Clinical trial NCT02904954
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Lung neoplasms Bronchial Neoplasms Carcinoma, bronchogenic Neoplasms Neoplasms by site Respiratory Tract Diseases Respiratory Tract Neoplasms Thoracic Neoplasms
Sponsor: Weill Medical College of Cornell University
Start date: 2016-12-02; Completion date: 2022-10-04
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to find out the effectiveness of the drug durvalumab (MEDI4736) with or without stereotactic body radiation therapy (SBRT) as treatment for stage I (tumors \> 2cm), II, and IIIA non-small cell lung cancer (NSCLC) prior to surgery and one year following surgery.

Detailed description:
This is a randomized open label phase II trial of preoperative anti-PD-L1 antibody durvalumab with or without concurrent non-ablative radiation followed by surgical resection and postoperative monthly maintenance durvalumab for twelve months, following standard of care postoperative therapy.

Arms: arm 1: Durvalumab (MEDI4736) 1.12 g administered pre-operatively every 3 weeks for 2 cycles followed by surgical resection. Durvalumab monotherapy 1.5 g will be given for 12 months post-operatively. arm 2: Durvalumab (MEDI4736) 1.12 g administered pre-operatively every 3 weeks for 2 cycles plus radiotherapy delivered in 3 daily fractions starting concurrently with the first cycle of durvalumab (MEDI4736) followed by surgical resection. Durvalumab monotherapy 1.5 g will be given for 12 months post-operatively.
Interventions: intervention 1: Durvalumab intervention 2: Durvalumab plus SBRT
Intervention descriptions: intervention 1: Intravenously intervention 2: Intravenously plus radiotherapy

Protocol documents:
Prot_SAP_002.pdf: 
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IND Number: 132371 
IRB Protocol Number: 1501015795 
NCT Number: NCT02904954  
 
A randomized phase 2 trial of Durvalumab (MEDI4736) with or without SBRT in clinical stage 
I, II, and IIIA non-small cell lung cancer (NSCLC) 
 
 
Weill Cornell Medical College of Cornell University 
The Sandra and Edward Meyer Cancer Center 
 
New York, NY 
 
Nasser Altorki, M.D. (Thoracic Surgery) 
 
 
 
 
 
 
 
 
 
Version number 1  
January 28, 2015 
Version number 2 
February 29, 2016 
Version number 3 
June 15, 2016 
Version number 4 
October 11, 2016 
Version number 5 
May 24, 2017 
Version number 6 
December 19, 2017 
Version number 7 
March 6, 2018 
 
 
 
 
Version number 8 
October 1, 2018 
                                                    Version number 9 
February 6, 2019 
 
 
 
 
Version number 10 
February 13, 2020 
 
Version number 11 
July 14, 2020 
 
Version number 12 
November 25, 2020 
                                                     Version number 13       November 17, 2021 
 
Version number 14 
March 3, 2022 
 
 
 


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Table of Contents 
Table of Contents ............................................................................................................................. 2 
SCHEMA ......................................................................................................................................... 4 
1.0 OBJECTIVES ............................................................................................................................ 4 
1.1 Primary Objective .................................................................................................................. 4 
1.2 Secondary Objectives ............................................................................................................ 4 
1.3 Exploratory Objective ............................................................................................................ 4 
1.4 Rationale and Hypothesis ...................................................................................................... 4 
1.4.1 Targeting PD-L1 is a safe and promising strategy ............................................................. 5 
1.4.2 Non-ablative doses of radiation will potentiate anti-PD-L1 therapy in PD-L1 +ve and –ve  
tumors .......................................................................................................................................... 5 
1.4.3 Hypothesis .......................................................................................................................... 6 
2.0 BACKGROUND ....................................................................................................................... 6 
2.1 Cancer and immune system function ..................................................................................... 6 
2.2 Durvalumab in Solid Tumors ................................................................................................ 7 
2.2.1 Preclinical overview ........................................................................................................... 7 
    2.2.2 Durvalumab Clinical Review .............................................................................................. 8 
2.2.3  Pharmacokinetics and Product Metabolism ....................................................................... 8 
    2.2.4 Safety .................................................................................................................................. 9 
    2.2.5 Efficacy ............................................................................................................................. 11 
    2.2.6 Targeting the PD1/PD-L1 pathway in NSCLC  ................................................................ 13 
    2.2.7 Radiation and tumor immunity  ........................................................................................ 14 
    2.2.8 Radiation combined with immune checkpoint inhibition ................................................. 15 
3.0 PATIENT SELECTION .......................................................................................................... 16 
    3.1 Inclusion criteria .................................................................................................................. 16 
3.2 Exclusion criteria ................................................................................................................. 17 
4.0 REGISTRATION AND RANDOMIZATION PROCEDURES ............................................. 18 
4.1 Registration .......................................................................................................................... 18 
4.2 Randomization ..................................................................................................................... 19 
5.0 STUDY DESIGN ..................................................................................................................... 19 
     5.1 Treatment Plan .................................................................................................................... 19 
5.2 Limiting normal tissue toxicities with non-ablative SBRT ................................................. 20 
    5.3 Duration of follow-up .......................................................................................................... 20 
5.4 Withdrawal of Subjects from Study Treatment and/or Study .............................................. 20 
    5.4.1 Permanent discontinuation of Durvalumab  ...................................................................... 20 
5.4.2 Withdrawal of consent ...................................................................................................... 21 
5.5 Study Procedures ................................................................................................................. 22 
6.0 DOSE DELAYS/DOSE MODIFICATIONS. ......................................................................... 29 
    6.1 Dose Modification and Toxicity Management . .................................................................. 29 
    6.2 Study restrictions and Concomitant Medications . .............................................................. 29 
6.2.1 Contraception ................................................................................................................... 29 
6.2.2 Blood donation  ................................................................................................................ 31 
6.2.3 Permitted Concomitant Medications ................................................................................ 31 
6.2.4 Excluded Concomitant Medications ................................................................................. 31 
7.0 ASSESSMENT OF SAFETY. ................................................................................................. 32 
7.1 Safety Parameters ................................................................................................................ 32 
7.1.1.1 Definition of Adverse Events ........................................................................................ 32 
7.1.2 Definition of Serious Adverse Events…………………………………………………...32 
7.1.3 Definition of Adverse Events of Special Interest (AESI) ................................................. 32 


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7.1.4  Pneumonitis ..................................................................................................................... 33 
7.1.5 Hypersensitivity reactions ................................................................................................ 34 
7.1.6 Hepatic function abnormalities (hepatotoxicity) .............................................................. 34 
7.1.7 Gastrointestinal disorders  ................................................................................................ 34 
7.1.8 Endocrine disorders .......................................................................................................... 34  
7.1.9 Pancreatic disorders .......................................................................................................... 35 
7.1.10 Neurotoxicity .................................................................................................................. 35 
7.1.11 Nephritis ......................................................................................................................... 35 
    7.1.12 Radiation risks. ............................................................................................................... 35           
7.2 Assessment of safety parameters ......................................................................................... 35 
7.2.1 Adverse event characteristics ........................................................................................... 35 
7.3 Recording of adverse events ................................................................................................ 35 
    7.3.1 Study recording period and follow-up for AEs and SAEs  ............................................... 36 
    7.3.2 Serious Adverse Event (SAE) Reporting .......................................................................... 36 
7.3.3 Reporting of SAE to IRB .................................................................................................. 36 
    7.3.4 Reporting of SAE to FDA and Sponsor ............................................................................ 37 
7.3.5 Reporting of deaths ........................................................................................................... 37 
7.3.6 Other events requiring reporting  ...................................................................................... 38 
7.3.7 Overdose ........................................................................................................................... 38 
7.3.8 Hepatic function abnormality ........................................................................................... 38 
7.3.9 Pregnancy ......................................................................................................................... 38 
7.3.10 Paternal  .......................................................................................................................... 39 
7.4 Data Safety Monitoring Plan ............................................................................................... 39 
8.0 PHARMACEUTICAL INFORMATION ................................................................................ 39 
8.1 Investigational Agent ........................................................................................................... 39 
    8.1.1 Durvalumab ....................................................................................................................... 39 
    8.1.2 Formulation/packaging/storage ......................................................................................... 39 
 8.1.3 Study drug preparation ...................................................................................................... 39 
 8.1.4 Monitoring of dose administration .................................................................................... 41 
 8.1.5 Agent Accountability ......................................................................................................... 41 
9.0 MEASUREMENT OF EFFECT .............................................................................................. 41 
    9.1  Assessment of disease-free survival  .................................................................................. 41 
    9.2  Assessment of clinical response .......................................................................................... 41 
    9.3  Assessment of pathological response …………………………………………………….42 
10.0 DATA REPORTING / REGULATORY CONSIDERATIONS ........................................... 42 
    10.1 Data Collection .................................................................................................................. 42 
    10.1.1 REDCap .......................................................................................................................... 42 
    10.2 Regulatory Considerations ................................................................................................. 42 
 10.3 Ethical conduct of the study ............................................................................................... 42 
11.0 STATISTICAL CONSIDERATIONS ................................................................................... 42 
    11.1 Specific Aims ..................................................................................................................... 42 
    11.1.1 Primary Aim .................................................................................................................... 42 
    11.1.2 Secondary Aim ................................................................................................................ 43 
    11.2 Analysis Plan for Endpoints ............................................................................................... 43 
    11.2.1 Primary Endpoint ............................................................................................................ 43 
    11.2.2 Secondary Endpoints....................................................................................................... 43 
REFERENCES .............................................................................................................................. 45 
APPENDICES ............................................................................................................................... 50 
    APPENDIX A: Durvalumab  Dose Calculations ....................................................................... 50 
    APPENDIX B: Dosing Modifications and Toxicity Management Guidelines .......................... 51 


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    APPENDIX C  WCMC SAE Reporting Form  ......................................................................... 80 
 
SCHEMA 
 
1.0 OBJECTIVES 
 
1.1 Primary Objective 
• 
To compare the pathological response rate after 2 cycles of anti-PD-L1 monotherapy and anti-
PD-L1 with SBRT. 
 
1.2 Secondary Objectives 
• 
To determine whether pre-operative anti-PDL-1 therapy with or without radiation leads to an 
improvement in DFS in patients with clinical stage I (tumors > 2 cm), II, and IIIA NSCLC 
from a historical control rate of 75% at 2 years to 89%. 
• 
To determine if non-ablative doses of radiotherapy given concurrently with neo-adjuvant 
durvalumab will lead to a clinical response rate of 35% compared to a clinical response rate of 
15% predicted in the antibody alone arm. The response rate of 15% selected for the antibody 
alone arm is consistent with response rates with durvalumab in patients with advanced 
refractory lung cancer. 
• 
To determine the safety of 2 cycles of preoperative durvalumab with and without radiation 
followed by surgery and adjuvant durvalumab every 4 weeks for 12 cycles post-operatively. 
 
1.3 Exploratory Objective 
• 
To determine whether the improvement in response rate in the radio-immunotherapy arm will 
translate into an improvement in DFS. Though the trial is not powered to adequately test this 
hypothesis, it may generate data suggesting future trial designs 
 
1.4 Rationale and Hypothesis 


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Approximately 20-25% of the 220,000 patients diagnosed with NSCLC in the United States in 2014 
will have early stage disease (stages I-IIIA) 1. Although surgical resection is the treatment of choice, 
five year overall survival is only 55% and disease-free survival (DFS) maybe as low as 40% at five 
years. Over the past decade three large international randomized trials have shown that adjuvant 
chemotherapy after complete resection leads to a significant improvement in survival 2-5. A meta-
analysis of all randomized trials confirmed these results and showed that the absolute improvement in 
5-year survival after chemotherapy is only 5.4% 5. Despite this statistically significant improvement in 
survival, 40-50% of patients develop locally recurrent or metastatic disease 6, 7. More recently, large 
international adjuvant trials tested the efficacy of targeted therapies such as the anti-VEGF antibody 
bevacizumab or the EGFR tyrosine kinase inhibitor, erlotinib, after surgical resection 8, 9. Both trials 
did not meet their primary endpoint of improved DFS. Similarly, a large international randomized trial 
using vaccination with the recombinant MAGE-A3 protein in patients with MAGE-A3 positive tumors 
failed to meet the primary endpoint of improving DFS10. Clearly there is an urgent unmet clinical need 
to develop novel neo-adjuvant or adjuvant therapies for patients with early stage lung cancer. 
 
1.4.1 Targeting PD-L1 is a safe and promising strategy 
Several clinical trials in patients with advanced refractory NSCLC have shown that antibodies 
targeting the PD1/PD-L1 pathway resulted in clinical response rates in approximately 15-25% of 
patients with advanced chemo-refractory NSCLC11-18. Responses occurred in patients with either 
squamous or non-squamous cancers and in patients with and without mutations or rearrangements in 
driver oncogenes. Although responses were more frequently seen in patients whose tumors expressed 
PD-L1, responses were also observed in patients with PD-L1 negative tumors. Unlike patients treated 
by chemotherapy or targeted agents, responses achieved by targeting these inhibitory checkpoints were 
durable in over 80% of responders and occasionally response was maintained even after drug 
discontinuation. The favorable safety profile and impressive response rates of these antibodies in 
advanced disease strongly justify evaluation of their efficacy in patients with early stage disease. 
However, the more frequent association of anti-PD-1 antibodies with grades 3/4 pneumonitis may limit 
the utility of anti-PD-1 agents in the neoadjuvant setting in patients with early stage lung cancer. In 
contrast, anti-PD-L1 antibodies appear to be associated with a more favorable safety profile and to-
date have rarely been associated with pneumonitis grade 3 or above. Therefore, we anticipate that neo-
adjuvant anti-PD-L1 therapy in early stage NSCLC will be safe and well tolerated. Beyond safety 
concerns, recent evidence from ongoing neoadjuvant trials in early stage NSCLC shows an 
unexpectedly high rate of major and complete pathological response rate (20-45%) than would have 
been anticipated from response rates from trials of immune-check point inhibitors (ICIs) in advanced 
disease. The association between pathological response and survival has been clearly shown following 
neoadjuvant therapy for breast cancer70. An association between pathological response rate and 
survival has not been definitively shown in NSCLC. An ongoing international project that investigates 
pathological response as a surrogate endpoint for survival in the context of neoadjuvant ICIs in early 
stage lung cancer has been initiated by the International Association for Study of Lung Cancer 
(IASLC).  
 
1.4.2 Non-ablative doses of radiation will potentiate anti-PD-L1 therapy in PD-L1 +ve and –ve 
tumors 
The immuno-modulatory effects of radiation cited below and the results of preclinical studies 
combining radiation with immune checkpoint inhibitors strongly suggest that combination radio-
immunotherapy may potentiate the anti-tumor effects of PD-L1 blockade in PD-L1 positive tumors 19-
22. Furthermore, the induction of PD-L1 expression in tumor and immune cells by radiation may render 
PD-L1 negative tumors more susceptible to anti-PD-L1 therapy23. Given the emerging data on the high 
pathological response rates from following neoadjuvant ICIs in early NSCLC71, we postulate that the 


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addition of subablative SBRT to ICI will significantly increase the rate of pathological response 
compared to ICI alone. 
 
 
1.4.3 Hypothesis 
In this randomized trial design we will test the hypothesis that non-ablative doses of radiation 
delivered in combination with PDL-1 blockade will lead to a significant improvement in pathological 
response rates compared to preoperative anti-PD-L1 alone and provide a hint whether such 
improvement in response translates to improved survival. We will also test the hypothesis that 
neoadjuvant anti-PDL-1 will significantly improve DFS compared to reported and institutional 
historical controls. The demonstration that non-ablative doses of radiation can be a potent immuno-
modulator will be a paradigm shift and will set the stage for further evaluation of this strategy in 
NSCLC and other solid tumors. 
2.0 BACKGROUND 
2.1 Cancer and immune system function 
Immune responses directed against tumors are one of the body’s natural defenses against the growth 
and proliferation of cancer cells. However, over time and under pressure from immune attack, cancers 
develop multiple strategies to evade immune-mediated killing allowing tumor growth and progression. 
One such mechanism involves upregulation of surface proteins that deliver inhibitory signals to 
cytotoxic T cells. Programmed cell death ligand 1 is one such protein, and is upregulated in a broad 
range of cancers with a high frequency. In a number of these cancers, including lung 24, kidney 25-27, 
pancreatic 28-30, and ovarian cancer 31, tumor cell expression of PD-L1 is associated with reduced 
survival and an unfavorable prognosis. For example, in ovarian cancer, the 5-year survival rate in 
patients with low expression of PD-L1 was 80.2% compared to 52.6% in patients with high expression 
levels of PD-L1 31.In lung cancer Mu et al reported that only 20% of patients with tumors expressing 
PD-L1 survived for more than 3 years compared to 49% of patients with tumors lacking PD-L1 
expression 24. However that association of PD-L1 expression with survival in lung cancer is 
inconsistent.  
Programmed cell death ligand 1 is part of a complex system of receptors and ligands that are involved 
in controlling peripheral T-cell activation. PD-L1 acts at multiple sites in the body to help regulate 
normal immune responses and its expression by tumors is one mechanism of innate or acquired tumor 
immune resistance. In the lymph nodes, PD-L1 on antigen-presenting cells binds to PD-1 or CD80 on 
activated T cells and delivers an inhibitory signal to the T cell 32, 33. This results in reduced T-cell 
activation and fewer activated T cells in circulation. In the tumor microenvironment, PD-L1 expressed 
on tumor cells binds to PD-1 and CD80 on activated T cells reaching the tumor. This delivers an 
inhibitory signal to those T cells, preventing them from killing target cancer cells and protecting the 
tumor from immune elimination 34.  
Based on in vitro studies, an antibody that blocks the interaction between PD-L1 and its receptors can 
relieve PD-L1-dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor T 
cells 35. The levels of tumor-infiltrating lymphocytes, and more specifically cytotoxic T cells, have 
been correlated with improved prognosis in a number of cancers including colorectal, melanoma, and 
lung 36, suggesting that an antitumor immune response is beneficial to patients. Based on these 
findings, an anti-PD-L1 antibody could be used therapeutically to enhance antitumor immune 
responses in patients with cancer. Results of several preclinical studies using mouse tumor models 
support this hypothesis 37-40. In these studies, antibodies directed against PD-L1 or its receptor, PD-1, 
demonstrated antitumor activity.  
Stimulating an antitumor immune response is a mechanism employed successfully by a number of 
approved cancer therapies. For example, aldesleukin (Proleukin®), a recombinant human interleukin 
(IL)-2, in renal cancer 41 and sipuleucel-T (Provenge®) in prostate cancer42 both directly stimulate 
immune activation. Ipilimumab (Yervoy®) also stimulates the immune response, but does so by 


Page 7 of 85 
 
blocking the T-cell co-inhibitory molecule, CTLA-4, thereby removing an immunosuppressive signal. 
Blocking PD-L1 is an approach similar to CTLA-4 inhibition, but with some distinct differences. First, 
the expression of CTLA-4 and its ligands is restricted to the hematopoietic system and thus, the site of 
action for molecules targeting CTLA-4 is solely the peripheral lymphoid organs. In contrast, PD-L1 is 
expressed on cells of the hematopoietic system and on a range of tumor types. Therefore, targeting PD-
L1 should have additional effects within the tumor microenvironment. Second, CTLA-4 plays an early 
and critical role in controlling T-cell activation. This is reflected in the phenotype of CTLA-4 
knockout mice, which die between 3 and 4 weeks of age due to lymphoproliferative disease and tissue 
destruction. In contrast, PD-L1 acts later in the process of T-cell activation 43 and is considered less 
critical to the control of initial T-cell activation. This is reflected in the phenotype of PD-L1 knockout 
mice, which are viable and have normal T-cell numbers and activation levels but show increased T-cell 
activation in response to antigen and increased susceptibility in certain autoimmune models 44, 45. 
Similarly, mice lacking PD-1, a PD-L1 receptor, show strain-specific phenotypes that are milder than 
those seen in CTLA-4 knockouts 46, 47. Therefore, inhibition of the PD-L1/PD-1 pathway might be 
expected to result in less toxicity relative to CTLA-4 inhibition. In support of these findings, recent 
Phase 1 clinical studies assessing the tolerability of agents targeting PD-1 have demonstrated a toxicity 
profile that is more favorable than that of CTLA-4 48-51. 
 
