/severity) 
General Guidance 
− 
− 
− 
For Any Grade 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, infections, recent IV 
contrast, medications, fluid 
status). 
Consult a nephrologist. 
Monitor for signs and symptoms 
that may be related to changes in 
renal function (e.g., routine 
urinalysis, elevated serum BUN 
and  


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
102 (147) 
 
 
creatinine, decreased creatinine 
clearance, electrolyte imbalance, 
decreased urine output, or 
proteinuria). 
Grade 1 
− Consider using steroids in the 
absence of a clear alternative 
etiology even for low-grade 
events (Grade 2), in order to 
prevent potential progression to 
higher grade events. 
No dose modifications. 
For Grade 1 
− Monitor serum creatinine weekly 
and any accompanying 
symptoms. 
• 
If creatinine returns to 
baseline, 
resume 
its 
regular monitoring per 
study protocol. 
• 
If creatinine worsens, 
depending 
on 
the 
severity, treat as Grade 2, 
3, or 4. 
Grade 2 
− Consider symptomatic 
treatment, including hydration, 
electrolyte replacement, and 


C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
1 0 3  (1 4 7 ) 
di ur etics.  
H ol d st u d y dr u g/st u d y r e gi m e n u ntil r es ol uti o n t o 
Gr a d e ≤1 or b as eli n e.  
 If t oxicit y i m pr o v es t o Gr a d e ≤1 or b as eli n e, 
t h e n r es u m e st u d y dr u g/st u d y r e gi m e n aft er 
c o m pl eti o n of st er oi d t a p er ( < 1 0 m g 
pr e d nis o n e, or e q ui v al e nt).  
− 
− 
F or Gr a de 2  
C o nsi d er s y m pt o m atic 
tr e at m e nt, i ncl u di n g h y dr ati o n, 
el ectr ol yt e r e pl ac e m e nt, a n d 
di ur etics.  
C ar ef ull y m o nit or s er u m 
cr e ati ni n e e v er y 2 t o 3 d a ys a n d 
as cli nic all y w arr a nt e d.  
 
 
− C o ns ult n e p hr ol o gist a n d 
c o nsi d er r e n al bi o ps y if cli nic all y 
i n dic at e d. 
 
 
− If e v e nt is p ersist e nt b e y o n d 3 t o 
5 d a ys or w ors e ns, pr o m ptl y st art 
pr e d nis o n e 1 t o 2 m g/ k g/ d a y P O 
or I V e q ui v al e nt.  
Gr a de 3 or 4  
 
− If e v e nt is n ot r es p o nsi v e wit hi n 
3 t o 5 d a ys or w ors e ns d es pit e 
pr e d nis o n e at 1 t o 2 m g/k g/ d a y 
P O or I V e q ui v al e nt, c o nsi d er 
a d diti o n al w or k u p. W h e n e v e nt 
r et ur ns t o b as eli n e, r es u m e 
st u d y dr u g/st u d y r e gi m e n a n d 
r o uti n e s er u m cr e ati ni n e 
m o nit ori n g p er st u d y pr ot oc ol.  
P er m a n e ntl y disc o nti n u e st u d y dr u g/st u d y 
 
F or Gr a de 3 or 4  


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
104 (147) 
regimen. 
 
− Carefully monitor serum 
creatinine daily. 
− Consult nephrologist and 
consider renal biopsy if clinically 
indicated. 
− Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− If event is not responsive within 
3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, consider 
additional workup and prompt 
treatment with an 
immunosuppressant in 
consultation with a nephrologist. 
Rash or 
Dermatitis 
(Including 
Pemphigoid) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in  
study protocol 
for definition 
of  
severity/grade  
General Guidance 
− 
− 
− 
For Any Grade 
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology. 
Monitor for signs and symptoms 
of dermatitis (rash and pruritus). 
HOLD STUDY DRUG IF 
STEVENSJOHNSON 
SYNDROME (SJS), TOXIC  
EPIDERMAL 
NECROLYSIS 
(TEN),  OR  


C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
1 0 5  (1 4 7 ) 
d e p e n di n g o n 
t y p e of s ki n 
r as h) 
O T H E R  
  
S E V E R E 
C U T A N E O U S  A D V E R S E 
R E A C TI O N  ( S C A R)  I S 
S U S P E C T E D.  
 
 
 
− P E R M A N E N T L Y 
DI S C O N TI N U E  
S T U D Y 
D R U G  I F 
S J S,  T E N,  O R 
S C A R I S C O N FI R M E D.  
Gr a de 1  
N o d os e m o dific ati o ns.  
 
