Clinical trial NCT03871153
Conditions: Non Small Cell Lung Cancer Stage III Non-small-cell Lung Cancer
Sponsor: Greg Durm, MD
Start date: 2019-08-02; Completion date: 2022-03-09
Enrollment: 7 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is an open label, multi-institutional, single arm Phase II trial. All patients will be treated with Carboplatin, Paclitaxel, Durvalumab and Radiation. All patients with non-PD after induction therapy who remain surgical candidates will undergo surgical resection 4-12 weeks following induction therapy.

After surgical resection, all patients who remain eligible will be treated with adjuvant Durvalumab every 4 weeks for 6 cycles beginning 4-12 weeks after surgical resection.

Detailed description:

Arms: arm 1: Neoadjuvant chemotherapy(Durvalumab, Paclitaxel, Carboplatin), radiation and immunotherapy (durvalumab) followed by surgical resection followed by adjuvant immunotherapy (durvalumab)
Interventions: intervention 1: Durvalumab intervention 2: Paclitaxel intervention 3: Carboplatin intervention 4: Radiation intervention 5: Surgical Resection
Intervention descriptions: intervention 1: Neoadjuvant Durvalumab 750 mg IV on Days 1, 15 and 29

Adjuvant Durvalumab 12 weeks after undergoing surgical resection 1,500 mg IV on Day 1 intervention 2: Paclitaxel 45 mg/m2 IV Days 1, 8, 15, 22, 29 and +/- 36 intervention 3: Carboplatin AUC of 2 IV Days 1, 8, 15, 22, 29 +/- 36 intervention 4: 1.8-2.0 Gy per day (5 days/week) for a total of 45-61.2 Gy over 5-6 weeks. Treatment will be delivered using IMRT or 3DCRT using typically 6-10MV photons. Proton therapy is also allowed. 4D simulation and appropriate IGRT are encouraged. Radiation therapy must begin within one week of the first day of chemotherapy (or vice versa). intervention 5: Patients will undergo repeat imaging between 4 and 12 weeks after completing neoadjuvant therapy. Those without evidence of progressive disease and found to be a surgical candidate by a thoracic surgeon will undergo surgical resection between 4 and 12 weeks after neoadjuvant therapy.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN LUN17-321 
 
A Phase II study of Concurrent Chemoradiation plus Durvalumab (MEDI4736) followed 
by Surgery followed by Adjuvant Durvalumab (MEDI4736) in medically operable patients 
with surgically resectable Stage III (N2) Non-Small Cell Lung Cancer 
A Hoosier Cancer Research Network Clinical Trial LUN 17-321 
 
Sponsor Investigator 
Greg Durm, MD 
Department of Medicine, IU School of Medicine  
IU Simon Cancer Center 
 
Co-Investigators 
Nasser Hanna, MD 
Tim Lautenschlaeger, MD 
Thomas Birdas, MD 
John Heymach, MD 
Mary Jo Fidler, MD 
Vamsi Velcheti, MD 
 
Statistician 
Yong Zang, PhD 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
7676 interactive way, Suite 120 
Indianapolis 46278 
 
 
Trial Supported by  
AstraZeneca ESR-18-13794 
 
IND EXEMPT per FDA 2/25/19 
 
 
 
Initial Protocol Version Date: 19DEC2018 
Protocol Amendment Version Date:  
14MAY2021 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A Phase II study of Concurrent Chemoradiation plus Durvalumab followed by Surgery followed 
by Adjuvant Durvalumab in medically operable patients with surgically resectable Stage III (N2) 
Non-Small Cell Lung Cancer:  
A Hoosier Cancer Research Network Clinical Trial LUN 17-321 
 
VERSION DATE: 14MAY2021 
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). 
 
 
 
 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 
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Signature of Site Investigator
Date
Location of Facility (City and State)
____________________________________


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SYNOPSIS 
TITLE 
A Phase II study of Concurrent Chemoradiation plus Durvalumab 
followed by Surgery followed by Adjuvant Durvalumab in 
medically operable patients with surgically resectable Stage III 
(N2) Non-Small Cell Lung Cancer:  
A Hoosier Cancer Research Network Clinical Trial LUN 17-321 
PHASE  
II 
OBJECTIVES 
Primary Objective 
 Estimate the pathological complete response rate at the time 
of surgery in patients with stage IIIA (N2) NSCLC treated 
with concurrent Carboplatin/Paclitaxel/Durvalumab plus 
radiation therapy followed by surgical resection followed by 
adjuvant Durvalumab 
 
Secondary Objectives 
 Estimate the pathological N0 rate at the time of surgery in 
patients with stage IIIA (N2) NSCLC treated with 
concurrent Carboplatin/Paclitaxel/Durvalumab plus 
radiation therapy followed by surgical resection  
 Assess the feasibility of incorporating Durvalumab 
concurrently with Carboplatin/Paclitaxel plus radiation prior 
to surgery  
 Assess the feasibility of giving adjuvant Durvalumab 
following concurrent Carboplatin/Paclitaxel/Durvalumab 
plus radiation followed by surgical resection for patients 
with stage IIIA (N2) NSCLC.    
 Define the toxicity profile of concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation therapy 
for patients with stage IIIA (N2) NSCLC 
 Define the toxicity profile of adjuvant Durvalumab 
following concurrent Carboplatin/Paclitaxel/Durvalumab 
plus radiation followed by surgery in patients with stage 
IIIA (N2) NSCLC 
 Estimate the 1-year disease free survival (DFS) of patients 
treated with concurrent Carboplatin/Paclitaxel/Durvalumab 
plus radiation therapy followed by surgical resection 
followed by adjuvant Durvalumab 


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STUDY DESIGN 
This is an open label, multi-institutional, single arm Phase II trial. 
All patients will be treated with: 
 
Carboplatin AUC 2 IV days 1, 8, 15, 22, 29 +/- 36  
Paclitaxel 45 mg/m2 IV. days 1, 8, 15, 22, 29, +/- 36 
Durvalumab 750 mg IV days 1, 15, 29 
Radiation 45-61.2 Gy 
 
All patients with non-PD after induction therapy who remain 
surgical candidates will undergo surgical resection 4-12 weeks 
following induction therapy. 
 
After surgical resection, all patients who remain eligible will be 
treated with adjuvant Durvalumab 1500 mg once every 4 weeks for 
6 cycles beginning 4-12 weeks after surgical resection. 
KEY ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility criteria) 
Inclusion Criteria 
1. ECOG Performance Status of 0 or 1 within 28 days prior to 
registration.  
2. Histological or cytological confirmation of NSCLC 
(Adenocarcinoma, Squamous Cell Carcinoma, Large Cell 
Carcinoma). A pathology report (from the last 6 months) 
confirming the diagnosis of NSCLC must be obtained and 
reviewed by the treating physician prior to registration to study. 
3. Must have resectable and medically operable stage III (N2) 
NSCLC with biopsy-proven N2 disease. Subjects must be 
considered resectable or operable based on the judgment of the 
treating physician. Stage III (N2) defined as per the 8th edition 
TNM staging (T1a, T1b, T1c, T2a, T2b, T3 or T4)N2M0.  
4. Cannot have contralateral neck or contralateral mediastinum 
nodal involvement.  
5. Cannot have distant metastasis, defined as M0 in the TMN 
staging system. 
6. Demonstrate adequate organ function within 28 days prior to 
registration. 
 
Exclusion Criteria 
1. Persons who do not meet the Stage III (N2) NSCLC 
classification criteria outlined above. 
2. Persons who have small cell carcinoma. 
3. Prior therapy with a PD-1, PD-L1 (including Durvalumab), PD-
L2 or CTLA-4 inhibitor or a lung cancer-specific vaccine 
therapy.  
4. Active second cancers.  
5. Interstitial lung disease or history of pneumonitis requiring 
treatment with corticosteroids.


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6. Diagnosis of immunodeficiency or is receiving chronic 
systemic corticosteroid therapy or other immunosuppressive 
therapy (excludes inhaled corticosteroids) within 7 days of first 
dose of study drug.  Patients treated with “physiologic” doses of 
steroids (≤ Prednisone 10mg PO daily or its equivalent) will 
still be eligible for enrollment. 
7. Known history of human immunodeficiency virus (HIV) 
infection or chronic hepatitis B or C.  
STATISTICAL 
CONSIDERATIONS 
 
Simon's two-stage optimal design for this single arm Phase II study 
will be used (Simon, 1989). The trial is designed to conclude that 
concurrent chemoradiation plus Durvalumab would worth further 
investigation if the pathological complete response rate is 40% or 
more. The therapy will be deemed not worthy of further 
investigation, if the pathological complete response rate is 20% or 
less, which is the historically observed rate and the null hypothesis 
that will be tested against a one-sided alternative.  
 
Under these assumptions, the maximum sample size is 25 
evaluable patients, with 12 patients accrued in the first stage and 
13 subjects accrued in the second stage.  A patient who completes 
the follow up for pathological response would be considered 
evaluable. If not, the patient will not be evaluable and will be 
replaced.  In the first stage, if among these 12 patients, there are 2 
or fewer patients who have pathological complete responses, then 
the study will be stopped for lack of efficacy. Otherwise, 13 
additional patients will be accrued for a total of 25.  The 
concurrent Carboplatin/Paclitaxel/Durvalumab plus radiation 
therapy will be considered to be worthy of further investigation if 8 
or more patients who have pathological complete responses are 
observed among the 25 patients. 
TOTAL  
NUMBER OF 
SUBJECTS 
N = 25  
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 24 months 
ESTIMATED 
STUDY DURATION  
Estimated 36 months 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................... 7 
1. 
Background and Rationale ..................................................................................... 8 
2. 
Study Objectives and Endpoints........................................................................... 12 
3. 
Eligibility Criteria .................................................................................................. 13 
4. 
Subject Registration............................................................................................... 17 
5. 
Treatment Plan....................................................................................................... 18 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 23 
7. 
Study Calendar & Evaluations ............................................................................. 26 
8. 
Biospecimen Studies and Procedures ................................................................... 30 
9. 
Criteria for Disease Evaluation ............................................................................ 31 
10 
Drug Information ................................................................................................... 32 
12 
Statistical Methods ................................................................................................. 41 
13 
Trial Management ................................................................................................. 43 
14. Data Handling and Record Keeping .................................................................... 46 
15 
Ethics ....................................................................................................................... 47 
16 
References ............................................................................................................... 48 
 
 
 
 
 


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SCHEMA 
 
 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Stage IIIA Non-Small Cell Lung Cancer (NSCLC)  
Lung cancer is the leading cause of cancer related deaths amongst men and women in the U.S. 
Non-small cell lung cancer (NSCLC) comprises 85% of lung cancers diagnosed. Stage IIIA 
NSCLC has a projected survival of 41% at 5 years [15], and the optimal treatment for medically 
operable patients with surgically resectable stage IIIA NSCLC remains undefined.   
 
1.2 
Current Standard of Care 
The treatment for stage III NSCLC is varied and complex. Most patients with stage IIIA NSCLC 
are medically inoperable due to co-morbidities, most commonly cardiopulmonary compromise.  
Those who are medically operable frequently have surgically unresectable disease due to extent 
of nodal involvement or proximity to major structures, including the pulmonary artery, main 
stem bronchus, or superior vena cava.  For patients with medically inoperable disease or 
surgically unresectable stage IIIA NSCLC, standard therapies include radiation, chemoradiation, 
and chemoradiation followed by Durvalumab.    
 