2.2 Durvalumab in Solid Tumors  
 
2.2.1 Preclinical overview  
Durvalumab Background 
Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid 
tumors. Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa 
(IgG1κ) subclass that inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-
H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1).  
Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an overall 
molecular weight of approximately 149 kDa. Durvalumab contains a triple mutation in the constant 
domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein C1q 
and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector function. 
Preclinical data with durvalumab suggest that targeting PD-L1 with a biologic agent could be an 
effective antitumor therapy. Durvalumab is a human mAb that selectively binds human PD-L1 with 
high affinity and blocks its ability to bind to PD-1 and CD80. Blockade of PD-L1 with durvalumab 
relieved PD-L1-mediated suppression of human T-cell activation in vitro. In a xenograft model, 
durvalumab inhibited human tumor growth via a T-cell-dependent mechanism. Moreover, an anti-
mouse PD-L1 antibody demonstrated improved survival in a syngeneic tumor model when given as 
monotherapy and resulted in complete tumor regression in > 50% of treated mice when given in 
combination with chemotherapy.  
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction with 
PD-1 and CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-
L1 on primary human T cells, resulting in their restored proliferation and release of interferon gamma 
(IFN-γ). Additionally, durvalumab demonstrated a lack of antibody-dependent cell-mediated 
cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based functional assays. 
In vivo studies show that durvalumab inhibits tumor growth in a xenograft model via a T lymphocyte 
(T-cell) dependent mechanism. Moreover, an anti-mouse PD-L1 antibody demonstrated improved 
survival in a syngeneic tumor model when given as monotherapy and resulted in complete tumor 
regression in > 50% of treated mice when given in combination with chemotherapy. Combination 
therapy (dual targeting of PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) resulted 
in tumor regression in a mouse model of colorectal cancer.  


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Cynomolgus monkeys were selected as the only relevant species for evaluation of the 
pharmacokinetics (PK)/pharmacodynamics and potential toxicity of durvalumab. Following 
intravenous (IV) administration, the PK of durvalumab in cynomolgus monkeys was nonlinear. 
Systemic clearance (CL) decreased and concentration half-life (t1/2) increased with increasing doses, 
suggesting saturable target binding-mediated clearance of durvalumab. No apparent gender differences 
in PK profiles were observed for durvalumab. 
In general, treatment of cynomolgus monkeys with durvalumab was not associated with any 
durvalumab -related adverse effects that were considered to be of relevance to humans. Adverse 
findings in the non-Good Laboratory Practice (GLP) PK/pharmacodynamics and dose range-finding 
study, and a GLP 4-week repeat-dose toxicity study were consistent with antidrug antibody (ADA)-
associated morbidity and mortality in individual animals. The death of a single animal in the non-GLP, 
PK/pharmacodynamics, and dose range-finding study was consistent with an ADA-associated acute 
anaphylactic reaction. The spectrum of findings, especially the clinical signs and microscopic 
pathology, in a single animal in the GLP, 4-week, repeat-dose study was also consistent with ADA 
immune complex deposition, and ADA: durvalumab immune complexes were identified in a 
subsequent non-GLP, investigative immunohistochemistry study. Similar observations were reported 
in cynomolgus monkeys administered human mAbs unrelated to durvalumab. Given that 
immunogenicity of human mAbs in nonclinical species is generally not predictive of responses in 
humans, the ADA-associated morbidity and mortality were not considered for the determination of the 
no-observed-adverse-effect level (NOAEL) of durvalumab.  
Finally, data from the pivotal 3-month GLP toxicity study with durvalumab in cynomolgus monkeys 
showed that subchronic dosing of durvalumab was not associated with any adverse effects. Therefore, 
the NOAEL of durvalumab in all the general toxicity studies was considered to be 100 mg/kg, the 
highest dose tested in these studies. In addition to the in vivo toxicology data, no unexpected 
membrane binding of  durvalumab to human or cynomolgus monkey tissues was observed in GLP 
tissue cross-reactivity studies using normal human and cynomolgus monkey tissues. 
 
2.2.2 
Summary of clinical experience 
As of the data cut-off (DCO) date of 12 July 2019, an estimated 8817 patients have received 
durvalumab in AstraZeneca or MedImmune-sponsored interventional studies in multiple 
tumour types, stages of disease and lines of therapy. Of these, 4067 patients received durvalumab 
monotherapy, 2423 patients received durvalumab in combination with tremelimumab, and 2327 
patients received durvalumab in combination with an investigational and/or an approved product. An 
estimated 8343 patients have been randomised to the various treatment/comparator arms in sponsor-
blinded studies. In addition, 2482 patients have participated in the durvalumab Early Access 
Programme (EAP; Study D4194C00002) for patients with locally advanced, unresectable NSCLC 
whose disease has not progressed following platinum-based chemoradiation therapy. The cumulative 
global post-marketing patient exposure to durvalumab (10 mg/kg) to 30 June 2019 has been estimated 
to be approximately 12385 patient-years. 
 
2.2.3 Pharmacokinetics and Product Metabolism  
Study CD-ON-durvalumab-1108: As of 09 Feb2015, PK data were available for 378 subjects in the 
dose-escalation and dose-expansion phases of Study CD ON-durvalumab-1108 following treatment 
with durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks (Q3W). The 
maximum observed concentration (Cmax) increased in an approximately dose-proportional manner 
over the dose range of 0.1 to 15 mg/kg. The area under the concentration-time curve from 0 to 14 days 
(AUC0-14) increased in a greater than dose proportional manner over the dose range of 0.1 to 3 mg/kg 
and increased dose-proportionally at ≥ 3 mg/kg. These results suggest durvalumab exhibits nonlinear 
PK likely due to saturable target-mediated CL at doses < 3 mg/kg and approaches linearity at doses ≥ 3 
mg/kg. Near complete target saturation (soluble programmed cell death ligand 1 [sPD L1] and 


Page 9 of 85 
 
membrane bound) is expected with durvalumab ≥ 3 mg/kg Q2W. Exposures after multiple doses 
showed accumulation consistent with PK parameters estimated from the first dose. In addition, PK 
simulations indicate that following durvalumab 10 mg/kg Q2W dosing, > 90% of subjects are expected 
to maintain PK exposure ≥ 40 µg/mL throughout the dosing interval. 
As of 09 Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 388 subjects 
(1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg cohort) were ADA 
positive with an impact on PK/pharmacodynamics in 1 subject in the 3 mg/kg cohort 
 
2.2.4 Safety  
Overall risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed cell death 
ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-1) or cytotoxic T-
lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune responses directed against tumor 
cells. By stimulating the immune system however, there is the potential for adverse effects on other 
tissues. 
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 mechanism and which may require more frequent monitoring and/or unique 
interventions such as immunosuppressants and/or endocrine replacement therapy. These risks include 
gastrointestinal AEs such as colitis and diarrhoea, pneumonitis /interstitial lung disease (ILD), renal 
AEs such as, nephritis and increases in creatinine, hepatic AEs such as hepatitis and liver enzyme 
elevations, skin events such as rash and dermatitis, endocrinopathies such as hypo- and 
hyperthyroidism, hypophysitis, adrenal insufficiency, diabetes mellitus type I and diabetes insipidus, 
and neurotoxicities such as myasthenia gravis and Guillain-Barre syndrome. 
 
Durvalumab 
Risks with durvalumab include diarrhea, colitis, pneumonitis /ILD, endocrinopathies (hypo- and 
hyperthyroidism, type I diabetes mellitus(which may present as diabetic ketoacidosis), diabetes 
insipidus, hypophysitis and adrenal insufficiency) hepatitis/hepatotoxicity/increases in transaminases, 
neurotoxicities, nephritis/increases in creatinine, pancreatitis, rash/pruritus/dermatitis (including 
pemphigoid), infusion-related reactions, anaphylaxis, encephalitis, subcutaneous injection site 
reaction,hypersensitivity or allergic reactions, and immune complex disease.  
Further information on these risks can be found in the current version of the durvalumab IB. 
In monotherapy clinical studies, AEs (all grades) reported very commonly (≥10% of patients) are 
fatigue, nausea, decreased appetite, dyspnea, cough,  diarrhea, vomiting, pyrexia, abdominal pain, 
peripheral edema, rash, pruritus, upper respiratory tract infection, and aspartate aminotransferase 
increased. Approximately 9.4% of patients experienced an AE that resulted in permanent 
discontinuation of durvalumab and approximately 6.5% of patients experienced an SAE that was 
considered to be related to durvalumab by the study investigator. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic treatment, and 
in the case of events suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity (see the Dosing Modification and Toxicity Management Guidelines in B. 


Page 10 of 85 
 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of the 
durvalumab IB. 
AEs reported with durvalumab monotherapy in key clinical studies are described below. 
 
Adverse Event Profile of durvalumab Monotherapy 
Study CD-ON-durvalumab-1108: The safety profile of durvalumab monotherapy in the 694 subjects 
with advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-durvalumab-1108 has been 
broadly consistent with that of the overall 1,279 subjects who have received durvalumab monotherapy 
(not including subjects treated with blinded investigational product) across the clinical development 
program. The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity. As of 07 May2015, among the 694 subjects treated 
with durvalumab 10 mg/kg Q2W in Study CD-ON-durvalumab-1108, a total of 378 subjects (54.5%) 
experienced a treatment-related AE, with the most frequent (occurring in ≥ 5% of subjects) being 
fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash 
(6.1%), and vomiting (5.0%). A majority of the treatment-related AEs were Grade 1 or Grade 2 in 
severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). Treatment-related ≥ Grade 3 events 
reported in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased aspartate 
aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase (GGT; 6 subjects, 
0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and colitis, vomiting, decreased 
appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had treatment-related Grade 4 AEs 
(upper gastrointestinal hemorrhage, increased AST, dyspnea, neutropenia, colitis, diarrhea, and 
pneumonitis) and 1 subject had a treatment-related Grade 5 event (pneumonia). Treatment-related 
serious adverse events (SAEs) that occurred in ≥ 2 subjects were colitis and pneumonitis (3 subjects 
each). A majority of the treatment-related SAEs were ≥ Grade 3 in severity and resolved with or 
without sequelae. AEs that resulted in permanent discontinuation of durvalumab were considered as 
treatment related in 18 subjects (2.6%), with colitis being the most frequent treatment-related AE 
resulting in discontinuation (3 subjects). A majority of the treatment-related AEs resulting in 
discontinuation of durvalumab were ≥ Grade 3 in severity and resolved with or without sequelae.  
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in Study CD-ON-
durvalumab-1108 is generally consistent with that of Study D4191C00003/ATLANTIC in subjects 
with locally advanced or metastatic non-small-cell lung cancer (NSCLC) treated with durvalumab 10 
mg/kg Q2W. As of 05May2015, 264 of 303 subjects (87.1%) reported any AE in Study 
D4191C00003/ATLANTIC. Overall, events reported in ≥ 10% of subjects were dyspnea (18.8%), 
fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), pyrexia (12.2%), asthenia (11.9%), and 
nausea (11.2%). Nearly two-thirds of the subjects experienced AEs that were Grade 1 or 2 in severity 
and manageable by general treatment guidelines as described in the current durvalumab study 
protocols. Grade 3 or higher AEs were reported in 107 of 303 subjects (35.3%). A total of 128 subjects 
(42.2%) reported AEs that were considered by the investigator as related to investigational product. 
Treatment-related AEs (all grades) reported in ≥ 2% of subjects were decreased appetite (6.6%); 
fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea, hyperthyroidism, 
hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased (2.3%); and vomiting (2.0%). 
Treatment-related Grade 3 AEs reported in ≥ 2 subjects were pneumonitis (3 subjects) and increased 
GGT (2 subjects). There was no treatment-related Grade 4 or 5 AEs. Ninety-four of 303 subjects 
(31.0%) reported any SAE. SAEs that occurred in ≥ 1.0% of subjects were dyspnea (6.6%); pleural 
effusion, general physical health deterioration (2.3% each); pneumonia (2.0%); hemoptysis, pulmonary 
embolism (1.3% each); and pneumonitis, respiratory failure, disease progression (1.0% each). Nine 
subjects had an SAE considered by the investigator as related to durvalumab. Each treatment-related 
SAE occurred in 1 subject each with the exception of pneumonitis, which occurred in 3 subjects. 


Page 11 of 85 
 
Fifteen of 303 subjects (5.0%) have died due to an AE (pneumonia [3 subjects]; general physical 
health deterioration, disease progression, hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, 
respiratory distress, cardiopulmonary arrest [verbatim term (VT)], hepatic failure, and sepsis [1 subject 
each]). None of these events was considered related to durvalumab. Twenty-three of 303 subjects 
(7.6%) permanently discontinued durvalumab treatment due to AEs. Events that led to discontinuation 
of durvalumab in ≥ 2 subjects were dyspnea, general physical health deterioration, and pneumonia. 
Treatment-related AEs that led to discontinuation were increased ALT and increased hepatic enzyme, 
which occurred in 1 subject each. 
 
2.2.5 Efficacy  
Study CD-ON-durvalumab-1108: Overall, 456 of 694 subjects treated with durvalumab 10 mg/kg 
Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, measurable disease at 
baseline, and ≥ 1 follow-up scan, or discontinued due to disease progression or death without any 
follow-up scan). In PD-L1 unselected patients, the objective response rate (ORR), based on 
investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged 
from 0% in uveal melanoma (n = 23) to 20.0% in bladder cancer (n = 15), and disease control rate at 
24 weeks (DCR-24w) ranged from 4.2% in triple-negative breast cancer (TNBC; n = 24) to 39.1% in 
advanced cutaneous melanoma (n = 23). PD-L1 status was known for 383 of the 456 response 
evaluable subjects. Across the PD-L1-positive tumors, ORR was highest for bladder cancer, advanced 
cutaneous melanoma, hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 
26.7%), and squamous cell carcinoma of the head and neck (SCCHN; n = 22, 18.2%). In the PD-L1-
positive subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 
86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%).  
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) treated in Study 
D4190C00007, 21 subjects had at least 1 post-baseline disease assessment. Among these subjects, the 
best overall responses were marrow complete remission (mCR) in 4 subjects (19.0%); stable disease 
(SD) in 4 subjects (19.0%); and progressive disease (PD) in 5 subjects (23.8%). The remaining 8 
subjects (38.1%) did not meet the criteria for complete remission (CR), mCR, partial remission (PR), 
SD, or PD at the date of assessment. 
Study CD-ON-durvalumab-1161: Of the 65 subjects with metastatic or unresectable melanoma 
treated with the combination of durvalumab and BRAF inhibitor (BRAFi; dabrafenib)/MEK inhibitor 
(MEKi; trametinib), 63 subjects were evaluable for response. A total of 35 subjects (55.6%) had a best 
overall response of confirmed or unconfirmed PR. The disease control rate (DCR; CR + PR [regardless 
of confirmation] + SD ≥ 12 weeks) was 79.4%.  
Dose rationale 
This study will utilize an open-label design due to the different treatment administration schedules and 
treatment durations. 
MEDI4736 
A dose of MEDI4736 15 mg/kg (or 1.12g fixed dose) every 3 weeks (q3w) is supported by in-vitro 
data, non-clinical activity, clinical pharmacokinetics (PK)/pharmacodynamics, biomarkers, and 
activity data from Study 1108 in patients with advanced solid tumors (ongoing first-time-in-humans 
study) and from a Phase I trial performed in Japanese patients with solid tumor (NCT01938612). 
PK/Pharmacodynamic data 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging from 0.1 
to 10 mg/kg every 2 weeks (q2w) or 15 mg/kg every 3 weeks (q3w), MEDI4736 exhibited non-linear 
(dose-dependent) PK consistent with target-mediated drug disposition. The PK approached linearity at 
≥3 mg/kg q2w (trough concentration ~40 µg/mL), suggesting near complete target saturation 


Page 12 of 85 
 
(membrane-bound and soluble PD-L1 [sPD-L1]), and further shows that the MEDI4736 dosing 
frequency can be adapted to a particular regimen given the linearity seen at higher doses than 3 mg/kg.   
The expected half-life with doses ≥3 mg/kg q2w is approximately 21 days.  A dose-dependent 
suppression in peripheral sPD-L1 was observed over the dose range studied, consistent with 
engagement of MEDI4736 with PD-L1. Dose-related changes in a variety of peripheral biomarkers 
have been observed over the dose range of 0.1 to 15 mg/kg.  A low level of immunogenicity has been 
observed.  No patients have experienced immune-complex disease following exposure to MEDI4736.  
Of the 388 patients who received MEDI4736 monotherapy and for whom PK/ antidrug antibody 
(ADA) data were available as of 9 Feb July 2015, 5 were ADA positive, with an impact on 
PK/pharmacodynamics reported in 1 patient at 3 mg/kg.   Population PK simulations indicate that 
following 15 mg/kgQ3W dose of MEDI4736, >90% patients are expected to maintain PK exposure 
yielding full target saturation throughout the dosing interval. In addition, PK simulation indicates 
similar overall exposure for both 10 mg/kg Q2W (dose selected for Phase 3 monotherapy studies) and 
15 mg/kg Q3W. This is supported by available limited PK data following 15 mg/kg Q3W cohort in 
study 1108.     
 