F or Gr a de 1  
 
 
 
− C o nsi d er s y m pt o m atic 
tr e at m e nt, i ncl u di n g or al 
a nti pr uritics ( e. g., 
di p h e n h y dr a mi n e or 
h y dr oxyzi n e) a n d t o pic al 
t h er a p y ( e. g., e m oli e nt, l oti o n, 
or i nstit uti o n al st a n d ar d). 
Gr a de 2  
F or p ersist e nt ( > 1 w e e k) Gr a d e 2 e v e nts, h ol d 
sc h e d ul e d st u d y dr u g/st u d y r e gi m e n u ntil 
r es ol uti o n t o Gr a d e ≤1 or b as eli n e. 
 If t oxicit y i m pr o v es t o Gr a d e ≤1 or b as eli n e, 
t h e n r es u m e dr u g/st u d y r e gi m e n aft er 
c o m pl eti o n of st er oi d t a p er ( < 1 0 m g 
− 
− 
F or Gr a de 2  
O bt ai n d er m at ol o g y c o ns ult.  
C o nsi d er s y m pt o m atic tr e at m e nt, 
i ncl u di n g or al a nti pr uritics ( e. g., 
di p h e n h y dr a mi n e or 
h y dr oxyzi n e) a n d t o pic al t h er a p y  


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
106 (147) 
prednisone, or equivalent). 
− Consider moderate-strength 
topical steroid. 
 
− If no improvement of rash/skin 
lesions occurs within 3 days or is 
worsening despite symptomatic 
treatment and/or use of 
moderate strength topical 
steroid, consider discussing with 
Clinical Study Lead, as needed, 
and promptly start systemic 
steroids such as prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− Consider skin biopsy if the event 
persists for >1 week or recurs. 


C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
1 0 7  (1 4 7 ) 
Gr a de 3 or 4  
 
 
F or Gr a de 3  
H ol d st u d y dr u g/st u d y r e gi m e n u ntil 
r es ol uti o n t o Gr a d e ≤1 or b as eli n e. 
If t oxicit y i m pr o v es t o Gr a d e ≤1 or b as eli n e, 
t h e n r es u m e dr u g/st u d y r e gi m e n aft er 
c o m pl eti o n of st er oi d t a p er ( < 1 0 m g 
pr e d nis o n e, or e q ui v al e nt).  
   
F or Gr a de 4  
P er m a n e ntl y disc o nti n u e st u d y dr u g/st u d y 
r e gi m e n. 
− 
− 
− 
− 
− 
F or Gr a de 3 or 4 
C o ns ult d er m at ol o g y.  
Pr o m ptl y i niti at e e m piric I V 
m et h yl pr e d nis ol o n e 1 t o 2 
m g/ k g/ d a y or e q ui v al e nt.  
C o nsi d er h os pit aliz ati o n.  
M o nit or ext e nt of r as h [ R ul e of 
Ni n es].  
C o nsi d er s ki n bi o ps y ( pr ef er a bl y 
m or e t h a n 1) as cli nic all y 
f e asi bl e. C o nsi d er, as n ec ess ar y, 
disc ussi n g wit h Cli nic al St u d y 
L e a d. 
E n d ocri n o p at h y  
( e. g., 
h y p ert h yr oi dis m,  
t h yr oi ditis,  
h y p ot h yr oi dis m,  
t y p e 1 di a b et es 
m ellit us, 
h y p o p h ysitis,  
h y p o pit uit aris m, 
a n d a dr e n al 
i ns uffici e ncy) 
A n y Gr a de  
( D e p e n di n g o n 
t h e t y p e of  
e n d ocri n o p at h y, 
r ef er  t o  N CI  
C T C A E  
a p plic a bl e v ersi o n 
i n st u d y pr ot oc ol 
f or  
d efi ni n g t h e C T C A E 
gr a d e/s e v erit y)  
Ge ner al G ui d a nce  
− 
− 
− 
− 
F or A n y Gr a de  
P ati e nts s h o ul d b e t h or o u g hl y 
e v al u at e d t o r ul e o ut a n y 
alt er n ati v e eti ol o g y ( e. g., dis e as e 
pr o gr essi o n i ncl u di n g br ai n 
m et ast as es, or i nf ecti o ns).  
C o nsi d er c o ns ulti n g a n 
e n d ocri n ol o gist f or e n d ocri n e 
e v e nts.  
C o nsi d er disc ussi n g wit h Cli nic al 
St u d y L e a d, as n e e d e d.  
M o nit or p ati e nts f or si g ns a n d 
s y m pt o ms of e n d ocri n o p at hi es. 
( N o n-s p ecific s y m pt o ms i ncl u d e 


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
108 (147) 
headache, fatigue, behaviour 
changes, mental status changes, 
photophobia, visual field cuts, 
vertigo, abdominal pain, unusual 
bowel habits,  
 
polydipsia, polyuria, hypotension, 
and weakness.) 
− Depending on the suspected 
endocrinopathy, monitor and 
evaluate thyroid function tests: 
thyroid stimulating hormone 
(TSH), free T3 and free T4 and 
other relevant endocrine and 
related labs (e.g., blood glucose 
and ketone levels, hemoglobin 
A1c (HgA1c)).If a patient 
experiences an AE that is thought 
to be possibly of autoimmune 
nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, or 
diabetes insipidus), the 


