Clinical trial NCT04364048
Conditions: Lung Cancer Non-small Cell Carcinoma
Sponsor: Rachel Sanborn
Start date: 2020-06-18; Completion date: 2024-02-05
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Single arm study of induction durvalumab (1500 mg IV) for 1 cycle (every 4 weeks), administered prior to starting concurrent definitive chemoradiation, followed by consolidation durvalumab (1500 mg IV every 4 weeks) for up to 12 cycles.

The study will include an initial safety run-in portion. Patients in the safety run-in will be monitored through completion of induction durvalumab, chemoradiation, and 2 cycles of consolidation durvalumab for assessment of safety prior to completion of enrollment.

Detailed description:

Arms: arm 1: Induction durvalumab at 1500 mg intravenously (IV) on Day 1 of a four week cycle for 1 cycle, followed by concurrent definitive chemoradiation, followed by consolidation durvalumab at 1500 mg IV Day 1 of every 4 week cycle for up to 12 cycles.
Interventions: intervention 1: Induction Durvalumab intervention 2: Chemotherapy intervention 3: Radiation intervention 4: Consolidation durvalumab
Intervention descriptions: intervention 1: Induction durvalumab at 1500 mg intravenously (IV) will be given on Day 1 of a four week cycle for 1 cycle, intervention 2: Concurrent chemoradiation will be with platinum-based chemotherapy (cisplatin or carboplatin, with etoposide, taxane, or pemetrexed) selected at the treating physician's discretion. The chemotherapy regimen used should be administered per institutional standards following the prescribing guidelines for each drug intervention 3: Treatment will be delivered using IMRT or 3DCRT using typically 6-10MV photons per institutional standards. 4D simulation and appropriate IGRT are encouraged. Radiation therapy must begin within one week of the first day of chemotherapy (or vice versa). Therapy will be 1.8-2 Gy per day; 5 days per week, excluding holidays per institutional standard as this is a standard of care regimen for this patient population. 54-66 Gy will be delivered. intervention 4: Durvalumab at 1500 mg intravenously (IV) will be given on Day 1 of a four week cycle for 12 cycles

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol  
HCRN LUN18-357  
 
 
  
Induction durvalumab followed by chemoradiation and consolidation durvalumab  
(MEDI4736) for stage III non-small cell lung cancer  
  
  
  
Sponsor Investigator Rachel 
E. Sanborn, M.D.  
Earle A. Chiles Research Institute  
Providence Cancer Institute  
  
Co-Investigators Clinical:  
Additional participating sites TBD  
  
Translational:  
William L. Redmond, Ph D.  
Earle A. Chiles Research Institute  
Providence Cancer Institute  
  
  
Statistician  
Shu-Ching Chang  
Medical Data Research Center, Providence St. Joseph Health  
  
Trial Management Provided by  Hoosier 
Cancer Research Network, Inc.  
500 N. Meridian, Suite 100  
Indianapolis, IN 46204  
  
  
Trial Supported by   
AstraZeneca  
ESR-18-14291  
  
  
IND exempt per FDA 3/12/2020  
  
  
  
  


Clinical Study Protocol  
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Confidential  
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Initial Protocol Version Date: 12MAR2020 Protocol 
Amendment Version Date:   
22MAR2021  
09MAY2022  
  
  
PROTOCOL SIGNATURE PAGE  
  
Induction durvalumab followed by chemoradiation and consolidation durvalumab for stage III 
non-small cell lung cancer  
  
  
VERSION DATE: 09MAY2022  
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the individual. 
I will accept the monitor’s overseeing of the study. I will promptly submit the protocol to 
applicable institutional review board(s).  
  
  
  
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN  
  


Clinical Study Protocol  
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SYNOPSIS  
TITLE  
Induction durvalumab followed by chemoradiation and 
consolidation durvalumab for stage III non-small cell lung cancer  
SHORT TITLE  
Induction durvalumab for stage III NSCLC  
PHASE   
Feasibility  
OBJECTIVES  
Primary Objectives  
• 
12-month progression-free survival from completion of 
chemoradiation (to be compared with PACIFIC trial 
12month progression-free survival as historical control).  
Progression-free survival will be measured beginning then 
at the start of consolidation durvalumab.  
• 
Safety and feasibility  
  
Secondary Objective  
• 
Overall response rate  
  
Exploratory Objectives  
• 
Correlation of PFS and toxicity based upon tumor and 
immune cell PD-L1 status in baseline tumor biopsy prior 
to therapy;  
• 
Correlation of toxicity based upon type of chemotherapy 
administered;  
• 
Correlation of outcomes based upon tumor mutation 
burden in baseline tumor biopsy prior to therapy;  
• 
Assessment of immune response via peripheral blood 
immune monitoring through multiple timepoints of 
therapy;  
• 
Correlation of immune response with outcomes in terms 
of disease control and toxicity;  
• 
Correlation of tumor immune score via quantitative 
multiplex tumor biopsy assay with clinical outcomes;  
• 
Exploration of immune response signal to indicate further 
exploration of a treatment schedule in a larger trial;  
• 
Collection of microbiome samples to correlate with 
outcomes and toxicity  


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STUDY DESIGN  
Single arm study of induction durvalumab (1500 mg IV) for 1 
cycle (every 4 weeks), administered prior to starting concurrent 
definitive chemoradiation, followed by consolidation durvalumab 
(1500 mg IV every 4 weeks) for up to 12 cycles.  
  
The study will include an initial safety run-in portion.  Patients in 
the safety run-in will be monitored through completion of  
induction durvalumab, chemoradiation, and 2 cycles of 
consolidation durvalumab for assessment of safety prior to 
completion of enrollment.  
KEY ELIGIBILITY  
CRITERIA (See  
Section 3 for complete 
eligibility details)  
Inclusion Criteria  
1. Histologically confirmed stage III NSCLC per AJCC, 8th 
edition (not surgical candidates either due to medical 
inoperability or surgically unresectable disease), eligible for 
curative-intent concurrent chemoradiation.  
2. Plan for treatment with concurrent chemoradiation and a dose 
of radiation ranging from 54-66Gy  
3. Planned mean dose delivery to the lung <20 Gy  
4. V20 < 35%  
5. Eastern Cooperative Oncology Group performance status 0 or 
1.  
6. Women of childbearing potential must have a negative 
pregnancy test and must avoid becoming pregnant as outlined 
in Section 5.7. Men must avoid fathering a child as outlined 
in Section 5.7.   
7. Adequate bone marrow, renal and hepatic function as defined 
by:  
 Hgb: ≥ 9 g/dL  
  WBC: ≥ 3,000/mm3  
  Platelets: ≥ 100,000/mm3  
  Total bilirubin: ≤ 1.5 x institutional upper limit of 
normal (ULN)  
  AST (SGOT)/ALT (SGPT): ≤ 2.5 x institutional ULN  


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8. Measurable disease by RECIST 1.1 criteria.  
  
Exclusion Criteria  
1. No prior therapy for stage III NSCLC.  
2. Prior exposure to anti-PD-1 or anti-PD-L1 antibodies  
3. No history of pulmonary fibrosis, interstitial lung disease, or 
pneumonitis requiring steroids.  
4. Active or prior documented autoimmune disease within the 
last 2 years. Patients with vitiligo, stable hypothyroidism, 
Grave’s disease, or psoriasis not requiring systemic treatment 
are not excluded.  
5. Active and ongoing steroid use, except for non-systemically 
absorbed treatments (such as inhaled or topical steroid 
therapy for asthma, COPD, allergic rhinitis).  
6. Uncontrolled concurrent illness or active ongoing infection.  
7. Active other malignancy, except for controlled basal cell or 
squamous cell skin cancer, in situ cervical or bladder cancer.  
8. 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. 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.  
9. Body weight < 30 kg   
  
Specific to Consolidation Therapy  
1. Patients must have recovered from toxicities associated with 
prior chemoradiation to CTCAE < Grade 2.  
2. Patients must not have progressed following chemoradiation 
therapy, as measured on imaging per RECIST 1.1.  
3. Confirmation of ECOG Performance Status of 0 or 1.  
4. Any grade pneumonitis from prior chemoradiation will not be 
permitted.  


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STATISTICAL  
CONSIDERATIONS  
  
In the PACIFIC study, 12-month progression-free survival was 
55.9% (1).    
  
This study will be planned to detect a 14% improvement in 
12month progression-free survival as a potential signal to move 
forward with further evaluation in a large randomized trial.  Thus, 
12-month progression-free survival of 69.9% would be felt to be 
clinically meaningful for further investigation.  
  
Assuming that 12-month PFS in the historical control group is 
55.9%, with an 18-month accrual interval and additional 12month 
follow up after the accrual interval, the required sample size 
would be 49 patients, with a one-sided test given type I error 0.05 
and power of 0.8.    
  
Accounting for a 10% dropout rate, a total of 54 patients would 
be enrolled in this study.  
TOTAL   
NUMBER OF  
SUBJECTS  
N = 54  
ESTIMATED  
ENROLLMENT  
PERIOD  
Estimated 18 months  
ESTIMATED STUDY  
DURATION   
Estimated 36 months  
TABLE OF CONTENTS  
  
Schema ..............................................................................................................................................7 
1. Background and Rationale ............................................................................................................8 
2. Study Objectives and Endpoints .................................................................................................12 
3.  Eligibility Criteria ......................................................................................................................13 
4.  Subject Registration ...................................................................................................................16 
5. Treatment Plan ............................................................................................................................16 
6. Toxicities and Dose Delays/Dose Modifications ........................................................................23 
7. Study Calendar & Evaluations ....................................................................................................25 
8.  Biospecimen Studies and Procedures ........................................................................................29 
9. Criteria for Disease Evaluation ...................................................................................................31 
10 Drug Information .......................................................................................................................34 
11. Adverse Events .........................................................................................................................37 
12. Statistical Methods ....................................................................................................................43 
13.  Trial Management ....................................................................................................................46 


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14.  Data Handling and Record Keeping ........................................................................................48 
15  Ethics ........................................................................................................................................49 
16  References .................................................................................................................................49 
 
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1.  
BACKGROUND AND RATIONALE  
  
1.1  
Non-Small Cell Lung Cancer Background  
Non-small cell lung cancer (NSCLC) is the most common cancer killer in the United States, and 
worldwide.  Despite indications of benefit of low dose CT screening for lung cancer in certain 
high-risk populations, most patients with NSCLC are diagnosed at more advanced stages.  The 
majority of patients with stage III NSCLC are not eligible for surgical resection, and despite 
curative-intent treatment with definitive chemoradiation, most will experience disease recurrence 
and will die.  
  
In a randomized phase III trial evaluating the addition of consolidation durvalumab after 
completion of standard of care concurrent platinum-doublet chemotherapy with radiation for 
patients with stage III NSCLC, progression-free survival (PFS) was significantly improved with 
durvalumab compared with placebo (16.8 months vs 5.6 months; P<0.001).  This benefit, 
including a benefit of 12-month and 18-month PFS, was demonstrated across all subgroups, and 
was independent of PD-L1 tumor expression prior to chemoradiation.  Median time to death or 
development of metastasis was significantly improved with durvalumab compared with placebo 
(23.2 months vs 14.6 months), and fewer patients receiving durvalumab developed brain 
metastases (5.5% vs 11%).  Objective response rate was significantly improved with durvalumab 
(28.4% vs 16%) (1).  Overall survival was also significantly improved with durvalumab (hazard 
ratio for death, 0.68; median overall survival with durvalumab not reached, versus 28.7 months 
with placebo) (2).  Despite prior concerns regarding potential increased risk of pneumonitis with 
checkpoint inhibition after radiation, no significant difference in grade 3 or 4 pneumonitis was 
seen with durvalumab, although an expected increase in immune-mediated adverse events was 
seen with durvalumab compared with placebo (24.2% vs 8.1%, respectively) (1).  
  
Nivolumab has been evaluated as neoadjuvant therapy for resectable stage IB-IIIA NSCLC in a 
small feasibility study (3).  Nivolumab, 3 mg/kg every 2 weeks, was administered for 2 doses 
prior to surgical resection in 22 patients.  Twenty patients underwent surgical resection (1 patient 
withdrew without toxicity or disease progression; 1 patient had unresectable disease).  
Interestingly, nine patients (45%) exhibited major pathologic response (defined as <10% viable 
tumor cells within the resected specimen) with just the two doses of neoadjuvant nivolumab.  In 
an interim report of short interval follow up (median postoperative follow up of 12 months), 80% 
(16 patients) were free of recurrence.  Correlation was noted between tumor mutation burden and 
neoantigen loads and pathologic response, as well as influx of PD-1+ CD8+ T cells as assessed 
by multiplex immunohistochemistry assay (3).  T cell receptor sequencing in peripheral blood 
demonstrated corresponding increases in T cell clones in the periphery compared with local 
tumor invasion (3).  Surgery was not delayed in this patient population.  Currently, multiple 
studies utilizing different checkpoint inhibitors are being evaluated in the neoadjuvant setting for 
resectable NSCLC (4).  
  
  
  
1.2  
Current Standard of Care, Stage III NSCLC  


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The current standard of care for patients with unresectable stage III NSCLC amenable for 
curative-intent therapy is combined modality chemoradiation, followed by consolidation 
durvalumab for 12 months, based upon the PACIFIC trial results (1).  Despite the compelling 
survival advantage with the addition of consolidation durvalumab, over 22% of patients still 
experience new lesions and recurrent disease (2).  
  
1.3  
Durvalumab  
The non-clinical and clinical experience is fully described in the most current version of the 
durvalumab Investigator’s Brochure. Durvalumab is a human monoclonal antibody (mAb) of the 
immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1 and is being developed 
by AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a wholly owned 
subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document).  The proposed mechanism of action (MOA) for durvalumab is 
interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1).  Blockade of PD-L1/PD-1 
and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that 
may result in tumor elimination.  In vitro studies demonstrate that durvalumab antagonizes the 
inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation of 
IFN-γ (5).  In vivo studies have shown that durvalumab inhibits tumor growth in xenograft 
models via a T-cell-dependent mechanism (5).  Based on these data, durvalumab is expected to 
stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting the balance 
toward an antitumor response. Durvalumab has been engineered to reduce antibody-dependent 
cellular cytotoxicity and complement-dependent cytotoxicity.   
  