1.2.1 Standard non-surgical management of stage III NSCLC 
Until recently, the standard of care for the treatment of medically inoperable or surgically 
unresectable stage IIIA NSCLC in a fit patient was chemoradiation alone [1].  This remained a 
standard for nearly 2 decades.  However, for fit patients eligible for treatment with Durvalumab, 
a new standard of care has been recently defined.  The PACIFIC trial is a phase III study in 
which patients with inoperable or unresectable stage III NSCLC were randomized to 
Durvalumab consolidation therapy vs. placebo after completing standard chemoradiation [2]. 
Those in the treatment arm received Durvalumab consolidation therapy, dosed at 10 mg/kg IV 
every 2 weeks for up to 12 months, beginning 1-42 days after completing chemoradiation. 
Participants in the Durvalumab arm had increased progression free survival of 16.8 vs. 5.6 
months in the placebo arm. Median time to death was prolonged in the treatment arm at 23.2 
months vs. 14.6 months in the placebo arm. Median Progression free survival was superior in the 
Durvalumab arm (at 12 months, 55.9% in the Durvalumab group compared with 35.3% in the 
placebo arm, and at 18 months 44.2% compared with 27% respectively). Based upon this trial, 
the FDA granted approval for the use of Durvalumab following chemoradiation for patients with 
unresectable or inoperable Stage III NSCLC.  However, it remains unknown if this is the optimal 
treatment for those with surgically resectable, medically operable stage IIIA disease.   
 
1.2.2 Standard approaches to treatment for patients with medically operable, surgically 
resectable stage III NSCLC 
Individuals who are medically operable and have surgically resectable disease may still be 
treated with non-surgical interventions only.  Other patients will be considered for surgery 
upfront followed by chemotherapy with or without sequential radiation; neo-adjuvant 
chemotherapy followed by surgery; or neo-adjuvant chemoradiation followed by surgery.   
 
 
 


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1.2.3 Surgery followed by adjuvant therapy 
The IALT trial evaluated survival in patients with stage I-III NSCLC treated with surgery alone 
vs. surgery followed by 4 cycles of adjuvant cisplatin-based chemotherapy [3].  Some patients 
also received sequential radiation after adjuvant chemotherapy was completed.   Those in the 
chemotherapy arm were found to have increased survival at 5 years compared to those in the 
observation arm (44.5% vs. 40.4% respectively).  The survival impact was greatest for those with 
stage IIIA disease. The ANITA trial was an open label, phase III randomized trial which 
compared overall survival of patients with stage IB-IIIA NSCLC treated with vinorelbine + 
cisplatin vs. observation after surgical resection [4]. Radiation was also permitted after 
completion of chemotherapy (or after surgery in the non-chemotherapy arm).  Overall survival at 
the 5-year mark was improved by 8.6%, favoring those receiving chemotherapy. Once again, the 
largest gain in survival was seen in those with stage IIIA disease.  The LACE meta-analysis 
provides further support for the use of cisplatin-based adjuvant chemotherapy, with the largest 
absolute improvement seen in those with stage IIIA disease [5]. 
 
1.2.4 Neo-adjuvant chemotherapy followed by surgery 
The delivery of chemotherapy prior to surgery (neo-adjuvant approach) results in a higher 
likelihood of receiving systemic therapy when compared to delivering the treatment after surgery 
(adjuvant approach).  Since many patients undergoing surgery are unable to receive adjuvant 
therapy due to prolonged recovery from surgery or other reasons, neo-adjuvant therapy has also 
been investigated in this patient population. Scagliotti, et al performed a phase III trial comparing 
surgery alone vs. neo-adjuvant cisplatin plus gemcitabine chemotherapy followed by surgery in 
Stage IB-IIIA NSCLC [6]. Median survival in the chemotherapy/surgery arm was 7.8 years 
compared with 4.8 years in the surgery alone arm. 3-year overall survival was also increased 
(67.6% vs. 59.8%). A meta-analysis evaluating platinum-based neo-adjuvant therapy in patients 
with stage I-III NSCLC further supports this approach [7].  The magnitude of gain appears to be 
similar between the neo-adjuvant and adjuvant approaches.  
 
1.2.5 Neo-adjuvant chemoradiation followed by surgery 
Another approach to the treatment of patients with medically operable, surgically resectable 
stage IIIA NSCLC is chemoradiation followed by surgery.  This approach maximizes the use of 
local modalities of therapy (surgery and radiation) along with delivering systemic therapy.  
Optimal local control and systemic control are both necessary to maximize long-term outcomes.  
The largest study to date which evaluates the role of chemoradiation followed by surgery in 
patients with stage IIIA NSCLC was the Intergroup LUN 0139 trial reported by Albain et al [8].  
Intergroup LUN 0139 was a Phase III randomized controlled multicenter cooperative group trial 
comparing concurrent chemoradiation with or without surgical resection in those with stage IIIA 
NSCLC.  Participants were required to have Stage IIIA(pN2) disease, considered resectable from 
the time of diagnosis, have a predicted post resection FEV1 of > 800 cc, a KPS 90-100, or if 
KPS was 70-80 an albumin of 85% of normal with <10% weight loss over the past 3 months.  
Induction therapy consisted of cisplatin (50 mg/m2 on days 1, 8, 29, 36) with etoposide (50 
mg/m2 on days 1-5 and 29-33), along with concurrent 45 Gy thoracic RT beginning day 1, in 1.8 
Gy daily fractions. After completion of this therapy, their disease was re-evaluated with CT 
imaging, and if no progression occurred, those in Arm 1 underwent complete surgical resection, 
while those in the control arm continued radiation therapy to 61 Gy. Patients in both arms were 
permitted to receive 2 additional cycles of cisplatin plus etoposide. 


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Of the 429 patients who were enrolled and randomized to an arm, 202 were randomized to 
surgery and 194 to chemoradiation alone. Progression free survival was superior for those on the 
surgery arm (median 12.8 months) vs. chemoradiation alone arm (median 10.5 months). Overall 
survival was 23.6 months vs. 22.2 month, favoring surgery. There were more early deaths 
without progression in the surgery arm (17.8% vs. 9.8%), but more patients in the surgery arm 
were alive without progression of cancer (21.3% vs. 11.3%). 5-year survival was 27.2% in the 
surgery arm vs. 20.3% with chemoradiation alone. The 5-year survival rates for those achieving 
a pathologic complete response in the surgery arm was 41.9%.  For those with a pathologic 
complete response in lymph nodes, the 5-year survival was 41%.  For those with persistent nodal 
disease, the 5-year survival was 23.8%. 
 
The results of the Intergroup 0139 study indicate that surgical resection can be curable in patients 
with stage IIIA NSCLC who undergo chemoradiation, even in those without a pathologic 
complete response, albeit at a lower cure rate than those with a pathologic complete response.  A 
pathologic complete response can serve as an important surrogate for long-term survival in this 
patient population.  Patient selection is important, however, when considering surgical resection 
after chemoradiation.  For example, those patients with multi-nodal N2 disease or significant 
weight loss appear to have worse outcomes.  In addition, those patients requiring a 
pneumonectomy after chemoradiation should be carefully selected to reduce the possibility of 
postoperative death.   
 
1.3 
The potential role of PD-1 or PD-L1 inhibitors in early stage NSCLC 
The discovery of PD-1 and PD-L1 inhibitors has revolutionized the treatment of NSCLC.  
Several agents, including Nivolumab, Pembrolizumab, and Atezolizumab are FDA approved to 
treat patients in the advanced/metastatic setting based upon improved survival when compared 
with chemotherapy.  Durvalumab, A PD-L1 inhibitor, is FDA approved as consolidation 
treatment in patients with stage III NSCLC undergoing chemoradiation in the non-surgical 
setting, heralding the emerging role of this class of agents to treat patients with earlier stage 
disease.   
 
In 2017, investigators from Johns Hopkins and Memorial Sloan Kettering Cancer Center 
reported the results of a phase II study of neo-adjuvant Nivolumab followed by surgery for those 
with stage I-III NSCLC [9].  Eligible patients received Nivolumab, dosed 3 mg/kg, every 2 
weeks for 2 treatments. Outcomes measured include safety, feasibility, radiologic/pathological 
responses to therapy, as well as immunologic, genomic, and pathological correlates of response 
in blood and tumor. Twenty-two patients were enrolled including 81% with Stage II or IIIA 
disease.  One patient was deemed ineligible due to small cell histology.  Only 1 patient 
experienced a grade 3 toxicity with nivolumab in the neo-adjuvant setting.   There were no 
treatment related surgical delays, defined as per the feasibility portion as no more than 37 days of 
planned surgery delay.   Twenty of 21 patients underwent a complete surgical resection of tumor.  
One patient was found to have tracheal invasion and was not resected. At a median of 12 months 
follow up, 80% who underwent resection were alive and disease free.  Nine of 20 patients 
achieved a major pathological response defined as no evidence of cancer or >90% necrosis in the 
surgical specimen.  This data suggests a potential role for the incorporation of PD-1 or PD-L1 
blockade early in the course of therapy for those patients with stage II or III NSCLC. 
 


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At the American Society of Clinical Oncology (ASCO) meeting in 2018, Peters et al. reported 
data on the safety of adding nivolumab concurrently with chemoradiation. All patients were 
treated with concurrent chemoradiation, and nivolumab 360mg IV every 3 weeks was added at 
the beginning of radiation.  At the time of the meeting, 58 patients were evaluable in the safety 
cohort (had received ≥1 dose of nivolumab).  There were no unexpected adverse events.  Six 
(10.3%) patients developed grade 3 pneumonitis and there were no grade 4 or 5 pneumonitis 
events [10]. While the efficacy data in this trial is not yet mature, this study provides evidence 
that concurrent chemoradiation + concurrent PD-1/PD-L1 inhibition is a safe and feasible 
approach.  In comparison, in the Hoosier Oncology Group study of consolidation docetaxel after 
concurrent chemoradiation for stage III NSCLC, rates of grade 3 or higher pneumonitis were 
9.6%.  In the HCRN 14-179 study of consolidation Pembrolizumab after concurrent 
chemoradiation, the rate of grade 3 or higher pneumonitis was 6.5% and in the PACIFIC trial 
with consolidation Durvalumab, it was around 4% [11-13].   
   
1.4 
Rationale 
Patients with stage III NSCLC continue to have a poor prognosis with surgery alone, surgery 
with chemotherapy, or chemoradiation alone. Trimodality therapy with chemoradiation and 
surgery has proven to cure some patients who were not cured with concurrent chemoradiation 
alone. Combining chemoradiation therapy followed by Durvalumab has also been shown to 
increase progression free survival compared to chemoradiation alone in patients with stage III 
NSCLC not undergoing surgical resection. Neo-adjuvant use of Nivolumab appears to result in a 
high pathological complete (or near complete) response rate for those undergoing surgery for 
stage II or III NSCLC. We, therefore, hypothesize that neoadjuvant Durvalumab will improve 
pathologic complete response rates when incorporated with chemoradiation prior to surgical 
resection.  The current study will evaluate the feasibility, toxicity, and efficacy of incorporating 
Durvalumab with concurrent chemoradiation followed by surgery in patients with surgically 
resectable, medically operable stage IIIA NSCLC.  This study will also evaluate the safety and 
feasibility of delivering up to 6 cycles of adjuvant Durvalumab following concurrent 
chemoradiaton/immunotherapy followed by surgery. 
 
1.5 
Durvalumab Information 
 
1.5.1  Drug Information 
Durvalumab is a human IgG1κ mAb selected from a panel of hybridomas secreting human 
antibodies recognizing human PD-L1. Durvalumab is composed of two identical heavy chains 
and two identical light chains, with an overall molecular weight of approximately 149 kDa. The 
antibody-coding deoxyribonucleic acid (DNA) sequence was recovered from a selected 
hybridoma and engineered by recombinant DNA technology to introduce a triple mutation in 
the constant domain of the IgG1 heavy chain that reduces binding to complement protein C1q 
and the fragment crystallisable gamma (Fcγ) receptors involved in triggering effector function. 
Functional binding properties of the modified antibody were confirmed. An expression plasmid 
was prepared for durvalumab production in Chinese hamster ovary (CHO) cells. Durvalumab is 
selective for human PD-L1 and blocks the binding of human PD-L1 to the human PD-1 and 
CD80 (B7.1) receptors (Durvalumab Investigator Brochure). 
 