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
109 (147) 
investigator should send a blood 
sample for appropriate 
autoimmune antibody testing. 
Grade 1 
− Investigators should ask subjects 
with endocrinopathies who may 
require prolonged or continued 
hormonal replacement, to 
consult their primary care 
physicians or endocrinologists 
about further monitoring and 
treatment after completion of 
the study. 
No dose modifications. 
For Grade 1 
− Monitor patient with appropriate 
endocrine function tests. 
− For suspected 
hypophysitis/hypopituitarism, 
consider consulting an 
endocrinologist to guide 
assessment of early-morning 
adrenocorticotropin hormone 
(ACTH), cortisol, TSH and free T4; 
also consider gonadotropins, sex 


C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
1 1 0  (1 4 7 ) 
h or m o n es, a n d pr ol acti n l e v els, 
as w ell as c os y ntr o pi n sti m ul ati o n 
t est (t h o u g h it m a y n ot b e us ef ul 
i n di a g n osi n g e arl y s ec o n d ar y 
a dr e n al i ns uffici e ncy).  
Gr a de 2, 3, or 4  
 
− If T S H < 0. 5 × LL N, or T S H > 2 × 
UL N, or c o nsist e ntl y o ut of r a n g e 
i n 2 s u bs e q u e nt m e as ur e m e nts, 
i ncl u d e fr e e T 4 at s u bs e q u e nt 
cycl es as cli nic all y i n dic at e d a n d 
c o nsi d er c o ns ult ati o n of a n 
e n d ocri n ol o gist.  
 F or Gr a d e 2 -4  e n d ocri n o p at hi es ot h er t h a n  
h y p ot h yr oi dis m a n d t y p e 1 di a b et es m ellit us  
( T 1 D M),  
− 
F or Gr a de 2, 3, or 4  
C o ns ult e n d ocri n ol o gist t o g ui d e 
e v al u ati o n of e n d ocri n e f u ncti o n 
a n d, as i n dic at e d b y  
c o nsi der h ol di n g st u d y dr u g/st u d y re gi me n d ose u ntil ac ute s y m pt o ms res ol ve. 
• 
St u d y dr u g/st u d y re gi me n ca n be res u me d o nce p atie nt sta bilizes a n d aft er c o m pleti o n 
of ster oi d ta per ( < 1 0 m g pre d nis o ne, or e q ui vale nt). 
• 
Patie nts wit h e n d ocri n o pat hies w h o ma y re q uire pr ol o n ge d or c o nti n ue d ster oi d 
re place me nt (e. g., a dre n al i ns ufficie nc y) ca n be retreate d wit h st u d y dr u g/st u d y re gi me n 
if t he patie nt is cli nicall y sta ble as per i n vesti gat or or treati n g p h ysicia n’s cli nical 
j u d ge me nt. 
s us pecte d e n d o cri n o pat h y a n d 
as cli nicall y i n dicate d, c o nsi der 
pit uitar y sca n. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
111 (147) 
− For all patients with abnormal 
endocrine work up, except those 
with isolated hypothyroidism or 
T1DM, and as guided by an  
endocrinologist, consider short-
term corticosteroids (e.g., 1 to 2 
mg/kg/day methylprednisolone 
or IV equivalent) and prompt 
initiation of treatment with 
relevant hormone replacement. 
− Isolated hypothyroidism may be 
treated with replacement 
therapy, without study 
drug/study regimen interruption, 
and without corticosteroids. 
− Isolated T1DM may be treated 
with appropriate diabetic 
therapy, and without 
corticosteroids. Only hold study 
drug/study regimen in setting 
of hyperglycemia when 
diagnostic workup is positive 
for diabetic ketoacidosis.  
− For patients with normal 
endocrine workup (laboratory 
assessment or magnetic 
resonance imaging (MRI) scans), 
repeat laboratory 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
112 (147) 
assessments/MRI as clinically 
indicated. 
Amylase/Lipase 
increased 
Any Grade 
(Refer to NCI 
CTCAE  
General Guidance
applicable 
version in 
study protocol 
for  
defining the 
CTCAE 
grade/severit
y) 
 
1.2.4. 
For 
Any Grade 
− Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g. disease 
progression, viral infection, 
concomitant medications, 
substance abuse). 
− For modest asymptomatic 
elevations in serum amylase and 
Grade 1
No dose


 
CONFIDENTIAL 
AND 
PROPRIETARY 
TMGs, Version 28 
October 2021 113 (
147) 
lipase, corticosteroid treatment is 
not indicated as long as there are 
no other signs or symptoms of 
pancreatic inflammation.  
− Assess for signs/symptoms of 
pancreatitis  
− Consider appropriate diagnostic 
testing (e.g., abdominal CT with 
contrast, MRCP if clinical 
suspicion of pancreatitis and no 
radiologic evidence on CT) 
1.2.5. Grade 2, 3, or 4 
For Grade 2, 3, or 4 
In consultation with relevant pancreatic specialist consider continuing study drug/study 
regimen if no clinical/radiologic evidence of pancreatitis ± improvement in 
amylase/lipase. 
 