To date durvalumab has been given to more than 6000 patients as part of ongoing studies either as 
monotherapy or in combination with other anti-cancer agents.  Refer to the current durvalumab 
Investigator’s Brochure for a complete summary of non-clinical and clinical information 
including safety, efficacy and pharmacokinetics.  
  
1.3.1 Overall risks of Checkpoint Blockade  
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 or immune mediated mechanism and which may require 
more frequent monitoring and/or unique interventions such as immunosuppressants and/or 
endocrine therapy. These immune mediated effects can occur in nearly any organ system, and are 
most commonly seen as gastrointestinal AEs such as colitis and diarrhoea, pneumonitis/interstitial 
lung disease (ILD), hepatic AEs such as hepatitis and liver enzyme elevations, skin events such as 
rash and dermatitis and endocrinopathies including hypo- and hyper-thyroidism.  
1.3.1.1 Durvalumab  


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Risks with durvalumab include, but are not limited to, diarrhea/colitis pneumonitis/ILD, 
endocrinopathies, hypo- and hyper-thyroidism, type I diabetes mellitus (which may present as 
diabetic ketoacidosis), diabetes insipidus, hypophysitis and adrenal insufficiency, encephalitis, 
hepatitis/increases in transaminases, nephritis/increases in creatinine, pancreatitis/increases in 
amylase and lipase, rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, other rare or less 
frequent inflammatory events including neurotoxicities, infusion-related reactions, 
hypersensitivity reactions, and infections/serious infections.   
  
For information on all identified and potential risks with durvalumab please always refer to 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, constipation, diarrhea, vomiting, back pain, 
pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus.  
Approximately 4% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 7% 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 (Appendix A). A detailed summary of durvalumab 
monotherapy AE data can be found in the current version of the durvalumab IB.  
  
1.3.2 Rationale for Durvalumab Dosing  
A durvalumab dose of 20 mg/kg Q4W is supported by in-vitro data, non-clinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with advanced 
solid tumors and from a Phase I trial performed in Japanese patients with advanced solid tumor 
(6).  
  
1.3.2.1  
PK/Pharmacodynamic data  
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging from 
0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited non-linear  
(dose-dependent) PK consistent with target-mediated drug disposition. The PK approached 
linearity at ≥3 mg/kg Q2W, suggesting near complete target saturation (membrane-bound and 
sPD-L1), and further shows that the durvalumab dosing frequency can be adapted to a particular 
regimen given the linearity seen at doses higher than 3 mg/kg. The expected half-life with doses 
≥3 mg/kg Q2W is approximately 17 days. A dose-dependent suppression in peripheral sPD-L1 
was observed over the dose range studied, consistent with engagement of durvalumab with 
PDL1. A low level of immunogenicity has been observed. No patients have experienced 
immunecomplex disease following exposure to durvalumab (For further information on 
immunogenicity, please see the current IB).   
  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
Q2W or 15 mg/kg Q3W) (Error! Reference source not found.). Multiple simulations indicate that 
a similar overall exposure is expected following both 10 mg/kg Q2W and 20 mg/kg Q4W 


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regimens, as represented by AUCss (4 weeks). Median Cmax,ss is expected to be higher with 20 
mg/kg Q4W (~1.5 fold) and median Ctrough,ss is expected to be higher with 10 mg/kg Q2W (~1.25 
fold). Clinical activity with the 20 mg/kg Q4W dosing regimen is anticipated to be consistent 
with 10 mg/kg Q2W with the proposed similar dose of 20 mg/kg Q4W expected to (a) achieve 
complete target saturation in majority of patients; (b) account for anticipated variability in PK, 
pharmacodynamics, and clinical activity in diverse cancer populations; (c) maintain sufficient PK 
exposure in case of ADA impact; and (d) achieve PK exposure that yielded maximal antitumor 
activity in animal models.  
  
Given the similar area under the plasma drug concentration-time curve (AUC) and modest 
differences in median peak and trough levels at steady state, the observation that both regimens 
maintain complete sPD-L1 suppression at trough, and the available clinical data, the 20 mg/kg 
Q4W and 10 mg/kg Q2W regimens are expected to have similar efficacy and safety profiles, 
supporting further development with a dose of 20 mg/kg Q4W.   
  
1.3.2.2  
Clinical data  
Refer to the current durvalumab Investigator’s Brochure for a complete summary of clinical 
information including safety, efficacy and pharmacokinetics at the 20mg/kg Q4W regimen.  
  
1.3.2.3 Rationale for Fixed Dosing  
A population PK model was developed for durvalumab using monotherapy data from a Phase I 
study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on the PK of 
durvalumab (coefficient of ≤0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed dose of 
750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 
1000 patients were simulated using body WT distribution of 40–120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state PK 
concentrations with slightly less overall between-patient variability with fixed dosing regimen.   
  
Similar findings have been reported by others (7, 8, 9, 10). Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, with 
fixed dosing being better for 7 of 12 antibodies (8). 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 pharmacokinetic/pharmacodynamics parameters (9).   
  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, we 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a 
fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the current 
study.  
  
1.4  
Rationale  


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Given that checkpoint inhibition with nivolumab delivered for a defined interval in the small 
patient population with resectable NSCLC did not delay surgery, and induced a major pathologic 
response in 43% of patients (3), consideration of checkpoint inhibition as induction prior to 
definitive chemoradiation for patients with stage III NSCLC is intriguing.  Despite previous 
concerns regarding potential risk for increased toxicity (particularly pneumonitis) with 
checkpoint inhibition after chemoradiation, consolidation durvalumab after definitive 
chemoradiation was demonstrated to be safe and feasible, with improvement in progression-free 
and overall survival.  The addition of a checkpoint inhibitor, such as durvalumab, as induction 
therapy prior to definitive chemoradiation and consolidation checkpoint inhibition for stage III 
NSCLC, offers an intriguing question as to the potential for the further improvement of immune 
recognition and response.    
  
We hypothesize that the addition of durvalumab as induction therapy prior to definitive 
chemoradiation, followed by consolidation durvalumab, as a “sandwich” approach to 
immunotherapy with chemoradiation, will improve efficacy in terms of 12-month progressionfree 
survival, for patients with stage III NSCLC, as compared with historical controls (using the 
PACIFIC study).  In this study, we will utilize the monthly “flat dose” administration of 
durvalumab, 1500 mg intravenously every 4 weeks.  
  
2.  
STUDY OBJECTIVES AND ENDPOINTS  
  
2.1  
Objectives  
  
2.1.1 Primary Objectives  
• 
Estimate 12-month progression-free survival (PFS) after completion of chemoradiation in 
patients with Stage III non-small cell lung cancer (NSCLC), measured from the start of 
consolidation durvalumab. Compare with PACIFIC trial 12-month progression-free 
survival as historical control (which was measured from the start of consolidation 
durvalumab).    
• 
Assess the safety and feasibility of induction durvalumab followed by chemoradiation and 
consolidation durvalumab for stage III NSCLC.  
  
2.1.2 Secondary Objectives  
• 
Estimate Objective response rate (ORR).    
  
2.1.3 Correlative/Exploratory Objectives  
• 
Correlation of outcomes and toxicity based upon tumor and immune cell PD-L1 status in 
baseline tumor biopsy prior to therapy.  
• 
Correlation of toxicity based upon type of chemotherapy administered.  
• 
Correlation of outcomes based upon tumor mutation burden in baseline tumor biopsy 
prior to therapy.  
• 
Assessment of immune response via peripheral blood immune monitoring through 
multiple timepoints of therapy.  
• 
Correlation of immune response with outcomes in terms of disease control and toxicity.  


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• 
Correlation of tumor immune score via quantitative multiplex tumor biopsy assay with 
clinical outcomes.  
• 
Exploration of immune response signal to indicate further exploration of a treatment 
schedule in a larger trial.  
• 
Collection of microbiome samples to correlate with outcomes and toxicity.  
  
2.2  
Endpoints  
  
2.2.1  
Primary Endpoints  
• 
12-month progression-free survival will be measured using imaging after completion of 
chemoradiation, prior to C1 consolidation durvalumab (1-42 days after completion of 
chemoradiation). This will be compared with PACIFIC trial 12-month progression-free 
survival as historical control.   
• 
Toxicity will be measured by the NCI Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v5.   
  
2.2.2  
Secondary Endpoints  
• 
Objective response rate (ORR).  ORR will be measured using two timepoints, per 
RECIST 1.1. “ORR1” will be assessed using baseline imaging in comparison to imaging 
obtained after completion of induction durvalumab and chemoradiation.  “ORR2” will be 
assessed using imaging after completion of induction durvalumab and chemoradiation in 
comparison to imaging obtained while receiving, and after completion of, consolidation 
durvalumab.  
  
3.  
ELIGIBILITY CRITERIA  
  
3.1  
Inclusion Criteria  
Subjects must meet all of the following applicable inclusion criteria to participate in this study:  
  
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately.  
  
2. Age ≥ 18 years at the time of consent.  
  
3. ECOG Performance Status of 0 or 1.  
  
4. Histological or cytological confirmation of stage III non-small cell lung cancer per AJCC, 
8th edition, eligible for curative-intent concurrent chemoradiation. NOTE:  
subjects are not candidates for surgical resection either due to medical inoperability or 
surgically unresectable disease.  
  
5. Measurable disease according to RECIST 1.1 criteria.   
  


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6. Plan for treatment with concurrent chemoradiation with a dose of radiation ranging from 
54-66 Gy:  
• 
Planned mean dose delivery to the lung <20 Gy  
• 
V20 <35%  
  
7. No prior therapy for stage III NSCLC.  
8. Demonstrate adequate organ function as defined in the table below. All screening labs to 
be obtained within 14 days prior to registration.   
  
System  
Laboratory Value  
Hematological  
 
Hemoglobin  
≥ 9.0 g/dL  
White blood cell (WBC)  
≥ 3,000/mm3  
Absolute neutrophil count (ANC)  
≥ 1,500/mm3  
Platelet count  
≥ 100,000/mm3  
Renal  
 
Calculated creatinine clearance1  
≥ 40 mL/min   
Hepatic  
 
Bilirubin  
≤ 1.5 x institutional upper limit of normal (ULN). 2  
Aspartate aminotransferase (AST)  
≤ 2.5 x institutional ULN  
Alanine aminotransferase (ALT)  
≤ 2.5 x institutional ULN  
1 Cockcroft-Gault formula will be used to calculate creatinine clearance   
2 This will not apply to patients with Gilbert’s syndrome.  Patients with Gilbert’s syndrome will be permitted 
to enroll.  
  
9. Females of childbearing potential must have a negative serum pregnancy test within 24 
hours of C1D1. NOTE: Females are considered of child bearing potential unless they are 
surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.  
  
10. Females of childbearing potential must be willing to abstain from heterosexual intercourse 
or to use contraception as outlined in Section 5.7.    
  
11. Men who are sexually active with WOCBP must be willing to abstain from heterosexual 
intercourse or to use contraception as outlined in Section 5.7.  
  
12. Life expectancy of at least 12 weeks per investigator discretion.  
  
13. As determined by the enrolling physician or protocol designee, ability of the subject to   
understand and comply with study procedures for the entire length of the study.  
  


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3.2  
Exclusion Criteria  
Subjects meeting any of the criteria below may not participate in the study:  
  
1. Prior therapy for stage III NSCLC  
  
2. Mixed histology with small cell lung cancer will not be allowed.  
  
3. Sequential chemoradiation will not be permitted.  
  
4. Induction and consolidation chemotherapy (separate from concurrent chemoradiation) 
will not be allowed.  
  
5. Prior exposure to anti-PD-1 or anti-PD-L1 antibodies including durvalumab.  
  
6. Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab. The following are exceptions to this criterion:  
• 
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular 
injection)  
• 
Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of 
prednisone or its equivalent  
• 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication)  
  
7. History of pulmonary fibrosis, interstitial lung disease, or pneumonitis requiring steroids.  
  
8. Active or prior documented autoimmune disease within the last 2 years. Patients with 
vitiligo, stable hypothyroidism, Grave’s disease, or psoriasis not requiring systemic 
treatment are not excluded.  
  
9. Body weight < 30 kg   
  
10. Active and ongoing steroid use, except for non-systemically absorbed treatments (such as 
inhaled or topical steroid therapy for asthma, COPD, allergic rhinitis).  
  
11. Active infection requiring systemic therapy.  
  
12. Uncontrolled current illness that in the opinion of the investigator renders the 
investigational treatment plan unsafe.  
  
13. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days 
after the last dose of IP.  
  


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14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP. NOTE: Local surgery of isolated lesions for palliative intent is acceptable.  
  
15. Active other malignancy; exceptions include basal cell or squamous cell skin cancer, in 
situ cervical or bladder cancer.  
  
16. 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 
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.  
  
17. Treatment with any investigational drug within 30 days prior to registration.   
18. History of organ transplantation (including allogeneic stem cell transplantation).  
  
19. Other medical or psychiatric conditions that in the opinion of the site investigator would 
preclude safe participation in this protocol.  
  
3.3  
Eligibility Criteria for Consolidation Durvalumab  
1. Patients must have recovered from toxicities associated with prior chemoradiation to 
CTCAE < Grade 2.  
  
2. Patients must not have progressed following chemoradiation therapy, as measured on 
imaging per RECIST 1.1.  
  
3. Confirmation of ECOG Performance Status of 0 or 1.  
  
4. Any grade pneumonitis from prior chemoradiation will not be permitted.  
  
4.  
SUBJECT REGISTRATION  
All subjects must be registered through HCRN’s electronic data capture (EDC) system. A subject 
is considered registered when an “On Study” date is entered into the EDC system. Subjects must 
be registered prior to starting protocol therapy.   
  
5.  
TREATMENT PLAN  
This is a single arm study of induction durvalumab at 1500 mg intravenously (IV) on Day 1 of a 
four week cycle for 1 cycle, followed by concurrent definitive chemoradiation, followed by 
consolidation durvalumab at 1500 mg IV Day 1 of every 4 week cycle for up to 12 cycles.    
  