Clinical data 
The initial safety data from a small subset of patients receiving the 15 mg/kg q3w on the 1108 study 
suggests that the nature and frequency of toxicities observed with 15 mg/kg q3w are consistent with 
the 10 mg q2w regimen. As of 07 May2015, 736 subjects were treated across all dose levels in Study 
1108. Among the 694 subjects treated with MEDI4736 10 mg/kg Q2W, a total of 378 subjects (54.5%) 
experienced a treatment-related AE, with the most frequent (occurring in ≥ 5% of subjects) being 
fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash 
(6.1%), and vomiting (5.0%). A majority of the treatment-related AEs were Grade 1 or Grade 2 in 
severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). Treatment-related ≥ Grade 3 events 
reported in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased aspartate 
aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase (GGT; 6 subjects, 
0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and colitis, vomiting, decreased 
appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had treatment-related Grade 4 AEs 
(upper gastrointestinal hemorrhage, increased AST, dyspnea, neutropenia, colitis, diarrhea, and 
pneumonitis) and 1 subject had a treatment-related Grade 5 event (pneumonia).  AEs that resulted in 
permanent discontinuation of MEDI4736 were considered as treatment related in 18 subjects (2.6%), 
with colitis being the most frequent treatment-related AE resulting in discontinuation (3 subjects). A 
majority of the treatment-related AEs resulting in discontinuation of MEDI4736 were ≥ Grade 3 in 
severity and resolved with or without sequelae. As of this same data cutoff, 7 subjects were treated 
with MEDI4736 15 mg/kq3w. Among these 7 subjects, 6 experienced a treatment-related AE, with the 
most frequently reported events being fatigue and nausea (2 subjects each). At this dose level, 2 
subjects experienced a treatment-related ≥ Grade 3 AE (peripheral motor neuropathy and fatigue in 1 
subject each). One treatment-related AE resulted in permanent discontinuation of MEDI4736 (Grade 3 
peripheral motor neuropathy). There were no dose-limiting toxicities (DLTs) or drug-related deaths 
observed in the 15 mg/kg q3w cohort. Overall, at both the 10 mg/kg q2w and 15 mg/kg q3w dose 
levels, AEs were manageable with dose delays, symptomatic treatment, and in the case of events 
suspected to have an immune basis, the use of established treatment guidelines for immune-mediated 
toxicity. 
Data presented at the European Society for Medical Oncology (ESMO) meeting 2014 with a later 
cutoff of 21 August 2014 showed that MEDI4736 was well tolerated at all doses in the non-small-cell 
lung cancer (NSCLC) subset of patients enrolled into Study 1108, with drug-related Grade ≥3 AEs 
reported in 3% of patients and drug-related AEs leading to discontinuation reported in 1% of patients.  
No drug-related colitis or hyperglycemia of any grade, no Grade ≥3 pneumonitis reported, and no 


Page 13 of 85 
 
drug-related AEs leading to death were reported.  At present, the data do not suggest that the safety 
profile of MEDI4736 will be different in the 15 mg/kg q3w dosing regimen when compared to 
10 mg/kg q2w regimen.   
Efficacy data on the Study 1108, presented at ESMO 2014 (cutoff date of 21 August 2014), showed a 
disease control rate (DCR) at 12 weeks of 41% and objective response rate (ORR) of 16% among 162 
evaluable patients, with activity observed in both squamous and non-squamous histologies.  The ORR 
was higher (25%; 12 CR/PR; n=48) in patients with PD-L1 positive tumors, defined as those with 
≥25% of tumor cells with membrane staining for PD-L1, compared to patients with PD-L1 negative 
tumors (10%; 7 CR/PR; n=74).   
Fixed dosing rationale 
A population PK model was developed for MEDI4736 using monotherapy data from Study 1108 
(Phase I study; N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors).  Population PK 
analysis indicated only a minor impact of body weight (WT) on the PK of MEDI4736 (coefficient of 
≤0.5).  The impact of body WT-based (10 mg/kg q2w) and fixed dosing (750 mg q2w) of MEDI4736 
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 a median body WT of approximately 75 kg).  A total of 1000 patients were simulated 
using a body WT distribution of 40 to 120 kg.  Simulation results demonstrated that body WT-based 
and fixed dosing regimens yield similar median steady state PK concentrations with slightly less 
overall between-patient variability with the fixed dosing regimen.   
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, Wang et al 2009, 
Zhang et al 2012).  Wang and colleagues investigated 12 mAbs and found that fixed and body size-
based dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies 
(Wang et al 2009).  In addition, they investigated 18 therapeutic proteins and peptides and showed that 
fixed dosing performed better for 12 of 18 in terms of reducing the between-patient variability in 
PK/pharmacodynamics parameters (Zhang et al 2012).  
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced 
dosing errors.  Given the expectation of similar PK exposure and variability, AstraZeneca considered it 
feasible to switch to fixed dosing regimens.  Based on an average body WT of 75 kg, fixed doses of 
1.12 g q3w (equivalent to 15 mg/kg q3w) of MEDI 4736 is included in the current study. 
 
2.2.6 Targeting the PD1/PD-L1 pathway in NSCLC 
The use of monoclonal antibodies that target immune checkpoints has unleashed intratumoral T cell 
mediated immune responses in a manner that has the potential to revolutionize lung cancer treatment. 
Two immune check point pathways that have been investigated and targeted for therapeutic purposes 
are the membrane receptors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and programmed 
cell death protein 1 (PD1) and its ligand PD-L1. In contrast to anti-CTLA-4 antibodies, where there 
has been no significant single-agent activity in advanced NSCLC, blockade of the PD1/PD-L1 
pathway resulted in significant single agent activity in heavily pretreated patients with NSCLC 11-18. A 
trial of the anti- PD1 antibody, nivolumab, in 129 heavily pretreated patients with NSCLC was 
recently reported 14. The objective response rate was 17% and was similar in squamous and non-
squamous NSCLC. Impressively the duration of response was 17 months; an unprecedented duration 
of response compared to that seen after either chemotherapy or oncogene targeted therapy. These 
impressive response rates translated into a significant improvement in survival (1 year: 42% and 2 
year: 24%). Although adverse events were generally mild, immune-related pneumonitis developed in 
7% of patients and was associated with the death of three patients. Similar results were reported in a 
clinical trial that enrolled 495 patients with stage IIIB/IV NSCLC treated with the anti-PD1 antibody 
pembrolizumab 15. The overall objective response rate was 19% and the median duration of response 
was 12.5 months. Interestingly the objective response rate and median duration of response were 


Page 14 of 85 
 
higher in 101 treatment naïve patients (24.8% and 23 months) compared to those in previously treated 
patients (18% and 10 months). Grade 3 or higher adverse events occurred in 9.5% of patients including 
grade 3 pneumonitis that developed in 9 patients (1.8%) and resulted in one of two treatment related 
deaths. Finally, Rizvi et al reported the results of a phase II trial of nivolumab monotherapy in 117 
patients with refractory advanced squamous cell lung cancer 16. The objective response rate was 14.5% 
and an additional 26% of patients had stable disease. Grade 3-4 events developed in 20 patients (17%) 
including pneumonitis that occurred in 4 patients and was associated with one treatment-related death. 
There are currently two anti-PD-L1 antibodies that have completed phase I expansion trials in patients 
with refractory advanced solid tumors: durvalumab and MPDL3280A 17, 18. Both are fully humanized 
IgG1 antibodies engineered to bind with high affinity to PD-L1 (not PD-L2) and with an Fc 
modification that 2 prevents antibody-dependent cellular cytotoxicity, thus precluding lysis of 
activated T cells. MPDL3280A resulted in an objective response rate in 12 of 53 (23%) patients with 
refractory NSCLC and was durable in eleven 7. Response was not significantly associated with tumor 
cell expression of PD-L1. No grade 3- 5 pneumonitis were reported. Rizvi et al reported on 198 
patients with refractory heavily pretreated patients with NSCLC treated using durvalumab (the 
antibody selected for this proposal) in a global multicenter phase I expansion trial 18. Objective 
responses by RECIST criteria were observed in 14% of patients (PD-L1+ve: 23%, PD-L1-ve: 10%). 
Responses were observed in patients with and without EGFR mutations, ALK re-arrangement or 
KRAS mutations. Responses occurred early and were durable in 76% of responders. Drug-related 
adverse events (AEs) of any grade occurred in 48% of patients 52. Drug-related 
AEs ≥3 developed in 6% of patients. There was no drug-related colitis or hyperglycemia of any grade 
and importantly no grade ≥3 pneumonitis was reported. Because of the encouraging early results of 
anti-PDL1 antibodies in NSCLC and their favorable toxicity profiles, clinical trials have already been 
activated in early stage NSCLC. Two separate randomized phase III trials testing adjuvant therapy 
with durvalumab (NCT02273375/NCIC CTG BR.31) or MPDL3280A (Roche pharmaceutical) have 
been activated internationally including in the United States and Canada. Patients with completely 
resected NSCLC pathological stages 1B/II/IIIA will be randomized to either anti-PD-L1 antibody or 
placebo. Disease free survival is the primary endpoint in both trials 
 
2.2.7 Radiation and tumor immunity 
Radiation therapy is an essential component of the treatment of many solid tumors. Delivered alone, or 
in combination with chemotherapy, the aim of radiotherapy is to provide definitive and potentially 
curative tumor eradication for localized disease or palliation in the metastatic setting. In such instances 
the benefits of radiotherapy are generally attributed to a direct cytoreductive or cytocidal effect 
mediated by radiation induced DNA damage. However, emerging pre-clinical evidence suggests that 
radiotherapy, in addition to its direct cytocidal effects, can be a potent modulator of the local 
intratumoral and possibly systemic anti-tumor immune response, and thereby have specific anti-tumor 
effects beyond its direct effects on the cancer cells. Ionizing radiation may potentiate antitumor 
immunity by acting directly on tumor cells rendering them more immunogenic and by inducing 
adjuvant signals in the tumor microenvironment in a manner that favors an anti-tumor immune milieu. 
For example, radiation by acting directly on tumor cells can lead to “immunogenic cell death”; a 
phenomenon characterized not only by simple neo-antigen release from cancer cells but also by the 
release of various danger signals that favor dendritic cell maturation and activation, and the 
recruitment of tumor antigen specific CD8 T-cells 53-54. These signals include the release of the nuclear 
protein high mobility group box 1, adenosine tri-phosphate as well as the translocation of calreticulin 
from the endoplasmic reticulum to the plasma membrane where it acts as an “eat me” signal for 
antigen presenting cells55-57. These cell death associated molecules bind their respective receptors on 
intra-tumoral immature dendritic cells leading to activation of the inflammasome with DC maturation, 
secretion of IL1ß and evolution of antigen specific CD8 T cells 52. Radiation can enhance tumor 
antigen presentation by up-regulation in cancer cells of MHC class I molecules that are necessary for 


Page 15 of 85 
 
endogenous peptide presentation as well as by up-regulating the expression of tumor specific antigens 
such as cancer testis antigens 58-59. Radiation can also render tumor cells more susceptible to T cell 
cytolytic activity by enhancing Fas gene expression60. Beyond its direct effect on cancer cells, ionizing 
radiation can modify the tumor microenvironment by triggering a cytokine/chemokine mediated 
inflammatory response with the recruitment of immune/inflammatory cells including monocytes, 
macrophages, DCs as well as effector T cells 18. Other radiation induced changes in the tumor 
microenvironment demonstrated in preclinical experiments include the up-regulation in endothelial 
cells of the adhesion molecules VCAM-1 and ICAM-1 that facilitate trafficking of immune cells into 
the tumor microenvironment61. 
Many of these radiation-induced effects on the cancer cell and its microenvironment have been 
demonstrated to occur in human cancer cell lines and preclinical models even with sub-lethal doses of 
radiation 62. Despite its role in generating or potentiating an anti-tumor immune response, ionizing 
radiation can also contribute to an immuno-suppressive tumor microenvironment by the recruitment of 
myeloid derived suppressor cells, tumor associated macrophages and T-regs as well as by the inducing 
the secretion of the immunosuppressive cytokine, TGFß63-65. The net balance between the pro and anti-
immunogenic effects of radiation therapy likely influences whether or not radiation results in an 
effective anti-tumor immune response. However, the currently available evidence supports the concept 
that radiation even at sub lethal doses can render cancer cells more immunogenic. 
 
2.2.8 Radiation combined with immune checkpoint inhibition 
Despite the success of radiation in controlling local disease, the majority of patients develop either 
regional or systemic relapse. Clearly the pro-immunogenic effects of radiation are insufficient to either 
initiate or sustain an effective and durable anti-tumor immune response. Combining radiotherapy with 
immune checkpoint blockade has been tested in several preclinical models. In an orthotopic mouse 
model of glioma, stereotactic radiation (10Gyx1) was given in combination with an anti-PD1 
antibody23. Long-term cures were observed in some mice treated by combination therapy but in none 
treated by either modality alone. Post-mortem examination showed that the brains of cured animals 
contained increased cytotoxic T cells. Furthermore, when cured mice were re-challenged several 
months later by flank injections of isogenic tumor cells, they failed to establish flank tumors in contrast 
to tumor naïve mice consistent with a systemic tumor antigen-specific memory immune response. 
Using a breast cancer mouse model with a primary tumor on one flank and a secondary tumor on the 
other flank, Dewan et al tested various fractionation schemes of radiation (20Gyx1, 8Gyx3 and 6Gyx5) 
given with or without an anti-CTLA-4 antibody 20. Radiation was delivered to the primary but not to 
the secondary site. Treatment with the antibody alone had no discernible effect on tumor growth. All 
fractionation schemes of radiation resulted in tumor growth delay in the irradiated primary tumor. 
Combination therapy resulted in enhanced tumor response at the primary site in all radiation treated 
animals. A tumor response at the secondary non-irradiated site (an abscopal effect) occurred only in 
mice treated with fractionated radiotherapy and was abrogated by T cell depletion21. Recently, Dovedi 
et al reported that in animal models of triple negative breast cancer, melanoma and colon cancer 
treatment with 5 daily fractions of radiation (2Gyx5) and anti-PDL1 antibody was curative in 66% of 
mice22. Long-term survival was associated with efficacious CD8+ T–cell responses and the induction 
of tumor antigen-specific memory immune response protecting against isogenic tumor re-challenge. 
The authors also found that treatment sequencing was critical for a favorable outcome with long-term 
survival associated with concurrent rather than sequential administration of combined therapy. The 
dose and fractionation of radiation necessary for optimal immune potentiation as well the exact 
sequencing of immune checkpoint inhibition have yet to be fully investigated. However, the preclinical 
studies by Dewan and Dovedi highlight the importance of using multiple fractions of radiation and 
concurrent administration of immune checkpoint blockade for generating efficacious CD8 T-cell 
responses necessary for tumor control and generation of antigen-specific immune memory to protect 
against re-challenge. This synergism between radiation and immune checkpoint inhibition is currently 


Page 16 of 85 
 
being tested in controlled clinical trials in some advanced solid tumors. Interestingly there are at least 
three well documented case reports of an abscopal effect observed in two patients with metastatic 
melanoma and two patients with metastatic lung cancer all of whom were treated by targeted 
hypofractionated radiation and ipilumumab 66-68. Both patients with NSCLC had refractory disease and 
required localized multiple fractions of radiation to a metastatic site along with anti-CTLA-4. A 
complete clinical response was documented in both patients including in metastatic sites outside the 
radiation field29. In the two patients with melanoma, tumor regression was associated with evidence of 
epitope spreading, strongly suggesting an immune contribution to the clinical outcome 66, 67. 
 
 
3.0 PATIENT SELECTION 
3.1 Inclusion Criteria  
1. Patient has histologically or cytologically proven clinical stages I (tumors > 2 cm), II, and IIIA 
NSCLC and is considered eligible for surgical resection with curative intent. Patients with 2 
primary non-small cell lung cancers are allowed. 
2. Measureable disease, as defined by RECIST v1.1.  
3. Written informed consent and HIPAA obtained from the subject prior to performing any 
protocol-related procedures. 
4.  Age > 18 years at time of study entry 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
6. Adequate normal organ and marrow function as defined below:   
• 
Haemoglobin ≥ 9.0 g/dL 
• 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)  
• 
Platelet count ≥ 100 x 109/L (>100,000 per mm3)  
• 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will not apply to 
subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia 
that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), 
who will be allowed only in consultation with their physician. 
• 
AST (SGOT)/ALT (SGPT), and alkaline phosphatase ≤ 2.5 x institutional upper limit of 
normal (ULN). 
• 
Serum creatinine CL>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 
1976) or by 24-hour urine collection for determination of creatinine clearance: 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)       . 
72 x serum creatinine (mg/dL) 
 
 
 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age)        x 0.85 
72 x serum creatinine (mg/dL) 
 
7. 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 


Page 17 of 85 
 
amenorrheic for 12 months without an alternative medical cause. The following age-specific 
requirements apply:  
Women <50 years of age would be considered post-menopausal if they have been amenorrheic 
for 12 months or more following cessation of exogenous hormonal treatments and if they have 
luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for 
the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).  
Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic 
for 12 months or more following cessation of all exogenous hormonal treatments, had 
radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced 
menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy). 
8. Subject is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
9. No prior therapy for their lung cancer. 
 