 
 


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1.5.2 Rationale for Fixed Dosing 
A population PK model was developed for durvalumab using monotherapy data as detailed in the 
durvalumab IB. Population PK analysis indicated only minor impact of body weight on PK of 
durvalumab (coefficient of ≤0.5). The impact of body weight-based (10 mg/kg Q2W or 20 mg/kg 
Q4W) and fixed dosing (750 mg Q2W or 1500 mg Q4W) of durvalumab was evaluated by 
comparing predicted steady state PK exposures (AUCss,0-28, Cmax,ss, and Cmin,ss) using the 
population PK model. A fixed dose of 750 mg Q2W was selected to approximate 10 mg/kg Q2W 
and a fixed dose of 1500 mg Q4W was selected to approximate 20 mg/kg Q4W (based on 
median body weight of ~75 kg). A total of 1000 patients were simulated using body weight 
distribution of 40 to 110 kg. Simulation results demonstrate that body weight-based (10 mg/kg 
Q2W) and fixed dosing (750 mg Q2W) regimens yield similar median steady-state exposures 
and associated variability, supporting the potential switch of durvalumab from weight-based to 
fixed dose. Similar considerations hold for the Q4W dosing regimens (20 mg/kg Q4W versus 
1500 mg Q4W) (Durvalumab Investigator Brochure). 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Estimate the pathologic complete response rate in patients with stage IIIA NSCLC treated with 
concurrent Carboplatin/Paclitaxel/Durvalumab plus radiation therapy followed by surgery 
followed by adjuvant Durvalumab. 
 
2.1.2 Secondary Objectives 
 Estimate the pathological N0 rate in patients with stage IIIA NSCLC treated with 
concurrent Carboplatin/Paclitaxel/Durvalumab plus radiation therapy followed by 
surgical resection. 
 Assess the feasibility of incorporating Durvalumab concurrently with 
Carboplatin/Paclitaxel plus radiation prior to surgery  
 Assess the feasibility of giving adjuvant Durvalumab following concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation followed by surgical resection for 
patients with stage IIIA NSCLC.    
 Define the toxicity profile of concurrent Carboplatin/Paclitaxel/Durvalumab plus 
radiation therapy for patients with stage IIIA NSCLC 
 Define the toxicity profile of adjuvant Durvalumab following concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation followed by surgery followed by 
adjuvant Durvalumab in patients with stage IIIA NSCLC 
 Estimate the 1-yr DFS of patients treated with concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation followed by surgical resection 
followed by adjuvant Durvalumab 
 
 
 


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2.1.3 Correlative/Exploratory Objectives 
 Explore the association between tissue PD-L1 and tumor mutational burden with 
pathologic complete response and N0 rates following resection 
 Explore the association between tissue PD-L1 and tumor mutational burden with 1-yr 
PFS following concurrent Carboplatin/Paclitaxel/Durvalumab plus radiation therapy 
followed by surgical resection followed by adjuvant Durvalumab  
 Explore frequency of circulating tumor DNA at time of diagnosis, following surgery, and 
following treatment with adjuvant Durvalumab 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
 Pathologic complete response rate following concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation therapy followed by surgical resection.  
This is defined as a lack of evidence of viable cancer in the surgical specimen at the time 
of surgery.  
 
2.2.2 Secondary Endpoints 
 Pathologic N0 rate following concurrent Carboplatin/Paclitaxel/Durvalumab plus 
radiation therapy followed by surgical resection.  This is defined as a lack of evidence of 
viable cancer in the removed lymph nodes at the time of surgery.  
 Feasibility of incorporating Durvalumab concurrently with Carboplatin/Paclitaxel + 
radiation prior to surgery.  This will be defined as no grade 4 or 5 toxicities and no grade 
3 toxicities not previously defined.  It will also include the delivery of at least 2 of 3 
planned doses of Durvalumab, the delivery of at least 4 planned doses of chemotherapy, 
the delivery of at least 45 Gy of radiation, and the ability to undergo surgery within a 
maximum of 12 weeks after finishing chemoradiation. 
 Feasibility of giving adjuvant Durvalumab following concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation followed by surgical resection for 
patients with stage IIIA NSCLC. This will be defined as no grade 4 or 5 toxicities and no 
grade 3 toxicities not previously defined. It will also include the delivery of at least 2 of 6 
planned doses of Durvalumab. 
 Toxicities will be defined by the NCI Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v5.  
 Disease free survival will be defined as the time from surgical resection until the criteria 
for disease recurrence is met or death as a result of any cause. Disease recurrence is 
return of the cancer to where it started (local) or in another part of the body (distant).   
 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject 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. NOTE: HIPAA authorization may be included in the informed consent or 
obtained separately.  


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2. Age ≥ 18 years at the time of consent.  
 
3. ECOG Performance Status of 0 or 1 within 28 days prior to registration.  
  
4. Histological or cytological confirmation of NSCLC (Adenocarcinoma, Squamous Cell 
Carcinoma, Large Cell Carcinoma). A pathology report (from the last 6 months) confirming 
the diagnosis of NSCLC must be obtained and reviewed by the treating physician prior to 
registration to study.  
 
5. Must have resectable and medically operable stage III (N2) NSCLC with clinical or biopsy-
proven N2 disease. If patients have clinical N2 disease they need to be biopsy-proven (with 
EBUS or mediastinoscopy) during screening and have confirmed prior to study enrollment). 
Subjects must be considered resectable and medically operable based on the judgment of the 
treating physician. Stage III (N2) defined as per the 7th edition of the TNM staging system 
(T1a, T1b, T1c, T2a, T2b, T3, or T4)N2M0. 
 
6. Individuals cannot have contralateral neck or contralateral mediastinum nodal involvement. 
 
7. Subjects must have a life expectancy of at least 12 weeks to qualify.  
 
8. Individuals must not have distant metastasis, defined as M0 in the TMN staging system.  
 
9. Demonstrate adequate organ function as defined in the table below; all screening labs to be 
obtained within 28 days prior to registration.  
  
System  
Laboratory Value  
Hematological  
 
Absolute Neutrophil Count (ANC) 
≥ 1.5 K/mm3  
Hemoglobin (Hgb)  
≥ 9 g/dL (may be transfused) 
Platelets  
≥100,000/mcl 
Renal  
 
Serum creatinine OR  
Measured or calculated creatinine 
clearance (GFR can also be used in place 
of creatinine or CrCl)  
≤ 1.5 x upper limit of normal (ULN) 
OR ≥ 40 mL/min for subjects with 
creatinine levels >1.5 x institutional 
ULN  
Hepatic  
 
Bilirubin  
≤ 1.5 × ULN OR  
Direct bilirubin of ≤ ULN for subjects 
with total bilirubin levels of >1.5x ULN  
Aspartate aminotransferase (AST)  
≤ 2.5 × ULN  
Alanine aminotransferase (ALT)  
≤ 2.5 × ULN  
  


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10. All CT or PET imaging studies must be completed within 6 weeks (42 days) prior to 
registration. 
 
11. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to 
registration. NOTE: Women are considered of childbearing potential unless they are 
surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or are postmenopausal. Menopause is defined clinically as 12 months of 
amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In 
addition, women under the age of 62 must have a documented serum follicle stimulating 
hormone (FSH) level greater than 40 mIU/mL.  
  
12. Women of childbearing potential must be willing to abstain from heterosexual activity or use 
an effective method of contraception from the time of informed consent until 90 days after 
treatment discontinuation.  
 
13. Men who are sexually active with WOCBP must use any contraceptive method with a failure 
rate of less than 1% per year. Men receiving study drug and who are sexually active with 
WOCBP will be instructed to adhere to contraception for a period of 90 days after the last 
dose of investigational product.  
 
14. 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. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study:  
  
1. History of a major surgical procedure (as defined by investigator) within 28 days prior to the 
first dose of study drug. NOTE: Local surgery for isolated lesions for palliative intent is 
acceptable. 
 
2. History of another primary malignancy except for a) malignancy treated with curative intent 
and with no known active disease ≥ 5 years before the first dose of study drug, b) adequately 
treated non-melanoma skin cancer or lentigo maligna without evidence of disease, c) 
adequately treated carcinoma in situ without evidence of disease. 
 
3. History of leptomeningeal disease.  
 
4. Persons who have small cell carcinoma. 
 
5. Persons who do not meet the Stage IIIA NSCLC classification criteria outlined above. 
 
6. Presence of superior vena cava syndrome. 
 


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7. Pregnant, breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 90 days after 
the last dose of trial treatment.  
  
8. Active central nervous system (CNS) metastases. Subjects must undergo a head computed 
tomography (CT) scan or brain MRI within 42 days prior to registration for protocol therapy 
to exclude brain metastases if symptomatic or without prior brain imaging.   
 
9. Treatment with any investigational agent within 28 days prior to registration for protocol 
therapy.   
  
10. Patients should not have received any prior therapy for the current diagnosis of NSCLC.  
Treatments done for previously diagnosed malignancies are permitted. Prior therapy with a 
PD-1, PD-L1 (including Durvalumab), PD-L2 or CTLA-4 inhibitor or a lung cancer-specific 
vaccine therapy are not permitted.   
 
11. Presence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be evaluated 
with a CT or PET scan prior to registration for protocol therapy to exclude metastatic 
disease. 
  
12. Active or prior documented autoimmune or inflammatory disorders (including inflammatory 
bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of 
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, 
uveitis, etc]). The following are exceptions to this criterion: 
 Patients with vitiligo or alopecia 
 Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement  
 Any chronic skin condition that does not require systemic therapy 
 Patients without active disease in the last 5 years may be included but only after 
consultation with the study physician 
 Patients with celiac disease controlled by diet alone 
 
13. Interstitial lung disease or history of pneumonitis requiring treatment with corticosteroids  
  
14. 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., paclitaxel 
premedication and CT scan premedication) 
 


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15. History of psychiatric illness or social situations that would limit compliance with study 
requirements  
  
16. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the 
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria  
 Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the investigator. 
 Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with the 
investigator.  
  
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the site investigator.  
  
18. Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral 
therapy including tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and TB testing in line with local practice), hepatitis 
B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human 
immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved 
HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence 
of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. Subjects with HIV/AIDS with 
adequate antiviral therapy to control viral load would be allowed. Subjects with viral 
hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy. 
Testing not required. 
  
19. Has received a live vaccine within 30 days prior to planned start of study therapy.  
NOTE:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed.  
 
20. History of allograft or allogeneic bone marrow transplant.  
 
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. Subjects must begin therapy 
within 5 business days of registration.  
 


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5. 
TREATMENT PLAN 
This is an open label, multicenter single arm Phase II trial of concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation therapy followed by surgical resection 
followed by adjuvant durvalumab in medically operable patients with surgically resectable Stage 
IIIA Non-Small Cell Lung Cancer. Those who receive concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation therapy without progression of disease will 
continue to surgical resection. After surgical resection, if there is still no progression of disease 
on repeat imaging, then patients will receive adjuvant durvalumab every 4 weeks for up to 6 
cycles. 
 
5.1 
Pre-medication and Hydration 
Institutional guidelines may be used for pre-medication, hydration and treatment of infusion 
reactions during study treatment. A common regimen would include: Dexamethasone 12 mg, 
diphenhydramine 25-50mg and palonosetron 0.25 mg.  
 
For subjects who experience a Grade 1 or Grade 2 infusion reaction, prior to subsequent 
infusions it is recommended that diphenhydramine 50 mg (or equivalent) and/or paracetamol 
(acetaminophen) 325 to 1000 mg should be administered at least 30 minutes before additional 
durvalumab administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
 
5.2 
Neoadjuvant chemotherapy/radiation/immunotherapy  
 
Drug 
Dose1 
Route 
Schedule2 
Sequence
Durvalumab 
750 mg  
Intravenously (IV) 
over 1 hour 
(± 10 minutes)
Days 1, 15, and 29 
1st 
Paclitaxel 
45 mg/m2 
IV over 1 hour  
Days 1, 8, 15, 22, 29, ± 363 
2nd 
Carboplatin 
AUC of 2 
IV over 30 minutes 
Days 1, 8, 15, 22, 29, ± 363 
3rd 
Radiation 
1.8-2.0 Gy per day 
for a total of  
45-61.2 Gy over  
5-6 weeks
Per institutional 
standards 
5 days a week; excluding 
holidays 
 
1 Body surface area (BSA) should be recalculated when weight changes by ≥ 10% according to the 
Mosteller formula.  
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). 
3 Subjects receive chemotherapy throughout radiation and chemotherapy and course may be longer or 
shorter depending on overall radiation dose given.  
 