Chemoradiation should begin no earlier than 4 weeks and no later than 5 weeks after the dose of 
induction durvalumab.  Patients meeting required criteria for consolidation and without disease 
progression after chemoradiation should begin consolidation durvalumab within 1-42 days after 


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completion of chemoradiation. Subjects unable to start within the timeframes described should be 
discussed with the sponsor-investigator. Concurrent chemoradiation will be with platinumbased 
chemotherapy (cisplatin or carboplatin, with etoposide, taxane, or pemetrexed) selected at the 
treating physician’s discretion. Patients receiving different chemotherapeutic agents will be 
analyzed together for toxicity, with exploratory analysis of toxicity related to different 
chemotherapeutic regimens. Radiation will be administered using standard fractionation at a dose 
of 54-66 Gy.   
  
5.1  
Induction Durvalumab Administration  
  
Drug  
Dose  
Route  
Schedule2  
Cycle Length  
Total # of Cycles  
Durvalumab  
1500 mg  
Intravenously (IV)  
over 1 hour  
Day 1  
4 weeks   
1  
2 A window of ± 3 days may be applied to all study visits to accommodate observed holidays, inclement weather, 
scheduling conflicts etc. Date and time of each drug administration should be clearly documented in subject’s 
chart and electronic case report forms (eCRFs).  
  
5.1.1  Durvalumab  
Durvalumab will be administered over 1 hour (± 15 minutes). Please refer to the current IB for 
more detailed information.  
  
Patients will be monitored before, during and after the infusion with assessment of vital signs. 
Patients are monitored (pulse rate, blood pressure) every 30 minutes (with a window of - 5 
minutes/+ 10 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 
durvalumab may be decreased by 50% or interrupted until resolution of the event and re-initiated 
at 50% of the initial rate until completion of the infusion. For patients with a ≤ Grade 2 infusion 
related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen and/or an antihistamine (eg, 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.  
  
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit patients to an intensive care unit if necessary  
  
For management of patients who experience an infusion reaction, please refer to the toxicity and 
management guidelines in Appendix A.  
  
5.2  
Chemotherapy and Radiation Therapy Administration  
  


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5.2.1  
Chemotherapy Administration  
Concurrent chemoradiation will be with platinum-based chemotherapy (cisplatin or carboplatin, 
with etoposide, taxane, or pemetrexed) selected at the treating physician’s discretion. The 
chemotherapy regimen used should be administered per institutional standards following the 
prescribing guidelines for each drug. Information regarding chemotherapy regimen used will be 
captured in the EDC system.  
  
5.2.2  
Radiation Therapy Administration  
Treatment will be delivered using IMRT or 3DCRT using typically 6-10MV photons per 
institutional standards. 4D simulation and appropriate IGRT are encouraged.  Radiation therapy 
must begin within one week of the first day of chemotherapy (or vice versa). Therapy will be 1.8-
2 Gy per day; 5 days per week, excluding holidays per institutional standard as this is a standard 
of care regimen for this patient population. 54-66 Gy will be delivered. Interruptions in radiation 
treatment are strongly discouraged.  Dose interruptions are allowed, however, for toxicity 
management at treating investigator discretion to align with institutional standard of care.  
  
  
  
 


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5.3  
Consolidation Durvalumab Administration  
  
Drug  
Dose  
Route  
Schedule2  
Cycle Length  
Total # of Cycles  
Durvalumab  
1500 mg  
Intravenously (IV)  
over 1 hour  
Day 1  
4 weeks   
12  
2 A window of ± 3 days may be applied to all study visits to accommodate observed holidays, inclement weather, 
scheduling conflicts etc. Date and time of each drug administration should be clearly documented in subject’s 
chart and electronic case report forms (eCRFs).  
  
5.4  
Safety Run In-Portion  
This study will include an initial safety run-in portion.  The dose limiting toxicity (DLT) period is 
through completion of induction durvalumab, chemoradiation, and 2 cycles of consolidation 
durvalumab.  Enrollment will pause after the first 5 patients are enrolled. If 3 out of the first 5 
patients experience dose limiting toxicities during the DLT period, further enrollment will be 
halted, and subsequent accrual re-evaluated with site investigators and the sponsor-investigator. If 
stopping criteria are not met, enrollment will continue, and accrual will again pause after 10 total 
patients are enrolled.    
  
If 4 out of the first 10 patients experience dose limiting toxicities (DLT) during the DLT period, 
further enrollment will be halted, and subsequent accrual re-evaluated with site investigators and 
the sponsor-investigator. If stopping criteria are not met, enrollment will then continue for the full 
planned cohort. Patients in the safety run-in phase will be analyzed for PFS and outcomes as 
members of the full study cohort.  
  
Subjects in the safety run in group who do not remain on the study through completion of the 
DLT period for reasons other than DLT will be replaced with another subject.   
  
5.4.1  
Definition of Dose Limiting Toxicities  
The DLT period is through completion of induction durvalumab, chemoradiation, and 2 cycles of 
consolidation durvalumab. NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 
will be used in grading adverse events. A DLT will be defined as:  
• 
Any grade of febrile neutropenia regardless of duration or reversibility  Any Grade 4 
immune-mediated adverse event (imAE)  Any grade of immune-mediated neurotoxicity.  
• 
Grade ≥ 3 colitis  
• 
Grade 3 non-infectious pneumonitis irrespective of duration  
• 
Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation of 
maximal supportive care  
• 
Grade 3 imAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 
within 3 days after onset of the event despite optimal medical management including 
systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days  
• 
Grade 3 liver transaminase elevation with concurrent total bilirubin > 2 × ULN   Grade 
≥ 3 non-imAE, except for the exclusions listed below  


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The following conditions are excluded from the DLT definition:   
• 
Grade 3 fatigue lasting ≤ 7 days  
• 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic  
• 
Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc)  
• 
Concurrent vitiligo or alopecia of any AE grade  
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management  
• 
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days.   
• 
Grade 3 or 4 lymphopenia  
• 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention and improves by at least 1 grade within 3 days  
• 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days  
• 
Transient asymptomatic laboratory abnormalities that do not require hospitalization  
  
5.5  
Concomitant Medications  
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered more than 30 days after the last dose of trial treatment should be recorded for 
serious adverse events (SAE).  
  
5.5.1 Allowed Concomitant Medications  
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), and IV medications and fluids. If changes 
occur during the trial period, documentation of drug dosage, frequency, route, and date may also 
be included on the CRF.  
  
5.5.2 Prohibited Concomitant Medications  
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The site investigator should discuss any questions regarding this 
with HCRN who will then communicate with the sponsor-investigator and AstraZeneca regarding 
the situation.  The final decision on any supportive therapy or vaccination rests with the site 
investigator and/or the subject's primary physician. There are no prohibited therapies during the 
Post-Treatment Follow-up Phase.  
  


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Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:  
• 
Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol  
• 
Immunotherapy not specified in this protocol  
• 
Chemotherapy not specified in this protocol  
• 
Investigational agents other than Durvalumab   
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. 
FluMist®) are live attenuated vaccines, and are not allowed.  
• 
Systemic glucocorticoids (>10 mg prednisone equivalent) for any purpose other than to 
modulate symptoms from an event of clinical interest of suspected immunologic etiology.  
Brief, limited use of systemic corticosteroids (≤7 days) are permitted where such use is 
considered standard of care (e.g. as premedication for contrast allergy or for COPD 
exacerbation).  Inhaled or topical steroids, and adrenal replacement doses of steroids (for 
example prednisone 10mg daily) are permitted while on study.   
• 
Would advise patients avoid herbal or natural remedies with reported immunemodulating 
effects.  
• 
Hematopoietic growth factor support will not be allowed during chemoradiation.  
  
Subjects who, in the assessment by the site investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.   
  
There are no prohibited therapies during the Post-Treatment Follow-up Phase.  
  
5.6  
Supportive Care  
Subjects should receive appropriate supportive care measures as deemed necessary by the site 
investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include 
the use of oral or intravenous treatment with corticosteroids as well as additional 
antiinflammatory agents if symptoms do not improve with administration of corticosteroids.   
Note that several courses of steroid tapering may be necessary as symptoms may worsen when 
the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to Durvalumab.  
  
Early recognition of signs and symptoms potentially related to an inflammatory or 
immunemediated mechanism is important for proper management of toxicities. For guidance on 
identifying, evaluating, and treating imAE, see the Toxicity Management Guidelines in Appendix 
A.  


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ImAE observed with anti PD-L1/PD-1 agents may include pneumonitis, hepatitis, diarrhea/colitis 
and intestinal perforation, endocrinopathies (hypo- and hyper-thyroidism, adrenal insufficiency, 
hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, rash/dermatitis, 
pancreatitis, myocarditis, myositis/polymyositis and rare/less frequent imAE including 
neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome.  
  
Other inflammatory responses that are rare with a potential immune-mediated etiology are also 
considered as imAE and include, but are not limited to, pericarditis, sarcoidosis, uveitis and other 
events involving the eye, skin, hematological and rheumatological events. It is possible that 
events with an inflammatory or immune mediated mechanism could occur in nearly all organs.  
  
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered imAEs (Durvalumab IB).  
For guidelines on the treatment of immune-mediated adverse events, please refer to the published 
ASCO guidelines [14].  
  
5.7  
Reproductive Information  
Participants of childbearing potential who are sexually active and their partners must agree to 
abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception 
beginning with time of consent (females) or prior to C1D1 treatment (males), during the study 
treatment and for 90 days after last dose of durvalumab (or timeframe outlined per package insert 
for chemotherapy or institutional guidelines for radiation). Two contraception methods can be 
comprised of two barrier methods, or a barrier method plus a hormonal method. See below for 
options:  
  
Acceptable non-hormonal birth control methods:  
• 
Total sexual abstinence ie, refrain from any form of sexual intercourse in line with the 
patients’ usual and/or preferred lifestyle. Abstinence must be for the total duration as 
described above. Periodic abstinence (eg, calendar ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception.  
• 
Vasectomised sexual partner PLUS male condom. With participant assurance that partner 
received post-vasectomy confirmation of azoospermia.  
• 
Tubal occlusion PLUS male condom  
• 
Intrauterine Device (IUD) PLUS male condom. IUD coils should be copper-banded.  
  
Acceptable hormonal methods:  
• 
Etonogestrel implants (eg, Implanon®, Norplant®) PLUS male condom  
• 
Normal and low dose combined oral pills PLUS male condom  
• 
Hormonal shot or injection (eg, Depo-Provera) PLUS male condom  
• 
Intrauterine system device (eg, levonorgestrel-releasing intrauterine system -Mirena®) 
PLUS male condom  
  


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Female subjects should not breastfeed during treatment and for at least 3 months after the last 
dose of durvalumab (or timeframe outlined per package insert for chemotherapy or institutional 
guidelines for radiation).  
  
Male subjects should not donate sperm during treatment and for at least 3 months after the last 
dose of durvalumab (or timeframe outlined per package insert for chemotherapy or institutional 
guidelines for radiation).  
  
6.  
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events.   
  
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Study 
Calendar & Evaluations.  
  
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation as specified in Study Calendar & 
Evaluations.    
  
6.1  
Dose Delays/Dose Modifications  
  
6.1.1 Induction Durvalumab  
Dose reductions of durvalumab with induction therapy will not be permitted. See Appendix A for 
toxicity management guidelines.  
  
6.1.2 Chemoradiation   
Chemoradiation should not be initiated until any toxicity attributed to induction durvalumab has 
resolved to ≤ Grade 1.  If initiation of chemoradiation is delayed ≥ 1 week beyond the planned 
initiation date secondary to toxicity from durvalumab induction therapy, the HCRN Project 
Manager and sponsor-investigator should be notified.  
  
Dose reductions or delays of chemotherapy and/or radiation based upon toxicities from 
chemotherapy or radiation will be conducted per institutional standard of care at the discretion of 
the treating investigator.  
  
Chemotherapy doses held during chemoradiation should not be added after completion of 
radiation.  
  
6.1.3 Consolidation Durvalumab  
Dose reductions of durvalumab during consolidation therapy will not be permitted. See Appendix 
A for toxicity management guidelines.  
  
6.2  
Protocol Therapy Discontinuation  


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In addition to discontinuation from therapy related to toxicities as outlined above, a subject will 
also be discontinued from protocol therapy and followed per protocol under the following 
circumstances outlined below.  The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF).    
• 
Documented confirmed disease progression.  In the absence of clinical deterioration, if 
disease progression is identified per RECIST 1.1, confirmatory scan should be performed  
no earlier than 4 weeks after the initial assessment of progressive disease.  Study drug 
administration may continue between these assessment scans in the absence of prohibitive 
toxicity, and the patient must continue to meet eligibility criteria.  Patients with rapid 
clinical deterioration or rapid disease progression will not be eligible to continue 
treatment and will be discontinued from therapy.   
• 
Subjects who fall to ≤ 30 kg.  
• 
Site investigator determines a change of therapy would be in the best interest of the 
subject  
• 
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons  
o In a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), 
the subject should be asked if he or she may still be contacted for further scheduled 
study assessments. The outcome of that discussion should be documented in both the 
medical records and in the eCRF.  
• 
Female subject becomes pregnant   
• 
Protocol therapy is interrupted for ≥ 6 weeks.   
  
6.3  
Protocol Discontinuation   
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with an 
explanation of why the subject is withdrawing from the protocol. If the reason for removal of a 
subject from the study is an adverse event, it will be recorded on the eCRF.  