− If isolated elevation of enzymes 
without evidence of pancreatitis, 
continue immunotherapy.  
Consider other causes of 
elevated amylase/lipase 
− If evidence of pancreatitis, 
manage according to pancreatitis 
recommendations  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
114 (147) 
Acute 
Pancreatitis 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for  
defining the 
CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− Patients should be 
thoroughly evaluated to 
rule out any alternative 
etiology. 
− Consider Gastroenterology 
referral  
Grade 2, 3, or 
4 
For Grade 2 or 3 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
If toxicity improves to Grade <1 or baseline, then 
resume study drug/study regimen after completion 
of steroid taper (<10 mg prednisone, or equivalent). 
For Grade 4 
Permanently discontinue study drug/study regimen. 
− 
− 
For Grade 2, 3, or 4 
Promptly start systemic 
steroids prednisone 1 to 2 
mg/kg/day PO or IV 
equivalent. 
IV hydration 
Neurotoxicity 
(to include but 
not limited to non-
infectious 
meningitis, non- 
infectious 
encephalitis, 
Any Grade 
(Depending on 
the type of 
neurotoxicity, 
refer to NCI 
CTCAE applicable 
version in study 
General Guidance 
− 
− 
− 
For Any Grade 
Patients should be evaluated to 
rule out any alternative etiology 
(e.g., disease progression, 
infections, metabolic syndromes, 
or medications). 
Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
115 (147) 
and autonomic  
neuropathy, 
excluding  
Myasthenia Gravis 
and  
Guillain-Barre) 
protocol for  
defining the 
CTCAE 
grade/severity) 
weakness). 
Consider appropriate diagnostic 
testing (e.g., electromyogram 
and nerve conduction 
investigations). 
− Perform symptomatic treatment 
with neurological consult as 
appropriate. 
 
Grade 1 
− FOR TRANSVERSE 
MYELITIS, PERMANENTLY 
DISCONTINUE FOR ANY 
GRADE. 
No dose modifications. 
For Grade 1 
Grade 2 
Grade 3 or 
− See “Any Grade” 
recommendations above. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
116 (147) 
4 
• 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade ≤1. 
• 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study regimen 
dose until resolution to Grade ≤1. 
• 
Permanently discontinue study drug/study 
regimen if Grade 2 imAE does not resolve to 
Grade ≤1 within 30 days. 
− 
− 
− 
− 
− 
For Grade 2 
Consider, as necessary, discussing 
with the Clinical Study Lead. 
Obtain neurology consult. 
Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine). 
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
If no improvement within 2 to 3 
days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, 
consider additional workup and 
promptly treat with an additional 
immunosuppressant (e.g., IV IG 
or other immunosuppressant 
depending on the specific imAE). 
For Grade 3 or 4 
Permanently discontinue study drug/study regimen. − 
For Grade 3 or 4 
Consider, as necessary, discussing 
with Clinical Study Lead. 
− Obtain neurology consult. 
− Consider hospitalization. 
− Promptly initiate empiric IV 
methylprednisolone 1 to 2 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
117 (147) 
mg/kg/day or equivalent. 
− If no improvement within 2 to 3 
days despite IV corticosteroids, 
consider additional workup and 
promptly treat with an additional 
immunosuppressant (e.g., IV IG 
or other immunosuppressant 
depending on the specific imAE). 
 
Peripheral 
neuromotor 
syndromes 
(such as Guillain-
Barre and 
myasthenia gravis) 
− 
Any Grade 
(Refer to NCI CTCAE 
applicable version 
in study protocol 
for  
defining the CTCAE 
grade/severity) 
General Guidance 
− 
For Any Grade 
Patients should be evaluated to 
rule out any alternative etiology 
(e.g., disease progression, 
infections, metabolic syndromes 
or medications). It should be 
noted that the diagnosis of 
immune-mediated peripheral 
neuromotor syndromes can be 
particularly challenging in 
patients with underlying cancer, 
due to the multiple potential 
confounding effects of cancer 
(and its treatments) throughout 
the neuraxis. Given the 
importance of prompt and 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
118 (147) 
accurate diagnosis, it is essential 
to have a low threshold to obtain 
a neurological consult. 
− The prompt diagnosis of 
immune-mediated peripheral 
neuromotor syndromes is 
important, since certain patients 
may unpredictably experience 
acute decompensations that can 
result in substantial morbidity or 
in the worst case, death. Special 
care should be taken for certain 
sentinel symptoms that may 
predict a more severe outcome, 
such as prominent dysphagia, 
rapidly progressive weakness, 
and signs of respiratory 
insufficiency or autonomic 
instability. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
119 (147) 
− Neurophysiologic diagnostic 
testing  
(e.g., electromyogram and nerve 
conduction investigations, and 
“repetitive stimulation” if 
myasthenia is suspected) are 
routinely indicated upon 
suspicion of such conditions and 
may be best facilitated by means 
of a neurology consultation. 
− It is important to consider that 
the use of steroids as the 
primary treatment of Guillain-
Barre is not typically 
considered effective. Patients 
requiring treatment should be 
started with IV IG and followed 
by plasmapheresis if not 
responsive to IV IG. 
 Grade 1 
No dose modifications. 
For Grade 1 
− Consider discussing with the 
Clinical Study Lead, as needed. 
− Care should be taken to monitor 
patients for sentinel symptoms 
of a potential decompensation as 
described above. 
 