 
 


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5.2.1 Durvalumab 
Durvalumab is available as a 50 mg/mL solution for intravenous solution in single-dose vials. 
The product will be diluted in an IV container made of polyvinyl chloride (PVC) or non-PVC 
materials containing 0.9% (w/v) sodium chloride or 5% (w/v) dextrose, with a final durvalumab 
(MEDI4736) concentration ranging from 1-15 mg/mL. Diluted solutions should be used 
immediately. If not used immediately, store the IV bag for up to 24 hours under refrigeration (2-
8°C) or at room temperature (25°C) for up to 4 hours. Do not freeze or shake diluted solution. 
 
Administer durvalumab as an intravenous infusion over 1 hour (± 10 minutes) through an IV line 
containing a sterile, low-protein binding 0.22 micron filter. Durvalumab to be infused first prior 
to paclitaxel and carboplatin. There should be a 15 minute delay after the durvalumab infusion 
prior to administering the paclitaxel. Do not administer other medications through the same 
infusion line. Monitor during infusion for infusion related reactions. 
 
5.2.2 Paclitaxel 
Please refer to the current package insert for complete prescribing and toxicity information. 
Institutional standards may be used for all aspects regarding administration of paclitaxel. 
Paclitaxel is available as a 6 mg/mL solution for intravenous solution as a multi-dose vial. 
Prepare the product per institutional standards by diluting to a final concentration of 0.3-1.2 
mg/mL using non-PVC containers.  
 
Administer paclitaxel after completion of durvalumab as an intravenous infusion over 1 hour 
through an IV line containing a sterile, low-protein binding 0.22 micron in-line filter (must use 
new filter for each medication).  
 
Nab-paclitaxel may be utilized for subjects that do not tolerate paclitaxel. Please refer to package 
insert for complete prescribing and toxicity information. Institutional standards may be used for 
all aspects regarding administration of nab-paclitaxel. 
 
5.2.3 Carboplatin 
Please refer to the current package insert for complete prescribing and toxicity information. 
Institutional standards may be used for all aspects regarding administration of carboplatin. 
Carboplatin is available as a 10 mg/mL solution for intravenous solution as a multi-dose vial. 
Prepare the product per institutional standards by diluting to a final concentration greater than 
0.5 mg/mL using PVC or non-PVC containers.  
 
Administer carboplatin third after completion of durvalumab and paclitaxel as an intravenous 
infusion over 30 minutes.  
 
5.2.4 Radiation Therapy  
Treatment will be delivered using IMRT or 3DCRT using typically 6-10MV photons. Proton 
therapy is also allowed. 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. 45-61.2 Gy will be delivered. 
Interruptions in radiation treatment are strongly discouraged.  Dose interruptions are allowed for 
grade 4 dysphagia, odynophagia, or esophagitis, or for grade 4 hematologic toxicities resulting in 


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chemotherapy delays/modifications, or for a decline in ECOG performance status to 2, 3, or 4. If 
an interruption of > 3 consecutive days is planned, the sponsor-investigator should be contacted 
via the Hoosier Cancer Research Network project manager. Radiation treatment plans will be 
collected for future analysis.  These plans are not required prior to study enrollment or treatment 
but should be collected by the D30 Safety Visit.  Please email Radiation therapy records 
(DICOM files for planning CT, RT plan, RT structure, RT dose) to projects@hoosiercancer.org 
including HCRN LU17-321 in the subject line. 
 
5.3 
Surgical Resection 
Patients will undergo repeat imaging between 4 and 12 weeks after completing neoadjuvant 
therapy. Those without evidence of progressive disease and found to be a surgical candidate by a 
thoracic surgeon will undergo surgical resection between 4 and 12 weeks after neoadjuvant 
therapy. If there is progression of disease, the subject will be taken off study treatment and 
follow up schedule will be per Study Calendar in Section 7. 
 
5.3.1 Surgical guidelines/extent of resection 
Participants will undergo lobectomy, pneumonectomy, and/or thoracotomy per the discretion of 
the thoracic surgeon. The resection should be chosen with the goal of complete removal of the 
primary lesion with negative margins (R0). If positive margins (R1) or (R2), participants would 
still eligible to proceed to the adjuvant portion of the study. Lymph nodes that are visible and 
technically resectable should be removed, labeled, and sent to pathology for review. Mediastinal 
lymph nodes that are removed during a thoracotomy may include left side lesions 5-10L, and if 
possible 4L; right side lesions 4R, 7-10R, and if possible 2R. 
 
4-12 weeks after undergoing surgical resection as outlined above, all subjects will be evaluated 
including imaging studies. If there is no progression of disease, participants will move on to the 
adjuvant portion of the study, Durvalumab, as outlined below. Adjuvant treatment will begin 
between 4 and 12 weeks after surgery. If there is progression of disease, then the patient will go 
off study treatment and follow up schedule will be per Study Calendar in Section 7.   
 
5.4 
Adjuvant Immunotherapy 
 
Drug 
Dose1 
Route 
Schedule2 
Cycle Length 
Durvalumab 
1500 mg 
IV 
Day 1 
4 weeks for 6 cycles 
1 Body surface area (BSA) should be recalculated when weight changes by ≥ 10% according to the Mosteller 
formula.  
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).
 
5.5 
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). 
 


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5.5.1 Allowed Concomitant Medications 
All treatments that the site investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the site 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), herbal supplements, 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 Bristol-Myers Squibb 
Clinical team 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. 
 
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. Flu-
Mist®) 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 immune-
modulating effects. 
 
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. 
 


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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 anti-
inflammatory 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. 
 
5.7 
Suggested Supportive Care Measures for the Management of Immune-Mediated 
Adverse Events (imAE) 
Early recognition of signs and symptoms potentially related to an inflammatory or immune-
mediated mechanism is important for proper management of toxicities. For guidance on 
identifying, evaluating, and treating imAE, see the Toxicity Management Guidelines in 
Appendix A. 
 
ImAE observed with anti PD-L1/PD-1 agents such as 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]. 
 
5.8 
Reproductive Information 
Participants of childbearing potential who are sexually active and their partners must agree to 
abstain from heterosexual activity or to use 2 forms of effective methods of contraception 
beginning with time of consent, during the study treatment and for 90 days (female) and 90 days 
(male) after last dose of study treatment. Two contraception methods can be comprised of two 
barrier methods, or a barrier method plus a hormonal method. See below for options: 
 
 
 


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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, post-
ovulation 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 PLUS male condom. Provided coils are 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 
 
5.9 
Blood Donation 
Patients should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of durvalumab. 
 
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 
Carboplatin and Paclitaxel Toxicity Guidelines 
 If paclitaxel or carboplatin are held for more than 2 weeks, then the applicable drug 
should be held permanently for the duration of concurrent therapy 
 Renal Toxicity- Carboplatin doses should be recalculated if serum creatinine increases by 
10% or more.  
 
 
 


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6.1.1 Hematology Toxicity  
There are no dose adjustments.  Please see table below for guidelines on when therapy should be 
held.  
 
 
 
6.1.2 Non-hematologic Toxicity 
There are no dose adjustments.  Please see table below for guidelines on when therapy should be 
held.  
 
 
 
6.2 
Durvalumab Toxicity Guidelines 
There is no increase or decrease in durvalumab dosing. Please see Appendix A for toxicity 
management guidelines. 
 
 
 


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6.3 
Protocol Therapy Discontinuation 
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 disease recurrence (local or distant). 
 
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.  
 
6.4 
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 
 
Study Evaluation 
Cycle = 28 days 
Screen 
Neoadjuvant Therapy Cycle 1 (C1)11 
Surgical 
Resection 
Adjuvant 
Therapy  
C1-C6
Safety  
Follow Up  
(+ 7 days)12
Long-Term  
Follow up  
(± 14 days)13
-28 
days 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
± 36 
 
Day 1 
± 3 days 
30 and 90 
days post 
last dose
Every 3 
months 
REQUIRED ASSESSMENTS 
Informed Consent
X
Medical History1 
X
Physical Exam2 
X
X
X
X
X
X
X
X
X
D30
Vital signs and ECOG Performance Status3 
X
X
X
X
X
X
X
X
X
D30
AEs & concomitant medications
X
X
X
X
X
X
X
X
X
X
Radiation Treatment Plans14
D30
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)
X
X11 
X
X
X
X
X
X
X
D30
Comprehensive Metabolic Profile (CMP)
X
X11 
X
X
X
X
X
X
X
D30
PT/INR and aPTT
X
Thyroid Function Testing4 
X
X
X4 
Pregnancy test (serum or urine) (WOCBP)4 
X
DISEASE ASSESSMENT 
CT of chest5 
X
X5
X5 
X5 
D30
X5 
CT or MRI of abdomen5 
X
X5
X5 
X5 
D30
X5 
CT head or MRI Brain5 
X
Bone or PET Scan5
X
TREATMENT EXPOSURE 
Carboplatin6 
X
X
X
X
X
X
Paclitaxel6 
X
X
X
X
X
X
Durvalumab 750 mg6 
X
X
X
Radiation6 
X
X
X
X
X
Durvalumab 1500 mg7
X
 


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Study Evaluation 
Cycle = 28 days 
Screen 
Neoadjuvant Therapy Cycle 1 (C1)13 
Surgical 
Resection 
Adjuvant 
Therapy  
C1-C6
Safety  
Follow Up  
(+ 7 days)14
Long-Term  
Follow up  
(± 14 days)15
-28 
days 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
29 
Day 
± 36 
 
Day 1 
± 3 days 
30 and 90 
days post 
last dose
Every 3 
months 
SPECIMEN COLLECTION  
Archival Tumor Tissue or Fresh Tissue8
X
X8 
Plasma samples9 
 
X 
 
 
 
 
 
X9 
C1D1 
X9 
 
BANKING SAMPLES 
Tissue10 
X
Whole blood, serum and plasma10 
X
C1D1
D30 
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X
 
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  
 
Key to Footnotes  
 
1. Medical History; other data to obtained during this assessment includes: diagnosis and staging to include pathology report and staging 
documentation, a smoking history questionnaire and trial awareness question.  In addition, prior anti-cancer treatment should be documented 
including medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery.   
 
2. Physical exam by a medical oncologist should be performed at screening and during treatment. A radiation oncologist will assess the subject 
prior to radiation to establish a radiation plan. A thoracic surgery consultation should be completed at screening and prior to surgery to determine 
whether subject is able to undergo surgical resection.  
 
3. Vital signs to include blood pressure, weight, and height (screening only) and ECOG performance status.   
 
4. Thyroid function testing will be performed at screening, after completion of neoadjuvant therapy/prior to surgical resection and then every other 
cycle of adjuvant therapy starting with C1D1. TSH, free or total T4 will be performed. Free versus total T3 at investigator’s discretion. For women 
of childbearing potential (WOCBP): urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required.  Testing is required within 7 days prior to registration. 