3.2 Exclusion Criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Participation in another clinical study with an investigational product during the last 3 weeks. 
2. History of another primary malignancy except for: 
• 
Malignancy treated with curative intent and with no known active disease ≥3 years before 
the first dose of study drug and of low potential risk for recurrence. 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease. 
• 
Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in 
situ, in-situ urinary bladder cancer , treated localized prostate cancer and ductal 
carcinoma-in situ. 
• 
Indolent hematological malignancies 
3. Current or prior use of immunosuppressive medication within 14  days before the first dose of 
durvalumab, with the exceptions of intranasal,inhaled, topical steroids, or local steroid 
injections (e.g., intra articular injection), corticosteroids or systemic corticosteroids at 
physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent 
corticosteroid, and steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 
4. Any unresolved toxicity (CTCAE grade 2) from therapy for a prior malignancy with the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.  
• 
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 
• 
Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the 
investigational product may be included (e.g., hearing loss, peripherally neuropathy). 
5. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1. 
6. Active or prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease [e.g., colitis or Crohn's disease systemic lupus erythematosus, Sarcoidosis 
syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, 
rheumatoid arthritis, hypophysitis, uveitis, etc]). No active diverticulitis within the previous 3 
months. The following are exceptions to this criterion: 
• 
Patients with vitiligo or alopecia 
• 
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone 


Page 18 of 85 
 
replacement  
• 
Any chronic skin condition that does not require systemic therapy 
• 
Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician 
• 
Patients with celiac disease controlled by diet alone 
7. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis). 
8. History of active primary immunodeficiency. 
9. History of allogeneic organ transplant.  
10. History of hypersensitivity to durvalumab or any excipient.  
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
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 AEs or compromise the ability of the patient to give 
written informed consent. 
12. Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local practice), 
hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human 
immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of 
HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
13. History of leptomeningeal carcinomatosis. 
14. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of 
receiving durvalumab. 
15. Female patients who are pregnant or breastfeeding 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. 
16. Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of patient safety or study results 
17. Subjects with uncontrolled seizures. 
18. History of interstitial lung disease, idiopathic pulmonary fibrosis, pneumonitis (including drug 
induced), or evidence of active pneumonitis on screening chest CT scan. 
19. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a 
major surgical procedure during the course of the study. 
20. Receipt of the last dose of therapy (chemotherapy, immunotherapy, endocrine therapy, 
targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, or other 
investigational agent) for an accepted other malignancy as defined in Section 3.3.2 within 30 
days prior to the first dose of study drug for lung cancer. 
21. Prior randomisation or treatment in a previous durvalumab clinical study. regardless of 
treatment arm assignment. 
 
 
4.0 REGISTRATION AND RANDOMIZATION PROCEDURES 
4.1 Registration 
Eligible subjects will be identified by the Principal Investigator’s and co-investigators’ from the 
Thoracic or Medical Oncology clinics at NYP-Weill Cornell or collaborating institutions. Individuals 
will be approached and informed of the rationale for the study, investigational nature of the protocol 
and study drug and the voluntary nature of participation, potential risks and benefits, alternatives to 


Page 19 of 85 
 
participation, and study procedures.  Individuals will have the opportunity to read the written informed 
consent document with the understanding that should they decide not to participate, they will still be 
able to receive any available therapy off-trial.  Potential subjects will also have the opportunity to 
obtain the advice of their treating physician.  Investigators or delegates under their direct supervision 
will verify the subject’s understanding of the investigational and voluntary nature of the study, the 
potential risks and benefits, study procedures, and alternatives prior to signing of the written informed 
consent. Those who wish to participate in the trial will be required to sign an informed consent form 
after all their questions are answered. Subjects will be registered to the trial once they have met the 
eligibility criteria. Documentation of the consent process and that written consent was conducted must 
be documented in the subject’s medical record. 
 
4.2 Randomization 
Blocked randomization will be performed for the secondary aim. A series of randomized blocks of 4 
will be generated with a 1:1 allocation ratio. This will provide assurance that after four patients are 
enrolled in the study, there will be two patients assigned to the antibody + radiation arm and two 
patients assigned to the antibody + no radiation arm. This procedure will allow for a similar number of 
antibody + radiation patients (Arm 2) and antibody + no radiation patients (Arm 1). 
 
5.0 STUDY DESIGN 
This is a randomized open label phase II trial of preoperative anti-PD-L1 antibody durvalumab with or 
without concurrent non-ablative radiation followed by surgical resection and postoperative 
maintenance durvalumab every 4 weeks for 12 cycles.  
 
5.1 Treatment Plan 
Patients with biopsy proven NSCLC clinical stages I (tumors > 2 cm), II, and IIIA will be randomly 
assigned to 2 preoperative cycles of the anti-PD-L-1 antibody durvalumab followed by surgical 
resection or non-ablative stereotactic radiotherapy given concurrently with the first cycle of the anti-
PD-L1 antibody followed by an additional cycle of the antibody alone followed by surgical resection. 
In both arms of the trial, patients will receive adjuvant durvalumab every 4 weeks for a total of 12 
cycles. Patients randomized to the antibody alone arm will receive two cycles of durvalumab at a dose 
of 1.12 g every three weeks. Patients in the radio-immunotherapy arm will also be treated with two 
cycles of durvalumab (1.12 g q 3 weeks) plus radiotherapy delivered in 3 daily fraction of 8Gy starting 
concurrently with the first cycle of durvalumab (see trial schema). This delivered non-ablative 
radiation dose of 24 Gy is equivalent to a biologically effective dose (BED) of 43.2Gy, which is 
significantly lower than the standard therapeutic dose for ablation of T1-T2 NSCLC (BED>100Gy). 
The objective is to induce immunogenic cell death, enhance antigen presentation and increase 
cytotoxic T lymphocyte activity without tumor ablation. This non-ablative dose of radiation is selected 
based on the results of studies by one of our co-investigators showing that the 8 Gyx3 regimen resulted 
in significant immune modulation in preclinical models (24).  A research core biopsy for the collection 
of tumor tissue is suggested but not mandatory. If a tissue biopsy has already been obtained for 
diagnostic purposes, a core biopsy may be performed for research purposes only to obtain tumor tissue. 
If a tissue biopsy has not been performed yet for diagnostic purposes, a core biopsy may be performed 
for diagnosis and tissue will be obtained for research purposes. Tissue from the preoperative core 
samples and from the resected surgical specimens will be stored for future correlative studies. 
Although PDL-1 expression is not required for eligibility, preoperative and post-operative tissue will 
be stored for future determination of PDL-1 expression. All patients will proceed to surgical resection 
2-6 weeks after the second cycle of durvalumab regardless of local response assessment and provided 
that repeat imaging shows no evidence of systemic disease. Postoperative durvalumab will commence 
4-12 weeks postoperatively at a fixed dose of 1.5 g every 4 weeks for 12 cycles. Patients receiving 
adjuvant chemotherapy may commence adjuvant monthly anti-PD-L1 after completing chemotherapy. 


Page 20 of 85 
 
 
5.2 Limiting normal tissue toxicities with non-ablative SBRT 
The thoracic organs that are at risk for radiation injury (i.e., organs at risk [OARs] from non-ablative 
SBRT doses and are expected to be determinants of toxicity are lung, central airway/bronchi, 
esophagus, heart, great vessels, spinal cord, and brachial plexus). There is a large body of knowledge 
on the RT tolerance of those organs to conventionally fractionated RT (1.8-2 Gy per fraction), 
describing the RT tolerance in terms of volume of the organ irradiated to a certain dose (e.g., V20, 
volume irradiated to 20 Gy or more) or as mean RT dose to the entire organ. Recently the Task Group 
101 (TG-101) of the American Association of Physicists in Medicine (AAPM) has prepared a report to 
outline the best practice guidelines for SBRT, including protocols, equipment, resources, and quality 
assurance procedures.6 The TG-101 guidelines by the AAPM will be respected. Because the nidus of 
irradiated tumor and peri-tumoral lung will be removed at the time of surgery, we expect the 
probability of radiation pneumonitis to be minimal. 
• 
Immobilization: The SBRT frame serves to both immobilize the patient physically and 
provide an initial approximate target localization, which is refined by in-room image 
guided techniques. Abdominal compression can be used to minimize respiratory motion, 
but is not required. 
• 
Simulation imaging: Three-dimensional data sets assembled from 4DCT for visualization 
and dose calculation for SBRT. CT will be the primary imaging modality for SBRT and 
will form the basis for treatment calculations. Simulation will take place with the patient in 
the treatment position. A typical scan should extend at least 5-10 cm (15cm for non-
coplanar beams) superior and inferior beyond he treatment field. Along with the target, all 
OARs should be included and covered by the selected scan length so they can be 
considered by the treatment planning software and evaluated with dose-volume 
histograms. For SBRT applications, tomographic slice thickness of 1-3 mm will be used. 
• 
Data acquisition for mobile lung tumors and respiratory motion management: Techniques 
to image moving targets include slow CT, breath-hold techniques, gated approaches, 
4DCT used in conjunction with maximum-intensity projection, minimum-intensity 
projection, and respiration-correlated PET-CT. 
• 
Treatment planning: Planning will make use of the ICRU 50 and 62 definitions for gross 
tumor volume (GTV), clinical tumor volume (CTV), planning target volume (PTV) and 
OAR. With SBRT the GTV and CTV are considered identical. The PTV addresses all the 
possible geometrical variations by adding a variable margin for setup uncertainties, 
machine tolerances, and intratreatment variations to the CTV. By using the 4DCT to 
treatment planning the CTV to PTV expansion will be 0.5 cm in all directions. 
• 
Dose constraints: Dose constraints for OARs published by the TG-101 AAPM report will 
be respected.  
• 
Image-guided localization: Volumetric image guidance will allow for the precise 
localization of bone and soft tissue targets. This will be achieved with MV of kV cone 
beam scanning.  
 
5.3 Duration of follow-up 
Post-operatively, patients will be followed monthly from the date of the last infusion dose until month 
4, at month 6, and subsequently every 6 months for 2 years. Patients removed from the study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse event.  
Follow-up imaging will be performed by CT scan every 6 months for 2 years. Recurrent disease should 
be pathologically confirmed whenever possible. 
 
5.4 Withdrawal of Subjects from Study Treatment and/or Study 


Page 21 of 85 
 
5.4.1 Permanent discontinuation of Durvalumab 
An individual subject will not receive any further investigational product if any of the following occur 
in the subject in question: 
1. Withdrawal of consent or lost to follow-up 
2. Adverse event that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing 
3. Subject is determined to have met one or more of the exclusion criteria for study participation 
at study entry and continuing investigational therapy might constitute a safety risk 
4. Pregnancy or intent to become pregnant 
5. Any AE that meets criteria for discontinuation as defined in Section 6.0 
6. Adverse event related to durvalumab that is Grade ≥ 3, with the exception of toxicities that do 
not meet criteria for discontinuation as defined in Section 6.0 
7. Grade ≥ 3 infusion reaction 
8. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; eg, refusal to adhere to scheduled visits 
Initiation of alternative anticancer therapy including another investigational agent  
Subjects who are permanently discontinued from further receipt of investigational product, regardless 
of the reason (withdrawal of consent, due to an AE, other), will be identified as having permanently 
discontinued treatment. Subjects who are permanently discontinued from receiving investigational 
product will be followed for safety, including the collection of any protocol-specified blood specimens, 
unless consent is withdrawn or the subject is lost to follow-up or enrolled in another clinical study. All 
subjects will be followed for survival.  
 
5.4.2 Withdrawal of consent 
If consent is withdrawn, the subject will not receive any further investigational product or further study 
observation.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to: 
• 
all further participation in the study including any further follow up (e.g., survival contact 
telephone calls) 
• 
withdrawal of consent to the use of their study generated data 
• 
withdrawal to the use of any samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 22 of 85 
 
 
 
 
 
5.5 STUDY PROCEDURES 
The Schedules of Assessments during the screening and treatment period is provided below. 
 
Table 1. Schedule of study assessments: Screening and Treatment Period 
Visit  
(Assessments to be 
performed at the times 
stipulated in the table 
and as clinically 
required in the 
management of the 
subject.) 
 
Screeni
ng 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline 
Every 3 weeks 
 
Pre-
operative 
 
Surgical 
resection
m 
Postoperatively every 
4 weeks for 12 cycles 
Day 
-28 to -
1 
1 
22 
36-49  
36-69  
Day 1 of the week 
Week 
-4 to -1 
1 
4 
 6-7  
6-10 
11, 15, 19, 23, 27, 31, 
35, 39, 43, 47, 51, 55  
(±3 days) 
 
Written informed 
consent/assignment of  
subject identification 
number 
X 
 
 
 
 
 
Preliminary eligibility 
fulfilment 
(investigator’s opinion) 
X 
 
 
 
 
 
Demography and 
history of tobacco and 
alcohol use 
X 
 
 
 
 
 
Previous treatments for 
NSCLC 
X 
 
 
 
 
 
Core Biopsya 
X 
 
 
 
 
 
Formal verification of 
eligibility criteria 
X 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
Hepatitis A antibody, 
hepatitis B surface 
antigen, hepatitis C 
antibody; HIV antibody 
X 
 
 
 
 
 


Page 23 of 85 
 
Table 1. Schedule of study assessments: Screening and Treatment Period 
Visit  
(Assessments to be 
performed at the times 
stipulated in the table 
and as clinically 
required in the 
management of the 
subject.) 
 
Screeni
ng 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline 
Every 3 weeks 
 
Pre-
operative 
 
Surgical 
resection
m 
Postoperatively every 
4 weeks for 12 cycles 
Day 
-28 to -
1 
1 
22 
36-49  
36-69  
Day 1 of the week 
Week 
-4 to -1 
1 
4 
 6-7  
6-10 
11, 15, 19, 23, 27, 31, 
35, 39, 43, 47, 51, 55  
(±3 days) 
 
Urine hCG or serum 
βhCGb 
X 
X 
As clinically indicated 
ARM 1 
Durvalumab 
administration 
(monotherapy) 
 
X 
 
X 
 
 
 
 
X k (monotherapy) 
ARM 2 
Durvalumab 
administration plus 
SBRT 8 Gy  
 
 
Xl 
 
 
 
 
 
 
X k (monotherapy) 
Physical examinationc 
X 
X 
X 
X 
 
X 
Vital signs (pre- during 
and post-infusion vital 
signs assessments)d 
X 
X 
X 
X 
 
 
X 
Weight 
X 
X 
X 
X 
 
X 
Electrocardiograme 
X 
X 
 
 
 
 
Adverse event/serious 
adverse event 
assessment 
X 
X 
All visits 
Concomitant 
medications 
X 
X 
All visits 
ECOG performance 
status 
X 
X 
X 
X 
 
X 


Page 24 of 85 
 
Table 1. Schedule of study assessments: Screening and Treatment Period 
Visit  
(Assessments to be 
performed at the times 
stipulated in the table 
and as clinically 
required in the 
management of the 
subject.) 
 
Screeni
ng 
All assessments to be performed pre-infusion unless stated otherwise 
Baseline 
Every 3 weeks 
 
Pre-
operative 
 
Surgical 
resection
m 
Postoperatively every 
4 weeks for 12 cycles 
Day 
-28 to -
1 
1 
22 
36-49  
36-69  
Day 1 of the week 
Week 
-4 to -1 
1 
4 
 6-7  
6-10 
11, 15, 19, 23, 27, 31, 
35, 39, 43, 47, 51, 55  
(±3 days) 
 
Serum Chemistry 
(complete clin chem. 
panel including Liver 
enzymes)f 
X 
X 
X 
X 
 
 
X 
Gamma 
glutamyltransferase 
X 
X 
As clinically indicted 
X 
Thyroid function tests 
(TSH and fT3 and fT4)g 
X 
X 
X 
X 
 
X 
Hematologyf 
X 
X 
           X 
X 
 
X 
Urinalysish 
X 
X 
X 
 
 
X 
Coagulation 
parametersi 
X 
As clinically indicted 
X 
Tumor assessment 
(CT/PET scan) n 
X 
 
 
X 
 
 
 
Tumor assessment 
(Chest CT scan non-
contrast) j 
 
 
 
 
 
X 
a Tissue from core biopsies and resected specimens will be stored for future correlative studies . A 
research core biopsy for collection of tumor tissue is suggested but not mandatory. 
b  Pre-menopausal female subjects of childbearing potential only.  
c Full physical examination at baseline; targeted physical examination at other timepoints.  
d Vital signs are temperature, blood pressure, pulse rate, and respiratory rate. Subjects will have their 
blood pressure and pulse measured before, during and after the infusion at the following times (based 
on a 60-minute infusion): 
• 
At the beginning of the infusion (at 0 minutes) 
• 
At 30 minutes during the infusion (±5 minutes) 
• 
At the end of the infusion (at 60 minutes ±5 minutes) 


Page 25 of 85 
 
• 
In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 
120 minutes from the start of the infusion) (±5 minutes) – for the first infusion only and then 
for subsequent infusions as clinically indicated 
If the infusion takes longer than 60 minutes then blood pressure and pulse measurements 
should be collected every 30 minutes (±5 minutes) and as described above or more frequently 
if clinically indicated. 
e At screening and at Day 1-baseline,  and as clinically indicated.  Baseline and abnormal ECG at any 
time in triplicate, at screening in single. ECGs should be taken within an hour prior to the start of the 
infusion at Baseline C1D1.   
f If screening laboratory assessments are performed within 7 days prior to Day 1 they do not need to be 
repeated at Day 1. Results for safety bloods must be available and reviewed before commencing an 
infusion. Gamma glutamyltransferase (GGT) tested at Screening, Day 1 and as clinically indicated. 
g Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there 
is clinical suspicion of an adverse event related to the endocrine system. 
h Urinalysis performed at Screening, Day 1, Day 22,  every 4 weeks during adjuvant durvalumab 
treatment, and as clinically indicated. 
i Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically 
indicated. 
j  Post-operative CT scans  are performed every 6 months for 2 years. 
k Subjects in Arm 1 and Arm 2 will receive adjuvant treatment with durvalumab monotherapy at 1.5 g 
every 4 weeks for 12 cycles starting 4-12 weeks postoperatively, following standard of care 
postoperative therapy, as required. Refer to Section 8.1.3 for subjects weighing ≤ 30 kg. 
l SBRT 8 Gy will be given on days 1, 2, and 3 only. On day 1, SBRT will be given prior to the 
durvalumab administration. 
m Surgical resection will take place 2 -6 weeks after the last dose of durvalumab. Tumor, adjacent 
normal lung, and lymph node specimens will be obtained from the surgical resection specimen, snap 
frozen. 
n Standard of care CT/PET scans performed prior to obtaining informed consent and within 42 days 
prior to C1D1 may be used for screening.  
  