−Consult a neurologist. 
 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently 
discontinue 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
120 (147) 
study drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or if 
there are signs of respiratory insufficiency or 
autonomic instability. 
1.2.6. For Grade 2 
− Consult a neurologist. 
− Consider discussing with the 
Clinical Study Lead, as needed. 
− Care should be taken to monitor 
patients for sentinel symptoms of 
a potential decompensation as 
described above. 
− Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IV IG. Such decisions are best made in consultation 
with a neurologist, taking into account the unique 
needs of each patient. 
o 
If myasthenia gravis-
like  
neurotoxicity is present, 
consider starting AChE 
inhibitor therapy in 
addition to steroids. Such 
therapy, Grade 3 or 4
 
For Grade 3 or 4 
Permanently discontinue study 
drug/study regimen. 
if successful, can 
also serve to 
reinforce the 
diagnosis. 
o 
Avoid medications that 
can worsen myasthenia 
gravis (e.g. some 
antibiotics, beta 
blockers, calcium 
channel blockers, 
muscle relaxants). 
GUILLAIN-BARRE: 
o 
It is important to 
consider here that the 
use of steroids as the 
primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
121 (147) 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
1.2.7. 
For Grade 3 or 4  
− Consider discussing with Clinical Study Lead, as needed. 
−Recommend hospitalization. 
− Monitor symptoms and consult a neurologist. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. 
o 
If myasthenia gravis-like  
neurotoxicity 
present, consider 
starting AChE 
inhibitor therapy in 
addition to 
steroids. Such 
therapy, if 
successful, can also 
serve to reinforce 
the diagnosis. 
o 
Avoid medications 
that can worsen 
myasthenia gravis  
(e.g. some antibiotics, 
beta blockers, calcium 
channel blockers, 
muscle relaxants). 
GUILLAIN-BARRE: 
o 
It is important to 
consider here that the 
use of steroids as the 
primary treatment of 
Guillain-Barre is not 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
122 (147) 
typically considered 
effective. 
o 
Patients requiring 
treatment should be 
started with IV IG and 
followed by 
plasmapheresis if not 
responsive to IV IG. 
 
1.2.8. Myocarditis 
Any Grade General Guidance 
(Refer to NCI CTCAE  
Discontinue drug permanently if 
biopsy-proven immuneapplicable version in  
mediated 
myocarditis. 
study protocol for  
defining the CTCAE  
grade/severity) 
1.2.9. 
For Any Grade 
− Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, other medications, 
or infections) 
− The prompt diagnosis of 
immune-mediated myocarditis is 
important, particularly in patients 
with baseline cardiopulmonary 
disease and reduced cardiac 
function.  


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
123 (147) 
− Consider discussing with the 
Clinical Study Lead, as needed. 
− Monitor patients for signs and 
symptoms of myocarditis (new 
onset or worsening chest pain, 
arrhythmia, shortness of breath, 
peripheral edema). As some 
symptoms can overlap with lung 
toxicities, simultaneously 
evaluate for and rule out 
pulmonary toxicity as well as 
other causes (e.g., pulmonary 
embolism, congestive heart 
failure, malignant pericardial 
effusion). Consult a cardiologist 
early, to promptly assess 
whether and when to complete a 
cardiac biopsy, including any 
other diagnostic procedures. 
− Initial work-up should include 
clinical 
evaluation, 
B-type 
natriuretic peptide (BNP),  
cardiac enzymes, 
electrocardiogram (ECG), 
echocardiogram (ECHO), 
monitoring of oxygenation via 
pulse oximetry (resting and 
exertion), and additional 
laboratory work-up as indicated. 


C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
1 2 4  (1 4 7 ) 
S pir al C T or c ar di ac M RI c a n 
c o m pl e m e nt E C H O t o ass ess w all 
m oti o n a b n or m aliti es w h e n 
n e e d e d.  
 
Gr a de 2, 3 or 4   
If Gr a d e 2-4, p er m a n e ntly disc o nti n u e st u d y 
dr u g/st u d y r e gi m e n.  
− 
F or Gr a de 2 -4  
M o nit or s y m pt o ms d ail y, 
h os pit aliz e.  
 