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7.  
STUDY CALENDAR & EVALUATIONS  
  
Induction and Consolidation:   
Cycle = 28 days  
Screen  
Induction  
Chemoradiation  
Consolidation  
Safety follow up  
visit11  
Long-term Follow up12  
-28 days  
Cycle 1  
Cycle 1-12  
30 and 100 days 
post last dose  
Every 3 months 
(±14days)  
Day 1  
± 3  
Day 1 ± 
3  
Day 1 
± 3  
REQUIRED ASSESSMENTS  
  
  
  
  
  
  
Informed Consent  
X  
  
  
  
  
  
Medical History1  
X  
  
  
  
  
  
Diagnosis and Staging2  
X  
  
  
  
  
  
Physical Exam3  
X  
X  
X3  
X  
D30  
  
Vital signs and ECOG Performance Status4  
X  
X  
X3  
X  
D30  
  
ECG  
X  
  
  
  
  
  
AEs & concomitant medications  
X  
X  
X3  
X  
X  
  
LABORATORY ASSESSMENTS  
  
  
  
  
  
  
Complete Blood Cell Count with diff (CBC)  
X  
X13  
X  
X  
D30  
  
Comprehensive Metabolic Profile (CMP)  
X  
X13  
X  
X  
D30  
  
PT/INR and aPTT  
X  
  
  
  
  
  
Thyroid Function Testing5  
X  
  
  
X5  
  
  
Pregnancy test (serum or urine) (WOCBP)6  
X  
X6  
  
X6  
  
  
DISEASE ASSESSMENT  
  
  
  
  
  
  
CT of chest7  
X  
  
  
X7  
X7  
X7  
CT or MRI of abdomen and pelvis7  
  
  
  
X7  
X7  
X7  
MRI or CT Brain7  
X  
  
  
 
as clinically indicated  
PET Scan7   
X7  
  
  
 
as clinically indicated  


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TREATMENT EXPOSURE  
  
  
  
  
  
  
Durvalumab  
  
X  
  
X  
  
  
Chemoradiation per standard of care  
  
  
X  
  
  
  
SPECIMEN COLLECTION   
  
  
  
  
  
  
Archival Tumor Tissue8  
X  
  
  
  
  
  
Blood Samples9  
  
C1D1  
  
X9  
  
  
Stool Microbiome10  
  
X10  
  
  
  
  
FOLLOW-UP  
  
  
  
  
  
  
Survival Status, Subsequent Therapy  
  
  
  
  
  
X  
  
  
  
Key to Footnotes   
  
1: Medical History; other data to obtained during this assessment includes: (1) a smoking history questionnaire, (2) trial awareness question (3) 
documentation of prior anti-cancer treatment including medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery and (4) If prior 
genetic testing has been done those results should be made available.   
  
2: Diagnosis and Staging to include pathology report and staging documentation. AJCC version 8 will be used for recording of staging.  
  
3: Patients should have weekly physical exam and vital signs per good medical practice during chemoradiation.  AEs and concomitant meds should 
be recorded weekly during chemoradiation.  
  
4: Vital signs to include temperature, pulse, respirations, blood pressure, weight, and height (screening only) and ECOG performance status. 
Patients will be monitored before, during and after the durvalumab infusion with assessment of vital signs. Patients are monitored (pulse rate, 
blood pressure) every 30 minutes (- 5 minutes/+ 10 minutes), during the infusion period (including times where infusion rate is slowed or 
temporarily stopped).  
  
5: CBC with differential and platelet to include: WBC, ANC, Hgb, Hct, PLT. CMP to include sodium, potassium, chloride, creatinine, blood urea 
nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase. Thyroid Function testing should be performed at 


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screening, at start of consolidation durvalumab, then every 3 cycles during consolidation durvalumab. TSH will be obtained. T4 and T3 including 
free versus total testing is at the discretion of the site investigator.  
  
6: For women of childbearing potential (WOCBP): urine or serum βhCG will be done at screening and within 24 hrs of 1st dose of study drug. 
During treatment with consolidation durvalumab, a pregnancy test should be performed every 4 weeks. If a urine test is done and it is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.  
  
7: Tumor assessments to be performed at (1) screening (PET scan may be within 42 days prior to C1D1) (2) within 0-24 days after completion of 
chemoradiation/prior to C1D1 of consolidation durvalumab, then every 3 months (about every 3 cycles/± 7 business days) during consolidation 
durvalumab. Screening tumor assessment will consist of evaluation by CT scans of chest (contrast enhanced), PET scan, and contrast-enhanced 
MRI or CT of the brain.  Response assessment imaging will include CT scans of chest, abdomen, and pelvis (contrast enhanced).  MRI or CT brain 
or PET scan after screening should be performed as clinically indicated.  Imaging selected for each subject should remain the same throughout the 
study. Tumor imaging at treatment discontinuation/D30 safety follow up visit is at discretion of site investigator. If tumor assessments are available 
for subjects who have not yet experienced progressive disease (PD) at the time treatment is discontinued, the follow-up tumor evaluations will be 
documented in the eCRF until PD or death is confirmed, or until another treatment is initiated. A window of 7 days may be applied to obtain scans.  
  
  
  
8: Archival tissue is required if available and should be identified at screening and shipped prior to chemoradiation. PD-L1 testing may performed 
using either 22C3 or SP263 testing per the institution’s standard of care.  If not performed via the treating institution, PD-L1 testing to be 
performed through the Providence Cancer Institute, using in-house SP263 assay pending the availability of funding.  Tumor Mutation Burden 
testing and multispectral IHC will also be performed pending the availability of funding.  
  
9: Peripheral blood will be collected for serum, plasma, and peripheral blood mononuclear cells (PBMCs). Timepoints include (1) prior to Cycle 1  
Day 1 (C1D1) induction durvalumab, (2) prior to C1D1 consolidation durvalumab, and at (3) 8 weeks after starting consolidation durvalumab 
(prior to Cycle 3 Day 1 consolidation durvalumab). Immune monitoring testing and ctDNA analysis will be collected. Analysis to be performed 
pending the availability of funding. Subjects will be consented for optional storage of any remaining tissue/blood samples collected prior to C1D1 
treatment after protocol-specified studies are complete. These samples will be stored for future unspecified cancer-related research and are 
considered “banking samples”.   
  
10: Stool for microbiome analysis will be performed prior to treatment C1D1. Subjects will be provided a kit with detailed instructions regarding 
collection of the sample prior to the timepoint it is due. Analysis will be performed pending the availability of funding. Please see the CLM for 
additional details.  
  


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11: The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, progression, or at 
discretion of site investigator) and should be performed 30 days (± 7 days) and 100 days (±7 days) after the last dose of treatment. More frequent 
follow up for management of toxicity will be per institutional standard of care and the treating investigator. Subjects who have an ongoing Grade ≥ 
2 or serious AE (SAE) at this visit will continue to be monitored by a member of the study team until the event is resolved, stabilized, determined 
to be irreversible by the site investigator or until a new anti-cancer treatment starts, whichever occurs earlier. The D100 evaluation may be 
completed via phone call.  
  
12: After the D100 safety visit, subjects who discontinue treatment for any reason without documented disease progression will be followed for 
disease progression every 3 months up to 12 months after initiation of consolidation durvalumab.  Once disease progression is documented, subjects 
will enter a survival follow up period every 6 months for 1 year from the time of documented progression or until 1 year after initiation of 
consolidation durvalumab.  Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. A window of ± 14 days 
will be applied to follow up.  
  
13: If screening (baseline) CBC and CMP were performed within 7 days of Day 1 of treatment, these do not need to be repeated.  All laboratory 
assessments should be done prior to treatment.  
  
  


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8.  
BIOSPECIMEN STUDIES AND PROCEDURES  
While anti-PD-1/L1 improves clinical outcomes for patients with many cancers, it appears that 
these responses are best in tumors with dense lymphocytic infiltration or PD-L1 positivity, 
arguing that improved outcome is associated with a pre-existing anti-cancer immune response 
(59). Based on this, we hypothesize that strategies which can convert “cold” tumors, lacking T 
cell infiltrates and PD-L1+ cells, into “hot” tumors with brisk T cell infiltrates, will increase 
response rate and overall survival.    
  
This proposal seeks to perform Multiplex immunohistochemistry (mIHC) on pre-treatment 
biopsies of patients enrolled on this clinical trial.  This will help us identify patients whose 
pretreatment tumors lack TIL and/or PD-L1+ cells and determine whether the tumor micro 
environment (TME) may be associated with clinical outcomes. Our group has applied mIHC to 
develop a next generation of immunoscore, termed the cumulative suppressive index (CSI). The 
CSI incorporates PD-L1 and FoxP3+ cells as well as their respective distance to CD8 T cells to 
provide a prognostic biomarker (10). We are currently evaluating whether it can also serve as a 
predictive biomarker. Recently, a similar approach has used distance measurements to evaluate 
PD-1+ cells in close proximity to PD-L1+ cells and showed a significant correlation with 
response to checkpoint blockade (11). The same report also identified that close proximity of 
IDO and HLA-DR expression was also predictive of increased overall survival. Patients positive 
for both multiplex IHC assessments had a significantly (P=0.0018) improved overall survival. 
We posit that these two predictive biomarkers represent a surrogate of a T cell immune response 
to the patient’s cancer. Supporting this concept, a retrospective analysis of five clinical trials 
found that multiplex IHC was a better than gene expression profiling, tumor mutational burden 
or PD-L1 expression at predicting response to checkpoint blockade (12).  On this basis we 
propose performing the CSI, as well as the PD-1/PD-L1 and IDO/HLA-DR proximity assays on 
biopsy samples from patients enrolled on this study.  
  
Samples for immunological monitoring will include blood (including for circulating tumor DNA 
analysis), archival tumor tissue, and collecting peripheral blood mononuclear cells (PBMC) and 
serum. The main objectives of the monitoring will be to characterize circulating T-cell subsets 
and changes in the tumor microenvironment (TME) following treatment that may correlate with 
clinical responses.    
  
Flow cytometry analysis with a panel of markers including CD3, CD4, CD8, CD25, CD127, 
CCR7, FoxP3, ICOS, and CD45RA will be performed. T cell sub-populations of interest include 
effector, regulatory T cell (Treg), central memory, and effector memory cells. Other 
immunological measures may be evaluated including, but not limited to, immunohistochemistry 
analysis of biopsy samples and measurement of serum cytokine levels using multiplex ELISA 
(Luminex assay) to generate hypotheses for future studies and to gain insight into possible 
biomarkers of response.   
  
  
  
8.1  
Tissue  
  


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8.1.1 Archival Tissue  
Archival tissue is required if available and may be submitted for PD-L1 testing (if not performed 
by 22C3 or SP263 assay at treating institution per standard of care). Tissue should be identified 
at screening and shipped prior to chemoradiation. Testing for tumor mutation burden will be 
performed. TMB is calculated as the number of somatic mutations per megabase of DNA across 
a 500-gene panel. Archival tissue will be stored for future multispectral immunohistochemistry 
evaluation. Analysis to be performed pending the availability of funding.  
  
8.2  
Peripheral Blood Samples  
Analysis to be performed pending the availability of funding.  
  
8.2.1 Serum  
Specimens for serum will be collected prior to C1D1 induction durvalumab; prior to C1D1 
consolidation durvalumab; and at 8 weeks after consolidation durvalumab (prior to Cycle 3) for 
immune monitoring analysis. All specimens should be collected prior to drug administration.   
  
8.2.2  
Peripheral Blood Mononuclear Cells (PBMCs)  
Specimens for PBMCs will be collected prior to C1D1 induction durvalumab; prior to C1D1 
consolidation durvalumab; and at 8 weeks after consolidation durvalumab (prior to Cycle 3) for 
immune monitoring analysis. All specimens should be collected prior to drug administration.  
  
8.2.3  ctDNA  
Specimens will be collected prior to C1D1 induction durvalumab; prior to C1D1 consolidation 
durvalumab; and at 8 weeks after consolidation durvalumab (prior to Cycle 3) for circulating 
tumor DNA analysis.   
  
8.3  
Microbiome  
Microbiome stool specimens will be collected from each patient at screening or prior to C1D1 of 
induction durvalumab. Analysis to be performed pending the availability of funding.  
  
8.4  
Banking of Leftover Biospecimens  
Subject consent will be obtained to bank any leftover samples collected for study-specific 
correlative research prior to C1D1 treatment. Hoosier Cancer Research Network (HCRN) will 
manage the banked samples. Samples will be banked indefinitely in the Hoosier Cancer 
Research Network Biorepository and used for future unspecified cancer-related research.   
  
Please refer to the Correlative Laboratory Manual (CLM) for all sample collection, processing, 
labeling, and shipping instructions.  
  
8.5  
Confidentiality of Biospecimens  
Samples that are collected will be identified by a subject’s sequence ID assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and 
only identified by the subject’s study number.  
  


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9.  
CRITERIA FOR DISEASE EVALUATION  
Disease response will be assessed as per the Response Evaluation Criteria In Solid Tumors 
(RECIST) 1.1 (see Eisenhauer EA et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Can, 2009.45:p.228-247).   
  
Refer to the RECIST 1.1 publication for complete details on these criteria.  
  
9.1  
Measurable Disease  
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters).  
  
9.1.1 Malignant Lymph Nodes  
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.  
  
9.2  
Non-measurable Lesions  
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable.  
  
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions.  
  
9.3  
Target Lesions  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 


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reference to further characterize any objective tumor regression in the measurable dimension of 
the disease.  
9.4  
Non-target Lesions  
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
  
9.5  
Evaluation of Target Lesions  
NOTE: In addition to the information below, also see the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 
45;2009:228-247) for special notes on the assessment of target lesions.   
  
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 the diameters of target 
lesions, taking as reference the baseline sum diameters  
Progressive Disease 
(PD)  
At least a 20% increase in the sum of the 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 
progressions).  
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  
  
  
9.6  
Evaluation of Non-Target Lesions  
  
Complete Response (CR)  Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be 
nonpathological in size (<10 mm short axis)  
  
NOTE:  If tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response.  
Non-CR/ Non-PD  
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits  


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Progressive Disease (PD)  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
Unequivocal progression should not normally trump target 
lesion status. It must be representative of overall disease 
status change, not a single lesion increase.  
  
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator.  
  
9.7  
Evaluation of Best Overall Response  
  
Target Lesions  
Non-Target Lesions  
New Lesions  Overall Response 
CR  
CR  
No  
CR  
CR  
Non-CR/ Non-PD  
No  
PR  
CR  
Not evaluated  
No  
PR  
PR  
Non-PD/ or not all 
evaluated  
No  
PR  
SD  
Non-PD or not all evaluated  
No  
SD  
Not all evaluated  
Non-PD  
No  
Non-evaluable  
PD  
Any  
Yes or No  
PD  
Any  
PD*  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.  
  