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5. Tumor response assessment will consist of evaluation by CT scan of the chest and MRI or CT of abdomen at screening.  PET-CT scan be used 
in place of these at the discretion of the treating physician.  A bone scan or PET scan should be obtained at screening if any clinical or laboratory 
suspicion of metastatic bone involvement is identified. MRI or CT of the brain should be performed at screening for all patients to rule out the 
presence of metastatic disease. Post treatment imaging studies will be performed: (1) 4-12 weeks after completing neoadjuvant therapy (2) 4-12 
weeks after surgical resection (3) prior to C4D1 of adjuvant therapy and (4) at completion of adjuvant therapy (D30 safety visit).  This imaging 
should include Chest CT which includes the liver and adrenal glands or PET-CT at the discretion of the treating physician.  Further abdominal and 
pelvic imaging is not mandatory but can be obtained if there is clinical suspicion of progression in these areas at the discretion of the treating 
physician.  Radiology imaging window of ± 7 days. De-identified CT or PET/CT images obtained as part of routine imaging may be sent for 
exploratory radiomic analysis and central review of imaging response by RECIST v1.1. Please email Radiation therapy records (DICOM files for 
planning CT, RT plan, RT structure, RT dose) to projects@hoosiercancer.org including HCRN LU17-321 in the subject line. 
 
6. Neoadjuvant therapy consists of carboplatin, paclitaxel, Durvalumab and radiation. 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. 45-61.2 Gy will be delivered over a 
time period of 5-6 weeks, depending on the total Gy being received, without a break. Interruptions in radiation treatment are strongly discouraged. 
Dose interruptions are allowed for grade 4 dysphagia, odynophagia, or esophagitis, or for grade 4 hematologic toxicities resulting in chemotherapy 
delays/modifications, or for a decline in ECOG performance status to 2, 3, or 4.  If an interruption of > 3 consecutive days is planned, the sponsor-
investigator should be contacted via the Hoosier Cancer Research Network project manager. 
 
7. All subjects will be evaluated including imaging studies 4-12 weeks after undergoing neoadjuvant therapy. If there is no progression of local or 
distant metastasis and the subject is deemed an appropriate surgical candidate by a thoracic surgeon, they will undergo surgical resection (should 
occur within 12 weeks after neoadjuvant therapy. After undergoing surgical resection, all subjects will be evaluated including imaging studies 
within 4-12 weeks after surgery. If there is no progression of local or distant metastasis, subjects will move on to the adjuvant portion of the study 
which consists of durvalumab Day 1 of every Cycle for up to 6 cycles. Cycle = 4 weeks. 
 
8. Submission of unstained slides from an archived tumor block (within the last 6 months) for correlative analysis is required if available. Tissue 
should be identified before registration and submitted to Hoosier Cancer Research Network (HCRN) after the subject is successfully registered. A 
new biopsy is not required if archival tissue is not available. Analysis will include PD-L1 and tumor mutational burden. Submission of unstained 
slides from surgical sample after completion of neoadjuvant therapy is required if available. See Correlative Laboratory Manual (CLM) for 
additional details. 
 
9. A blood sample for plasma will be collected (1) prior to treatment C1D1 of neoadjuvant chemoradiation, (2) at the time of re-evaluation 
following chemoradiation (when the patient gets either their PET/CT or CT chest and abdomen) +/- 7 days, (3) after surgery (any time in the 
window of 1 week postoperatively until 12 weeks prior to start of adjuvant durvalumab treatment, then (4) D30 and (5) D90 safety visits. 


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10. Unstained slides will be obtained from the subject’s archived formalin fixed paraffin embedded tumor sample. Whole blood for banking will 
be collected at Pre-Treatment Cycle 1 Day 1 of neoadjuvant chemoradiation. Serum and plasma for banking will be collected at Pre-Treatment 
Cycle 1 Day 1 prior to initiation of adjuvant Durvalumab, and at the 30-Day Safety Follow up visit. Subjects will be consented for optional storage 
of any remaining blood samples after protocol-specified studies are complete. These samples will be stored for future unspecified cancer-related 
research and are considered “banking samples”.  See CLM for collection, processing, labeling and shipping instructions. 
 
11. 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. A window of ± 3 days may be applied to all study visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. 
 
12. The safety follow-up visits 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 and 90 days (±7 days) after the last dose of treatment. Subjects who have an 
ongoing Grade ≥ 2 or serious AE (SAE) at this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, deemed clinically 
insignificant, and/or until a new anti-cancer treatment starts, whichever is earlier. The Day 90 visit may be done via phone, email or other avenues 
as appropriate. 
 
13. After completion of protocol therapy, subjects who discontinue for reasons other than progressive disease will have post-treatment follow-up 
for disease status until disease progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up. After 
documented disease progression each subject will be followed for overall survival until death, withdrawal of consent, or the end of the study 
(whichever occurs first). Radiographic disease assessment should be performed every 12 weeks for up to one year from the data of study 
enrollment.  
 
14. Radiation treatment plans will be collected for future analysis.  These plans are not required prior to study enrollment or treatment but should 
be collected by the D30 Safety Visit.   
 
 
 
 


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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Analyses as described may be performed based on availability of funding. 
 
8.1 
Tissue 
 
8.1.1 Archival Tissue 
Submission of unstained slides from an archived tumor block (within the last 6 months) to 
perform correlative analysis is required if available. Analysis will include PD-L1 testing by 
immunohistochemistry and tumor mutational burden.  Patients without sufficient archival tissue 
will not be required to undergo repeat biopsy, and they will still be eligible for enrollment 
without tissue submission.  
 
8.1.2 Tissue from Surgical Resection 
Submission of unstained slides from surgical sample after completion of neoadjuvant therapy is 
required if available.  These samples will be used to explore the relationship between multiple 
pathological, immunological, and genomic characteristics of the cancers and clinical outcome in 
these patients. 
 
8.1.3 Analyses of Tissue Samples  
Analyses of pre and post treatment FFPE tissue samples will be prioritized as specified below: 
1. Pathology analyses 
2. PD-L1 IHC analysis 
3. Multiplex IF analysis 
4. DNA extraction and WES RNA isolation and sequencing 
5. Banking for unspecified cancer related research  
 
8.2 
Peripheral Blood Samples 
 
8.2.1 Plasma 
A blood sample for plasma will be collected prior to treatment C1D1 of neoadjuvant 
chemoradiation, at the time of re-evaluation following chemoradiation (when the patient gets 
either their PET/CT or CT chest and abdomen) +/- 7 days, after surgery (any time in the window 
of 1 week postoperatively until 12 weeks prior to start of adjuvant durvalumab treatment, then 
D30 and D90 safety visits. These samples will be used for ctDNA analysis.  
 
8.3 
Storage of Biospecimens 
Any specimens remaining (leftover) once protocol described biospecimen-based studies are 
complete will be stored for future unspecified cancer related research. Permission for this will be 
obtained from subjects. 
 
8.4 
Banking Samples for Future Unspecified Research 
Subject consent will be obtained to collect additional samples for future unspecified cancer 
related research studies. Hoosier Cancer Research Network (HCRN) will manage the banked 
samples. Samples will be banked indefinitely in the Hoosier Cancer Research Network 
Biorepository.  
 


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This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment 
on Cycle 1 Day 1, prior to starting adjuvant durvalumab, and at the 30-day Safety Follow-up 
visit.  
 Pre- and Post-treatment serum: Whole blood for plasma will be collected prior to treatment on 
Cycle 1 Day 1, prior to starting adjuvant durvalumab, and at the 30-day Safety Follow-up visit.  
 Unstained slides: Unstained slides will be obtained from the subject’s archived formalin fixed 
paraffin embedded tumor sample.  
 
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. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
 
9.1 
Pathologic Complete Response Rate 
Pathologic complete response rate is defined as a lack of evidence of viable cancer in the surgical 
specimen at the time of surgery. 
 
9.2 
Pathologic N0 Rate 
Pathologic N0 rate is defined as a lack of evidence of viable cancer in the removed lymph nodes 
at the time of surgery. 
 
9.3 
Disease Free Survival 
Disease free survival is defined as the time from surgical resection until the criteria for disease 
recurrence is met or death as a result of any cause.  
 
9.3.1 Disease Recurrence 
Disease recurrence is return of the cancer to where it started (local) or in another part of the body 
(distant).   
 
 
 
 


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10. 
DRUG INFORMATION 
 
10.1 
Carboplatin 
Please see the package insert for complete details regarding this drug.  
 
Carboplatin (Paraplatin) is a platinum coordination compound with a molecular weight of 
371.25. Mechanism of action is by creating interstrand DNA crosslinks. Dosing is based on the 
formula: Total Dose (mg) = (target AUC) x (GFR + 25). For this trial, AUC=2. 
 
10.1.2 Supplier/How Supplied 
Carboplatin is commercially available and should be obtained through a 3rd party. Carboplatin 
injection comes in many doses: 50 mg/5 mL, 150 mg/15 mL, 450 mg/45 mL, and 600 mg/60 mL 
aqueous solution in multidose vials (white flip-off seals), and individually cartooned. 
 
10.1.3 Administration 
Administer IV over 30 minutes. Avoid using aluminum containing products that may come into 
contact with Carboplatin (as it can lead to precipitation and decreased potency). 
 
10.1.4 Storage and Stability 
Unopened vials of Carboplatin are stable until the date indicated on the package. Storage should 
be at 25°C (77°F), but excursions are permitted from 15°-30°C (59°- 86°F). This drug requires 
protection from light. PARAPLATIN (carboplatin) injection multidose vials maintain microbial, 
chemical, and physical stability for up to 14 days at 25°C following multiple needle entries. 
 
10.1.5 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. Those interacting with Carboplatin must wear gloves at all 
times to prevent contact with skin. If contact with skin occurs, the handler should wash the area 
immediately with soap and water. 
 
10.1.6 Adverse Events 
Please refer to the Carboplatin Investigator’s Brochure for a complete list of adverse events.  
  
Hematologic toxicity: dose limiting bone marrow suppression that can lead to thrombocytopenia, 
leukopenia, and anemia. These effects are typically more severe in those with renal impairment 
and poor performance status. Gastrointestinal toxicity: Nausea and vomiting are common GI 
related side effects that are typically amenable to treatment with anti-emetics. Other effects 
include diarrhea, constipation, and pain. Neurologic toxicity: Peripheral neuropathies is the most 
frequent neurologic reported side effect. Nephrotoxicity: Increases in Cr measurements and BUN 
have been reported in 6% and 14% of individuals receiving Carboplatin respectively. 
Hepatotoxicity: Abnormal LFTs can occur, and are usually mild and reversible in about 50% of 
cases. Allergic Reactions: 2% of patients receiving Carboplatin have experienced 
hypersensitivity reactions and include rash, hives, pruritus, erythema, bronchospasm, and rarely 
anaphylactic reactions. These can be treated with antihistamines, steroids, and epinephrine 
therapy. Injection site reactions, including redness, swelling, and pain, have been reported 
Electrolyte disturbances: Various decreased electrolyte values have been reported after 
undergoing therapy with Carboplatin. Other adverse events: Cardiovascular, respiratory, 


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genitourinary, and mucosal side effects have been noted in < 6% of individuals receiving 
Carboplatin therapy. Malaise, anorexia, hypertension, dehydration, and stomatitis have been 
reported as well. 
 
10.2 
Paclitaxel 
Please see the package insert for complete details regarding this drug.  
 
Paclitaxel (Taxol) is an insoluble, lipophilic compound with a molecular weight of 853.9. 
 
10.2.1 Supplier/How Supplied 
Paclitaxel is commercially available and should be obtained through a 3rd party. Paclitaxel is a 
clear, colorless to slightly yellow viscous solution and is supplied as a nonaqueous solution 
intended for dilution with a suitable parenteral fluid prior to intravenous infusion. Paclitaxel is 
available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. 
 
10.2.2 Storage and Stability 
Vials should be stored in original cartons between 20°–25° C (68°–77° F). Needs to be protected 
from sunlight. Unopened vials of Paclitaxel are stable until the date indicated on the package. 
Freezing/refrigeration affects the stability of this product. However, if refrigerated it may 
precipitate, but will dissolve again at room temperature. Infusions are stable at ambient 
temperature (approximately 25° C) and lighting conditions for up to 27 hours. 
 
10.2.3 Handling and Disposal 
Paclitaxel must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Clinical supplies may not be used for any purpose other than 
that stated in the protocol. 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. 
 
10.2.4 Administration 
Paclitaxel should be diluted in .9% Sodium Chloride injection, 5% Dextrose injection, 5% 
Dextrose and .9% Sodium Chloride/Ringer’s to a concentration of .3 to 1.2 mg/mL. Prepared 
solutions are stable at 25 C up to 27 hours. Should avoid plasticized PVC containers and 
administrations sets is not recommended.  
 
10.2.5 Adverse Events 
Please refer to the Paclitaxel insert for a complete list of all adverse events. 
 
Hematologic: Bone marrow suppression limits the dosing of Paclitaxel. Common side effects 
include leukopenia/neutropenia, anemia, thrombocytopenia. Suppression of the immune system 
places patients at increased risk for infection. Hypersensitivity reactions: All patients should be 
premedicated prior to Paclitaxel therapy in order to reduce the risk of hypersensitivity reactions. 
2% of patients have severe reactions, usually in the first 3 courses of therapy, with symptoms of 
hypertension, flushing, chest pain, dyspnea, and tachycardia. Minor reactions included symptoms 
such as dyspnea, hypotension, tachycardia, hypertension, flushing, rash. Cardiovascular: 


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Includes hypotension, bradycardia; significant events occur in 1% of patients and includes 
syncope, arrhythmias, hypertension, venous thrombosis. Respiratory: Respiratory failure, pleural 
effusions, interstitial pneumonia, PE, lung fibrosis have all been reported. Neurologic: Peripheral 
neuropathy and paresthesia’s are the most common side effect neurologically. 
Arthralgia/myalgia: 60% of patients undergoing Paclitaxel therapy experience 
arthralgias/myalgias, usually occurring a few days after therapy and is usually transient. Hepatic: 
Elevated liver enzymes have been noted to occur on laboratory testing. Gastrointestinal: 
Diarrhea, nausea, vomiting, and mucositis are common side effects of Paclitaxel therapy. 
Injection site reaction: Extravasation reactions can occur and treatment at this time is unknown. 
Other injection site reactions include erythema, tenderness, swelling at the location. Other 
adverse events: Alopecia occurs in about 90% of patients undergoing this therapy. Other effects 
include edema, malaise, asthenia, vision changes, increased Creatinine have also been reported.  
 
10.3 
Durvalumab 
Please refer to Investigator’s Brochure (IB) 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 [B7-
H1], cluster of differentiation [CD]274) to programmed cell death 1 (PD-CD279) and CD80 (B7-
1). Durvalumab is composed of 2 identical heavy chains and 2 identical light chains, with an 
overall molecular weight of approximately 149 kDa.  Durvalumab contains a triple mutation in 
the constant domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to 
complement protein C1q and the fragment crystallizable gamma (Fcγ) receptors involved in 
triggering effector function. 
 
10.3.1 Supplier/How Supplied 
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 by AstraZeneca as a 500-mg vial solution for infusion after dilution. The solution 
contains 50 mg/mL durvalumab, 26 mM histidine/histidine hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0. The nominal fill 
volume is 10.0 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and 
must not be frozen. Drug product should be kept in secondary packaging until use to prevent 
excessive light exposure. 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. 
 
10.3.2 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 


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A dose of 750 mg or 1500 mg (for patients >30 kg) will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration 
ranging from 1 to 15 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-
μm filter.   
 
Add 15.0 mL of durvalumab (i.e., 750 mg of durvalumab) or 30.0 mL of durvalumab (i.e., 1500 
mg 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. 
 
If patient weight falls to ≤30 kg, weight-based dosing at 20 mg/kg will be administered using an 
IV bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set with 
a 0.2- or 0.22-μm filter.     
 
Standard infusion time is one hour ± 10 minutes, however if there are interruptions during 
infusion, the total allowed infusion time should not exceed 8 hours at room temperature.   
 
Do not co-administer other drugs through the same infusion line. 
 
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 and document if the line 
was not flushed. 
 
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.  
 
10.3.3 Storage and Stability 
Unopened vials of Durvalumab liquid Drug Product must be stored at 2°C to 8°C (36°F to 46°F).  
 
10.3.4 Adverse Events 
For information on all identified and potential risks with durvalumab please always refer to the 
current version of the durvalumab IB. 
 
Immunotherapy adverse related reactions: Individuals receiving Durvalumab therapy are at 
increased risk of pneumonitis, hepatitis, colitis, development of DM I, thyroid dysfunction, 
adrenal insufficiency, hypophysitis/hypopituitarism. Other effects include an immunotherapy-
induced rash, ITP, nephritis. Severe infections can also occur in those receiving Durvalumab 
therapy. In pregnant women, Durvalumab can cause fetal harm based on animal studies. 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. 
 


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Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus, 
hypophysitis and adrenal insufficiency) 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.  
 
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 9% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 6% 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 adverse events. 
 
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 Study 
Procedure Manual or 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 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests   
 
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. 
 
 
 


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11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
 Results in death. NOTE: 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) 
 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 Definition of adverse events of special interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring. An AESI may be 
serious or non-serious. If the investigator has any questions in regards to an event being an 
imAE, the investigator should promptly contact the sponsor-investigator. 
 
AESIs observed with durvalumab include: 
 Diarrhea/Colitis and intestinal perforation 
 Pneumonitis/ILD 
 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 immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and 
other events involving the eye, skin, haematological and rheumatological events. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological aetiology are also considered AESIs. 
 


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Further information on these risks (e.g. presenting symptoms) can be found in the current version 
of the durvalumab Investigator’s Brochure. More specific guidelines for their evaluation and 
treatment are described in detail in the Dosing Modification and Toxicity Management 
Guidelines (please see Appendix A). These guidelines have been prepared by the Funder to assist 
the investigator in the exercise of his/her clinical judgment in treating these types of toxicities.  
These guidelines apply to AEs considered causally related to the study drug/study regimen by the 
reporting investigator. 
 
11.1.4 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.   
 
11.1.5 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)  
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)  
 
11.2 
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. 
 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. 
 Asymptomatic laboratory abnormalities that do not require treatment will not be collected 
as adverse events. 
 
 
 


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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 follow-
up 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. AEMailboxClinicalTrialTCS@astrazeneca.com. 
 
11.3 
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 per 
SAE guidelines described above. 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. 
 
11.4 
Hepatic Function Abnormality 
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case in 
a subject, with or without associated clinical manifestations, is required to be reported as 
“hepatic function abnormal” per SAE guidelines described above unless a definitive 


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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). 
 
11.5 
Pregnancy 
If a patient becomes pregnant during the course of the study, study treatment 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, 
guidelines above regarding reporting of SAEs should be utilized. 
 
11.6 
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 90 days after the last dose 
of durvalumab + any drug combination therapy should, if possible, be followed up and 
documented.  
 
11.7 
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.   
 
11.8 
HCRN Responsibilities to FDA 
For protocols exempt from the requirements of an IND, the above stated requirements are not 
applicable. HCRN will continue to facilitate compliance of applicable requirements for the 
sponsor-investigator in relation to this study. This 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. 
 
11.9 
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.    
 


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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 
Simon's two-stage optimal design will be used for this single-arm Phase II study with the 
primary endpoint of pathological complete response among patients with stage IIIA (N2) 
NSCLC treated with concurrent Carboplatin/Paclitaxel/Durvalumab plus radiation therapy 
followed by surgical resection followed by adjuvant Durvalumab.   
 
The trial is designed to conclude that concurrent Carboplatin/Paclitaxel/Durvalumab plus 
radiation therapy would be worth further investigation if the pathological complete response rate 
is 40% or more. The therapy will be deemed not worthy of further investigation, if the 
pathological complete response rate is 20% or less, which is the historically observed rate and 
the null hypothesis that will be tested against a one-sided alternative. Under these assumptions, 
the maximum sample size is 25 evaluable patients, with 12 patients accrued in the first stage and 
13 subjects accrued in the second stage.  Given the rare disease of the study population, the trial 
will not be halt at the end of 1st stage while the interim analysis is performed.  If deemed 
appropriate, DSMB can instruct the trial to pause.  
 
In the first stage, if among these 12 patients, there are 2 or fewer patients who have pathological 
complete responses, then the study will be stopped for lack of efficacy. Otherwise, 13 additional 
patients will be accrued for a total of 25.  The concurrent Carboplatin/Paclitaxel/Durvalumab 
plus radiation therapy will be considered to be worthy of further investigation if 8 or more 
patients who have pathological complete responses are observed among the 25 patients. This 
design yields a type I error rate of 10%. When the true pathological complete response rate is 
indeed 40%, the power of the study is 81.5%, the expected sample size is 17.7 and the 
probability of early stopping is 55.8%. 
 
The sample size of 25 patients are patients who have evaluable pathological response.  If not, 
such as the case when a patient may not come back for surgery after taking the study drugs, such 
patient will not be evaluable and will be replaced.  If 10% of the enrolled patients are not 
evaluable, then the study would need to enroll about 28 patients.  
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
The primary endpoint is the pathologic complete response rate following concurrent 
Carboplatin/Paclitaxel/Durvalumab plus radiation therapy followed by surgical resection defined 
as a lack of evidence of viable cancer in the surgical specimen at the time of surgery. 
 
12.2.2 Definition of Secondary Endpoints 
In addition to the study of feasibility, the secondary endpoints include 1) the pathological N0 rate 
in patients with stage IIIA NSCLC treated with concurrent Carboplatin/Paclitaxel/Durvalumab 
plus radiation therapy followed by surgical resection, and 2) 1-yr DFS of patients treated with 


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concurrent Carboplatin/Paclitaxel/Durvalumab plus radiation therapy followed by surgical 
resection followed by adjuvant Durvalumab. 
 
12.3 
Sample Size and Accrual 
This sample size of the trial is a maximum of 25 evaluable patients. The sample size justification 
and rationale are described in Section 12.1. It is possible that not all patients may be evaluable 
for the pathologic complete response. If a patient is not evaluable, then the patient will be 
replaced. If 10% of the enrolled patients are not evaluable, then about 28 patients will need to be 
enrolled to satisfy the sample size requirement of 25 evaluable patients. Suppose that the accrual 
rate is 3 patients per months, then the trial can finish the accrual within 10 months.  
 
12.4 
Assessment of Safety 
All patients who receive one dose of treatment, regardless of whether they have surgery or not, 
will be evaluated for safety.  The Cancer Therapy Evaluation program (CTEP) Active Version 
(Version 5) of the NCI Common Terminology Criteria for Adverse Events (CTCAE) will be 
utilized for AE reporting.   
 
12.5 
Assessment of Efficacy 
All patients who have received concurrent Carboplatin/Paclitaxel/Durvalumab plus radiation 
therapy followed by surgical resection will be evaluable for the primary endpoint of pathologic 
complete response. The secondary point of 1-year PFS will be analyzed for those who were 
treated at least one dose of concurrent Carboplatin/Paclitaxel/Durvalumab plus radiation therapy.  
 
12.6 
Data Analysis Plans 
In general, parameter estimates and relevant summary statistics will be reported where 
appropriate. For continuous variables, summary statistics will include number of subjects, mean, 
median, standard deviation, minimum and maximum. Categorical endpoints will be summarized 
using number of subjects, frequency, and percentages. Missing data will not be imputed.  
 
12.6.1 Analysis Plans for Primary Objective 
The pathological complete response rate will be summarized and 95% confident interval will be 
calculated after adjusting for the two-stage nature of the study design. The details of the 
statistical methods for the inference for a two-stage design with binary response can be found in 
the following two papers:  
 
Jung SH and Kim KM. (2004). On the estimation of the binomial probability in multistage 
clinical trials. Statistics in Medicine 23, 881-896. 
 
Koyama T and Chen H. (2008). Proper inference from Simon's two-stage designs. Statistics in 
Medicine 27, 3145-3154. 
 
12.6.2 Analysis Plans for Secondary Objectives 
The pathological N0 rate will be summarized and 95% confident interval will be calculated after 
adjusting for the two-stage nature of the study design.  The details of the statistical methods for 
the inference for a two-stage design with binary response can be found in the following two 
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Jung SH and Kim KM. (2004). On the estimation of the binomial probability in multistage 
clinical trials. Statistics in Medicine 23, 881-896. 
 
Koyama T and Chen H. (2008). Proper inference from Simon's two-stage designs. Statistics in 
Medicine 27, 3145-3154. 
 
The method of Kaplan-Meier will be used to estimate and plot the progression-free survival 
(defined as the time from registration until disease progression or death from any cause). Patients 
who are alive without progressive disease at the time of analysis cut-off time will be censored at 
the date they were last assessed for disease status. One-year PFS will be estimated by the 
Kaplan-Meier method. 
 
12.6.3 Analysis Plans for Exploratory Objectives 
Data analysis for the correlative/exploratory objectives are mainly descriptive and exploratory. 
The association between tissue PD-L1 and tumor mutational burden with pathologic complete 
response and N0 rates will be tabulated and analyzed by the logistic regression. The association 
between tissue PD-L1 and tumor mutational burden with DFS will be analyzed by the Cox 
regression. The frequency of circulating tumor DNA at time of diagnosis, following surgery, and 
following treatment with adjuvant Durvalumab will be summarized and tabulated.  
 
12.6.4 Analysis Plans for Safety Data 
The analysis of the safety data will be descriptions. The toxicity events will be summarized and 
tabulated by patients and by events episodes.  
 
12.7 
Interim Analysis/Criteria for Stopping Study 
Because Simon's two-stage design will be used in this trial, a decision will be made at the end of 
the first stage based on the efficacy data, which serves effectively as an interim monitor for 
efficacy data. The stopping rule is described in Section 12.1. 
 
Additionally, a safety rule will be implemented in the first stage of the trial (for the first 12 
patients) as follows.  
 If there is an event of death, the study will be placed on hold until further evaluation of 
the reason of the patient death.  If it is determined that the patient death is unexpected and 
possibly related to durvalumab therapy (either in the induction phase or in the adjuvant 
phase), the study will be closed to further accrual. In the event the death is determined to 
be unlikely related to durvalumab in either the induction or adjuvant phase, the trial may 
continue to accrue.  
 The study will be stopped to further accrual if there are 2 or more deaths, regardless of 
the attribution.   
 The study will be stopped to further accrual if there are any unexpected, durvalumab-
related grade 4 toxicity in the 1st stage of the study (12 patients).  
 
When the study is determined to be stopped for further accrual, the study will be closed after the 
planned follow-up for the patients who have been already enrolled.  
 
 
 


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13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the Indiana University Melvin and Bren Simon 
Cancer Center’s (IUSCC) DSMP for Moderate Risk Trials. 
 
HCRN facilitated oversight activities for Moderate Risk Trials 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.  
 Investigators will conduct continuous review of data and patient safety. For any increase 
in frequency of grade 3 or above adverse events (above the rate reported in the Investigator 
Brochure), the sponsor investigator will notify HCRN who will notify the DSMC Chair 
and Compliance Officer immediately. The notification will include the incidence of study 
adverse events, grades, and attributions, as well as investigator statements regarding 
comparison with risks per the IB/package insert. 
 Notify participating sites of adverse events potentially requiring expedited reporting and 
subsequent DSMC recommendations for study modifications. 
 Coordinate monthly meetings which will include representation from each accruing site. 
o These meetings should include review of data, the number of subjects and significant 
toxicities as described in the protocol. HCRN should maintain meeting minutes and 
attendance for submission to the DSMC upon request. 
 Conduct data monitoring across all participating sites in accordance with the monitoring 
requirements set forth in the IUSCC DSMP. 
 
13.2 
Indiana University Data Safety Monitoring Committee 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of 
subject safety, regulatory compliance, and data integrity for this trial. The DSMC will review this 
study to assess toxicity, compliance, data integrity, and accrual per the Institutional DSMP. Trials 
managed by HCRN are not routinely audited or monitored by IUSCC; however, the IUSCC DSMC 
retains the right to audit HCRN trials on a for cause basis. 
 
The IUSCC DSMC will review study data annually during the active treatment and safety follow-
up portion of the trial, per the IUSCC DSMP.  
In preparation for the IUSCC DSMC review, HCRN will provide the following: 
 Monthly Summary Reports 
 Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary report (including serious adverse events) 
o Study accrual patterns 
o Protocol deviations 
 Audit and/or monitoring results, if applicable 
 Data related to stopping/ dose decision rules described in study design 
 HCRN monthly study meeting minutes/ attendance 
 


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Documentation of DSMC reviews will be provided to sponsor-investigator and HCRN. The 
IUSCC DSMC will notify the sponsor-investigator and other regulatory bodies, as appropriate, for 
issues of immediate concern. The sponsor-investigator will work with HCRN to address the 
DSMC’s concerns as appropriate. 
 
At any time during the conduct of the trial, if it is the opinion of the sponsor-investigator that the 
risks (or benefits) to the patient warrant early closure of the study, this recommendation should 
be made in writing to the DSMC Chair and Compliance Officer. Alternatively, the DSMC may 
initiate suspension or early closure of the study at any time based on its review of the study 
reports.   
 
13.3 
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.  
 
Participating sites may also be subject to quality assurance audits by AstraZeneca or its designee 
as well as inspection by appropriate regulatory agencies. 
 
13.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. Additional 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. 
 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
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.   
 
 
 


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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.  
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. 
 
 
 


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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.  
 
 
 


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16 REFERENCES 
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III Non-Small Cell Lung Cancer (NSCLC): Randomized phase III trial RTOG 9410. J 
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2. Antonia S, Villegas A, Daniel D., et al. Durvalumab after Chemoradiotherapy in Stage III 
Non–Small-Cell Lung Cancer; NEJM, 2017; 377:1919-1929. 
3. International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-Based 
Adjuvant Chemotherapy in Patients with Completely Resected Non-Small-Cell Lung 
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4. Douillard J, Rosell R, De Lena M et al. Adjuvant Vinorelbine plus Cisplatin versus 
Observation in Patients with Completely Resected Stage IB-IIIA Non-Small-Cell Lung 
Cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a Randomised 
Controlled Trial. Lancet Oncol 2006; 7(9): 719-27.   
5. Pignon J, Tribodet H, Scagliotti G, et al. Lung adjuvant cisplatin evaluation: a pooled 
analysis by the LACE Cooperative Group. J Clin Oncol 2008; 26(21): 3552-9. 
6. Scagliotti G, Pastorinio U, Vansteenkiste J., et al. Randomized Phase III Study of Surgery 
Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non-
Small Cell Lung Cancer. J Clin Oncol 2012;30(2):172-8.  
7. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small 
cell lung cancer: a systematic review and meta-analysis of individual participant data. 
Lancet 2014; 383:1561-71. 
8. Albain, K, Swann S, Rusch V, et al. Radiotherapy plus chemotherapy with or without 
surgical resection for stage III non-small-cell lung cancer: a phase III randomised 
controlled trial. Lancet; 2009; 374:379-86.  
9. Forde P, Chaft J, Smith K, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. 
NEJM 2018; 378:1976-86.  
10. Peters S, Ruysscher D, Dafni U, et al. Safety Evaluation of Nivolumab Added 
Concurrently to Radiotherapy in a Standard First-Line Chemo-RT Regimen in 
Unresectable Locally Advanced NSCLC: The ETOP NICOLAS Phase II Trial. J Clin 
Oncol 2018; 36(suppl; abstr 8510). 
11. Hanna N, Neubauer M, and Yiannoutsos C et al. Phase III study of cisplatin, etoposide, 
and concurrent radiation with or without consolidation docetaxel in patients with 
inoperable stage III non-small cell lung cancer: the Hoosier Oncology Group and U.S. 
Oncology. J Clin Oncol 2008;26:5755-5760.  
12. Durm G, Althouse S, and Sadiq A et al. Phase II trial of concurrent chemoradiation with 
consolidation pembrolizumab in patients with unresectable stage III non-small cell lung 
cancer: Hoosier Cancer Research Network LUN14-179. J Clin Oncol 2018; 36(suppl: 
abstr 8500). 
13. Antonia S, Villegas A, and Daniel D et al. Durvalumab after chemoradiotherapy in stage 
III non-small cell lung cancer. NEJM 2017;377:1919-29.  
14. 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. 
15. Goldstraw, JTO 2015, vol 11 39-51. 
 
 


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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 –  
17 November 2020  
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 treatment-emergent 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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Pediatric Considerations Regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks of initiating corticosteroids.  
− 
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended. 
− 
The recommendations for steroid dosing (i.e., mg/kg/day) provided for adult 
patients should also be used for pediatric patients. 
− 
The recommendations for IVIG and plasmapheresis use provided for adult 
patients may be considered for pediatric patients. 
− 
The infliximab 5 mg/kg IV one time dose recommended for adults is the 
same as recommended for pediatric patients ≥ 6 years old. For subsequent 
dosing and dosing in children < 6 years old, consult a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult a pediatric specialist. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring. 
 


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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 worsens, then treat as 
Grade 3 or Grade 4. 
 
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. 
− 
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. 
− 
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 


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be repeated at 2 and 6 weeks after initial dose at the 
discretion of the treating provider). Caution: It is 
important to rule out sepsis and refer to infliximab 
label for general guidance before using infliximab. 
Consider, as necessary, discussing with study 
physician. 
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 study physician, as needed. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
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). Caution: rule out 
sepsis and refer to infliximab label for general 
guidance before using infliximab. 
Diarrhea/Colitis 
 
 
 
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). 
− 
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.


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− 
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.  
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
 
No dose modifications. 
For Grade 1 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., 
American Dietetic Association colitis diet), 
loperamide, and other supportive care measures.  
− 
If symptoms persist,consider checking lactoferrin; if 
positive, treat as Grade 2 below. If negative and no 
infection, continue Grade 1 management. 
Grade 2 
 
Hold study drug/study regimen until 
resolution to Grade ≤1 
 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
 
If toxicity improves to Grade 
≤1, then study drug/study 
regimen can be resumed after 
completion of steroid taper. 
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. a Caution: it 
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using 
infliximab. 
− 
Consider, as necessary, discussing with study 
physician if no resolution to Grade ≤1 in 3 to 4 days. 


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Grade 3 or 4 
 
 
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  
Permanently discontinue  
study drug/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). 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 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General 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 dose modifications. 
 
If it worsens, then treat as Grade 
2. 
For Grade 1 
− 
Continue LFT monitoring per protocol. 


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Infliximab should not be used 
for management of immune-
related hepatitis. 
 
Grade 2 
 
 
Hold study drug/study regimen 
dose until Grade 2 resolution to 
Grade ≤1. 
 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
 
If toxicity improves to Grade ≤1 
or baseline, resume study 
drug/study regimen after 
completion of steroid taper. 
 
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 
For Grade 2 
− 
Regular and frequent checking of LFTs (e.g., every 1 
to 2 days) until LFT elevations improve or resolve. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, consider 
discussing with study physician, as needed. 
− 
If event is persistent (>2 to 3 days) or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
Grade 3 or 4 
  
For Grade 3 
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN: 
 Hold study drug/study regimen 
dose until resolution to Grade 
≤1 or baseline 
 Resume study drug/study 
regimen if elevations 
downgrade to Grade ≤1 or 
baseline within 14 days and 
after completion of steroid 
taper. 
 Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to 
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). 
Discuss with study physician if mycophenolate is not 
available. Infliximab should NOT be used. 
− 
Perform Hepatology Consult, abdominal workup, and 
imaging as appropriate. 
 
 
 
 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 


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Grade ≤1 or baseline within 
14 days 
 
For elevations in transaminases 
>8 × ULN or elevations in 
bilirubin >5 × ULN, 
discontinue study drug/study 
regimen. 
 
For Grade 4 
Permanently discontinue study 
drug/study regimen. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis  
(elevated LFTs) 
Infliximab should not be used 
for management of immune-
related hepatitis.  
See instructions at  
bottom of shaded area  
if transaminase rise is  
not isolated but (at any time) 
occurs in setting  
of either increasing bilirubin 
Any Elevations of AST, ALT, or 
TB as Described Below 
 
General Guidance 
 
For Any Elevations Described 
− 
Monitor and evaluate liver function test: AST, ALT, 
ALP, and TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, 
disease progression, concomitant medications, 
worsening of liver cirrhosis [e.g., portal vein 
thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral 
load, quantitative HBsAg, or HBeAg. 
− 
For HCV+ patients: evaluate quantitative HCV viral 
load. 
− 
Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or starting 
antiviral HBV medications if HBV viral load is >2000 
IU/ml. 
− 
Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or starting 
antiviral HCV medications if HCV viral load has 
increased by ≥2-fold. 
− 
For HCV+ with HBcAb+: Evaluate for both HBV and 
HCV as above. 
 
 
No dose modifications. 
 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients  


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or signs of DILI/liver 
decompensation 
 Isolated AST or ALT >ULN and 
≤5.0×ULN, whether normal or 
elevated at baseline  
 
If ALT/AST elevations 
represents significant worsening 
based on investigator 
assessment, then treat as  
described for elevations in the 
row below. 
 
For all  transaminase elevations 
, see instructions at bottom of 
shaded area if transaminase rise 
is not isolated but (at any time) 
occurs in setting of either 
increasing bilirubin or signs 
of DILI/liver decompensation
 
 Isolated AST or ALT >5.0×ULN 
and ≤8.0×ULN, if normal at 
baseline 
 
Isolated AST or ALT 
>2.0×baseline and ≤12.5×ULN, if 
elevated >ULN at baseline 
 
Hold study drug/study regimen 
dose until  resolution to AST or 
ALT ≤5.0×ULN . 
 
If toxicity worsens, then treat as  
described for elevations in the 
rows below.If toxicity improves 
to  AST or ALT ≤5.0×ULN , 
resume study drug/study 
regimen after completion of 
steroid taper. 
 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria, in 
the absence of any alternative 
cause.b 
− 
Regular and frequent checking of LFTs (e.g., every 1 
to 3 days) until elevations of these are improving or 
resolved. 
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver 
perfusion. 
− 
Consider, as necessary, discussing with study 
physician. 
− 
If event is persistent (>2 to 3 days) or worsens, and 
investigator suspects toxicity to be an imAE, start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 2 to 3 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup. If still no improvement 
within 2 to 3 days despite 2mg/kg/day of IV 
methylprednisolone, consider additional abdominal 
workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting 
immunosuppressants (e.g.,., mycophenolate mofetil 
0.5 – 1 g every 12 hours then taper in consultation 
with hepatology consult).a Discuss with study 
physician if mycophenolate mofetil is not available. 


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Infliximab should NOT be used. 
 
 Isolated AST or ALT >8.0×ULN 
and ≤20.0×ULN, if normal at 
baseline 
 
Isolated AST or ALT >12.5×ULN 
and ≤20.0×ULN, if  elevated 
>ULN at baseline 
 Hold study drug/study regimen 
dose until resolution to  AST or 
ALT ≤5.0×ULN Resume study 
drug/study regimen if elevations 
downgrade to  AST or ALT 
≤5.0×ULN  within 14 days and 
after completion of steroid 
taper. 
 Permanently discontinue study 
drug/study regimen if the 
elevations do not downgrade to  
AST or ALT ≤5.0×ULN within 
14 days 
 
− 
Regular and frequent checking of LFTs (e.g., every 1-
2 days) until elevations of these are improving or 
resolved. 
− 
Consult hepatologist (unless investigator is 
hepatologist); obtain abdominal ultrasound, including 
Doppler assessment of liver perfusion; and consider 
liver biopsy. 
− 
Consider discussing with study physician, as needed. 
− 
If investigator suspects toxicity to be immune-
mediated, promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or equivalent. 
− 
If no improvement within 2 to 3 days despite 1 to 
2 mg/kg/day methylprednisolone IV or equivalent, 
obtain liver biopsy (if it has not been done already) 
and promptly start treatment with an 
immunosuppressant (e.g.,., mycophenolate mofetil 0.5 
– 1 g every 12 hours then taper in consultation with a 
hepatologist). Discuss with study physician if 
mycophenolate is not available. Infliximab should 
NOT be used. 
 Isolated AST or ALT >20×ULN,  
whether normal or elevated at 
baseline 
Permanently discontinue study 
drug/study regimen. 
 
Same as above  
(except would recommend obtaining liver biopsy early) 
 
 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if 
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase rise 
- 
For example, manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT 
>2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and 
≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
 


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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 worsens, then treat as 
Grade 3 or 4. 
 
If toxicity improves to Grade ≤1 
or baseline, then resume study 
drug/study regimen after 
completion of steroid taper. 
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. 
− 
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 


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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). 
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 
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, 


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drug/study regimen after 
completion of steroid taper. 
consider discussing with study physician, 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 
 
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. 
 
If toxicity worsens, then treat as 
Grade 4. 
   
 
For Grade 4 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as 
clinically feasible. Consider, as necessary, discussing 
with study physician. 
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 study physician, 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. 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression 
including brain metastases, or infections). 


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− 
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). 
− 
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. 
Grade 2, 3, or 4 
 
For Grade 2-4  
endocrinopathies other than 
hypothyroidism and type 1 
diabetes mellitus, consider 
holding study drug/study 
regimen dose until acute 
symptoms resolve. 
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 


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 
Study drug/study regimen can 
be resumed once patient 
stabilizes and after completion 
of steroid taper. 
 
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. 
 
If toxicity worsens, then treat 
based on severity. 
 
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 pancreatitis  
− 
Consider appropriate diagnostic testing (e.g., 
abdominal CT with contrast, MRCP if clinical 
suspicion of pancreatitis and no radiologic evidence 
on CT) 
− 
If isolated elevation of enzymes without evidence of 
pancreatitis, continue immunotherapy.  Consider 
other causes of elevated amylase/lipase 
− 
If evidence of pancreatitis, manage according to 
pancreatitis recommendations  
 
Grade 1 
No dose modifications. 
 
Grade 2, 3, or 4 
For Grade 2, 3, or 4 
In consultation with relevant 
pancreatic specialist consider 
continuing study drug/study 
regimen if no clinical/radiologic 
evidence of pancreatitis ± 
improvement in amylase/lipase. 
Acute Pancreatitis 
Any Grade 
General Guidance 
For Any Grade 
− 
Consider Gastroenterology referral  


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(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
 
Grade 1 
No dose modifications. 
For Grade 1 
− 
IV hydration 
− 
Manage as per amylase/lipase increased 
(asymptomatic) 
 
Grade 2, 3, or 4 
For Grade 2 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
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 Guillain-Barre) 
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. 
− 
FOR TRANSVERSE MYELITIS, 
PERMANENTLY DISCONTINUE FOR ANY 
GRADE. 
 
 
Grade 1 
No dose modifications. 
For Grade 1 
− 
See “Any Grade” recommendations above. 


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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. 
 
If toxicity worsens, then treat as 
Grade 3 or 4. 
For Grade 2 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
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 study 
physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 2 to 3 days despite IV 
corticosteroids, consider additional workup and 
promptly treat with an additional immunosuppressant 
(e.g., IV IG or other immunosuppressant depending 
on the specific imAE). 
− 
Once stable, gradually taper steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre and 
myasthenia gravis) 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the 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 


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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 
− 
Consider discussing with the study physician, 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 
For Grade 2 
− 
Consider discussing with the study physician, as 
needed. 
− 
Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 


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or if there are signs of respiratory 
insufficiency or autonomic 
instability. 
− 
Consult a neurologist. 
− 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., gabapentin 
or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. It is important to 
consider that steroid therapy (especially 
with high doses) may result in transient 
worsening of myasthenia and should 
typically be administered in a monitored 
setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with 
plasmapheresis or IV IG. Such decisions are 
best made in consultation with a 
neurologist, taking into account the unique 
needs of each patient. 
o 
If myasthenia gravis-like neurotoxicity is 
present, consider starting AChE inhibitor 
therapy in addition to steroids. Such 
therapy, if successful, can also serve to 
reinforce the diagnosis. 
o 
Avoid medications that can worsen 
myasthenia gravis. 
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. 
Grade 3 or 4 
For Grade 3 
 
Hold study drug/study regimen 
dose until resolution to Grade 
≤1. 
For Grade 3 or 4  
− 
Consider discussing with study physician, as needed. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and consult a neurologist. 
MYASTHENIA GRAVIS: 


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 
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. 
o 
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with 
plasmapheresis or IV IG. 
o 
If myasthenia gravis-like neurotoxicity 
present, consider starting AChE inhibitor 
therapy in addition to steroids. Such 
therapy, if successful, can also serve to 
reinforce the diagnosis. 
o 
Avoid medications that can worsen 
myasthenia gravis. 
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. 
 
Myocarditis 
Any Grade 
(Refer to NCI CTCAE applicable 
version in study protocol for 
defining the CTC grade/severity) 
General Guidance 
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis. 
For Any Grade 
− 
The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in patients with 
baseline cardiopulmonary disease and reduced cardiac 
function.  
− 
Consider discussing with the study physician, 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 
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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. 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
other medications, or infections) 
 
Grade 1 
 
No dose modifications required 
unless clinical suspicion is high, in 
which case hold study drug/study 
regimen dose during diagnostic 
work-up for other etiologies. If 
study drug/study regimen is held, 
resume after complete resolution to 
Grade 0. 
For Grade 1  
- 
Monitor and closely follow up in 2 to 4 days for 
clinical symptoms,  BNP, cardiac enzymes, ECG, 
ECHO, pulse oximetry (resting and exertion), and 
laboratory work-up as clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 
 
Grade 2, 3 or 4 
 
 
 
 
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. 
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). 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. 


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 
If Grade 3-4, permanently 
discontinue study drug/study 
regimen. 
 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. 
− 
If poly/myositis is suspected, a Neurology 
consultation should be obtained early, with prompt 
guidance on diagnostic procedures. Myocarditis may 
co-occur with poly/myositis; refer to guidance under 
Myocarditis. Given breathing complications, refer to 
guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously 
unknown) autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study 
physician. 
− 
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 
work-up as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider whether 
a rheumatologist consultation is indicated and could 
guide need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase [such as 
anti-Jo-1], and/or signal-recognition particle 
antibodies). Confirmatory testing may include 
electromyography, nerve conduction studies, MRI of 
the muscles, and/or a muscle biopsy. Consider 
Barium swallow for evaluation of dysphagia or 
dysphonia. 


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− 
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 study 
physician. 
 
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 study 
physician. 
− 
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). 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab. 
 
Grade 3 or 4 
 
For Grade 3 
For Grade 3 or 4  
− 
Monitor symptoms closely; recommend 
hospitalization. 


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aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
cNCCN Clinical Practice Guidelines in Oncology “Management of Immunotherapy-Related Toxicities” Version 1.2020 – December  2019  
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; 
BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  
National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); 
PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 
 
 
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. 
− 
Obtain Neurology consult 
− 
Consider discussing with the study physician, 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). 
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. 


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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 study physician may be contacted for immune-mediated 
reactions not listed in the “specific immune-mediated 
reactions” section 
− 
Thorough evaluation to rule out any alternative etiology 
(e.g., disease progression, concomitant medications, and 
infections) 
− 
Consultation with relevant specialist 
− 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Monitor as clinically indicated 
Grade 2 
 
Hold study drug/study regimen until resolution to 
≤Grade 1 or baseline. 
 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
 
Study drug/study regimen can be resumed once event 
stabilizes to Grade ≤1 after completion of steroid 
taper. 
 
Consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality when they 
do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper 
For Grade 2, 3, or 4 
Treat accordingly, as per institutional standard, appropriate 
clinical practice guidelines, and other society guidelines 
(e.g., NCCN, ESMO)  
Grade 3 
Hold study drug/study regimen  
Grade 4 
 
Permanently discontinue study drug/study regimen  
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 


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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 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and famotidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 
 
 


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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 resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
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 Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.