 
− Pr o m ptl y st art I V 
m et h yl pr e d nis ol o n e 2 t o 4 
m g/ k g/ d a y or e q ui v al e nt aft er 
C ar di ol o g y c o ns ult ati o n h as 
d et er mi n e d w h et h er a n d w h e n 
t o c o m pl et e di a g n ostic 
pr oc e d ur es i ncl u di n g a c ar di ac 
bi o ps y.  
 
 
− S u p p orti v e c ar e ( e. g., oxy g e n).  
 
 
− If n o i m pr o v e m e nt wit hi n 2 t o 3 
d a ys d es pit e I V 
m et h yl pr e d nis ol o n e at 2 t o 4 
m g/ k g/ d a y, pr o m ptl y st art 
a d diti o n al  
i m m u n os u p pr essi v e t h er a p y s uc h 
as T N F i n hi bit ors ( e. g., i nflixi m a b 
at 5 m g/ k g I V, m a y b e r e p e at e d 
at 2 a n d 6 w e e ks aft er i niti al d os e 
at t h e discr eti o n of t h e tr e ati n g 


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
125 (147) 
1.2.10. Myositis/ Polymyositis Any Grade General Guidance 
(Refer to NCI CTCAE applicable version in study protocol for  
defining the CTCAE grade/severity) 
1.2.11. For Any Grade 
− Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, other medications, 
or infections). 
− Monitor patients for signs and 
symptoms of poly/myositis. 
Typically, muscle weakness/pain 
occurs in proximal muscles 
including upper arms, thighs, 
shoulders, hips, neck and back, 
but rarely affects the extremities 
including hands and fingers; also 
difficulty breathing and/or 
trouble  
swallowing can occur and 
provider or relevant practice 
guidelines). Caution: It is 
important to rule out sepsis and 
refer to infliximab label for 
general guidance before using 
infliximab.  Infliximab is 
contraindicated for patients 
who have heart failure. 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
126 (147) 
progress rapidly. Increased 
general feelings of tiredness and 
fatigue may occur, and there can 
be newonset falling, difficulty 
getting up from a fall, and 
trouble climbing stairs, standing 
up from a seated position, and/or 
reaching up. 
− If poly/myositis is suspected, a 
Neurology consultation should 
be obtained early, with prompt 
guidance on diagnostic 
procedures. Myocarditis may co-
occur with poly/myositis; refer to 
guidance under Myocarditis. 
Given breathing complications, 
refer to guidance under 
Pneumonitis/ILD. Given 
possibility of an existent (but 
previously unknown) 
autoimmune disorder, consider 
Rheumatology consultation. 
− Consider, as necessary, 
discussing with the Clinical 
Study Lead. 
− Initial work-up should include 
clinical evaluation, creatine 
kinase, aldolase, lactate 
dehydrogenase (LDH), blood 
urea nitrogen (BUN)/creatinine, 
erythrocyte sedimentation rate or 
C-reactive protein (CRP) level, 
urine myoglobin, and additional 


 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
1 2 7  (1 4 7 ) 
la b orat or y w or k u p as i n dicate d, 
i ncl u di n g a n u m ber of p ossi ble 
r he u mat ol o gical/a nti b o d y tests 
(i.e., c o nsi der w het her a 
r he u mat ol o gist c o ns ultati o n is 
i n dicate d a n d c o ul d g ui d e nee d 
f or r he u mat oi d fact or, a nti n uclear 
a nti b o d y, a nti-s m o ot h m uscle, 
a ntis y nt hetase [s uc h as a nti- J o-
1], a n d/ or si g nal-rec o g niti o n 
particle a nti b o dies). 
C o nfir mat or y testi n g ma y i ncl u de 
electr o m y o gra p h y, ner v e 
c o n d ucti o n st u dies, M RI of t he 
m uscles, a n d/ or a m uscle bi o ps y. 
C o nsi der Bari u m s wall o w f or 
e val uati o n of d ys p ha gia or 
d ys p h o nia. 
Gr a de 1  
N o d ose m o dificati o ns. 
F or Gr a de 1  
−  M o nit or a n d cl osel y f oll o w u p i n 
2 t o 4 da ys f or cli nical s y m pt o ms 
a n d i nitiate e val uati o n as 
cli nicall y i n dicate d.  
 
−C o nsi der Ne ur ol o g y c o ns ult. 