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment.  
  
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status.  
  
9.8  
Definitions for Response Evaluation – RECIST 1.1  
  
9.8.1  
First Documentation of Response  
The time between initiation of therapy and first documentation of PR or CR.  


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9.8.2  
Confirmation of Response  
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for 
response are first met.  
  
9.8.3  Duration of Response  
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started).  
9.8.4 Duration of Overall Complete Response  
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented.  
  
9.8.5  
Objective Response Rate   
Objective response rate (ORR).  ORR will be measured using two timepoints, per RECIST 1.1. 
“ORR1” will be assessed using baseline imaging in comparison to imaging obtained after 
completion of induction durvalumab and chemoradiation.  “ORR2” will be assessed using 
imaging after completion of induction durvalumab and chemoradiation in comparison to imaging 
obtained after completion of consolidation durvalumab.  
  
9.8.7 Time to Progression  
A measurement from the date of Cycle 1 Day 1 of induction durvalumab until the criteria for 
disease progression is met as defined by RECIST 1.1. Subjects who have not progressed or have 
died due to any cause will be right-censored at the date of the last disease evaluation or date of 
death.  
  
9.8.8 Progression Free Survival  
12-month progression-free survival will be measured using imaging prior to C1D1 consolidation 
durvalumab (between 1-42 days after completion of chemoradiation) as baseline. This timepoint 
is selected in order to compare with the PACIFIC trial 12-month progression-free survival as 
historical control. 12-month PFS will be defined as the time from the date of CT prior to 
beginning consolidation radiation until the date of objective disease progression or death (by any 
cause in the absence of progression), as measured for the 12-month period after initiation of 
consolidation durvalumab.  
  
10 DRUG INFORMATION  
  
10.1  
Durvalumab  
Please refer to Investigator’s Brochure for detailed information regarding this medication.   
  
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 


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[B7H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-CD279) and CD80 
(B71). 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.  
  
10.1.1 Supplier/How Supplied  
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab to the investigator as a solution for infusion after dilution. Durvalumab is 
manufactured by AstraZeneca/MedImmune.  AstraZeneca/MedImmune will supply durvalumab 
at no charge to subjects participating in this clinical trial.   
  
Durvalumab will be supplied 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 10.0 mL.  Durvalumab must be used within the individually 
assigned expiry date on the label.  
  
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations.  
  
10.1.2 Preparation and Administration  
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:   
• 24 hours at 2°C to 8°C (36°F to 46°F)  
• 4 hours at room temperature  
  
A dose of 1500 mg (for patients >30kg in weight) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration 
ranging from 1 to 15 mg/mL, and delivered through an IV administration set with a 0.2- or 
0.22μm filter.  Add 30.0 mL of durvalumab (i.e., 1500 mg of durvalumab) to the IV bag. The IV 
bag size should be selected such that the final concentration is within 1 to 15 mg/mL. Mix the 
bag by gently inverting to ensure homogeneity of the dose in the bag.  
  
Standard infusion time is one hour, however if there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature.    
  
The IV line will be flushed with a volume of IV diluent 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.    
  


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If either preparation time or infusion time exceeds the time limits a new dose must be prepared 
from new vials.  Durvalumab does not contain preservatives, and any unused portion must be 
discarded.   
  
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 durvalumab dose of 1500 mg will be administered using an IV bag containing 0.9% 
(w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15 
mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm filter.    
  
  
  
Add 30.0 mL of durvalumab to the IV bag. The IV bag size should be selected such that final 
concentration is within 1 to 15 mg/mL.  Mix the bag by gently inverting to ensure homogeneity 
of the dose in the bag.  
  
Durvalumab will be administered at room temperature (approximately 25°C) 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/+ 10 minutes), using a 0.2- or 0.22-μm filter. Less than 55 minutes is considered a 
deviation.  
  
Do not co-administer other drugs through the same infusion line.  
  
The IV line will be flushed with a volume of IV solution (0.9% [w/v] sodium chloride injection 
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   
  
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.  
  
  
In the event that either preparation time or infusion time exceeds the time limits outlined in the 
table, a new dose must be prepared from new vials.  Durvalumab does not contain preservatives, 
and any unused portion must be discarded.  
  
10.1.3 Storage and Stability  
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.  


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Unopened vials of Durvalumab liquid Drug Product must be stored at 2°C to 8°C (36°F to 46°F). 
Protect from light.  
  
10.1.4 Adverse Events  
For information on all identified and potential risks with durvalumab refer to the current version 
of the durvalumab IB.  
  
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 adverse events.  
  
Immunotherapy adverse related reactions: Individuals receiving Durvalumab therapy are at 
increased risk for immune related adverse events such as pneumonitis/interstitial lung disease, 
hepatitis/increases in transaminases, colitis and intestinal perforation, development of type  I 
diabetes mellitus, thyroid dysfunction, adrenal insufficiency, hypophysitis/hypopituitarism. 
Other effects include an immunotherapy-induced rash, immune thrombocytopenia, nephritis, 
pancreatitis/increases in amylase and lipase, and myocarditis. Severe infections can also occur in 
those receiving Durvalumab therapy. Infusion related reactions: Severe infusion related reactions 
have occurred and those with Grade III or IV reactions should have Durvalumab discontinued 
permanently. Other side effects: Fatigue, peripheral edema, pyrexia, decreased appetite, diarrhea, 
constipation, nausea/vomiting, cough, and dyspnea have also been reported.  
  
10.2 Chemotherapy  
Please refer to the current package insert for complete prescribing and toxicity information for 
each chemotherapy medication. Institutional guidelines may be used for preparation and 
administration of chemotherapy used. The chemotherapy utilized will be sourced commercially.   
  
11.  
ADVERSE EVENTS  
The descriptions and grading scales found in the NCI CTCAE v5 will be utilized for AE 
assessment. A copy of the CTCAE v5 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the EDC 
system (Documents and Information Tab).  
  
11.1  
Definitions  
  
11.1.1 Adverse Event (AE)  
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:   
• 
Unintended or unfavorable sign or symptom  
• 
A disease temporally associated with participation in the protocol  
• 
An intercurrent illness or injury that impairs the well-being of the subject  
  


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Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.   
  
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator.  
  
11.1.2 Serious Adverse Event (SAE) A 
SAE is an adverse event that:  
• 
Results in death.   
• 
Development of a new cancer. New primary cancers are those that are not the primary 
reason for the administration of the IP and have been identified after the patient’s 
inclusion in this study.  
• 
Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe)  
• 
Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events.  
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly or birth defect  
• 
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse.  
  
11.1.3 Unexpected Adverse Event  
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included 
in the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.    
  
11.1.4 Relatedness  
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:   
  
Unrelated  
Adverse Event is not related to the study drug(s)   


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Unlikely  
Adverse Event is doubtfully related to the study drug(s)   
Possible  
Adverse Event may be related to the study drug(s)   
Probable  
Adverse Event is likely related to the study drug(s)   
Definite  
Adverse Event is clearly related to the study drug(s)   
  
11.1.5 An adverse event of special interest (AESI)  
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of durvalumab and may require close monitoring. An AESI may be serious or 
non-serious.   
  
AESIs observed with durvalumab include:  
• 
Diarrhea/Colitis and intestinal perforation  
• 
Pneumonitis/ILD o If new or worsening pulmonary symptoms (e.g., dyspnea) or 
radiological abnormality suggestive of pneumonitis/ILD is observed, toxicity 
management as described in detail in the Dosing Modification and Toxicity Management 
Guidelines (see Appendix A) will be applied. The results of the full diagnostic workup 
(including high-resolution computed tomography [HRCT], blood and sputum culture, 
hematological parameters, etc.) will be captured in the eCRF. It is strongly recommended 
to perform a full diagnostic workup, to exclude alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the 
presence of confirmatory HRCT scans  
where other causes of respiratory symptoms have been excluded, a diagnosis of 
pneumonitis (ILD) should be considered and the Dosing Modification and Toxicity 
Management Guidelines should be followed.  o The sponsor-investigator is 
responsible for ensuring that all staff involved in the study is familiar with the 
content of this section.  
• 
hepatitis/transaminase increases  
• 
Endocrinopathies (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  
• 
Neuropathy/neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)  
• 
Other inflammatory responses that are rare / less frequent with a potential 
immunemediated etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving the eye, skin, hematological and rheumatological events, 
vasculitis, non-infectious meningitis and non-infectious encephalitis.  
• 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.  
  


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11.1.6 Death  
• 
Death due to disease progression should not be reported as a SAE, unless it is attributable 
by the site investigator to the study drug(s).   
• 
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to HCRN as an SAE as described below. It should 
also be documented in the EDC system. The report should contain a comment regarding 
the co involvement of PD, if appropriate, and should assign main and contributory causes 
of death.  
• 
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the EDC system. A post mortem may be helpful in the assessment of the 
cause of death, and if performed, a copy of the post-mortem results should be forwarded 
to AstraZeneca Patient Safety.  
• 
Deaths occurring after the protocol defined safety follow up period after the 
administration of the last dose of study drug should be documented in the EDC system. If 
the death occurred as a result of an event that started after the defined safety follow up 
period and the event is considered to be due to a late onset toxicity to study drug, then it 
should also be reported as an SAE. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.  
  
11.1.7 Overdose  
An overdose is defined as a patient receiving a dose of durvalumab in excess of that specified in 
the Investigator’s Brochure, unless otherwise specified in this protocol. Any overdose of a study 
patient with durvalumab, with or without associated AEs/SAEs, is required to be reported as a  
SAE to HCRN who will report to the sponsor-investigator. HCRN must report these to 
AstraZeneca Patient Safety as outlined in Section 11.2.2.2 within 7 calendar days. If the 
overdose results in an AE, the AE must also be recorded as an AE. Overdose does not 
automatically make an AE serious, but if the consequences of the overdose are serious, for 
example death or hospitalization, the event is serious and must be recorded and reported as an 
SAE. There is currently no specific treatment in the event of an overdose of durvalumab. The 
investigator will use clinical judgment to treat any overdose.  
  
11.1.8 Hepatic function abnormality  
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case in 
a study patient, with or without associated clinical manifestations, is required to be reported as 
“hepatic function abnormal” as a SAE to HCRN who will report to the sponsor-investigator. 
HCRN must report these events to AstraZeneca Patient Safety within 7 calendar days, unless a 
definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) 
that is unrelated to investigational product has been confirmed. The criteria for a potential Hy’s 
Law case is Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3x Upper 
Limit of Normal (ULN) together with Total Bilirubin (TBL) ≥2xULN at any point during the 
study following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  


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• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study patient 
will be based on the clinical judgment of the investigator.  
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study patient must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay.  
  
Each reported event of hepatic function abnormality will be followed by the site investigator and 
evaluated by the sponsor-investigator and AstraZeneca.   
  
11.1.9 Pregnancy  
  
11.1.9.1  
Maternal exposure  
If a patient becomes pregnant during the course of the study, durvalumab should be discontinued 
immediately. Pregnancy itself is not regarded as an AE unless there is a suspicion that 
durvalumab 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 site investigator or other site personnel should inform HCRN within 1 business day and 
HCRN will report to the sponsor-investigator. HCRN will work with the site investigator to 
ensure that all relevant information is provided within 1 to 5 calendar days.  HCRN must report 
to AstraZeneca Patient Safety within 7 calendar days for pregnancies with SAEs and within 30 
days for all other pregnancies. The same timelines apply when outcome information is available.   
  
  
  
11.1.9.2  
Paternal exposure   
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 180 days after the last 
dose of durvalumab, should, if possible, be followed up and documented.   
  
11.2  
Reporting  
  
11.2.1 Adverse Events   
• 
AEs will be recorded from time of signed informed consent until 90 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.   
• 
AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).    
• 
All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.  


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• 
AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first.  
  
11.2.2 Serious Adverse Events (SAEs)  
  
11.2.2.1  
Site Requirements for Reporting SAEs to HCRN  
• 
SAEs will be reported from time of signed informed consent until 90 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.   
• 
SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.    
• 
SAEs include events related and unrelated to the study drug(s).   
• 
All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.    
• 
All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first.  
  
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form may be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.    
  
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site.  
  
Once the SAE has resolved (see resolution guidelines listed above), sites must submit a followup 
SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.    
11.2.2.2  
HCRN Requirements for Reporting SAEs to AstraZeneca   
HCRN will report all SAEs to AstraZeneca within 1 business day of receipt of the SAE 
Submission Form from a site. Follow-up information will be provided to AstraZeneca as it is 
received from site. All SAE correspondence should be sent to AstraZeneca via the following 
address: AEMailboxClinicalTrialTCS@astrazeneca.com.  
  
11.3  
Sponsor-Investigator Responsibilities   
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.    
  
11.4  
HCRN Responsibilities to FDA  
For protocols exempt from the requirements of an IND, HCRN will continue to facilitate 
compliance of applicable requirements for the sponsor-investigator in relation to this study. This 


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includes but is not limited to 21 CFR 50.20 informed consent, 21 CFR Part 56 IRB, and 
pertinent sections of the Public Health Service Act and FDAAA.  
  
11.5  
IND Safety Reports Unrelated to this Trial  
AstraZeneca will provide to HCRN IND safety reports from external studies that involve the 
study drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator 
who will review these reports and determine if revisions are needed to the protocol or consent. 
HCRN will forward these reports to participating sites within 1 business day of receiving the 
sponsor-investigator’s review.  Based on the sponsor-investigator’s review, applicable changes 
will be made to the protocol and informed consent document (if required).  All IND safety 
reports will also be made available to sites via the EDC system.     
  
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies.  
  
12.  
STATISTICAL METHODS  
  
12.1  
Study Design  
This is a single arm study of induction durvalumab (1500 mg IV) for 1 cycle (every 4 weeks), 
administered prior to starting concurrent definitive chemoradiation, followed by consolidation 
durvalumab (1500 mg IV every 4 weeks) for up to 12 cycles.  
  