Screening laboratory procedures performed within 7 days of Cycle 1 Day 1 (C1D1) do not need to be 
repeated on C1D1. 
 
A 12-lead ECG will be recorded for all subjects on study days noted in Section 5.5, Schedule of Study 
Assessments. ECGs are required during Screening, at Baseline prior to starting study treatment on 
Cycle 1 Day 1 (C1D1), and at any other time point when clinically indicated. ECGs recorded during 
the screening period will be single tracing and ECGs recorded at Baseline prior to C1D1 will be 
obtained in triplicate (with 2-5 minute lag time between each). All 12-lead ECGs should be recorded 
while the subject is in the supine position. The same method of assessment should be used throughout 
the study. Twelve-lead ECGs will be obtained after the subject has been resting in a supine position for 
at least 5 minutes in each case. At Screening, a single ECG will be obtained on which QTcF must be 
<470 ms. In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 
additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the 
finding.  
 
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) will be measured on study 
days noted in the Schedule of Assessments. On durvalumab treatment days, vital signs will be 
measured within an hour prior to start of durvalumab administration, at 30 minutes during the infusion 
(± 5 minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 minutes) and 60 minutes (± 
5 minutes) post-infusion.  If the infusion takes longer than 60 minutes, then blood pressure and pulse 


Page 26 of 85 
 
measurements should follow the principles described here, or more frequently if clinically indicated.  
For subsequent doses the 1-hour observation period will not be required unless a subject experiences 
an infusion-related reaction.  


Page 27 of 85 
 
Table 2. Schedule of study procedures: follow-up for subjects who have completed or 
discontinued  Durvalumab treatment  
Evaluation 
Time Since Last Dose of  Durvalumab 
Day (±3) 
Months (±1 
week) 
Every 6 Months for 2 
years  
(±2 weeks) 
30 
2 
3 
4 
6 
 
Physical examinationa 
X 
 
 
 
 
 
Vital signs (temperature, respiratory rate, 
blood pressure, pulse) 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
Urine hCG or serum βhCG 
X 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
 
 
 
Concomitant medications 
X 
X 
X 
 
 
 
ECOG performance status 
X 
X 
X 
 
X  
X 
Adjuvant anti-cancer therapy, if required, as 
standard of care 
X 
X 
X 
X 
X 
X 
Phone contact with subjects 
 
 
 
X 
 
 
Hematology 
X 
X 
X 
 
 
 
Serum chemistry  
X 
X 
X 
 
 
 
Thyroid function tests (TSH, and fT3 and 
fT4)b  
X 
 
 
 
 
 
Tumour assessment (non-contrast Chest CT 
scan) 
Tumour assessments should be performed every 6 
months for 2 years  
 
a Full physical exam 
b Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there 
is clinical suspicion of an adverse event related to the endocrine system. 
The following clinical laboratory tests will be performed (see Schedule of study assessments and 
Schedule of procedures: follow-up) for the timepoints of each test): 
• 
Coagulation parameters: Activated partial thromboplastin time and International normalised 
ratio to be assessed at baseline and as clinically indicated  
• 
Pregnancy test (female subjects of childbearing potential only) 
o Urine human chorionic gonadotropin 
o Serum beta-human chorionic gonadotropin (at screening only) 
• 
Thyroid Stimulating Hormone 
o free T3 and free T4 only if TSH is abnormal or if there is a clinical suspicion of an 
AE related to the endocrine system  
• 
Other laboratory tests 
o Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody 
o HIV antibody 


Page 28 of 85 
 
 
Hematology Laboratory Tests 
Basophils 
Mean corpuscular volume 
Eosinophils 
Monocytes 
Hematocrit 
Neutrophils 
Hemoglobin 
Platelet count 
Lymphocytes 
Red blood cell count 
Mean corpuscular hemoglobin 
Total white cell count 
Mean corpuscular hemoglobin 
concentration 
 
 
 
 
Clinical chemistry(serum or plasma) Laboratory Tests 
Albumin 
Glucose 
Alkaline phosphatase (ALP) 
Lactate dehydrogenase 
Alanine aminotransferase (ALT) 
Lipase 
Amylase 
Magnesium 
Aspartate aminotransferase (AST) 
Potassium 
Bicarbonate 
Sodium 
Calcium  
Total bilirubina 
Chloride 
Total protein 
Creatinine 
Urea or blood urea nitrogen, depending on local practice 
Gamma glutamyltransferaseb (GGT)   
Uric acid 
a   If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and 
indirect bilirubin 
b At baseline and as clinically indicated 
 
Urinalysis Tests 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Colour and appearance 
a  Microscopy should be used as appropriate to investigate white blood cells and use the high power 
field for red blood cells 
 
Assessments for subjects who have completed durvalumab treatment or have discontinued durvalumab 
due to toxicity in the absence of confirmed progressive disease are provided in confirmed progressive 
disease are provided in Table 2 above.   
 
 
 
 
 


Page 29 of 85 
 
6.0 DOSE DELAYS/DOSE MODIFICATIONS 
6.1 Dose Modification and Toxicity Management 
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and non-
immune-mediated reactions for durvalumab are in the Dosing Modification and Toxicity Management 
Guidelines in Appendix B. Patients should be thoroughly evaluated and appropriate efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support an 
imAE diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune related. In addition, there are certain circumstances in which durvalumab should be 
permanently discontinued (see section 5.4.1 and the Dosing Modification and Toxicity Management 
Guidelines in Appendix B). 
Following the first dose of durvalumab, subsequent administration of durvalumab can be modified 
based on toxicities observed as described in the Dosing Modification and Toxicity Management 
Guidelines in APPENDIX B.  Dose reductions are not permitted. Based on the mechanism of action of 
durvalumab leading to T-cell activation and proliferation, there is the possibility of observing immune 
related Adverse Events (irAEs) during the conduct of this study.  Potential irAEs include immune 
mediated enterocolitis, dermatitis, hepatitis, and endocrinopathies. Subjects should be monitored for 
signs and symptoms of irAEs.  In the absence of an alternate etiology (e.g., infection or PD) signs or 
symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to be 
immune-related.   
Dose modification recommendations and toxicity management guidelines for immune-mediated 
reactions, for infusion-related reactions, and for non-immune-mediated reactions are detailed in 
Appendix B, Tables 1, 2, and 3 respectively.   
In addition, management guidelines for adverse events of special interest (AESIs) are detailed in 
Appendix B, Table 1. All toxicities will be graded according to NCI CTCAE v4.03. 
 
6.2 Study Restrictions and Concomitant Treatment 
6.2.1 Contraception 
Females of childbearing potential who are sexually active with a nonsterilised male partner must use 1 
highly effective method of contraception from screening and must agree to continue using such 
precautions for 90 days after the final dose of investigational product; cessation of birth control after 
this point should be discussed with a responsible physician.  Non-sterilized male partners of a female 
patient must use male condom plus spermicide throughout this period. 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. 
• 
Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal. 
• 
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 or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).  
- 
Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic 
for 12 months or more following cessation of all exogenous hormonal treatments, had 
radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced 
menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy). 
• 
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., less 
than 1% per year) when used consistently and correctly are described in Table 2. Note that some 


Page 30 of 85 
 
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). 
  
• 
Nonsterilised males who are sexually active with a female partner of childbearing potential must use 
use male condom plus spermicide (see Table 1) from Day 1 and for 90 days after receipt of the final 
dose of investigational product.  
 
 
Table 1. 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 
 
 
6.2.2 Blood donation 
Subjects should not donate blood while participating in this study 
 
6.2.3 Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care except for 
those medications identified as “excluded” as listed in Section 6.2.4. 
 
 
 
 
 
 
 


Page 31 of 85 
 
Table 2. Supportive Medications 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications identified 
as “prohibited,” as listed above  
To be administered as prescribed by the 
Investigator 
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to non-target lesions, etc]) 
Should be used, when necessary, for all 
patients 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
 
6.2.4 Excluded Concomitant Medications 
The following medications are considered exclusionary during the study.  
1. Any investigational anticancer therapy other than the protocol specified therapies  
2. mAbs against CTLA-4, PD-1, or PD-L1 other than those under investigation in this study. 
3. Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy 
for cancer treatment, other than the protocol specified therapy.  Concurrent use of hormones 
for noncancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) 
is acceptable.   
4. Immunosuppressive medications including, but not limited to systemic corticosteroids at doses 
not exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α 
blockers. Use of immunosuppressive medications for the management of investigational 
product-related AEs or in subjects with contrast allergies is acceptable. In addition, use of 
inhaled and intranasal corticosteroids is permitted. 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). 
5. Live attenuated vaccines within 30 days of durvalumab dosing (i.e., 30 days prior to the first 
dose, during treatment with durvalumab and for 30 days post discontinuation of durvalumab).  
Inactivated viruses, such as those in the influenza vaccine, are permitted. 
6. EGFR TKIs should not be given concomitantly and should be used with caution in the 90 days 
post last dose of durvalumab. Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has been given concomitantly.  
7. Herbal and natural remedies which may have immune-modulating effects. 
 
 
 
 
 


Page 32 of 85 
 
7.0 ASSESSMENT OF SAFETY 
7.1. Safety Parameters 
7.1.1.1 Definition of adverse events 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6 
(R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-existing 
condition. An abnormal laboratory finding (including ECG finding) that requires an action or 
intervention by the investigator, or a finding judged by the investigator to represent a change beyond 
the range of normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of investigational 
product) or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been obtained 
but before the subject has received investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
subject being enrolled into the study) for a documented pre-existing condition, that did not worsen 
from baseline, is not considered an AE (serious or nonserious). An untoward medical event occurring 
during the prescheduled elective procedure or routinely scheduled treatment should be recorded as an 
AE or SAE. The term AE is used to include both serious and non-serious AEs. 
 
7.1.2 Definition of serious adverse events 
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, treatment, 
wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital abnormality or birth defect in offspring of the subject 
• 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this 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 causality of SAEs (their relationship to all study treatment/procedures) will be assessed by the 
investigator(s) and communicated to AstraZeneca 
 
7.1.3 Definition of adverse events of special interest (AESI) 
An AESI is one of scientific and medical interest specific to understanding of the investigational 
product and may require close monitoring and rapid communication by the investigator to 
AstraZeneca/Medimmune. An AESI may be serious or nonserious. The rapid reporting of AESIs 
allows ongoing analysis of these events in order to characterize and understand them in association 
with the use of this investigational product. 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or immune-


Page 33 of 85 
 
mediated mechanism and which may require more frequent monitoring and/or interventions such as 
steroids, immunosuppressants and/or hormone replacement therapy. These AESIs are being closely 
monitored in clinical studies with durvalumab monotherapy and combination therapy. An immune-
related adverse event (irAE) is defined as an adverse event that is associated with drug exposure and is 
consistent with an immune-mediated mechanism of action and where there is no clear alternate 
etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 
support an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the irAE.  
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
• 
Diarrhea/Colitis and intestinal perforation 
• 
Pneumonitis/ILD 
• 
Hepatitis/transaminase increases 
• 
Neuropathy / neuromuscular toxicity (Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e. events of hypophysitis, hypopituitarism adrenal insufficiency, , hyper- 
and hypothyroidism, and type I diabetes mellitus),  
• 
Rash/Dermatitis 
• 
Nephritis/blood creatinine increases 
• 
Pancreatitis  (serum lipase and amylase increases)   
• 
Myocarditis 
• 
Myositis/Polymyositis 
• 
Intestinal perforations 
 
Other inflammatory responses that are rare with a potential immune-mediated aetiology 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 Brochure. 
7.1.4 Pneumonitis 
Adverse events of pneumonitis are of interest for AstraZeneca/Medimmune, as pneumonitis has been 
reported with anti-PD-1 MAbs 51. Initial work-up should include high-resolution CT scan, ruling out 
infection, and pulse oximetry. Pulmonary consultation is highly recommended.  
Guidelines for the management of subjects with immune-mediated events including pneumonitis are 
outlined in Appendix B, Table 1. 


Page 34 of 85 
 
 
7.1.5 Hypersensitivity reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti PD-L1 and 
anti-PD-1 therapy 51, 69. As with the administration of any foreign protein and/or other biologic agents, 
reactions following the infusion of MAbs can be caused by various mechanisms, including acute 
anaphylactic (immunoglobulin E-mediated) and anaphylactoid reactions against the MAb, and serum 
sickness. Acute allergic reactions may occur, may be severe, and may result in death. Acute allergic 
reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, 
angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness. 
Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) and 
infusion related reactions are outlined in Appendix B, Table 1. 
 
7.1.6 Hepatic function abnormalities (hepatotoxicity) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 antibodies 69. 
Inflammatory hepatitis has been reported in 3% to 9% of subjects treated with anti CTLA-4 
monoclonal antibodies (e.g., ipilimumab).  The clinical manifestations of ipilimumab-treated subjects 
included general weakness, fatigue, nausea and/or mild fever and increased liver function tests such as 
AST, ALT, alkaline phosphatase, and/or total bilirubin. 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN and 
concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are those that 
derive from a single blood draw or from separate blood draws taken within 8 days of each other. 
Follow-up investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective evidence that clearly 
supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with distended 
gallbladder) or an agent other than the investigational product. Guidelines for management of subjects 
with hepatic function abnormality are outlined in Appendix B, Table 1. 
Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need to be 
reported as SAEs, These cases should be reported as SAEs if, after evaluation they meet the criteria for 
a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE criteria. 
Criteria for Hy’s Law (FDA Guidance 2009) 
• 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3 fold or 
greater elevations above the ULN of ALT or AST  
• 
Among trial subjects showing such aminotransferase elevations, often with aminotransferases 
much greater than 3 x ULN, one or more also show elevation of serum total bilirubin to >2 x 
ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase)  
• 
No other reason can be found to explain the combination of increased aminotransferases and 
total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury. 
 
7.1.7 Gastrointestinal disorders 
Diarrhea/colitis is the most commonly observed treatment emergent SAE when tremelimumab is used 
as monotherapy.  In rare cases, colon perforation may occur that requires surgery (colectomy) or can 
lead to a fatal outcome if not properly managed.  Guidelines on management of diarrhea and colitis in 
patients receiving durvalumab are provided in Table 1. 
 
7.1.8 Endocrine disorders 
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine events 
are provided in Table 1. 


Page 35 of 85 
 
 
7.1.9 Pancreatic disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase elevation.  
Guidelines for the management of patients with immune-mediated pancreatic disorders are provided in 
Table 1. 
 
7.1.10 Neurotoxicity 
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of patients with 
immune-mediated neurotoxic events are provided in Table 1. 
 
7.1.11 Nephritis 
Consult with Nephrologist. Monitor for signs and symptoms that may be related to changes in renal 
function (e.g. routine urinalysis, elevated serum BUN and creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, proteinuria, etc). Patients should be thoroughly 
evaluated to rule out any alternative etiology (e.g., disease progression, infections etc.). 
Steroids should be considered in the absence of clear alternative etiology even for low grade events 
(Grade 2), in order to prevent potential progression to higher grade event. Guidelines for the 
management of patients with immune-mediated neurotoxic events are provided in Table 1. 
 
 
7.1.12 Radiation Risks 
This is a non-ablative subclinical radiation dose that is expected to be associated with minimal or no 
risk. 
 
7.2 Assessment of safety parameters 
7.2.1 Adverse Event Characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  A copy of the CTCAE version 4.0 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. 
 
 
 
7.3 Recording of Adverse Events 
All adverse events will be recorded on a patient specific adverse event log.  The AE log will be 
maintained by the research staff and kept in the patient’s research chart.    
 
 
Adverse events will be recorded using a recognized medical term or diagnosis that accurately reflects 
the event. Adverse events will be assessed by the investigator for severity, relationship to the 
investigational product, possible etiologies, and whether the event meets criteria of an SAE and 
therefore requires immediate notification to AstraZeneca/MedImmune Patient Safety.  
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 


Page 36 of 85 
 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against durvalumab (yes or no) 
• 
Action taken with regard to durvalumab  
• 
Outcome 
 
In addition, the following variables will be collected for SAEs as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
Reason AE is serious  
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s 
7.3.1 Study recording period and follow-up for AEs and SAEs 
Adverse events and serious adverse events will be recorded from time of signature of informed 
consent, throughout the treatment period and including the follow-up period (90 days after the last 
dose of durvalumab or initiation of new anti-cancer therapy, whichever occurs first). During the course 
of the study all AEs and SAEs should be proactively followed up for each subject. Every effort should 
be made to obtain a resolution for all events, even if the events continue after discontinuation/study 
completion. 
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain chronic, 
even if this extends beyond study participation. 
 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the investigator 
for as long as medically indicated, but without further recording in the eCRF.  After 90 days, only 
subjects with ongoing investigational product-related SAEs will continue to be followed for safety. 
AstraZeneca/MedImmune retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
 
7.3.2 Serious Adverse Event (SAE) Reporting 
7.3.3 Reporting of SAE to IRB 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy.  The IRB 
requires immediate reporting of all unexpected and study-related (definite or probable) adverse events.  
The following procedure will be followed for reporting SAE to the IRB: 
 
• 
Complete the SAE Cover Sheet (See Appendix C) 
• 
If the event is unexpected AND definitely or probably related to the study, complete the IRB 
Unexpected, Study-related Adverse Events, Incidents, and Information Reporting Form.  This 
form should be submitted within 24 hours of investigator notification of the event. 
• 
If the event is expected OR possibly or unrelated to the study, only the SAE Cover Sheet will 
be completed.  These events will be reported to the IRB at the time of continuing renewal on 
the Adverse Event & IND Safety Reporting Cumulative Table. 
 
Forms may also be downloaded from the IRB website at: 
http://www.med.cornell.edu/research/for_pol/ins_rev_boa.html 


Page 37 of 85 
 
 
7.3.4 Reporting of SAE to FDA  
All SAEs will be reported, whether or not considered causally related to the investigational product, or 
to the study procedure(s). The investigator is responsible for informing the IRB of the SAE as per 
section 7.5.2. The reporting period for SAEs is the period immediately following the time that written 
informed consent is obtained through 90 days after the last dose of durvalumab or until the initiation of 
alternative anticancer therapy.   
The Investigator will inform the FDA, via a MedWatch/AdEERs form, of any serious or unexpected 
adverse events that occur in accordance with the reporting obligations of 21 CFR 312.32, and will 
concurrently forward all such reports to AstraZeneca. A copy of the MedWatch/AdEERs report will be 
faxed to AstraZeneca at the time the event is reported to the FDA. It is the responsibility of the 
investigator to compile all necessary information and ensure that the FDA receives a report according 
to the FDA reporting requirement timelines and to ensure that these reports are also submitted to 
AstraZeneca at the same time. 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
• 
“Notification from an Investigator Sponsored Study” 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number (ESR-##-
#####) 
* The investigator will also indicate, either in the SAE report or the cover page, the causality of events 
in relation to all study medications and if the SAE is related to disease progression, as determined by 
the principal investigator. 
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox:    AEMailboxClinicalTrialTCS@astrazeneca.com 
 
If a non-serious AE becomes serious, this and other relevant follow-up information will also be 
provided to AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA still need to be reported to 
AstraZeneca preferably using the MedDRA coding language for serious adverse events.  This 
information should be reported on a monthly basis and under no circumstance less frequently than 
quarterly.  
 
7.3.5 Reporting of deaths 
All deaths that occur during the study or within the protocol-defined 90-day post-last dose of 
durvalumab safety follow-up period will be reported as follows: 
• 
Death that is clearly the result of disease progression should be documented but 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 will be reported to as a SAE within 24 hours. The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, and should 
assign main and contributory causes of death.   
• 
Deaths with an unknown cause should always be reported as a SAE.   
• 
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab safety 
follow-up period will be documented, but will not be reported as an SAE. 


Page 38 of 85 
 
 
7.3.6 Other events requiring reporting 
7.3.7 Overdose 
An overdose is defined as a subject 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 subject with durvalumab, with or without associated AEs/SAEs, is required to 
be reported within 24 hours of knowledge of the event to AstraZeneca/MedImmune Patient Safety or 
designee using the designated Safety e-mailbox AEMailboxClinicalTrialTCS@astrazeneca.com. If the 
overdose results in an AE, the AE will 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 will be recorded and reported as an SAE. There is currently no 
specific treatment in the event of an overdose of durvalumab. The investigator will use clinical 
judgment to treat any overdose. 
 
 
7.3.8 Hepatic function abnormality 
Hepatic function abnormality (as defined section 7.1.6) in a study subject, with or without associated 
clinical manifestations, is required to be reported as “hepatic function abnormal” within 24 hours of 
knowledge of the event to AstraZeneca/MedImmune Patient Safety using the designated Safety e-
mailbox, unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct 
obstruction) that is unrelated to investigational product has been confirmed. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated 
to investigational product, the decision to continue dosing of the study subject will be based on 
the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries will be 
initiated by the Investigator without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and evaluated 
by AstraZeneca.  
 
7.3.9 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 appropriate AstraZeneca representatives within 1 day, ie, immediately, but no later than 24 
hours of when he or she becomes aware of it.   
The designated AstraZeneca representative will work with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 to 5 calendar days 
for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available.   
 
 
 


Page 39 of 85 
 
7.3.10 Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 90 days 
after the last dose of durvalumab monotherapy.   
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented.   
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator will obtain the consent of the patient’s partner.  An IRB approved consent will be obtained 
prior to use.   
 
7.4 Data Safety Monitoring Plan 
Subjects will be carefully monitored and evaluated for adverse events by history, physical 
examination, and laboratory investigations prior to their scheduled durvalumab infusion and on a 
monthly basis after surgical resection for 4 months. All toxicities encountered during the study will be 
evaluated on an ongoing basis according to the NCI Common Toxicity Criteria version 4.0. All study 
treatment associated adverse events that are serious, at least possibly related and unexpected, and 
caused subject harm, will be reported to the IRB. Any modifications necessary to ensure subject safety 
and decisions to continue, or close the trial to accrual are also discussed during these meetings. 
 
If there are 3 or more postoperative deaths in the first 20 patients this would be considered outside of 
our historical control, and thus the study would be stopped. The Weill Cornell Medical College DSMC 
will perform data and safety monitoring for this study every 4 months. The Weill Cornell Medical 
College DSMC will review interim data to evaluate research subject safety, rates of accrual, and 
efficacy of the experimental intervention. After each evaluation, the Board will provide the principal 
investigator with recommendations for protocol modification, continuation or termination. 
 
8. PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with Investigational Agent can be found in 
Section 7.1.   
 
8.1 Investigational Agent  
8.1.1 Durvalumab 
The Investigational Products Supply section of AstraZeneca/MedImmune will supply durvalumab to 
the investigator as a 500-mg vial solution for infusion after dilution. 
8.1.2 Formulation/packaging/storage 
Durvalumab will be supplied by AstraZeneca as a 500 mg vial solution for infusion after dilution. The 
solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% (weight/volume) polysorbate 80; it has a pH of 6.0 and density of 1.054 g/ml. 
The nominal fill volume is 10 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 
46°F) and must not be frozen. Drug product should be kept in original packaging until use to prevent 
prolonged light exposure.  
8.1.3 Study drug preparation 
For patients weighing > 30 kg a fixed dose of durvalumab at 1.12 g every 3 weeks for 2 cycles will be 
administered pre-operatively and 1.5 g every 4 weeks for 12 cycles post-operatively. 
 
For patients ≤ 30 kg weight based dosing is required.  For the 1.5 g dose a 20 mg/kg dose Q4W would 
be used and for the 1.12 g dose a 15 mg/kg dose Q3W would be used.   
 


Page 40 of 85 
 
Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration will be prepared using aseptic technique. Total time from 
needle puncture of the durvalumab vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed. 
 
A dose of 1.5 g durvalumab for patients >30 kg will be administered using an IV bag containing 0.9% 
(w/v) saline with a final durvalumab concentration ranging from 1 to 20 mg/mL, and delivered through 
an IV administration set with a 0.2- or 0.22-μm in-line filter. Add 30.0 mL of durvalumab (ie, 1.5 g of 
durvalumab) to the IV bag. The IV bag size should be selected such that the final concentration is 
within 1 to 20 mg/mL Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
 
A dose of 1.12 g durvalumab for patients >30 kg will be administered using an IV bag containing 0.9% 
(w/v) saline with a final durvalumab concentration ranging from 1 to 20 mg/mL, and delivered through 
an IV administration set with a 0.2- or 0.22-μm in-line filter. Add 22.4 mL of durvalumab (ie, 1.12 g of 
durvalumab) to the IV bag. The IV bag size should be selected such that the final concentration is 
within 1 to 20 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
 
Weight-based dosing (for patients ≤ 30 kg) will be a administered using an IV bag containing 0.9% 
(w/v) saline with a final durvalumab concentration ranging from 1 to 20 mg/mL, and delivered through 
an IV administration set with a 0.2- or 0.22-μm in-line filter. For the 1.5 g dose a 20 mg/kg dose Q4W 
would be used and for the 1.12 g dose a 15 mg/kg dose Q3W would be used.  The Appendix A 
includes an example of a weight-based dose calculation.  Patient weight at baseline should be used for 
dosing calculations in patients ≤30 kg unless there is a ≥10% change in weight.  Dosing day weight 
can be used for dosing calculations instead of baseline weight per institutional standard.   
 
Durvalumab will be administered at room temperature by controlled infusion into a peripheral or 
central vein. Following preparation of durvalumab, the entire contents of the IV bag should be 
administered as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2 or 0.22-μm in-
line filter. Less than 55 minutes is considered a deviation. 
 
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline) equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document if the 
line was not flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature.  The table below summarizes time allowances 
and temperatures. 
 
Durvalumab hold and infusion times 
Maximum time from needle puncture of vial to 
start of administration 
4 hours at room temperature,  
24 hours at 2°C to 8°C (36°F to 46°F) 
Maximum time for IV bag infusion, 
including interruptions 
8 hours at room temperature 


Page 41 of 85 
 
 
In the event that either preparation time or infusion time exceeds the time limits outlined above, a new 
dose must be prepared from new vials.  Durvalumab does not contain preservatives, and any unused 
portion must be discarded. 
 
8.1.4 Monitoring of dose administration 
Subjects will be monitored before, during and after the infusion with assessment of vital signs at the 
times specified in the Schedule of Assessment. Subjects are monitored (pulse rate, blood pressure) 
every 30 minutes during the infusion period (including times where infusion rate is slowed or 
temporarily stopped). 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be decreased 
by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial 
rate until completion of the infusion.  For subjects with a ≤Grade 2 infusion-related reaction, 
subsequent infusions may be administered at 50% of the initial rate.  Acetaminophen and/or an 
antihistamine (e.g., diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the investigator.  If the infusion-related reaction is Grade 3 or higher 
in severity, study drug will be discontinued. The standard infusion time is one hour, however if there 
are interruptions during infusion, the total allowed time from infusion start to completion of infusion 
should not exceed4 hours at room temperature.  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. For management of patients who experience an infusion 
reaction, please refer to the toxicity and management guidelines in Appendix B. 
 
8.1.5 Agent Accountability 
The investigator, or a responsible party designated by the investigator, will maintain a careful record of 
the inventory and disposition of all agents received from Sponsor on a Drug Accountability Record 
Form (DARF).  
 
9.0 MEASUREMENT OF EFFECT 
9.1 Assessment of disease-free survival 
All patients will be followed in our thoracic oncology follow-up clinic for disease recurrence using 
history, physical examination and CT scanning every 6 months for 2 years. This follow-up protocol 
represents our institutional standard of care. Recurrence will be histologically or cytologically 
confirmed whenever possible. For the purpose of this trial DFS is defined as confirmed disease 
recurrence or death from any cause. 
 
9.2 Assessment of clinical response.  
All patients will have pre-treatment and post-treatment standard imaging including a positron emission 
tomography (PET)/computerized tomography scan (PET/CT scan) to determine disease stage and 
assess response to therapy. All imaging will be downloaded to our imaging data evaluation and 
analysis laboratory (IDEAL); a state of the art imaging facility operated by the Weill Cornell 
Department of Radiology. Independent radiologists blinded to treatment allocation will assess tumor 
shrinkage using conventional RECIST criteria 1.1. 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
 


Page 42 of 85 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
 
9.3 Assessment of pathological response 
 
Major Pathologic Response (MPR): ≤10% residual viable tumor in the resected specimen on 
histopathological examination. 
 
Complete Pathological Response (CPR): The absence of tumor cells in the resected specimen on 
histopathological examination. 
 
10.0 DATA REPORTING / REGULATORY CONSIDERATIONS 
10.1 Data Collection 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, and 
efficacy data for all enrolled patients.  
 
10.1.1 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. 
 
10.2 Regulatory Considerations 
All protocol amendments and consent form modifications will be made by the Principal Investigator. 
AstraZeneca will have the opportunity to review and approve the changes prior to submission of these 
changes to the local IRB and distribution to participating sites. 
 
10.3 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable regulatory 
requirements Subject data protection. 
 
11. STATISTICAL CONSIDERATIONS  
11.1 Specific Aims 
11.1.1 Primary Aim: 
The primary aim of this study is to determine that subablative SBRT at a dose of 8Gyx3 given 
concurrently with neoadjuvant durvalumab will increase the major pathological response (MPR) 
proportion from an estimated 15% in Arm 1 (Durva alone) to 35% in Arm 2 (SBRT+Durvalumab). A 
two-group chi-square test with a 0.20 one-sided significance level will have approximately 83% power 
to detect the difference between the Arm 1 MPR proportion of 0.15 and the arm 2 MPR proportion of 
0.35 when the sample size is 30 in each arm. 


Page 43 of 85 
 
 
11.1.2 Secondary Aim: 
The first secondary aim of this study is to demonstrate that the use of durvalumab (with/without 
radiation) is associated with an improvement in the 2-year disease-free survival (DFS) proportion from 
75% (historical control) to approximately 88% with the use of the new antibody. The historical control 
rate was determined from the DFS rate reported by Strauss et al from CALGB 9633, a US based 
randomized trial of adjuvant chemotherapy versus observation in patients with pathological stages IB 
and II NSCLC 34. The reported 2-year DFS was 68% in the observation arm and 75% in the 
chemotherapy arm 34. Our institutional data are consistent with these results. Among patients in our 
database who were assigned a clinical stage, there were 215 patients with clinical stages IB and II 
some of whom received adjuvant chemotherapy. DFS for these 215 patients is shown in Figure 2 and 
was 75% at 2 years. We did not use DFS reported from other randomized trials since these were 
international trials and approximately 20-25% of patients enrolled had stage IIIA disease. In our 
proposed trial, an improvement in DFS by 13% (75% to 88% at 2 years) represents a 17% relative 
improvement in DFS; a difference that we believe to be both achievable and clinically meaningful. 
These results will necessarily lead to larger randomized trials for further confirmation.  
 
Another secondary aim is to compare the clinical response between patients receiving the durvalumab 
alone (Arm 1) and patients receiving the antibody with radiation (Arm 2). Assuming clinical response 
proportions of 15% and 35% in Arms 1 and 2, respectively, 95% confidence intervals for the clinical 
response proportions can be constructed to be within ± 12.8% and ± 17.1% of the observed clinical 
response proportions in each arm, respectively.  
 
A third secondary aim is to determine the safety of 2 cycles of preoperative durvalumab with and 
without radiation followed by surgery and adjuvant durvalumab for 12 months post-operatively. 
 
The fourth secondary aim (exploratory) is to compare DFS between the two arms; however, this 
comparison will be for exploratory purposes only (this comparison will not be statistically powered to 
detect specific differences between the two arms). 
 
 
11.2 Analysis Plan for Endpoints 
11.2.1 Primary Endpoint: 
The primary endpoint of the MPR proportion will be calculated for both treatment arms and 80% one-
sided confidence intervals will be estimated via binomial proportions. The chi-square test or Fisher’s 
exact test will be used, as appropriate, to compare the MPR proportions between the two arms.  We 
will also generate the odds ratio and a corresponding 95% confidence interval to contrast the difference 
in MPR proportions between the two arms. Logistic regression will be used to generate the odds ratio 
and corresponding CI.  
 
 
11.2.2 Secondary Endpoints: 
The first secondary endpoint of 2-year DFS proportion will be calculated for the pooled group of 
patients (N=60) and a 95% confidence interval will be estimated via binomial proportions. An 
additional calculation will also be stratified by Arm 1 vs. Arm 2. The chi-square test or binomial exact 
test, whichever is appropriate, will be used to compare the 2-year DFS proportion in the 60 patients to 
the historical 2-year DFS proportion of 75%. The chi-square test or Fisher’s exact test will be used, as 
appropriate, to compare the 2-year DFS proportion between the two arms.  


Page 44 of 85 
 
The clinical response proportion will be calculated for both treatment arms and 95% confidence 
intervals will be estimated via binomial proportions. The chi-square test or Fisher’s exact test will be 
used, as appropriate, to compare the clinical response proportions between the two arms.  
The safety of durvalumab with and without low dose SBRT in the neoadjuvant setting in NSCLC will 
be investigated. All AEs in both arms ≥G3 with and without possible or probable attribution to study 
drug will be tabulated. The frequency of subjects experiencing toxicities will be tabulated for each 
arm. Toxicities will be assessed and graded according to CTCAE v. 4.0 terminology. Exact 95% 
confidence intervals around the toxicity proportions will be calculated to assess the precision of the 
obtained estimates. All analyses will be performed in SAS Version 9.4 (SAS Institute, Inc., Cary, 
North Carolina) and STATA Version 13.0 (Stata Corporation, College Station, Texas). 
DFS will also be estimated using the Kaplan-Meier method, and 95% confidence intervals for DFS 
estimates will be calculated using Greenwood’s formula. Median DFS will also be estimated along 
with a 95% confidence interval. These calculations will also be stratified by Arm 1 vs. Arm 2 for the 
purpose of the secondary aim. The log-rank test will be used to compare Kaplan-Meier DFS between 
the two arms (for exploratory purposes only; this comparison will not be statistically powered to detect 
specific differences between the two arms). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 45 of 85 
 
 
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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):1012–24. 
Zhang et al 2012 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 50 of 85 
 
APPENDIX A 
DURVALUMAB DOSE CALCULATIONS 
 
 
 
Durvalumab Dosing 
The dosing should be done depending on subject weight (if subject is ≤ 30kg): 
1. Cohort dose: X mg/kg 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration  
The corresponding volume durvalumab should be rounded to the nearest tenth mL (0.1 mL). Dose 
adjustments for each cycle only needed for greater than 10% change in weight. 
5. The number of vials required for dose preparation is the next greatest whole number of vials from 
the following formula: 
Number of vials = Dose (mL) / 10 (mL/vial) 
 
Please ensure the correct dose level is used.  Below is an example for a 20 mg/kg weight-based 
dose 
Example:  
1. Cohort dose: 20 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 600 mg = 20 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 600 mg / 50 (mg/mL) = 12.0 mL 
5. The number of vials required for dose preparation:  
Number of vials = 12.0 (mL) / 10.0 (mL/vial) = 2


Page 51 of 85 
 
 
 
APPENDIX B 
DOSING MODIFICATIONS AND TOXICITY MANAGEMENT GUIDELINES 
Tables 1, 2 and 3 
 
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 imAEis 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 should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid should be tapered over 
≥ 28 days.  More potent immunosuppressive  agents such as TNF inhibitors (e.g., infliximab) 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 long-term steroid and other immunosuppressive use, consider need for Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis carinii pneumonia) 
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. 
 
 
Relevant Society Guidelines for Management of imAEs 


Page 52 of 85 
 
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. 
1.5. Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related toxicities version 3.2021. Published May 14, 
2021. 
 
 
 
Specific Immune-Mediated Reactions 
 
 
 
Grade of the 
Event (NCI 
CTCAE version 
4.03) 
Dose Modifications 
Toxicity Management 
 
Pneumonitis/I
nterstitial 
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. 


Page 53 of 85 
 
− Initial work-up may include clinical evaluation, monitoring 
of oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up and high-resolution computed 
tomography (CT) scan.  
− Consider Pulmonary and Infectious Diseases consults 
Grade 1 
 
No dose modification required. However, 
consider holding study drug/study regimen 
dosing as clinically appropriate and during 
diagnostic work-up for other etiologies 
For Grade 1 
− Monitor and closely follow up in 2-4 days for clinical 
symptoms, pulse oximetry (resting and exertion) and 
laboratory work-up and then as clinically indicated 
Grade 2 
 
 Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1 
•  
• If toxicity improves to < Grade 1 then 
the decision to reinitiate study 
drug/regimen will be based upon 
treating physician’s clinical judgment 
and after completion of steroid taper (≤. 
10mg prednisone or equivalent). 
 
For Grade 2 
− Monitor symptoms daily and consider hospitalization 
− Obtain Pulmonary and Infectious Diseases Consults; 
consider discussing with Clinical Study Lead, as needed. 
− Promptly start systemic steroids (e.g., prednisone 1-
2mg/kg/day PO or IV equivalent) 
− Reimage as clinically indicated, consider chest CT with 
contrast 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 2-4mg/kg/day started  
− If no improvement within 2-3 days despite IV 
methylprednisolone at 2-4/g/kg/day, promptly start 
immunosuppressive therapy such as tumor necrosis factor 
(TNF) inhibitors (e.g. infliximab at 5mg/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: Important to rule out sepsis and refer to infliximab 
label for general guidance before using infliximab. Consider, 
as necessary, discussing with Clinical Study Lead. 


Page 54 of 85 
 
Grade 3 or 4 
 
 
Permanently discontinue study drug/study 
regimen 
 
For Grade 3 or 4 
− 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 5mg/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: rule out sepsis and 
refer to infliximab label for general guidance before using 
infliximab  
 


Page 55 of 85 
 
Diarrhea/ 
Colitis 
 
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 A 
PERFORATION IS SUSPECTED, CONSULT A 
SURGEON EXPERIENCED IN ABDOMINAL 
SURGERY IMMEDIATELY WITHOUT ANY DELAY. 
- PERMANENTLY DISCONTINUE STUDY DRUG FOR 
ANY GRADE OF INTESTINAL PERFORATION. 
- Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, infections including testing for clostridium 
difficile toxin, etc.) 
- Steroids should be considered in the absence of clear 
alternative etiology, even for low grade events, in order to 
prevent potential progression to higher grade event, 
including intestinal perforation. 
- Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis 
Grade 1 
No dose modification 
Grade 1 
- Close monitoring 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 


Page 56 of 85 
 
positive, treat as Grade 2 below. If negative and no 
infection, continue Grade 1 management. 
Grade 2 
 
 
 
 
 
 
 
 
 
 
 
 
  
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• 
 
• 
If toxicity improves to < Grade 1 then 
study drug/study regimen can be 
resumed after completion of steroid 
taper (<10 mg prednisone, or 
equivalent).    
For Grade 2: 
- Consider symptomatic treatment including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide  
- Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent  
- If event is not responsive within 2 to 3 days or worsens 
despite prednisone at 1-2 mg/kg/day PO or IV equivalent, 
consult a gastroinestinal (GI) specialist for consideration of 
further workup such as imaging and/or colonoscopy to 
confirm colitis and rule out perforation,     
- If still no improvement within   2 to 3days despite 1 to 2 
mg/kg IV methylprednisolone, promptly start 
immunosuppressant agents such as infliximab at 5mg/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: Important to rule out bowel perforation 
and refer to infliximab label for general guidance before 
using infliximab   
- If perforation is suspected, consult a surgeon experienced in 
abdominal surgery immediately without any delay. 
-  Consider, as necessary, discussing with Clinical Study Lead 
if no resolution to ≤ Grade 1 in 3 to 4 days. 


Page 57 of 85 
 
Grade 3 or 4  
 
 
 
; 
 
 
Grade 3 
 
• 
For patient treated with durvalumab 
monotherapy, hold study drug/study 
regimen until resolution to 
Grade ≤1; study drug/study 
regimen can be resumed after 
completion of steroid taper (<10 mg 
prednisone per day, or equivalent). 
Grade 4 
Permanently discontinue study 
drug/study regimen. 
 
For Grade 3 or 4 diarrhea: 
- Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent  
- Monitor stool frequency and volume and maintain hydration   
- Urgent GI consult and imaging and/or colonoscopy as 
appropriate 
- If still no improvement within 2 days, continue steroids and 
promptly add further immunosuppressants (e.g. infliximab 
at 5mg/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: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab.  
- If perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately without 
any delay. 
 
 
Hepatitis 
(Elevated 
liver function 
tests (LFTs)) 
Infliximab 
should not be 
used for 
management 
of Immune 
Related 
Hepatitis 
 
 
 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., viral hepatitis, disease progression,   
concomitant medications). 
- Monitor and evaluate LFTs: aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP) and total bilirubin ( T. bili). 
- Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications)  
Grade 1 
 
• 
No dose modifications. 
• 
If it worsens, then consider holding 
therapy. .  
For Grade 1 
- Continue LFT monitoring per protocol   


Page 58 of 85 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 2 
 
• 
Hold study drug/study regimen dose 
until Grade 2 resolution to Grade ≤1.   
• If toxicity worsens, then treat as Grade 
3 or Grade 4  
• If toxicity improves to Grade ≤1 or 
baseline and there were no elevations 
in bilirubin, resume study drug/study 
regimen after completion of steroid 
taper(<10mg prednisone or equivalent). 
• Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (AST and/or 
ALT >3 × ULN + bilirubin >2 × ULN 
without initial findings of cholestasis 
(i.e., elevated ALP) and in the absence 
of any alternative cause.b 
For Grade 2: 
- Regular and frequent checking of LFTs (e.g., every 1 to 2 
days) until LFT elevations improve or resolve. 
- If no resolution to≤ Grade 1 in in 1 to 2 days, consider, as 
necessary, discussing with Clinical Study Lead as needed. 
- If event is persistent (>2 to 3 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
 
 
 
Grade 3 or 4 
 
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 Grade 
<1 or baseline. 
•  
• Resume study drug/study regimen if 
elevations downgrade to grade ≤1 or 
baseline after completion of steroid 
taper (<10mg prednisone or 
equivalent). 
• Discontinue study drug/study regimen 
for elevations in transaminases >8 X 
ULN or any elevations in bilirubin > 5 
X ULN.  
• . 
For Grade 3 or 4: 
- Promptly initiate empiric IV methylprednisolone at 1 to 2 
mg/kg/day or equivalent 
- If still no improvement within2 to 3 days despite 1 to 
2 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with an immunosuppressant therapy (i.e., 
mycophenolate mofetil 0.5-1g 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. 
 
 
 


Page 59 of 85 
 
 
 
                       For Grade 4: 
Permanently discontinue study 
drug/study regimen 
 
 
 
 
 
 
Amylase/Lipa
se increased 
Any Grade 
(Refer to NCI 
CTCAE 
applicable 
version in 
study protocol for 
defining the 
CTCAE  
grade/severity) 
General Guidance 
 
 
 
 
For Any Grade: 
 
 
 
− 
For modest asymptomatic elevations in serum amylase and 
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) 
− 
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 
Grade 1 
 
 
No dose modifications 
 
 
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. 
 
 
 
 


Page 60 of 85 
 
 
 
 
 
Acute 
Pancreatitis 
Any Grade 
 
 
General Guidance 
 
 
For Any Grade: 
 
   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 
(<10mg 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 
Nephritis or 
Renal 
Dysfunction 
(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: 
- 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 creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine output, proteinuria, 
etc.)  
- Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, infections. 
Recent IV contrast, medications, fluid status) 
-  Consider using steroids in the absence of clear alternative 
etiology even for low grade events (Grade 2), in order to 
prevent potential progression to higher grade events. 


Page 61 of 85 
 
Grade 1 
No dose modification 
For Grade 1: 
- Monitor serum creatinine weekly and any accompanying 
symptom 
• 
If creatinine returns to baseline, resume its 
regular monitoring per study protocol. 
• 
If it worsens, depending on the severity, treat as 
Grade 2 or Grade 3 or 4  
- Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc. 
Grade 2 
 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline 
• 
 
• 
If toxicity improves to ≤ Grade 1 or 
baseline then resume study drug/study 
regimen after completion of steroid 
taper (<10mg prednisone or 
equivalent) 
For Grade 2: 
- Consider symptomatic treatment including hydration, 
electrolyte replacement, diuretics, etc.  
- Carefully monitor serum creatinine every 2-3 days and as 
clinically warranted 
- Consult Nephrologist and consider renal biopsy if clinically 
indicated 
- If event is persistent beyond > 3-5 days or worsens, 
promptly start prednisone 1 to 2 mg/kg/day or IV equivalent  
- If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day or IV equivalent, consider 
additional workup When event returns to baseline, resume 
study drug/study regimen and routine serum creatinine 
monitoring per study protocol. 


Page 62 of 85 
 
Grade 3 or 4  
 
Permanently discontinue study drug/study 
regimen 
For Grade 3 or 4: 
- Carefully monitor serum creatinine on daily basis 
- Consult Nephrologist and consider renal biopsy if clinically 
indicated 
- Promptly start prednisone 1 to 2 mg/kg/day or IV equivalent  
- If event is not responsive within 3-5 days or worsens despite 
prednisone at 1-2 mg/kg/day or IV equivalent, consider 
additional workup and prompt treatment with an 
immunosuppressant in consultation with a nephrologist.  
Rash or 
Dermatitis  
(including 
Pemphigoid) 
Any Grade 
(Please refer to 
NCICTCAE 
version 4.03 for 
definition of 
severity/grade 
depending on 
type of skin rash)  
General Guidance 
For Any Grade: 
- Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
- HOLD STUDY DRUG IF STEVENS-JOHNSON 
SYNDROME (SJS), TOXIC EPIDERMAL 
NECROLYSIS (TEN), OR OTHER SEVERE 
CUTANEOUS ADVERSE REACTION (SCAR) IS 
SUSPECTED. 
- PERMANENTLY DISCONTINUE STUDY DRUG IF 
SJS, TEN, OR SCAR IS CONFIRMED 
 
Grade 1 
No dose modification 
For Grade 1: 
- Consider symptomatic treatment including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., emollient lotion or institutional standard) 


Page 63 of 85 
 
 
Grade 2 
For persistent (> 1 week) Grade 2 events, 
hold scheduled study drug/study 
regimen until resolution to ≤ Grade 1 
or baseline  
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of 
steroid taper (< 10 mg 
prednisone,or equivalent). 
For Grade 2: 
- Obtain Dermatology consult  
- Consider symptomatic treatment including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy  
- 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 
study physician, as needed and promptly start systemic 
steroids prednisone  1-2 mg/kg/day PO or IV equivalent.  
- Consider skin biopsy if the event persists for >1-week or 
recurs 
Grade 3 
• Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper (10mg prednisone, or equivalent). 
• 
 
For Grade 3 or 4: 
- Consult Dermatology  
-  Promptly initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent  
- Consider hospitalization 
- Monitor extent of rash [Rule of Nines] 
- Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
- Consider, as necessary, discussing with Clinical Study Lead. 
Grade 4 
Permanently discontinue study drug/study 
regimen  
Endocrinopat
hy (e.g., 
hyperthyroidi
sm, 
thyroiditis, 
hypothyroidis
m, type 1 
Any Grade  
(Depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE version 
in study protocol 
General Guidance 
For Any Grade: 
- Consider consulting an Endocrinologist for endocrine 
events. 
- Consider discussing with Clinical Study Lead as needed 
- Monitor patients for signs and symptoms of 
endocrinopathies.  Non-specific symptoms include 
headache, fatigue, behavior changes, c mental status 


Page 64 of 85 
 
diabetes 
mellitus, 
hypophysitis, 
hypopituitari
sm, adrenal 
insufficiency) 
for defining the 
CTCAEgrade/sev
erity)  
changes, photophobia, visual field cuts, vertigo, abdominal 
pain, unusual bowel habits, polydipsia, polyuria hypotension 
and weakness. 
- Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including 
brain metastases, infections, etc.) 
- Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: thyroid stimulating hormone 
(TSH), free T3 and free T4 and other relevant 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, diabetes insipidus), the investigator should 
send a blood sample for appropriate autoimmune antibody 
testing. 
- 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. 
Grade 1 
 
No dose modification 
For Grade 1: 
- Monitor patient with appropriate endocrine function tests. 
- For suspected hypophysitis/hypopituitarism, consider 
consulting of an endocrinologist to guide assessment of 
early-morning adrenocorticotropin hormone (ACTH), 
cortisol, TSH and free T4; also consider gonadotropins, sex 
hormones, and prolactin levels, as well as cosyntropin 
stimulation test (though it may not be useful in diagnosing 
early secondary adrenal insufficiency). 
- If TSH < 0.5X LLN, or TSH >2X ULN or consistently out 
of range in 2 subsequent measurements, include FT4 at 
subsequent cycles as clinically indicated and consider 


Page 65 of 85 
 
consultation of an endocrinologist. 
Grade 2, 3, or 4 
 
 
• 
For Grade 2-4 endocrinopathies other 
than hypothyroidism and Type 1 
diabetes mellitus, consider holding 
study drug/study regimen dose until 
acute symptoms resolve.  
• 
Study drug/study regimen can be 
resumed once patient stabilizes and 
after completion of steroid taper 
<10mg prednisone or equivalent). 
• 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g. adrenal 
insufficiency) can be retreated with 
study drug/study regimen if the patient 
is clinically stable as per Investigator 
or treating physician’s clinical 
judgement. 
 
For Grade 2, 3 or 4: 
-  Consult endocrinologist to guide evaluation of endocrine 
function, and as indicated by suspected endocrinopathy and 
as clinically indicated consider pituitary scan 
- For all  patients with abnormal endocrine work up, except  
those  with isolated hypothyroidism or type 1 DM, and as 
guided by an endocrinologist, corticosteroids (e.g., 1-
2mg/kg/day methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant hormone 
replacement (e.g. Levothyroxine, hydrocortisone, or sex 
hormones). - 
 
- Isolated type 1 diabetes mellitus (DM) 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 work up (laboratory 
assessment or magnetic resonance imaging (MRI scans), 
repeat laboratory asseseements/MRI as clinically indicated. 
Neurotoxicity 
(to include 
but not 
limited to 
non-
infectious 
meningitis, 
non-
infectious 
 
 
Any Grade 
(Depending on 
the type of 
neurotoxicity , 
refer to NCI 
CTCAE 
applicable 
General Guidance 
For Any Grade: 
- Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes and medications, etc.)  
- Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness) 
- Consider appropriate diagnostic testing (e.g. 


Page 66 of 85 
 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-
Barre)   
 
version in study 
protocol for 
defining the 
CTCAE 
grade/severity) 
 
 
 
 
 
electromyogram and nerve conduction investigations) 
- Perform symptomatic treatment with Neurology consult as 
appropriate 
- FOR TRANSVERSE MYELITIS, PERMANENTLY 
DISCONTINUE FOR ANY GRADE. 
 
Grade 1 
 No dose modifications 
See “Any Grade” recommendations above. 
Grade 2 
• 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to ≤ 
Grade 1 
• 
For sensory neuropathy/neuropathic 
pain, consider holding study 
drug/study regimen dose until 
resolution to ≤ Grade 1. 
• 
Permanently discontinue study 
drug/study regimen if Grade 2 imAE 
does not resolve to Grade ≤1 within 30 
days. 
• 
  
- 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, duloxetine, etc.) 
- Promptly start systemic steroids prednisone 1-2mg/kg/day 
PO or IV equivalent  
- If no improvement within 2 to 3 days despite 1-2mg/kg/day 
prednisone PO or IV equivalent consider additional workup 
and promptly treat with an additional immunosuppressive 
therapy (e.g. IVIG or other immunosuppressant depending 
on the specific imAE)  
 
 
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 
 
 
 


Page 67 of 85 
 
mg/kg/day or equivalent  
- If no improvement within 2 to 3- days despite IV 
corticosteroids, consider additional workup and promptly 
treat with additional immunosuppressants (e.g. IV IG or 
other immunosuppressant depending on the specific imAE)  
- Once stable, gradually taper steroids over ≥28 days 
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: 
- The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients 
may unpredictably experience acute decompensations which 
can result in substantial morbidity or in the worst case, 
death. Special care should be taken for certain sentinel 
symptoms which may predict a more severe outcome, such 
as prominent dysphagia, rapidly progressive weakness, and 
signs of respiratory insufficiency or autonomic instability 
- Patients should be evaluated to rule out any alternative 
etiology (e.g., disease progression, infections, metabolic 
syndromes and medications, etc.). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding 
effects of cancer (and its treatments) throughout the 
neuraxis. Given the importance of prompt and accurate 
diagnosis, it is essential to have a low threshold to obtain a 
Neurology consult 
- Neurophysiologic diagnostic testing (e.g., electromyogram 
and nerve conduction investigations, and  “repetitive 
stimulation” if myasthenia is suspected) are routinely 
indicated upon suspicion of such conditions and may be best 
facilitated by means of a Neurology consultation  
- 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 


Page 68 of 85 
 
started with IVIG and followed by plasmapheresis if not 
responsive to IVIG  
Grade 1 
No dose modification 
- 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 study 
drug/study regimen if it does not 
resolve to ≤ Grade 1 within 30 days or 
if there are signs of respiratory 
insufficiency or autonomic instability 
 
Grade 2 
- 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 
- Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
− Steroids may be successfully used to treat Myasthenia 
Gravis. Important to consider that steroid therapy (especially 
with high doses) may result in transient worsening of 
myasthenia and should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
− Patients unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIG. Such decisions are 
best made in consultation with a neurologist, taking into 
account the unique needs of each patient. 
− If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase (AChE) inhibitor therapy in 
addition to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis. 
− Avoid medications that can worsen myasthenia gravis (e.g. 
some antibiotics, beta blockers, calcium channel blockers, 


Page 69 of 85 
 
muscle relaxants).  
GUILLAIN-BARRE:  
− 
Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. 
− Patients requiring treatment should be started with 
IVIG and followed by plasmapheresis if not 
responsive to IVIG. 
Grade 3 or 4 
• 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
• 
Permanently discontinue Study 
drug/study regimen if Grade 3 irAE 
does not resolve to ≤ Grade 1 within 
30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability 
For Grade 3 or 4 
- Consider, discussing with Clinical Study Lead, as needed. 
- Recommend hospitalization 
- Monitor symptoms and consult neurologist  
MYASTHENIA GRAVIS 
− 
Steroids may be successfully used to treat Myasthenia 
Gravis.  It should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
− 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IVIG. 
− 
If Myasthenia Gravis-like neurotoxicity present, 
consider starting acetylcholine esterase (AChE) 
inhibitor therapy in addition to steroids. Such 
therapy, if successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE:  
− 
Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. 
− 
Patients requiring treatment should be started with IVIG 
and followed by plasmapheresis if not responsive to 
IVIG 
− 
Avoid medications that can worsen myasthenia gravis.  
Grade 4 
Permanently discontinue study drug/study 
regimen  


Page 70 of 85 
 
 
Myocarditis 
 
 
 
Any Grade 
 
(Refer to NCI 
CTCAE 
applicable 
version in 
study protocol for 
defining the 
CTCAE 
grade/severity) 
 
 
 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis. 
 
For Any Grade: 
− The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.  
− 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 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. 
Spiral CT or cardiac MRI can complement ECHO to assess 
wall motion abnormalities when needed. 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections) 


Page 71 of 85 
 
 
 
 
Grade 2, 3 or 4 
 
 
 
 
 
. 
 
- If Grade 2-4, permanently discontinue 
study drug/study regimen. 
 
 
 
For grade 2-4: 
 
− Monitor symptoms daily, hospitalize. 
− Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures 
including a cardiac biopsy. 
− Supportive care (e.g., oxygen). 
− If no improvement within 2 to 3  despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
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: 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. 
 
 
 
 
 
 
Myositis/Poly
myositis  
 
 
 
 
 
Any Grade 
 
Refer to NCI 
CTCAE 
applicable version 
in 
study protocol for 
General Guidance 
 
 
 
 
 
 
 
 
 
 
 
For Any Grade: 
− 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 progress rapidly. Increased 
general feelings of tiredness and fatigue may occur, and 
there can be new-onset 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 


Page 72 of 85 
 
defining the  
CTCAE 
grade/severity) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated 
and could guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as anti-
Jo-1], and/or signal-recognition particle antibodies). 
Confirmatory testing may include electromyography, nerve 
conduction studies, MRI of the muscles, and/or a muscle 
biopsy. Consider Barium swallow for evaluation of 
dysphagia or dysphonia. 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections). 
Grade 1 
 
 
 
 
 
For Grade 1: 
No dose modifications. 
 
 
 
 
For Grade 1: 
− Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− Consider Neurology consult. 
− Consider, as necessary, discussing with the Clinical Study 
Lead. 
 


Page 73 of 85 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3 or 4 
 
 
For Grade 2: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
-Permanently discontinue study drug/study 
regimen if it does not resolve to Grade ≤1 
within 30 days or if there are signs of 
respiratory insufficiency. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the 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 4 
mg/kg/day there is no improvement within 2 to 3 , 
consider starting  another 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: It is important to rule 
out sepsis and refer to infliximab label for general 
guidance before using infliximab. 
 
 
 
 
For Grade 3 or 4 (severe or life-threatening events): 


Page 74 of 85 
 
signs of respiratory insufficiency. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Grade 4: 
-Permanently discontinue study drug/study 
regimen. 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult. 
− 
Consider, discussing with the Clinical Study Lead as 
needed. 
− 
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 3days, 
consider starting another  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: 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. 
 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth. 
 
 
 
 
 


Page 75 of 85 
 
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and Non Immune-mediated 
Reactions for Durvalumab Monotherapy 
Table 1- Other – Immune- Mediated Reactions 
Severity 
Grade of 
the Event 
(NCI 
CTCAE 
version 
4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
Note: It is possible that events with an 
inflammatory or immune mediated mechanism 
could occur in nearly all organs, some of them 
are not noted specifically in these guidelines 
(e.g. immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis). 
- The Clinical Study Lead may be contacted for immune-mediated 
reactions not listed in the “specific immune-mediated reactions” section 
 
-  Thorough evaluation to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) 
 
-  Consultation with relevant specialist 
 
- Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
− 
Monitor as clinically indicated. 
Grade 2 
 
Hold study drug/study regimen until resolution 
to 
≤Grade 1 or baseline. 
• If toxicity worsens, then treat as Grade 3 or 
Grade 4. 
• 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 
- For Grade 2, 3, or 4 
 
- Treat accordingly, as per institutional standard, appropriate 
- clinical practice guidelines, and society guidelines 
- (e.g., NCCN, ESMO) 


Page 76 of 85 
 
 
Grade 3 
 
Hold study drug/study regimen 
 
Grade 4 
Permanently 
discontinue 
study 
drug/study 
regimen 
 
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and Non Immune-mediated 
Reactions for Durvalumab Monotherapy 
Table 2- 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 Management 
Any Grade 
General Guidance 
 
- Management per institutional standard at the discretion of investigator 
- Monitor patients for signs and symptoms of infusion-related reactions 
(e.g., fever and/or shaking chills, flushing and/or itching, alterations in 
heart rate and blood pressure, dyspnea or chest discomfort, skin rashes 
etc.) and anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, 
hypotension, tachycardia, etc.) 
Grade 1 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution of 
the event 
For Grade 1 or Grade 2: 
- Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator  
- Consider premedication per institutional standard prior to subsequent 


Page 77 of 85 
 
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 
doses 
- Steroids should not be used for routine premedication of ≤Grade 2 
infusion reactions 
Grade 3/4 
Permanently discontinue study drug/study 
regimen 
                            For Grade 3 or 4:  
Manage severe infusion-related reactions per institutional standard appropriate 
clinical practice guidelines and society guidelines. 


Page 78 of 85 
 
 
Abbreviations:AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST 
= aspartate aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = intramuscular; irAE = 
immune-related adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PO = by mouth; TNF = tumor 
necrosis factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal. 
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 the Clinical Study Lead.” 
 
 
Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and Non Immune-mediated Reactions for 
Durvalumab Monotherapy 
Table 3- Non-immune Mediated Reactions 
Severity Grade of 
the Event (NCI 
CTCAE version 
4.03) 
Dose Modification  
Toxicity Management  
Any Grade 
Note: dose modifications are not required for adverse events not deemed to be related to 
study treatment (i.e. events due to underlying disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly as per institutional 
standard  
1 
No dose adjustment  
Treat accordingly as per institutional 
standard  
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per institutional 
standard  
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline 
within 14 days, resume study drug/study regimen administration. Otherwise, discontinue 
study drug/study regimen 
Treat accordingly as per institutional 
standard  
 
 
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue 
would be based on accompanying clinical signs/symptoms and as per Investigator’s 
clinical judgment and in consultation with the sponsor)  
Treat accordingly as per institutional 
standard  


Page 79 of 85 
 
 
List of Abbreviations 
 
AChE 
Acetylcholinesterase 
ILD 
Interstitial lung disease 
ACTH 
Adrenocorticotropic hormone 
imAE(s) Immune-mediated adverse event(s) 
ALT 
Alanine aminotransferase 
INR 
International normalized ratio 
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 Network 
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 reaction 
HBcAb 
Hepatitis B core antibody 
SITC 
Society for Immunotherapy of Cancer 
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 
 


Page 80 of 85 
 
 
 
Human Research Protections Program 
Immediate Report Form         
 
 
 
 
 
 
The Immediate Reporting Policy that governs what you must report using this form is available at the following web address: 
http://researchintegrity.weill.cornell.edu/institutional_review_board/irb_policies_and_procedures.html.  The policy spans 5 categories: Adverse 
Events/Unexpected Adverse Device Effects (Section A of this form), Other Risk Reporting (Section B of this form), Protocol Deviation 
Reporting (Section C of this form) and Other Compliance Reporting (Section D of this form). 
 
 
If you have any questions, please email immediatereports@med.cornell.edu or call 646-962-8200. 
 
DIRECTIONS:  
 
(a) Fill out questions 1 through 8 on this page. 
(b) Then choose the section on this form that corresponds to the type of Immediate Report you are making. Any given section you choose 
will have only 1 to 7 questions. 
(c) Create a PDF of this form and attach the most current WCMC IRB consent document and any supplemental information. 
(d) Sign this form with Principal Investigator signature on the last page and send to immediatereports@med.cornell.edu. 
 
NOTE:  
 
• 
If you are using the Clinical and Translational Science Center (CTSC) you must also CC your Immediate Report to 
ctscrsa@med.cornell.edu.  
• 
If you are using the Weill Cornell Medical College Data Safety Monitoring Board (WCMC DSMB) you must also CC your Immediate 
Report to dsmb@med.cornell.edu. 
• 
If your protocol is subject to the requirements of the Institutional Biosafety Committee (IBC), you must also CC your Immediate 
Report to submit2ibc@med.cornell.edu.  
 
 
 


Page 81 of 85 
 
1. Principal Investigator:  
 
2. Protocol #: 
 
3. Protocol Title: 
 
4. Brief One Sentence Description of Report (This will be used to reference this specific submission in all IRB correspondence about 
this Immediate Report):  
 
5. Status of Protocol at WCMC Site 
 
 Open    
 Open, Closed to Subject Accrual    
 Open, Data Analysis Only 
 
6. Funding Source:  
 
7. Does this protocol involve use of FDA-regulated product(s) including those that are FDA-approved? 
 Yes  
 No 
 
 
a. If yes, is this protocol conducted under an IND or IDE? 
 Yes  
 No 
 
b. If yes, name IND or IDE sponsor: 
 
 
8. Check (and email this submission to) all that apply: I use the: 
 WCMC Data Safety Monitoring Board  (WCMC DSMB) 
 WCMC Institutional Biosafety Committee (IBC)     
 Clinical and Translational Science Center (CTSC) 
 
 
A: ADVERSE EVENT REPORTING / UNANTICIPATED ADVERSE DEVICE EFFECTS 
 
Tip: The goal of this section is to capture emergent risk information that has an impact on the rights and welfare of WCMC subjects 
and may also require compliance management. 
 
1. I am reporting (check all that apply): 
 
 Adverse Event that meets all 3 conditions as outlined in Section I(A) of the Immediate Reporting Policy 
http://researchintegrity.weill.cornell.edu/institutional_review_board/irb_policies_and_procedures.html.  
 
 


Page 82 of 85 
 
 Adverse Event that requirements for reporting and a death or serious injury due to a defect of a Humanitarian Use Device, as outlined in 
Section I(C) of the Immediate Reporting Policy 
http://researchintegrity.weill.cornell.edu/institutional_review_board/irb_policies_and_procedures.html.  
 
 
 Unanticipated adverse device effect as outlined in Section II(A) of the Immediate Reporting Policy 
http://researchintegrity.weill.cornell.edu/institutional_review_board/irb_policies_and_procedures.html.  . 
 
 
Describe the adverse event, its cause, and indicate any actions taken to date at the WCMC site to protect the rights and welfare of WCMC 
research subjects. Provide as much detail as possible. If the PI or any committee/board determines that the Immediate Report requires an 
amendment to the protocol or consent, the PI has 30 days from the date of making the Immediate Report (or release of the sponsor amendment) 
to submit a protocol amendment to the IRB. If this requirement cannot be met, a request for an extension must be made. 
 
 
 
1. Please explain whether you believe this adverse event suggests that the research places WCMC subjects at a greater risk of harm than 
was previously known or recognized. If so, include what additional action you intend to take in your management of this change in risk. 
E.g., Documented contact with subjects by the PI or medically qualified co-I; amendment to protocol or consent).  
 
2. Name any agencies or entities (E.g., FDA, NIH, sponsor, DSMB, etc.) that have been notified of this adverse event.  
 
 
B: OTHER RISK REPORTING 
 
Tip: The goal of this section is to capture emergent risk information that has an impact on the rights and welfare of WCMC subjects. If 
none of the below checkboxes apply, submit an acknowledgment submission instead of an Immediate Report. 
 
1. I am reporting (check all that apply): 
 
 An interim analysis, safety monitoring report, publication in the literature, or revised Investigator Brochure that indicates an increase in the 
frequency or magnitude of a given harm, uncovers a new risk, or provides more information about the benefits of the human research. 
(PLEASE ATTACH THE ADDITIONAL DOCUMENTATION) 
 
 Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in the human research protocol. 


Page 83 of 85 
 
 
 Clinical Hold, Enrollment Hold (excluding planned holds for interim analysis), or Study Termination due to Emergent Risk Information 
 
 Complaint of a participant that indicates participants or others might be at increased risk of harm or at risk of a new harm. 
 
2. Please summarize the information and how you intend to manage the new risk posed to WCMC research participants. Include any 
actions taken to date. 
 
 
C: PROTOCOL DEVIATIONS 
 
Tip: The sponsor and the IRB are separate and distinct entities with different protocol deviation reporting requirements. Please 
consult with your sponsor to find out what protocol deviations you must submit to your sponsor. This form is meant to capture 
protocol deviations that must be reported to the IRB. Note that, if WCMC is the lead/coordinating site, then protocol deviation reports 
submitted from other sites must be submitted to the WCMC IRB. 
 
1. I am reporting (check all that apply): 
 Protocol deviation that was made in order to eliminate an apparent immediate hazard to participants. 
 
 Breach of Confidentiality 
 
 Protocol deviation that represents a failure to follow the protocol or IRB policies and determinations due to the action or inaction of the 
investigator or research staff. (Exception: Rescheduling of research appointments due to holidays, vacations, accommodation of research 
subject, etc.) which meets both of the following conditions: 
 
a. The deviation has the potential to negatively impact subject safety or integrity of study data (ability to draw conclusions 
from the study data), or affect the subject’s willingness to participate in the study AND 
 
b. The deviation places WCM subjects at greater risk of harm (including physical, psychological, economic or social harm). 
 
 
 
2. Did this deviation occur at an external site (non-WCMC research site for which WCMC is the lead/coordinating site)? 
 No     
 Yes, answer (a) 
 


Page 84 of 85 
 
a) 
 What is the status of the research protocol at the non-WCMC research site? 
 
 
 
 Open     
 Open, Closed to Subject Accrual     
 Open, Data Analysis Only 
 
3. Date the Protocol Deviation Occurred: 
 
4. Date the WCMC PI was notified: 
 
5. Describe the protocol deviation and clearly state how this protocol deviation differs from what the IRB-approved protocol and/or IRB 
policy allows. Include why the deviation occurred. If the deviation occurred because of an error, please assess the root cause of that 
error. 
 
 
 
6. Describe what actions have been taken to date to ensure the rights and welfare of the participant(s).  
 
 
 
7. What preventative actions have been taken to ensure this deviation does not reoccur? Note: While some deviations occur due to human 
error, some represent systemic issues that need to be resolved. If the research staff will be more careful in the future, please help the 
IRB understand how the research staff will do this. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 85 of 85 
 
 
 
D: OTHER COMPLIANCE REPORTING 
 
1. I am reporting (check all that apply): 
 
 Finding of noncompliance or allegation of noncompliance 
 
 Complaint of a participant that cannot be resolved by the research team. 
 
 Incarceration of a participant in a protocol not approved to enroll prisoners. 
 
 
2. Please describe the scenario in detail and indicate any actions taken to date:  
 
 
 
 
 
WCMC Principal Investigator’s Signature ______________________________ Date: _________________ 
 
IMPORTANT: Before providing your digital signature, combine this form and supporting documents into a single PDF. 
 
Note on dates of receipt: In order to ensure the effective review of emergent risks to research subjects, the IRB cannot honor the 
received date of Immediate Report submissions with questions left blank or without the information requested. Immediate Reports are 
considered received as of the date this form is received with all questions on the form answered as instructed. 
 
Certain adverse events and incidents must be immediately reported to NewYork-Presbyterian Patient Services, Risk Management, 
and/or the Department of Health.  Please refer to the following policies/offices to determine whether this event qualifies for reporting to 
any of the aforementioned groups. 
 
Risk Management Incident Reporting (x66180): http://weill.cornell.edu/risk-management/insurance/incident_reporting.html  
SAEs/Sentinel Events Reporting: https://infonet.nyp.org/QA/HospitalManual/S120SeriousAdverseEvents.pdf  
NYPH Patient Services 212-746-4293 
NYPH Westchester Patient Services 917-997-592