 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
1 2 8  (1 4 7 ) 
Gr a de 2  H ol d st u d y dr u g/st u d y re gi me n d ose u ntil res ol uti o n t o 
Gra de ≤1. 
 Per ma ne ntl y disc o nti n ue st u d y dr u g/st u d y 
re gi me n if it d oes n ot res ol ve t o Gra de ≤1 wit hi n 
3 0 da ys or if t here are si g ns of res pirat or y 
i ns ufficie nc y. 
− C o nsi d er, as n ec ess ar y, 
disc ussi n g wit h t h e Cli nic al 
St u d y L e a d.  
F or Gr a de 2  
− M o nit or s y m pt o ms d ail y a n d 
c o nsi d er h os pit aliz ati o n. 
− O bt ai n N e ur ol o g y c o ns ult, a n d 
i niti at e e v al u ati o n. 
− C o nsi d er,
 as
 n ec ess ar y,
 
disc ussi n g wit h t h e  


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
129 (147) 
Clinical Study Lead. 
− If clinical course is rapidly 
progressive (particularly if 
difficulty breathing and/or 
trouble swallowing), promptly 
start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids 
along with receiving input from 
Neurology consultant  
− If clinical course is not rapidly 
progressive, start systemic 
steroids (e.g., prednisone 1 to 2 
mg/kg/day PO or IV equivalent); 
if no improvement within 2 to 3 
days, continue additional work 
up and start treatment with IV 
methylprednisolone 2 to 4 
mg/kg/day 
− If 
after 
start 
of 
IV 
methylprednisolone at 2 to  
mg/kg/day 
there 
is 
no 
improvement within  
to 3 days, consider starting 
another immunosuppressive 
therapy such as a TNF inhibitor 
(e.g., infliximab at 5 mg/kg  IV, 
may be repeated at 2 and 6 
weeks after initial dose at the 
discretion of the treating provider 
or relevant practice guidelines). 
Caution: It is important to rule 
out sepsis and refer to 
infliximab label for general 
guidance before using 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
130 (147) 
1.2.12. Grade 3 or 4 For Grade 3 
• 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
• 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 30 
days or if there are signs of respiratory 
insufficiency. 
 
1.2.13. For Grade 
4 
• 
Permanently discontinue study 
drug/study regimen. −
 
Promptly start IV 
methylprednisolone 2 to 4 
mg/kg/day systemic steroids 
along with receiving input from 
Neurology consultant. 
−If after start of IV methylprednisolone at 2 to  
4 mg/kg/day there is no improvement within 2 to 3 
days, consider starting another immunosuppressive 
therapy such as a TNF inhibitor (e.g., infliximab at 
5 mg/kg  IV, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the treating 
provider  or relevant practice guidelines). Caution: 
It is important to rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab. 
− Consider 
whether 
patient 
may require IV IG, plasmapheresis. 
infliximab. 
For Grade 3 or 4  
− Monitor symptoms closely; 
recommend hospitalization. 
− Obtain Neurology consult 
− Consider discussing with the 
Clinical Study Lead, as needed. 


 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
T M Gs, Versi o n 2 8 Oct o ber 2 0 2 1  
1 3 1  (1 4 7 ) 
Gr a de 2  
 
H ol d st u d y dr u g/st u d y 
re gi me n u ntil res ol uti o n t o 
≤Gra de 1 or baseli ne. 
• 
If t o xicit y w orse ns, t he n 
treat as Gra de 3 or Gra de 4. 
Ot her – I m m u ne-Me di ate d Re acti o ns  
S e verit y Gr a de of t he E ve nt  
( Ref er t o N CI C T C A E 
a p plic a ble versi o n i n 
st u d y pr ot oc ol f or 
defi ni n g t he C T C A E 
gr a de/se verit y)  
D ose M o dific ati o ns  
 
T o xicit y M a n a ge me nt  
A n y Gr a de  
N ot e: It is p ossi bl e t h at ev e nts wit h a n 
i nfl a m m at or y or i m m u n e m e di at e d 
m ec h a nis m c o ul d occ ur i n n e arl y all or g a ns, 
s o m e of t h e m ar e n ot n ot e d s p ecific all y i n 
t h es e g ui d eli n es ( e. g. i m m u n e 
t hr o m b ocyt o p e ni a, h a e m ol ytic a n a e mi a, 
u v eitis, v asc ulitis).  
− 
− 
P ati e nts s h o ul d b e t h or o u g hl y e v al u at e d t o 
r ul e o ut a n y alt er n ati v e eti ol o g y ( e. g., 
dis e as e pr o gr essi o n, ot h er m e dic ati o ns, or 
i nf ecti o ns). 
T h e Cli nic al St u d y L e a d m a y b e c o nt act e d f or 
i m m u n e m e di at e d r e acti o ns n ot list e d i n t h e 
“s p ecific i m m u n e m e di at e d r e acti o ns” 
s ecti o n 
 
 
− C o ns ult ati o n wit h r el e v a nt s p eci ali st 
 
 
− Tr e at acc or di n gl y, as p er i nstit uti o n al 
st a n d ar d. 
Gr a de 1  
N o d os e m o dific ati o ns.  
 
M o nit or as cli nic all y i n dic at e d  
 


 
CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
132 (147) 
• 
Study drug/study regimen can be 
resumed once event stabilizes to 
Grade ≤1 after completion of 
steroid taper. 
• 
Consider whether study 
drug/study regimen should be 
permanently discontinued in 
Grade 2 events with high 
likelihood for morbidity and/or 
mortality when they do not 
rapidly improve to Grade <1 
upon treatment with systemic 
steroids and following full taper 
Hold study drug/study regimen  
Grade 4 
Permanently discontinue study drug/study 
regimen  
1.2.14. For Grade 2, 3, or 4 
Treat accordingly, as per institutional standard, 
appropriate clinical practice guidelines, and society 
guidelines. (See page 4). 
Grade 3


Protocol #  
Version Date 
 
  
Page # 1 
 
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 Clinical Study Lead.” 
Infusion-Related Reactions 
Severity Grade of the 
Event  
(Refer to NCI 
CTCAE applicable 
version in study  
protocol for defining the  
CTCAE grade/severity) 
Dose Modifications 
Toxicity Managem
Any Grade 
General Guidance 
For Any Grade 
− Manage per institutional standa
discretion of investigator. 
− Monitor patients for signs and s
infusion-related reactions (e.g., 
shaking chills, flushing and/or it
in heart rate and blood pressure
chest discomfort, or skin rashes
(e.g., generalized urticaria, angi
wheezing, hypotension, or tach
Grade 1 or 2 
For Grade 1 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution of 
the event. 
For Grade 2 
• 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until resolution 
of the event. 
• 
Subsequent infusions may be given at 
50% of the initial infusion rate. 
− 
− 
− 
For Grade 1 or 2
Acetaminophen and/or antihist
administered per institutional s
discretion of the investigator. 
Consider premedication per ins
or study protocol prior to subse
Steroids should not be used for 
premedication of Grade ≤2 infu


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
2 (147) 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue study drug/study 
regimen. 
− 
For Grade 3 or 4
Manage severe infusion-related
institutional standard, appropri
practice guidelines, and society 
Non-Immune-Mediated Reactions 
Severity Grade of the 
Event  
(Refer to NCI 
CTCAE applicable 
version in study  
protocol for defining the  
CTCAE grade/severity) 
Dose Modifications 
Toxicity Managem
Any Grade 
Note: Dose modifications are not required for 
AEs not deemed to be related to study treatment 
(i.e., events due to underlying disease) or for 
laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institut
Grade 1 
No dose modifications. 
Treat accordingly, as per institut
 
baseline. 
Treat accordingly, as per institut
Grade 3 
Hold study drug/study regimen until resolution 
to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline within 14 
days, resume study drug/study regimen 
administration. Otherwise, discontinue study 
drug/study regimen. 
Treat accordingly, as per institut
Grade 4 
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue should 
be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the Sponsor.). 
Treat accordingly, as per institut
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 Clinical Study Lead.” 
1.3. 
List of Abbreviations 
AChE 
Acetylcholinesterase 
ILD 
Interstitial lung disease 
ACTH 
Adrenocorticotropic hormone 
imAE(s) 
Immune-mediated adverse event(
ALT 
Alanine aminotransferase 
INR 
International normalized ratio 


CONFIDENTIAL AND PROPRIETARY 
TMGs, Version 28 October 2021 
3 (147) 
ASCO 
American Society of Clinical Oncology 
IU 
International units 
AST 
Aspartate aminotransferase 
IV 
Intravenous 
(T) Bili 
(Total) Bilirubin 
IVIG 
Intravenous immunoglobulin 
BNP 
B-type natriuretic peptide 
LDH 
Lactate dehydrogenase 
BUN 
Blood urea nitrogen 
LFTs 
Liver function tests 
CRP 
C-reactive protein 
LLN 
Lower limit of normal 
CT 
Computed tomography 
MRCP 
Magnetic resonance 
cholangiopancreatography 
CTCAE 
Common Terminology Criteria for Adverse Events 
MRI 
Magnetic resonance imaging 
CTLA-4 
Cytotoxic T-lymphocyte antigen-4 
NCCN 
National Comprehensive Cancer N
DILI 
Drug-induced liver injury 
NCI 
National Cancer Institute 
ECG 
Electrocardiogram 
PD-L1 
Programmed cell death ligand-1 
ECHO 
Echocardiogram 
PJP 
Pneumocystis jerovicii pneumonia
ESMO 
European Society of Medical Oncology 
PO 
By mouth 
GI 
Gastrointestinal 
SCAR 
Severe cutaenous adverse reactio
HBcAb 
Hepatitis B core antibody 
SITC 
Society for Immunotherapy of Can
HBeAg 
Hepatitis B envelope antigen 
SJS 
Stephen Johnson Syndrome 
HBsAg 
Hepatitis B surface antigen 
T1DM 
Type 1 diabetes mellitus 
HBV 
Hepatitis B virus 
T3 
Triiodothyronine 
HCC 
Hepatocellular cancer 
T4 
Thyroxine 
HCV 
Hepatitis C virus 
TEN 
Toxic Epidermal Necrolysis 
HgA1c 
Hemoglobin A1C 
TMG(s) 
Toxicity management guideline(s)
ICI(s) 
Immune checkpoint inhibitor(s) 
TSH 
Thyroid stimulating hormone 
 
 
ULN 
Upper limit of normal