12.2  
Endpoints  
  
12.2.1 Definition of Primary Endpoint  
1. Estimate 12-month progression-free survival (PFS) in patients with Stage III non-small 
cell lung cancer (NSCLC). Compare with PACIFIC trial 12-month progression-free 
survival as historical control. In the PACIFIC study, 12-month progression-free survival 
was 55.9% and was measured using baseline imaging from the time of patient 
randomization after completion of chemoradiation (1-42 days after completion of 
chemoradiation).  For this study, in order to allow for comparison with this historical 
control, 12-month PFS will be measured starting at imaging performed 1-42 days   
after completion of chemoradiation, prior to initiation of consolidation durvalumab.    
2. Assess the safety and feasibility of induction durvalumab followed by chemoradiation 
and consolidation durvalumab for stage III NSCLC. Toxicity will be measured and 
recorded as defined by the NCI Common Terminology Criteria for Adverse Events (NCI 
CTCAE) v5.  
  
Patients receiving different chemotherapeutic agents will be analyzed together for toxicity, with 
exploratory analysis of toxicity related to different chemotherapeutic regimens.  
  
12.2.2 Definition of Secondary Endpoints  
1. Objective response rate (ORR).  ORR will be measured using two timepoints, using 
RECIST 1.1. “ORR1” will be assessed after completion of induction and chemoradiation 


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in comparison with baseline imaging.  “ORR2” will also be assessed comparing first 
imaging after completion of induction and chemoradiation to imaging after consolidation 
durvalumab.  
  
12.2.3 Correlative/Exploratory Endpoints  
Data analysis for the correlative/exploratory objectives are descriptive and exploratory.  Refer to 
Sections 12.6.3 and 12.6.5, below, for details of analysis plan for the correlative and exploratory 
endpoints.  
• 
Correlation of outcomes and toxicity based upon tumor and immune cell PD-L1 status in 
baseline tumor biopsy prior to therapy.  
• 
Correlation of toxicity based upon type of chemotherapy administered.  
  
Patients receiving different chemotherapeutic agents will be analyzed together for toxicity, with 
exploratory analysis of toxicity related to different chemotherapeutic regimens.  
  
• 
Correlation of outcomes based upon tumor mutation burden in baseline tumor biopsy 
prior to therapy  
• 
Assessment of immune response via peripheral blood immune monitoring through 
multiple timepoints of therapy  
• 
Correlation of immune response with outcomes in terms of disease control and toxicity  
• 
Correlation of tumor immune score via quantitative multiplex tumor biopsy assay with 
clinical outcomes  
• 
Exploration of immune response signal to indicate further exploration of a treatment 
schedule in a larger trial  
• 
Collection of microbiome samples to correlate with outcomes and toxicity  
  
12.3 
Sample Size and Accrual  
This study will be planned to detect a 14% improvement in 12-month progression-free survival 
as a potential signal to move forward with further evaluation in a large randomized trial.  Thus, 
12-month progression-free survival of 69.9% would be felt to be clinically meaningful for 
further investigation.  
  
Assuming that 12-month PFS in the historical control group is 55.9%, with an 18-month accrual 
interval and additional 12-month follow up after the accrual interval, the required sample size 
would be 49 patients, with a one-sided test given type I error 0.05 and power of 0.8.    
Accounting for a 10% dropout rate, a total of 54 patients would be enrolled in this study.  
  
12.4 
Assessment of Safety  
All subjects receiving at least one dose of durvalumab will be evaluable for toxicity.  The  
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
version 5.0, will be used for toxicity grading.  Please refer to the study calendar for the schedule 
of toxicity assessment.  
  
12.5 
Assessment of Efficacy  


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All subjects who have received at least one dose of consolidation durvalumab and have their 
disease re-evaluated will be evaluable for the primary endpoint of 12-month PFS.   In order to 
compare with the PACIFIC study as historical control, 12-month PFS will be measured 
starting at imaging performed 1-42 days after completion of chemoradiation, prior to initiation 
of consolidation durvalumab.  See Section 12.6.1 for details regarding statistical analysis of 
the primary objective.  
  
12.6 
Data Analysis Plans  
  
12.6.1 Analysis Plans for Primary Objective  
The progression-free survival analyses will be performed considering the risk of dying from 
another cause before experiencing progression related events using the competing risk egression 
method (de Glas et al., 2016). Cumulative incidence functions will be displayed and summarized 
for the median time to progression as well as percentage of progression patients at 12, 18, and 24 
months. In addition, competing risk regression will be used to estimate sub distribution hazard 
ratios of the study arm versus historical control arm and 95% confidence intervals, adjusted for 
patient demographic, clinical, pathological, and tumor related factors. To compare the overall 
survival between groups, Kaplan-Meier survival curves will be displayed and summarized. 
Survival curves will be statistically compared using the log-rank test. If the proportional hazards 
assumption is met, survival curves will also be compared using proportional Cox regression, 
adjusting for risk factors.     
  
12.6.2 Analysis Plans for Secondary Objectives  
ORR between two time points will be compared, using Chi-square or Fisher exact test for 
independent samples, and McNemar's Chi-squared test for related or paired samples.  
  
12.6.3 Analysis Plans for Exploratory Objectives  
To assess the immune response via peripheral blood immune monitoring through multiple time 
points of therapy, the patterns of change will be described using descriptive statistics and plots of 
means (standard deviation) as well as quantiles over time. Additionally, longitudinal data 
analysis will be employed to calculate the trajectory of change between repeated measures. 
Various variance-covariance structures will be explored to obtain an efficient model. We will 
also perform repeated measures ANOVA to test for a time by intervention interaction.   
  
To evaluate the association between outcomes and predictors, controlling for other risk factors, 
we will perform linear regression analysis for continuous outcome; logistic and ordinal logistic 
regression analyses for binary and ordinal outcomes, respectively.  
  
12.6.4 Other Planned Analyses  
Summary tables (descriptive statistics and/or frequency tables) will be provided for all baseline, 
efficacy, and safety variables (i.e., treatment-related or serious adverse events), as appropriate. 
Frequency counts and percentage of subjects within each category will be provided for 
categorical data. Measures of central tendency (mean, median and mode), measures of variability 
and dispersion (standard deviation, range and quantiles) will be calculated for continuous 


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variables. Chi-square or Fisher exact test will be used to detect the difference of percentage 
between treatment arms. Kruskal-Wallis rank sum or ANOVA analyses will be performed to test 
the homogeneity of continuous variables between groups. All variables will be examined for 
normality and transformed as needed prior to analysis.  
  
12.7  
Criteria for Stopping Study  
The study will include an initial safety run-in portion.  Patients in the safety run-in will be 
monitored through completion of induction durvalumab, chemoradiation, and 2 cycles of 
consolidation durvalumab for assessment of safety prior to completion of enrollment.  
  
If 3 out of the first 5 patients or 4 out of the first 10 patients experience dose limiting toxicities 
(DLT), further enrollment will be halted and subsequent accrual re-evaluated with investigators 
and sponsor-investigator. Patients in the safety run-in phase will be analyzed for PFS and 
outcomes as members of the full study cohort.    
  
The stopping rule criterion was based on the sequential probability ratio test H0: DLT rate = 10% 
vs H1: DLT rate = 30%, given type I error of 0.05 and power 0.8.  
  
Enrollment will thus first be paused after the first 5 patients are enrolled and complete the above 
safety window.  If stopping criteria are not met, enrollment will then continue with another pause 
after 10 total patients are enrolled and complete the above safety window.  If stopping criteria are 
not met, enrollment will then continue for the full planned cohort.  
  
Patients in the safety run-in phase will be analyzed for PFS and outcomes as members of the full 
study cohort.  
  
13.  
TRIAL MANAGEMENT  
  
13.1  Data and Safety Monitoring Plan (DSMP) HCRN 
oversight activities include:  
• 
Review and processing of all adverse events requiring expedited reporting as defined in 
the protocol  
• 
Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator   
• 
Submit data summary reports to the DSMB for review according to DSMB Charter  
This study will have a Data and Safety Monitoring Board (DSMB). The DSMB is chaired by an 
independent medical oncologist external to this trial. The DSMB will provide a recommendation 
to the sponsor-investigator after all information is reviewed. This information will also be 
provided to HCRN who will distribute to the site investigator/participating sites for submission 
to their respective IRB according to the local IRB’s policies and procedures.  
  
The DSMB review will include but is not limited to:  
• 
Adverse event summary report  
• 
Audit results if applicable  


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• 
Data related to stopping/decision rules described in study design  
• 
Study accrual patterns   
• 
Protocol deviations  
  
The DSMB will meet after the first 5 patients are enrolled and have completed 2 cycles of 
consolidation durvalumab, or after 3 patients of the first 5 in the safety run-in cohort have 
experienced DLT (whichever comes first), to review data for stopping rules as above.  The 
DSMB will again meet after the first 10 patients are enrolled and have completed 2 cycles 
consolidation durvalumab, or after 4 patients of the first 10 in the safety run-in cohort have 
experienced DLT (whichever comes first), to review data for stopping rules as above. Additional 
DSMB meetings may be convened upon request of the sponsor-investigator, DSMB, or other 
applicable oversight body.   
  
After the safety lead-in period, the next regular meeting will occur within 6 months of the 11th 
subject beginning study drug administration. The DSMB will continue to meet approximately 
every 6 months during the active study drug administration of the study. At the discretion of the 
DSMB, they may meet more frequently during the course of the study, as more data becomes 
available. The timing of the next scheduled meeting will be documented in the minutes from the 
prior meeting.  
  
The DSMB will review the data regularly until at least 100 days after the last participant goes off 
study treatment. At this point, the DSMB will conduct reviews as needed until the study    
terminates.  
  
13.2 
Data Quality Oversight Activities  
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel.   
  
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause visits may occur as necessary.  Selected source 
documents will be reviewed for verification of agreement with data entered into the EDC 
system. It is important for the site investigator and their relevant personnel to be available for a 
sufficient amount of time during the monitoring visits or audit, if applicable. The site 
investigator and institution guarantee access to source documents by HCRN or its designee.  
  
The trial site may also be subject to quality assurance audit by AstraZeneca or its designee as 
well as inspection by appropriate regulatory agencies.  
  
13.3 
Compliance with Trial Registration and Results Posting Requirements  
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 


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requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.    
  
14.  
DATA HANDLING AND RECORD KEEPING  
  
14.1  
Data Management  
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform (EDC system), a system compliant with Good 
Clinical Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. Select data will be collected and entered 
into the EDC system by study site personnel from participating institutions.    
  
14.2  
Case Report Forms and Submission  
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.   
  
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate  
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN.  
  
14.3  
Record Retention  
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, 
and detailed records of drug disposition. All source documents are to remain in the subject’s file 
and retained by the site investigator in compliance with the site contract with HCRN.  No 
records will be destroyed until HCRN confirms destruction is permitted.  
  
  
  
14.4  
Confidentiality  
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.   
  


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Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, AstraZeneca, IRB, or government agencies, like the 
FDA, may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  
  
If the results of the study are published, the subject’s identity will remain confidential.  
  
15  
ETHICS  
  
15.1  
Institutional Review Board (IRB) Approval  
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.    
  
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.   
  
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines.  
  
15.2  
Ethical Conduct of the Study  
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws.  
  
15.3  
Informed Consent Process  
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided.  
  
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.   
  
16  
REFERENCES  
1. Antonia SJ, Villegas A, Daniel D, et al.  Durvalumab after chemoradiotherapy in stage III 
non-small-cell lung cancer.  NEJM, 2017;377: 1919-1929.   
2. Antonia SJ, Villegas A, Daniel D, et al.  Overall survival with durvalumab after 
chemoradiotherapy in stage III NSCLC.  NEJM 2018; 379: 2342-2350.  


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3. Forde PM, Chaft JE, Smith KN, et al.  Neoadjuvant PD-1 blockade in resectable lung 
cancer.  NEJM 2018; 378: 1976-1986.  
4. Clinicaltrials.gov (Accessed 9-13-2018).  
5. Stewart R et al.  Identification and Characterization of MEDI4736, an Antagonistic 
AntiPD-L1 Monoclonal Antibody. Cancer Immunol Res. 2015 Sep;3(9):1052-62. doi:  
10.1158/2326-6066.CIR-14-0191. Epub 2015 May 5.  
6. NCT01693562  
7. Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of 
pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm Res 
2006;23(6):1275–84.    
8. 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.  
9. 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.  
10. Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferonalpha monoclonal antibody, in systemic lupus 
erythematosus. Clin Pharmacokinet 2013;52:1017–27.  
11. Taube JM, Galon J, Sholl LM, Rodig SJ, Cottrell TR, Giraldo NA, Baras AS, Patel SS, 
Anders RA, Rimm DL, Cimino-Mathews A. Implications of the tumor immune 
microenvironment for staging and therapeutics. Mod Pathol. 2018;31(2):214-34. doi:  
10.1038/modpathol.2017.156. PubMed PMID: 29192647.  
12. Yuan J, Hegde PS, Clynes R, Foukas PG, Harari A, Kleen TO, Kvistborg P, Maccalli C, 
Maecker HT, Page DB, Robins H, Song W, Stack EC, Wang E, Whiteside TL, Zhao Y, 
Zwierzina H, Butterfield LH, Fox BA. Novel technologies and emerging biomarkers for 
personalized cancer immunotherapy. J Immunother Cancer. 2016;4:3. doi:  
10.1186/s40425-016-0107-3. PubMed PMID: 26788324; PMCID: PMC4717548.  
13. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, 
Cheng JD, Kang SP, Shankaran V, Piha-Paul SA, Yearley J, Seiwert TY, Ribas A, 
McClanahan TK. IFN-gamma-related mRNA profile predicts clinical response to PD-1 
blockade. J Clin Invest. 2017;127(8):2930-40. doi: 10.1172/JCI91190. PubMed PMID: 
28650338; PMCID: PMC5531419.  
14. Sabari JK, Leonardi GC, Shu CA, Umeton R, Montecalvo J, Ni A, Chen R, Dienstag J,  
Mrad C, Bergagnini I, Lai WV, Offin MD, Arbour KC, Plodkowski AJ, Halpenny DF,  
Paik PK, Li BT, Riely GJ, Kris MG, Rudin CM, Sholl LM, Nishino M, Hellmann MD,  
Rekhtman N, Awad MM, Drilon A. PD-L1 Expression, Tumor Mutational Burden, and 
Response to Immunotherapy in Patients with MET exon 14 Altered Lung Cancers. Ann 
Oncol. 2018. doi: 10.1093/annonc/mdy334. PubMed PMID: 30165371.  
15. Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, Rittmeyer A, 
Fehrenbacher L, Otto G, Malboeuf C, Lieber DS, Lipson D, Silterra J, Amler L, Riehl T, 
Cummings CA, Hegde PS, Sandler A, Ballinger M, Fabrizio D, Mok T, Shames DS.  
Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell 
lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441-8. doi:  
10.1038/s41591-018-0134-3. PubMed PMID: 30082870.  


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16. Feng Z, Bethmann D, Kappler M, Ballesteros-Merino C, Eckert A, Bell RB, Cheng A,  
Bui T, Leidner R, Urba WJ, Johnson K, Hoyt C, Bifulco CB, Bukur J, Wickenhauser C, 
Seliger B, Fox BA. Multiparametric immune profiling in HPV- oral squamous cell 
cancer. JCI Insight. 2017;2(14). doi: 10.1172/jci.insight.93652. PubMed PMID: 
28724788; PMCID: PMC5518563.  
17. Johnson DB, Bordeaux JM, Kim JY, Vaupel CA, Rimm DL, Ho TH, Joseph RW, Daud  
AI, Conry RM, Gaughan EM, Hernandez-Aya LF, Dimou A, Funchain P, Smithy JW,  
Witte JS, McKee SB, Ko J, Wrangle J, Dabbas B, Tangri S, Lameh J, Hall JM,  
Markowitz J, Balko JM, Dakappagari NK. Quantitative Spatial Profiling of PD-1/PD-L1 
Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of anti-PD-1 Therapies in 
Metastatic Melanoma. Clin Cancer Res. 2018. doi: 10.1158/1078-0432.CCR-18-0309. 
PubMed PMID: 30021908.  
18. Lu S, Danilova L, Rimm D, Hoyt C, Hellmann M, Taube J. Comparison of biomarker 
assay modalities in anti-PD-(L)1 monotherapy: a meta-analysis. Journal for 
ImmunoTherapy of Cancer 2018;6(Suppl 1):Abstract O6.  
19. Brahmer J, Lacchetti C, Schneider B, et al. Management of Immune-Related Adverse 
Events in Patients with Immune Checkpoint Inhibitor Therapy: American Society of 
Clinical Oncology Practice Guideline. J Clin Oncol 2018; 36:1714-1768.  
  
  
  
 


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APPENDIX A: DOSING MODIFICATION AND TOXICITY MANAGEMENT  
GUIDELINES (TMGS) FOR DURVALUMAB MONOTHERAPY, DURVALUMAB IN  
COMBINATION WITH OTHER PRODUCTS, OR TREMELIMUMAB MONOTHERAPY – 
28OCT2021  
  
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., NCCN, 
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 immune-mediated adverse events (imAEs) are essential 
to ensure safe use of the study drug.  Monitor patients closely for symptoms and signs that may 
be clinical manifestations of underlying immune-mediated adverse events. 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 
treatmentemergent toxicities graded per NCI CTCAE version in the applicable study protocol.  
  
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; 
imAE immune-mediated adverse event; NCI National Cancer Institute; NCCN National Comprehensive Cancer 
Network; ESMO European Society for Medical Oncology  
  


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Relevant Society Guidelines for Management of imAEs  
These society guidelines are provided as references to serve in support of best clinical practice  
and the TMGs. Please note, these were the current versions of these guidelines at the time of  
updating TMGs. Please refer to the most up to date version of these guidelines.  
  
1. Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice 
guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer 
2021;9:e002435  
2. Brahmer JR, et al. Management of immune-related adverse events in patients treated with 
immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical 
Practice Guideline. J Clin Oncol 2018;36(17):1714-1768.   
3. Haanen JBAG, et al. Management of toxicities for immunotherapy: European Society for 
Medical Oncology (ESMO) clinical practice guidelines for diagnosis, treatment, and 
follow-up. Annals Oncol 2017;28(Suppl4):i119-i1142.  
4. Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors 
in hepatocellular carcinoma. J Hepatol 2020;72(2):320-341.  
5. Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management 
of immunotherapy-related toxicities version 3.2021. Published May 14, 2021.  


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Specific Immune-Mediated Reactions  
Adverse Events  
Severity Grade of 
the Event   
Dose Modifications  
Toxicity Management  
Pneumonitis/Interstitial 
Lung Disease (ILD)  
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
grade/severity)  
General Guidance  
−  
For Any Grade  
Monitor patients for signs and 
symptoms of pneumonitis or ILD 
(new onset or worsening 
shortness of breath or cough). 
Evaluate patients with imaging 
and pulmonary function tests, 
including other diagnostic 
procedures as described below.   
−  
Suspected pneumonitis should be 
confirmed with radiographic 
imaging and other infectious and 
disease-related aetiologies 
excluded, and managed as 
described below.  
−  
Initial work-up may include 
clinical evaluation, monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), laboratory 
work-up, and high- resolution 
CT scan.  
−  
Consider Pulmonary and  
Infectious Diseases consults.  
Grade 1  
  
No dose modifications required. 
However, consider holding 
study drug/study regimen dose 
as clinically appropriate and 
during diagnostic work-up for 
other etiologies.  
−  
For Grade 1   
Monitor and closely follow up in  
2 to 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/study 
regimen will be based 
upon treating physician’s 
clinical judgment and 
after completion of 
steroid taper.  
−  
−  
−  
−  
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 to 2 
mg/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 to 4 
mg/kg/day started.  


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−  
If no improvement within 2 to 
3 days 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  
once, may be repeated at 2 and 6 
weeks after initial dose at the 
discretion of the treating provider 
or relevant practice guidelines). 
Caution: It is important to rule 
out sepsis and refer to infliximab 
label for general guidance before 
using infliximab. Consider, as 
necessary, discussing with  
Clinical study lead  
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).  
Diarrhea/Colitis  
  
  
  
−  
If no improvement within 2 to 3 
days, additional workup should 
be considered and prompt 
treatment with additional 
immunosuppressive therapy such 
as TNF inhibitors  
(e.g., infliximab at 5 mg/kg IV, 
may be repeated at 2 and 6 
weeks after initial dose at the 
discretion of the treating provider 
or relevant practice guidelines). 
Caution: rule out sepsis and refer 
to infliximab label for general 
guidance before using 
infliximab.  
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
grade/severity)  
General Guidance  
−  
For Any Grade  
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).  


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−  
WHEN SYMPTOMS OR  
EVALUATION INDICATE  
AN INTESTINAL  
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, 
or 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 events, including intestinal 
perforation.   
Grade 1  
−  
Use analgesics carefully; they 
can mask symptoms of 
perforation and peritonitis.  
No dose modifications.  
For Grade 1  
  
−  
Monitor closely for worsening 
symptoms.  
−  
Consider symptomatic 
treatment, including hydration, 
electrolyte replacement, dietary 
changes (e.g., American Dietetic 
Association colitis diet), 
loperamide, and other supportive 
care measures.   
Grade 2  
  
−  
If symptoms persist, consider 
checking lactoferrin; if positive, 
treat as Grade 2 below. If 
negative and no infection, 
continue Grade 1 management.  


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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 to 2 mg/kg/day 
PO or IV equivalent, consult a 
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 3 days despite 1 to 2 mg/kg IV 
methylprednisolone,  
promptly start  
immunosuppressants such as 
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. a Caution: it 
is 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.  


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Grade 3 or 4   
  
  
  
Perman 
study dr 
Grade 3  
For patient treated with 
PDL-1  
inhibitors, hold study 
drug/study regimen 
until resolution to 
Grade  
≤1; study 
drug/study regimen 
can be resumed 
after completion of 
steroid taper. 
Permanently 
discontinue study 
drug/study regimen 
for Grade 3 if 
toxicity does not 
improve to Grade 
≤1 within 14 days. 
Permanently 
discontinue study 
drug for 1) Grade 3 
colitis in patients 
treated with 
CTLA-4 inhibitors 
or 2) Any grade of 
intestinal 
perforation in any 
patient treated with 
ICI.    
Grade 4  ently 
discontinue  
ug/study 
regimen.  
−  
−  
−  
−  
−  
For Grade 3 or 4  
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 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: 
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 
LFTs)  
Any Grade  
Gen 
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
grade/severity)  
eral Guidance  
−  
−  
For Any Grade  
Monitor and evaluate liver 
function test: AST, ALT, ALP, and 
TB.  
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 
medications).  
Grade 1  
  
No d 
  If it 
consi 
thera 
ose modifications.  
worsens, then 
der holding 
py.  
−  
For Grade 1  
Continue LFT monitoring per 
protocol.  
Grade 2  
  
Hold study drug/study  
regimen dose until 
Grade 2 resolution to 
Grade ≤1.  
−  
For Grade 2  
Regular and frequent checking of 
LFTs (e.g., every 1 to 2 days)  
 


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Infliximab should not be  
  
If toxicity improves to used for management of 
 
Grade ≤1 or baseline immune-related hepatitis.  and there were no  
elevations in bilirubin, resume study drug/study regimen after completion of steroid 
taper < 10 mg 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 alkaline P04) 
and in the absence of any alternative 
cause.b  
 
Grade 3 or 4  
For Grade 3  
    
Hold study drug/study  
regimen for elevations in 
transaminases ≤8 × ULN (and 
no elevations in bilirubin), or 
elevations in bilirubin ≤5 × ULN 
until resolution to Grade < 1 or 
baseline:  
• 
Resume study  
drug/study regimen if 
elevations downgrade to 
Grade ≤1 or baseline after 
completion of steroid taper 
(< 10 mg prednisone or 
equivalent).  
• 
Permanently 
discontinue 
study 
drug/study regimen for elevations in 
transaminases >8 × ULN or elevations 
in bilirubin >5 × ULN.   
For Grade 4 Permanently 
discontinue study drug/study 
regimen.  
For Grade 3 or 4  
−  
Promptly initiate empiric IV 
methylprednisolone at 1 to  
2 mg/kg/day or equivalent.  
−  
If still no improvement within 2 
to 3 days despite 1 to  
2 mg/kg/day methylprednisolone
IV or equivalent, promptly start 
treatment with an 
immunosuppressants (e.g., 
mycophenolate mofetil 0.5 – 1 g 
every 12 hours then taper in 
consultation with hepatology 
consult or relevant practice 
guidelines). Discuss with clinical
study lead if mycophenolate is 
not available. Infliximab should 
NOT be used.  
−  
 
Perform Hepatology Consult, 
abdominal workup, and imaging 
as appropriate.  
  
  
   
  
  
   
  
  
   
  
  
   
  
  
until LFT elevations improve or 
resolve.  
−  
If no resolution to Grade ≤1 in 1 
to 2 days, consider 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.  
PLEASE SEE  
shaded area  
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC  
patients  


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90  
Nephritis or renal 
dysfunction  
(elevated serum 
creatinine)  
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
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, decreased urine 
output, or proteinuria).  
−  
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 a clear alternative 
etiology even for low-grade 
events (Grade 2), in order to 
prevent potential progression to 
higher grade events.  
Grade 1  
No dose modifications.  
For Grade 1  
  
−  
Monitor serum creatinine 
weekly and any accompanying 
symptoms.  
• 
If creatinine returns to 
baseline, resume its 
regular monitoring per 
study protocol.  
• 
If creatinine worsens, 
depending on the 
severity, treat as Grade 
2, 3, or 4.  
−  
Consider symptomatic 
treatment, including hydration, 
electrolyte replacement, and 
diuretics.  
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 (< 10 mg 
prednisone or equivalent).  
−  
−  
−  
For Grade 2 Consider 
symptomatic treatment, 
including hydration, 
electrolyte replacement, and 
diuretics.  
Carefully monitor serum 
creatinine every 2 to 3 days 
and as clinically warranted. 
Consult nephrologist and 
consider renal biopsy if 
clinically indicated.  
−  
If event is persistent beyond 3 to 
5 days or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent.  


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−  
If event is not responsive within 
3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, consider 
additional workup. When event 
returns to baseline, resume study 
drug/study regimen and routine 
serum creatinine monitoring per 
study protocol.  
Grade 3 or 4  
  
  
Permanently discontinue study 
drug/study regimen.  
−  
For Grade 3 or 4  
Carefully 
monitor 
serum 
creatinine daily.  
−  
Consult nephrologist and 
consider renal biopsy if 
clinically indicated.  
−  
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent.  
−  
If event is not responsive within 
3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, consider 
additional workup and prompt 
treatment with an 
immunosuppressant in 
consultation with a nephrologist.  
Rash or Dermatitis  
  
(Including Pemphigoid)  
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol 
for definition of 
severity/grade  
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 modifications.  
For Grade 1  
−  
Consider symptomatic treatment, 
including oral  
antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy  
(e.g., emolient, lotion, or 
institutional standard).  


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Grade 2  
For persistent (>1 week) 
Grade 2 events, hold 
scheduled study drug/study 
regimen until resolution to 
Grade ≤1 or baseline.  
• 
If toxicity worsens, then 
treat as Grade 3.  
• 
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 clinical study 
lead, as needed, and promptly 
start systemic steroids such as 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent.  
−  
Consider skin biopsy if the event 
persists for >1 week or recurs.  
 
Grade 3 or 4  
For Grade 3  
For Grade 3 or 4  
• 
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 (< 10 mg 
prednisone or 
equivalent).  
  
For Grade 4  
Permanently discontinue study 
drug/study regimen.  
−  
−  
−  
−  
−  
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.  
Endocrinopathy  
(e.g., hyperthyroidism, 
thyroiditis,  
hypothyroidism,  type 1 
diabetes 
mellitus, 
hypophysitis,  
hypopituitarism, and  
adrenal insufficiency)  
  
Any Grade  
(Depending on the 
type of  
endocrinopathy, 
refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
grade/severity)  
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, behaviour 
changes, mental status changes, 
photophobia, visual field cuts, 
vertigo, abdominal pain, unusual 
bowel habits, polydipsia, 
polyuria, hypotension, and 
weakness.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 63 of 
90  
−  
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression including brain 
metastases, or infections).  
−  
Depending on the suspected 
endocrinopathy, monitor and 
evaluate thyroid function tests: 
TSH, free T3 and free T4 and 
other relevant endocrine and 
related labs (e.g., blood glucose 
and ketone levels, HgA1c).If a 
patient experiences an AE that is 
thought to be possibly of 
autoimmune nature (e.g., 
thyroiditis, pancreatitis, 
hypophysitis, or diabetes 
insipidus), the 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 modifications.  
For Grade 1  
−  
Monitor patient with appropriate 
endocrine function tests.  
−  
For suspected  
hypophysitis/hypopituitarism, 
consider consulting an 
endocrinologist to guide 
assessment of early-morning 
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).  
Grade 2, 3, or 4  
−  
If TSH < 0.5 × LLN, or TSH >2 
× ULN, or consistently out of 
range in 2 subsequent 
measurements, include free T4 at 
subsequent cycles as clinically 
indicated and consider 
consultation of an 
endocrinologist.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 64 of 
90  
• 
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 (< 10 mg 
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, consider short-
term corticosteroids (e.g.,  
1 to 2 mg/kg/day 
methylprednisolone or IV 
equivalent) and prompt initiation 
of treatment with relevant 
hormone replacement (e.g., 
hydrocortisone, sex hormones). 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study 
regimen interruption, and 
without corticosteroids.  
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 workup (laboratory 
assessment or MRI scans),  
repeat laboratory 
assessments/MRI as 
clinically indicated.  
 
Amylase/Lipase 
increased  
  
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
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  
  
  
Grade 1 Grade 
2, 3, or 4  
No dose modifications.  
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.  
−  
−  
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.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 65 of 
90  
Consider other causes of 
elevated amylase/lipase  
−  
If evidence of pancreatitis, 
manage according to 
pancreatitis recommendations   
Acute Pancreatitis  
  
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
grade/severity)  
General Guidance  
−  For Any Grade  
Consider 
Gastroenterology referral   
Grade 2, 3, or 4  
For Grade 2 Hold 
study drug/study regimen 
dose until resolution to 
Grade ≤1.  
If toxicity improves to 
Grade <1 or baseline, then 
resume study drug/study 
regimen after completion 
of steroid taper (<10 mg 
prednisone, or equivalent).  
  
For Grade 3 or 4 
Permanently discontinue 
study drug/study regimen.  
−  
−  
For Grade 2, 3, or 4 
Promptly start 
systemic steroids 
prednisone 1 to 2 
mg/kg/day PO or IV 
equivalent.  
IV hydration  
Neurotoxicity  
(to include but not limited 
to non-infectious  
meningitis, non-infectious 
encephalitis, and  
autonomic neuropathy,  
excluding Myasthenia  
Gravis and 
GuillainBarre)  
Any Grade  
(Depending on the 
type of  
neurotoxicity,  
refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
grade/severity)  
General Guidance  
−  
−  
−  
For Any Grade  
Patients should be evaluated to 
rule out any alternative 
etiology (e.g., disease 
progression, infections, 
metabolic syndromes, or 
medications).  
Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness).  
Consider appropriate 
diagnostic testing (e.g., 
electromyogram and nerve 
conduction investigations).  
−  
Perform symptomatic treatment 
with neurological consult as 
appropriate.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 66 of 
90  
−  
FOR TRANSVERSE  
MYELITIS,  
PERMANENTLY 
DISCONTINUE FOR ANY 
GRADE.  
Grade 1  
No dose modifications.  
For Grade 1  
−  
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.  
  
−  
−  
−  
−  
−  
For Grade 2 Consider, as 
necessary, discussing with the 
clinical study lead.  
Obtain neurology consult. 
Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications (e.g., 
gabapentin or duloxetine). 
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO 
or IV equivalent.  
If no improvement within 2 to 3 
days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, 
consider additional workup and 
promptly treat with an additional 
immunosuppressant (e.g., IV IG 
or other immunosuppressant 
depending on the specific 
imAE).  
Grade 3 or 4  
For Grade 3 or 4 
Permanently discontinue study 
drug/study regimen.  
−  
For Grade 3 or 4 Consider, 
as necessary, discussing with 
clinical study lead.  
−  
Obtain neurology consult.  
−  
Consider hospitalization.  
−  
Promptly initiate empiric IV 
methylprednisolone 1 to  
2 mg/kg/day or equivalent.  
Peripheral neuromotor 
syndromes  
(such as Guillain-Barre 
and myasthenia gravis)  
−  
If no improvement within 2 to 3 
days despite IV corticosteroids, 
consider additional workup and 
promptly treat with an additional 
immunosuppressant (e.g., IV IG 
or other immunosuppressant 
depending on the specific 
imAE).  
 


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 67 of 
90  
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
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 that can result 
in substantial morbidity or in 
the worst case, death. Special 
care should be taken for certain 
sentinel symptoms that may 
predict a more severe outcome,  
such as prominent dysphagia, 
rapidly progressive weakness, 
and signs of respiratory 
insufficiency or autonomic 
instability.  
−  
Patients should be evaluated to 
rule out any alternative etiology 
(e.g., disease progression, 
infections, metabolic syndromes 
or medications). It should be 
noted that the diagnosis of 
immune-mediated peripheral 
neuromotor syndromes can be 
particularly challenging in 
patients with underlying cancer, 
due to the multiple potential 
confounding effects of cancer 
(and its treatments) throughout 
the neuraxis. Given the 
importance of prompt and 
accurate diagnosis, it is essential 
to have a low threshold to obtain 
a neurological 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 started with IV IG and 
followed by plasmapheresis if 
not responsive to IV IG.  
Grade 1  
No dose modifications.  
For Grade 1  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 68 of 
90  
−  
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.  
For 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 or duloxetine).  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 69 of 
90  
MYASTHENIA GRAVIS:  
o 
Steroids may be  
successfully used to 
treat myasthenia 
gravis. It is important 
to consider that steroid 
therapy (especially 
with high doses) may  
result in transient 
worsening of 
myasthenia and should  
typically be 
administered in a monitored 
setting under supervision of 
a consulting neurologist. o 
 
Patients unable to 
tolerate steroids may be 
candidates for treatment 
with plasmapheresis or IV 
IG. Such decisions are best 
made in consultation with a 
neurologist, taking into 
account the unique needs of 
each patient.  
o 
If myasthenia gravis- 
like neurotoxicity is 
present, consider 
starting AChE inhibitor 
therapy in addition to 
steroids. Such therapy, 
if successful, can also 
serve to reinforce the 
diagnosis.  
o 
Avoid medications that 
can worsen myasthenia 
gravis (e.g. some 
antibiotics, beta 
blockers , calcium 
channel blockers, 
relaxants).  
  
GUILLAIN-BARRE: o 
 
It is important to 
consider here that the use 
of steroids as the primary 
treatment of Guillain-
Barre is not typically 
considered effective.  
o 
Patients requiring 
treatment should be 
started with IV IG and 
followed by 
plasmapheresis if not 
responsive to IV IG.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 70 of 
90  
  
Grade 3 or 4  
  
For Grade 3  
  
For Grade 3 or 4   
• 
Hold study drug/study regimen dose until resolution to Grade 
≤1.  
• 
Permanently discontinue study drug/study regimen if Grade 3 
imAE does not resolve to Grade ≤1 within 30 days or if there 
are signs of respiratory insufficiency or autonomic instability.  
  
For Grade 4 Permanently discontinue study drug/study regimen.  
−  
Consider discussing with clinical 
study lead, as needed.  
−  
Recommend hospitalization.  
−  
Monitor symptoms and consult a 
neurologist.  
MYASTHENIA GRAVIS:  
o  
Steroids may be 
successfully used to 
treat myasthenia 
gravis. They should 
typically be 
administered in a 
monitored setting 
under supervision of a 
consulting neurologist.  
o  
Patients unable to 
tolerate steroids may 
be candidates for 
treatment with 
plasmapheresis or IV 
IG.  
o  
If myasthenia 
gravislike 
neurotoxicity present, 
consider starting AChE 
inhibitor therapy in 
addition to steroids. 
Such therapy, if 
successful, can also 
serve to reinforce the 
diagnosis.  
o  
Avoid medications that 
can worsen myasthenia 
gravis(e.g. some 
antibiotics, beta 
blockers , calcium 
channel blockers, 
relaxants).  
  


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consider here that the use 


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considered effective.  


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treatment should be started 


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with IV IG and followed 


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by plasmapheresis if not 


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Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 84 of 90  
Myocarditis  
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
General Guidance 
Discontinue drug 
permanently if biopsyproven 
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.   
grade/severity)  
 
−  
Consider discussing with the 
clinical study lead, as needed.  
−  
Monitor patients for signs and 
symptoms of myocarditis (new 
onset or worsening chest pain, 
arrhythmia, shortness of breath, 
peripheral edema). As some 
symptoms can overlap with lung 
toxicities, simultaneously 
evaluate for and rule out 
pulmonary toxicity as well as 
other causes (e.g., pulmonary 
embolism, congestive heart 
failure, malignant pericardial 
effusion). Consult a cardiologist 
early, to promptly assess whether 
and when to complete a cardiac 
biopsy, including any other 
diagnostic procedures.  
−  
Initial work-up should include 
clinical evaluation, BNP, cardiac 
enzymes, 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.  
  
Grade 2, 3 or 4   
  
  
−  
Patients should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g., disease 
progression, other medications, 
or infections)  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 85 of 90  
  
  
If Grade 2 -- Hold study 
drug/study regimen dose 
until resolution to Grade 
0. If toxicity rapidly 
improves to Grade 0, 
then the decision to 
reinitiate study 
drug/study regimen will 
be based upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper. If toxicity does 
not rapidly improve, 
permanently.  
discontinue study 
drug/study regimen. 
If Grade 3-4,  
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 days 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/ Polymyositis   
Any Grade  
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTC  
grade/severity)  
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.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 86 of 90  
−  
If poly/myositis is suspected, a 
Neurology consultation should 
be obtained early, with prompt 
guidance on diagnostic 
procedures. Myocarditis may 
cooccur 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, LDH, 
BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive 
protein level, urine myoglobin, 
and additional laboratory 
workup 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, antismooth 
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  
  
  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.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 87 of 90  
 
 
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 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 
days,  
consider starting another 
immunosuppressive therapy such 
as a TNF inhibitor  
(e.g., infliximab at 5 mg/kg  IV, 
may be repeated at 2 and 6 
weeks after initial dose at the 
discretion of the treating provider 
or relevant practice guidelines). 
Caution: It is important to rule 
out sepsis and refer to infliximab 
label for general guidance before 
using infliximab.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  Page 88 of 90  
  
Grade 3 or 4  
For Grade 3  
• 
Hold study drug/study  
regimen dose until resolution to 
Grade ≤1.  
• 
Permanently discontinue study 
drug/study regimen if Grade 3 
imAE does not resolve to Grade 
≤1 within 30 days or if there are 
signs of respiratory 
insufficiency.  
  
For Grade 4  
• 
Permanently discontinue study 
drug/study regimen.  
 
  
  
Other–Immune-Mediated Reactions  
Severity Grade of the  
Event (Refer to NCI  
CTCAE applicable 
version in study protocol for 
defining the CTC 
grade/severity)  
Dose Modifications  
Toxicity Management  
Any Grade  
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  
For Grade 3 or 4   
−  
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 3 
days,  
consider starting another 
immunosuppressive therapy 
such as a TNF inhibitor  
(e.g., infliximab at 5 mg/kg  IV, 
may be repeated at 2 and 6 
weeks after initial dose at the 
discretion of the treating 
provider or relevant practice 
guidelines). Caution: It is 
important to rule out sepsis and 
refer to infliximab label for 
general guidance before using 
infliximab.  
−  
Consider whether patient may 
require IV IG, plasmapheresis.  


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  
Page 89 of 90  
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)   
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, 
please discuss with clinical study lead.”  
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.  
Infusion-Related Reactions  
Severity Grade of the  
Event (Refer to NCI  
CTCAE 
applicable 
version in study  
protocol for defining the 
CTC grade/severity)  
Dose Modifications  
Toxicity Management  
Any Grade  
General Guidance  
For Any Grade  
−  
Manage 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, or skin rashes) 
and anaphylaxis (e.g., generalized urticaria, 
angioedema, wheezing, hypotension, or 
tachycardia).  
Grade 1 or 2  
For Grade 1  
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution of 
the event.  
  
For Grade 2  
• 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until 
resolution of the event.  
• 
Subsequent infusions may be given 
at 50% of the initial infusion rate.  
−  
−  
−  
For Grade 1 or 2  
Acetaminophen and/or antihistamines may 
be administered per institutional standard at 
the discretion of the investigator.  
Consider premedication per institutional 
standard prior to subsequent doses. 
Steroids should not be used for routine 
premedication of Grade ≤2 infusion 
reactions.  
Grade 3 or 4  
For Grade 3 or 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.  
 
 
 
 
 


Clinical Study Protocol  
HCRN LUN18-357  
Version Date: 09MAY2022  
Confidential  
Page 90 of 90  
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute.  
  
  
Non-Immune-Mediated Reactions  
Severity Grade of the  
Event (Refer to NCI  
CTCAE 
applicable 
version in study  
protocol for defining the  
CTC grade/severity)  
Dose Modifications  
Toxicity Management  
Any Grade  
Note: Dose modifications are not required for 
AEs not deemed to be related to study 
treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant.  
Treat accordingly, as per institutional standard.  
Grade 1  
No dose modifications. 
 
Treat accordingly, as per institutional standard. Grade 2  
Hold study drug/study regimen until  
Treat 
accordingly, as per institutional standard. resolution to ≤Grade 1 or baseline.  
Grade 3  
Hold study drug/study regimen until resolution 
to ≤Grade 1 or baseline.  
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline within 
14 days, resume study drug/study regimen 
administration. Otherwise, discontinue study 
drug/study regimen.  
Treat accordingly, as per institutional standard.  
Grade 4  
  
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue should 
be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the Sponsor.).  
Treat accordingly, as per institutional standard.  
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, 
please discuss with clinical study lead.”  
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute