Clinical trial NCT03102242
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Alliance Foundation Trials, LLC.
Start date: 2017-11-01; Completion date: 2022-10-01
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase II trial of induction immunotherapy with atezolizumab for patients with unresectable stage IIIA and IIIB NSCLC eligible for chemoradiotherapy with curative intent.

Detailed description:
This phase II pilot trial will combine neoadjuvant immunotherapy with Atezolizumab q 21 days for 12 weeks with standard chemoradiotherapy with curative intent for good PS patients with unresectable stage IIIA/B NSCLC. Because of the consequences of progression in this curative-intent population, restaging CT scans will be carried out after the first 2 cycles of neoadjuvant therapy. Non progressing patients will complete a total of one year of anti-PDL1 therapy with an interruption during chemoradiotherapy. Patients with evidence of progression at the first restaging evaluation will proceed immediately to chemoradiotherapy if still eligible for curative intent therapy.

Arms: arm 1: Induction immunotherapy: atezolizumab 1200 mg IV q 21 days x 4 cycles. Restaging after cycle 2 and cycle 4 induction: patients with progression of disease (PD) at the post-cycle 2 assessment will stop atezolizumab and go immediately to chemoradiotherapy if still stage III and eligible for curative intent therapy.

Chemoradiotherapy: carboplatin AUC = 2 + paclitaxel 50 mg/m2 IV weekly x 6 weeks concurrent with radiation to a total dose of 60 Gy given in 2 Gy fractions daily M-F x 30 fractions

Consolidation chemotherapy: Carboplatin AUC = 6 + paclitaxel 200 mg/m2 IV q 21 days x 2 cycles beginning 3-5 weeks after completion of radiation.

Adjuvant immunotherapy: atezolizumab 1200 mg IV q 21 days to complete one year of therapy (from start of induction).
Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Single arm phase II trial of induction immunotherapy with anti-PD-L1 for patients with unresectable stage III NSCLC and PS 0-1.

Protocol documents:
Prot_SAP_000.pdf: 
                                                                                                    
 
 
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ALLIANCE FOUNDATION TRIALS (AFT)  
 
 
PROTOCOL NUMBER 
AFT – 16 
 
 
Protocol title 
Phase II trial of induction immunotherapy with atezolizumab for patients with unresectable stage IIIA and 
IIIB NSCLC (AJCC 7th Edition) eligible for chemoradiotherapy with curative intent. 
 
 
Protocol Version:  
Protocol Version Date: 08-19-2019 
 
Investigational Product: Atezolizumab 
IND Sponsor: AFT 
 
ClinicalTrials.gov Identifier: NCT03102242 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Principal Investigator 
 
 
 


                                                                                                    
 
 
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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title: Phase II trial of induction immunotherapy with atezolizumab for patients with unresectable 
stage IIIA or IIIB NSCLC (AJCC 7th Edition) eligible for chemoradiotherapy with curative 
intent. 
 
 
 
 
 
 
Protocol Number: 
 
AFT-16 
 
 
 
 
 
 
 
US Sponsor Name: 
Alliance Foundation Trials (AFT), LLC 
 
 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the described 
trial in compliance with all stipulations of the protocol, all applicable regulations, ICH Good Clinical 
Practice (GCP) and Declaration of Helsinki. 
 
 
 
------------------------------------------------- 
 
 
 
-------------------------------------- 
First Name, Last Name  
 
 
 
 
 
Date, Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                                                                    
 
 
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I. 
Synopsis 
 
Study Title 
Phase II trial of induction immunotherapy with atezolizumab for 
patients with unresectable stage IIIA or IIIB NSCLC (AJCC 7th 
Edition) eligible for chemoradiotherapy with curative intent 
Study Number 
AFT-16 
Study Type/Phase 
Phase II 
Clinical Indication 
Stage III NSCLC eligible for chemoradiotherapy with curative 
intent 
ClinicalTrials.gov Identifier 
NCT03102242 
IND Number 
N/A 
Number of Trial Patients 
63 
Estimated Duration of Trial 
3 years 
Rationale 
Lung cancer remains the leading cause of cancer death in the US. 
While advances in diagnosis and treatment have improved 
survival, these improvements have been gradual and the overall 
case fatality rate remains greater than 80%. Most US patients are 
diagnosed with locally advanced or advanced disease with an 
estimated more than 40,000 cases per year of stage III NSCLC.   
 
These patients are of particular interest in that they can be treated 
with curative intent although only approximately 25% will be 
cured by conventional chemoradiotherapy.  Their generally better 
health compared to patients with metastatic NSCLC makes these 
patients ideal candidates for an immunologic approach. The 
combination of checkpoint inhibition to counter tumor related 
immunosuppression along with standard chemoradiotherapy that 
depletes T-regulatory cells might create immunologic “space” to 
facilitate clonal expansion of effector T-cells in an environment 
that has potentially improved tumor immunogenicity by blocking 
PD-L1. Further, both chemotherapy and radiation may expose 
otherwise hidden antigens that can present additional targets to the 
reconstituting immune system.  
 
Immunotherapy has come to the forefront of promising new 
modalities of care over the past few years. Immunotherapies have 


                                                                                                    
 
 
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been successful enough in melanoma that several drugs are now 
FDA approved in this disease.  Similar strategies have shown 
promise in advanced NSCLC and checkpoint inhibitors targeting 
PD-1 and PD-L1 are of particular interest given their apparently 
manageable toxicity and the long response durations that have 
been seen in early clinical trials.i, ii 
Nivolumab and atezolizumab are FDA approved in second line 
therapy for metastatic squamous and non-squamous lung cancer 
based on the activity seen in the Checkmate 017 and 057 trials and 
the POPLAR and OAK trials.iii 
 
Pembrolizumab is approved for patients with metastatic NSCLC 
progressing after initial platinum based chemotherapy and whose 
tumors express PD-L1 based on the Keynote clinical trials. It is 
also approved for front-line therapy in high PD-L1 expressers. 
Expanded approvals of several immune agents in locally advanced 
and metastatic NSCLC are occurring rapidly.  
 
PD-1 is a T-cell co-receptor found on activated T-cells. Some 
tumors, including a substantial minority of NSCLC, seem to be 
able to exploit this receptor through expression of the inhibitory 
PD-L1 ligands whose interaction with PD-1 can suppress the 
antitumor immune response. Expression of PD-L1 within lung 
cancers is thought to contribute to activated T-cell down-
regulation and to the immunosuppressed state of lung cancer 
patients.i 
 
Initial trials in advanced lung cancer patients have reported 
response rates in the 20% range overall but with response 
durations that can be significantly longer than would be expected 
with chemotherapy. Many studies suggest that response correlates 
with degree of PD-L1 expression, but optimal biomarkers are not 
yet known and some non-expressers have responded well. Despite 
the clinical uncertainties, the checkpoint inhibition strategy is 
promising and is particularly attractive in patients with the 
possibility of cure such as those with stage III NSCLC in whom 
reversal of cancer mediated immunosuppression might reasonably 
be hoped to improve long-term survival rates. 
 
An estimated 30-50% of late-stage NSCLC patients may express 
PD-L1. Preclinical data suggest that an even higher percentage of 
tumors from stage III patients are PD-L1 positive (Genentech 
personal communication), hence these patients are likely to be the 
best candidates for neoadjuvant trials of checkpoint inhibition. 
This trial is intended to lead directly into a phase III trial of 
neoadjuvant 
atezolizumab 
followed 
by 
combined 
chemoradiotherapy/immunotherapy 
compared 
to 
chemoradiotherapy followed by adjuvant immunotherapy. 
 


                                                                                                    
 
 
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Radiotherapy can affect host immune response and impact tumor 
control and spread.  In preclinical studies, Formenti and colleagues 
demonstrated that the abscopal effect of radiotherapy is, in part, 
immune mediated and that T cells are required for regression of 
distant metastases after radiotherapy.  Lee and Weichselbaum 
demonstrated that CD-8+ T cells are required for distant 
radiotherapy effects.  Radiation therapy (RT) can increase tumor 
expression of PD-L1, and combined RT plus PD-1-pathway 
targeting results in synergistic decrease in suppressor T-cells, 
thereby promoting anti-tumor immunity.  These pre-clinical data 
combined with recent case reports of immune checkpoint inhibitor 
mediated abscopal effects provide support for a trial combining 
anti-PD-L1 therapy with atezolizumab before and after definitive 
chemoradiotherapy. 
 
Primary Objective 
Determine the disease control rate (DCR) of neoadjuvant 
atezolizumab therapy in the study population. 
 
The goal of the primary objective of the phase II trial is to 
determine whether neoadjuvant anti-PDL-1 therapy with 
atezolizumab is worthy of further investigation in the target 
population. 
 
The primary endpoint will test the disease control rate (DCR), i.e., 
the rate of complete/partial response and stable disease, in 
response to neoadjuvant atezolizumab. If the disease control rate 
after neoadjuvant therapy is high, and in the absence of clinically 
significant toxicity, further study of this approach in locally 
advanced NSCLC will be merited. 
 
Secondary Objectives  
Determine progression-free survival (PFS) after neoadjuvant 
atezolizumab therapy followed by standard chemoradiotherapy, 
consolidation and adjuvant atezolizumab in the study population. 
 
Evaluate safety of neoadjuvant atezolizumab therapy combined 
with 
standard 
chemoradiotherapy 
followed 
by 
adjuvant 
atezolizumab. 
 
Determine response rates (RR) to neoadjuvant atezolizumab and 
to the overall treatment regimen. 
 
Determine overall survival (OS) at 12 and 18 months.  
 
Translational Science Objectives 
 
Principal: Define the role of PD-L1 biomarker testing in selecting 
the population most likely to respond to neoadjuvant and adjuvant 
immunotherapy together with standard chemoradiotherapy. 
 
Additional: Study the association of biomarkers, including 
immunologic signatures, and outcomes. Analyses may include, 


                                                                                                    
 
 
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but are not limited to, multipanel immunohistochemistry, gene 
expression profiling by Nanostring, RNAseq or RT-PCR, whole 
exome and T cell receptor sequencing, cytokine/chemokine 
analysis, flow cytometry, and T cell function analysis. Specimens 
will include blood, serum, whole blood/plasma for additional 
evaluation of circulating tumor DNA (ctDNA), and FFPE tissue.  
Other Correlative Sciences 
Objectives 
Quality of life endpoints will be assessed during induction 
atezolizumab, during chemoradiotherapy, and during adjuvant 
atezolizumab at 3 month intervals and will be measured by the 
EORTC QLQ-30. 
 
Trial Design and Schema 
Induction immunotherapy: atezolizumab 1200 mg IV q 21 days x 
4 cycles. 
Restaging after cycle 2 and cycle 4 induction: patients with 
progression of disease (PD) at the post-cycle 2 assessment will 
stop atezolizumab and go immediately to chemoradiotherapy if 
still stage III and eligible for curative intent therapy. Subjects may 
remain on study despite proceeding directly to chemoradiotherapy 
due to PD on restaging after cycle 2 induction if, in the 
investigator’s view, the subject may benefit clinically. 
Chemoradiotherapy: carboplatin AUC = 2 + paclitaxel 50 mg/m2 
IV weekly x 6 weeks concurrent with radiation to a total dose of 
60 Gy given in 2 Gy fractions daily M-F x 30 fractions 
Consolidation chemotherapy: Carboplatin AUC = 6 + paclitaxel 
200 mg/m2 IV q 21 days x 2 cycles beginning 3-5 weeks after 
completion of radiation.  
Adjuvant immunotherapy: atezolizumab 1200 mg IV q 21 days to 
complete one year of therapy (from start of induction).   
If, as anticipated, this study leads into a phase III trial, the 
comparator arm will be standard chemoradiotherapy followed by 
immunotherapy.  
 
Study Design: 
This phase II trial will combine neoadjuvant immunotherapy with 
atezolizumab q 21 days for 12 weeks followed by standard 
chemoradiotherapy with curative intent for good PS patients with 
unresectable stage IIIA/B NSCLC. Because of the consequences 
of progression in this curative-intent population, restaging CT 
scans will be obtained after the first 2 cycles of neoadjuvant 
therapy. Real-time monitoring will be used to provide reassurance 
that there is not an unacceptable rate of early PD in PD-L1 
negative patients. Non-progressing patients will complete a total 
of one year of anti-PD-L1 therapy with an interruption during 
chemoradiotherapy.  
 
Assumptions include:  
• 
DCR of at least 70% with neoadjuvant immunotherapy,  
• 
That 85% of the study population will complete radiation,  


                                                                                                    
 
 
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• 
That 60% of the study population will complete the entire 
treatment course including consolidation chemotherapy 
and adjuvant immunotherapy with atezolizumab.  
 
If the pilot study reaches its preplanned endpoints, a randomized 
phase III trial is planned in which patients will be randomized 2:1 
to 
neoadjuvant 
immunotherapy 
followed 
by 
chemoradioimmunotherapy and adjuvant immunotherapy vs 
standard chemoradiotherapy and adjuvant immunotherapy.  
 
A key component of the successful completion of this study will 
be quality assurance of the radiotherapy delivery.  Augmentation 
of the immune system by immune checkpoint inhibition has the 
potential to increase risk of pulmonary, cardiac and esophageal 
toxicity.  Data on the use of PD-1/PD-L1 pathway agents in 
sequence with radiotherapy are limited.  Out of 129 patients with 
NSCLC on a phase I trial for the PD-1 inhibitor nivolumab, 75 
(58%) had previously received RT although the site of RT, dosing 
parameters and timing are not known.  Out of the 129 NSCLC 
cases, there were 9 cases of pneumonitis (7.0%) and 3 cases of 
grade 3-4 pneumonitis (2.3%). There is some suggestion from 
early trials that the risk of pneumonitis may be less with 
atezolizumab than previously seen with nivolumab.  Recent trials 
of the anti-PD-L1 BMS agent 936559 reported no cases of 
pneumonitis. However, given the possibility that the immune 
mediated risk of pneumonitis could be higher in a lung cancer 
population being treated with definitive thoracic radiotherapy, 
tight quality control through the cooperative group process will be 
critical.  In multiple datasets, the quality of radiotherapy has been 
integral to the outcome in combined modality therapy trials. 
  
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
1) Newly diagnosed stage IIIA/B (per AJCC 7) 
NSCLC, PS 0-1.  
2) No active autoimmune disease or uncontrolled 
infection; normal bone marrow, renal, hepatic 
function; FEV1 ≥ 1.2L; no significant 
underlying heart or lung disease. 
3) Pathologically proven diagnosis of NSCLC. 
4) Measurable Stage IIIA or IIIB disease per AJCC 
7. 
5) Patients must be considered unresectable or 
inoperable. Patients with nodal recurrence after 
surgery for early-stage NSCLC are eligible if 
the following criteria are met: 


                                                                                                    
 
 
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• 
No prior chemotherapy or radiation for this 
lung cancer. 
• 
Prior curative-intent surgery at least 3 
months prior to the nodal recurrence. 
6) Stage III A or B disease (per AJCC 7) with 
minimum diagnostic evaluation within 6 weeks 
to include: 
• 
History/physical examination 
• 
Contrast enhanced CT of the chest and 
upper abdomen  
• 
MRI of the brain with contrast (or CT with 
contrast 
if 
MRI 
is 
medically 
contraindicated) 
• 
PET/CT 
7)  If pleural fluid is visible on CT scan 
thoracentesis to exclude malignancy should be 
obtained. Patients with effusions that are too 
small to tap are eligible. 
8) Patients must be at least 4 weeks from major 
surgery and must be fully recovered. 
9) Age ≥ 18 years. 
10) Availability of representative formalin-fixed 
paraffin-embedded (FFPE) tumor specimens in 
paraffin blocks (blocks are preferred) or at least 
4 (preferably 20) unstained slides, with an 
associated pathology report, for central testing 
of tumor PD-L1 expression. 
• 
If an archived tumor block exists, then 
either the block (preferred) or at least 4 
(preferably 20) unstained slides from the 
block should be submitted. Tumor tissue 
should be of good quality based on total 
and viable tumor content, i.e. at least 50 
viable tumor cells and intact tissue 
architecture.  Fine-needle aspiration, 
brushing, and lavage samples are not 
acceptable.  If the block is tissue from a 
core-needle biopsy, then the block should 


                                                                                                    
 
 
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contain tissue from at least three cores to 
be sufficient for evaluation.   
• 
Patients who do not have existing 
(archived) tissue specimens meeting 
eligibility requirements may undergo a 
biopsy during the screening period.  
Acceptable samples include core-needle 
biopsies for deep tumor tissue (minimum 
of three cores) or excisional, or forceps 
biopsies for endobronchial or nodal 
lesions. The tissue should be fixed in 
formalin and embedded on site and sent 
as a block. 
11) Adequate hematologic and end organ function, 
defined by the following laboratory results 
obtained within 14 days prior to the first study 
treatment (Cycle 1, Day 1; if repeat labs are 
obtained on or prior to C1D1 they must re-meet 
eligibility criteria to treat the subject): 
• 
ANC ≥ 1500 cells/µL 
• 
WBC counts > 2500/µL 
• 
Lymphocyte count ≥ 300/µL 
• 
Platelet count ≥ 100,000/µL  
• 
Hemoglobin ≥ 10.0 g/dL 
• 
Total bilirubin ≤ 1.5 × upper limit of 
normal (ULN) with the following 
exception:  
­ 
Patients with known Gilbert disease 
who 
have 
serum 
bilirubin 
level ≤ 3 × ULN may be enrolled. 
• 
AST and ALT ≤ 3.0 × ULN  
• 
Alkaline phosphatase ≤ 2.5 × ULN  
• 
Serum 
creatinine 
≤ 1.5 × ULN 
or 
creatinine clearance ≥ 50 mL/min on the 
basis of the Cockcroft-Gault glomerular 
filtration rate estimation: 
­ 
(140 − age) × (weight in kg) × (0.85 
if 
 
female) 
72 × (serum creatinine in mg/dL) 


                                                                                                    
 
 
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12) Measurable disease per RECIST v1.1 (see 
Appendix 3). 
13) For female patients of childbearing potential 
and male patients with partners of childbearing 
potential, agreement (by patient and/or partner) 
to use highly effective form(s) of contraception 
(i.e., one that results in a low failure rate [< 1% 
per year] when used consistently and correctly, 
such as hormonal or barrier method of birth 
control, or abstinence) and to continue its use 
for 150 days after the last dose of atezolizumab. 
14) Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0 or 1 (see Appendix 5). 
 
Exclusion Criteria 
General Exclusion Criteria: 
1) Active autoimmune disease. 
2) Greater 
than 
minimal, 
exudative, 
or 
cytologically positive pleural effusions. 
3) Involved contralateral hilar nodes. 
4) 10% weight loss within the past month. 
5) Prior invasive malignancy (except non-
melanomatous skin cancer) unless disease free 
for a minimum of 3 years; non-invasive 
conditions such as carcinoma in situ of the 
breast, localized prostate cancer or thyroid 
nodules, carcinoma in situ of the oral cavity or 
cervix are all permissible. 
6) Prior systemic chemotherapy for the study 
cancer; note that prior chemotherapy for a 
different cancer is allowable. 
7) Prior radiotherapy to the region of the study 
cancer that would result in overlap of radiation 
therapy fields. 
8) Prior severe infusion reaction to a monoclonal 
antibody. 
9) Severe, active co-morbidity, defined as follows: 
10) Significant history of uncontrolled cardiac 
disease; 
i.e., 
uncontrolled 
hypertension, 
unstable angina, myocardial infarction within 
the last 6 months, uncontrolled congestive heart 
failure, and cardiomyopathy with decreased 
ejection fraction. 


                                                                                                    
 
 
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11) Acute bacterial or fungal infection requiring 
intravenous 
antibiotics 
at 
the 
time 
of 
registration or within 2 weeks of cycle 1 day 1. 
Chronic 
Obstructive 
Pulmonary 
Disease 
exacerbation or other respiratory illness 
requiring hospitalization or precluding study 
therapy within 30 days before registration. 
12) Hepatic insufficiency resulting in clinical 
jaundice and/or coagulation defects. 
13) Acquired 
Immune 
Deficiency 
Syndrome 
(AIDS) based upon current CDC definition; 
note, HIV testing is required for entry into this 
protocol due to the immunologic basis for 
induction treatment. 
14) Pregnancy, lactation or inability or unwillingness 
to 
use 
medically 
acceptable 
forms 
of 
contraception if pregnancy is a risk 
15) Any history of allergic reaction to paclitaxel or 
other taxanes, or to carboplatin 
16) Uncontrolled neuropathy grade 2 or greater 
regardless of cause 
17) Any approved anticancer therapy, including 
chemotherapy, 
hormonal therapy, 
or radiotherapy, within 3 weeks prior to 
initiation 
of 
study 
treatment; 
however, 
the following are allowed: 
i. Hormone-replacement therapy 
or oral contraceptives 
ii. Herbal therapy > 1 week prior 
to Cycle 1, Day 1 (herbal 
therapy intended as anticancer 
therapy must be discontinued 
at least 1 week prior to Cycle 1, 
Day 1) 
18) Known clinically significant liver disease, 
including active viral, alcoholic, or other 
hepatitis; cirrhosis; fatty liver; and inherited 
liver disease. 
19) Patients with past or resolved hepatitis B 
infection (defined as having a negative hepatitis 
B surface antigen [HBsAg] test and a positive 


                                                                                                    
 
 
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anti-HBc [antibody to hepatitis B core antigen] 
antibody test) are eligible 
20) Patients positive for hepatitis C virus (HCV) 
antibody are eligible only if polymerase chain 
reaction (PCR) is negative for HCV RNA. 
21) Known hypersensitivity to Chinese hamster 
ovary cell products or other recombinant human 
antibodies. 
22) Inability to comply with study and follow-up 
procedures. 
23) History 
of 
active 
autoimmune 
disease, 
including but not limited to systemic lupus 
erythematosus, 
rheumatoid 
arthritis, 
inflammatory 
bowel 
disease, 
vascular thrombosis 
associated 
with 
antiphospholipid 
syndrome, 
Wegener’s granulomatosis, 
Sjögren’s 
syndrome, 
Bell’s 
palsy, 
Guillain-Barré 
syndrome, multiple sclerosis, autoimmune 
thyroid 
disease, 
vasculitis, 
or 
glomerulonephritis. 
24) Patients with a history of autoimmune 
hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible 
25) Patients with controlled Type 1 diabetes 
mellitus on a stable insulin regimen may be 
eligible 
26) Patients with eczema, psoriasis, lichen simplex 
chronicus 
of 
vitiligo 
with 
dermatologic 
manifestations only (e.g., patients with psoriatic 
arthritis would be excluded) are permitted 
provided that they meet the following 
conditions: 
Patients with psoriasis must have a baseline 
ophthalmologic exam to rule out ocular 
manifestations. 
Rash must cover less than 10% of body surface 
area (BSA). 
Disease is well controlled at baseline and only 
requiring low potency topical steroids (e.g., 
hydrocortisone 2.5%, hydrocortisone butyrate 


                                                                                                    
 
 
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0.1%, fluocinolone 0.01%, desonide 0.05%, 
alclometasone dipropionate 0.05%). 
No acute exacerbations of underlying condition 
within the last 6 months (not requiring psoralen 
plus 
ultraviolet 
A 
radiation 
[PUVA], 
methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors; high potency or oral 
steroids). 
27) History of idiopathic pulmonary fibrosis, 
pneumonitis 
(including 
drug 
induced), 
organizing 
pneumonia 
(i.e., 
bronchiolitis 
obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on 
screening chest computed tomography (CT) 
scan. 
28) Any other diseases, metabolic dysfunction, 
physical examination finding, or clinical 
laboratory finding giving reasonable suspicion 
of a disease or condition that contraindicates the 
use of an investigational drug or that may affect 
the interpretation of the results or render the 
patient 
at 
high 
risk 
from 
treatment 
complications. 
29) Active tuberculosis. 
30) Major surgical procedure within 28 days prior 
to Cycle 1, Day 1 or anticipation of need for a 
major surgical procedure during the course of 
the study. 
31) Administration of a live, attenuated vaccine 
within 4 weeks before Cycle 1, Day 1 
or anticipation that such a live, attenuated 
vaccine will be required during the study. 
32) Patients must not receive live, attenuated 
influenza vaccine (e.g., FluMist) within 4 
weeks prior to Cycle 1, Day 1 or at any time 
during the study 
 
Medication-Related Exclusion Criteria: 
33) Prior treatment with anti−PD-1, or anti−PD-L1 
therapeutic 
antibody 
or pathway-targeting 
agents. 
34) Treatment with systemic immunostimulatory 
agents (including but not limited to interferon 


                                                                                                    
 
 
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[IFN]-α or interleukin [IL]-2) within 6 weeks or 
five half-lives of the drug (whichever is shorter) 
prior to Cycle 1, Day 1. 
35) Treatment with investigational agent within 4 
weeks prior to Cycle 1, Day 1 (or within 
five half-lives of the investigational product, 
whichever is longer). 
36) Treatment with systemic immunosuppressive 
medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, 
methotrexate, 
thalidomide, 
or 
anti-tumor 
necrosis factor [anti-TNF] agents) within 2 
weeks prior to Cycle 1, Day 1. 
37) Patients who have received acute, low-dose, 
systemic immunosuppressant medications (e.g., 
a one-time dose of dexamethasone for nausea) 
may be enrolled. 
38) The use of inhaled corticosteroids and 
mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or 
adrenocortical insufficiency is allowed. 
39) History of severe allergic, anaphylactic, or 
other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins. 
40) Patients with prior allogeneic bone marrow 
transplantation 
or 
prior 
solid 
organ 
transplantation. 
  


                                                                                                    
 
 
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Schema: 
 
 
 
 
 


                                                                                                    
 
 
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II. 
Table of Contents 
Protocol 
 
1. 
Background ......................................................................................................................................... 22 
1.1. 
Overview of Disease and Patient Population .............................................................................. 22 
1.2. 
Study Drug Mechanism of Action .............................................................................................. 23 
1.3. 
Preclinical Data ........................................................................................................................... 23 
1.4. 
Clinical Pharmacokinetics and Immunogenicity ........................................................................ 24 
1.5. 
Clinical Data ............................................................................................................................... 24 
1.6. 
Clinical Safety ............................................................................................................................. 27 
1.7. 
Study Design Rationale and Significance ................................................................................... 28 
2. 
Objectives ........................................................................................................................................... 31 
2.1. 
Primary Objective ....................................................................................................................... 31 
2.2. 
Secondary Objectives .................................................................................................................. 31 
2.3. 
Translational Science Principal Objective .................................................................................. 31 
2.4. 
Translational Science Additional Objectives .............................................................................. 31 
2.5. 
Other Correlative Science Objectives ......................................................................................... 32 
2.6. 
Study Design ............................................................................................................................... 32 
2.7. 
Sample Size ................................................................................................................................. 32 
2.8. 
Accrual Rate and Accrual Duration ............................................................................................ 32 
2.9. 
Primary Endpoint Completion Date ............................................................................................ 32 
2.10. 
Data Safety Monitoring ........................................................................................................... 32 
2.11. 
Analytic Methods .................................................................................................................... 33 
3. 
Patient Selection .................................................................................................................................. 33 
3.1. 
Inclusion Criteria ........................................................................................................................ 33 
3.2. 
Exclusion Criteria ....................................................................................................................... 35 
4. 
Patient Enrollment .............................................................................................................................. 38 
4.1. 
Site Enrollment Requirements .................................................................................................... 38 
4.2. 
Patient Enrollment Procedures .................................................................................................... 38 
5. 
Schedule of Assessments .................................................................................................................... 40 
6. 
Study Assessments and Procedures .................................................................................................... 43 
6.1. 
Medical History .......................................................................................................................... 43 
6.2. 
Physical Examination and Vital Signs ........................................................................................ 43 
6.3. 
Laboratory Assessments ............................................................................................................. 44 


                                                                                                    
 
 
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7. 
Data and Specimen Submission .......................................................................................................... 44 
7.1. 
Data Collection and Submission ................................................................................................. 44 
7.2. 
Biospecimen Collection, Shipping and Processing ..................................................................... 45 
7.3. 
Biospecimen Collection Schemas ............................................................................................... 45 
7.4. 
Biospecimen Logging and Tracking (AFT BioMS) ................................................................... 45 
7.5. 
Biospecimen Shipping ................................................................................................................ 46 
7.6. 
Biospecimen Collection .............................................................................................................. 46 
8. 
Study Treatment .................................................................................................................................. 47 
8.1. 
Treatment Plan ............................................................................................................................ 47 
8.2. 
Radiotherapy ............................................................................................................................... 48 
8.3. 
Chemotherapy and immunotherapy ............................................................................................ 55 
8.4. 
Study drug - Investigational Product (IP) ................................................................................... 56 
8.5. 
Non-Investigational Product (Non IP) ........................................................................................ 58 
8.6. 
Dose and Treatment Modifications ............................................................................................. 58 
8.7. 
Concomitant Medications ........................................................................................................... 67 
9. 
Dose Modifications and Management of Toxicity .............................................................................. 69 
9.1. 
Dose Modifications During Concurrent Chemoradiotherapy ..................................................... 69 
9.2. 
Dose Modifications During Consolidation Chemotherapy ......................................................... 71 
9.3. 
Dosing for Obese Patients ........................................................................................................... 72 
10. 
Measurement of Effect .................................................................................................................... 73 
10.1. 
Schedule of Evaluations: ......................................................................................................... 73 
10.2. 
Definitions of Measurable and Non-Measurable Disease ....................................................... 73 
10.3. 
Guidelines for Evaluation of Measurable Disease .................................................................. 74 
10.4. 
Measurement of Treatment/Intervention Effect ...................................................................... 75 
11. 
End of Treatment ............................................................................................................................ 78 
11.1. 
Duration of Treatment ............................................................................................................. 78 
11.2. 
Managing ineligible patients and registered patients who never receive protocol intervention
 
79 
11.3. 
Extraordinary Medical Circumstances .................................................................................... 79 
12. 
Safety Instructions and Guidance ................................................................................................... 79 
12.1. 
Adverse Event Reporting Period ............................................................................................. 79 
12.2. 
Assessment of Adverse Events ............................................................................................... 79 
12.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events ..................................... 80 
13. 
Statistical Considerations and Methodology ................................................................................... 87 
13.1. 
Overview of the Study Design ................................................................................................ 87 
13.2. 
Endpoints ................................................................................................................................ 87 


                                                                                                    
 
 
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13.3. 
Primary Objective ................................................................................................................... 87 
13.4. 
Secondary Objectives .............................................................................................................. 87 
13.5. 
Translational Science Principal Objective .............................................................................. 87 
13.6. 
Translational Science Additional Objectives .......................................................................... 87 
13.7. 
Other Correlative Science Objectives (e.g., QoL, PRO, etc) .................................................. 88 
13.8. 
Sample Size, Accrual time, and Study Duration ..................................................................... 88 
13.9. 
Study Team - Safety Monitoring ............................................................................................ 88 
14. 
Correlative Sciences ........................................................................................................................ 88 
15. 
General Regulatory and Other considerations ................................................................................ 89 
15.1. 
Compliance with Trial Registration and Results Posting Requirements ................................ 89 
15.2. 
Regulatory and ethical compliance ......................................................................................... 89 
15.3. 
Ethics and Good Clinical Practice........................................................................................... 89 
15.4. 
Confidentiality ........................................................................................................................ 89 
15.5. 
Protocol Amendments ............................................................................................................. 90 
15.6. 
Informed Consent .................................................................................................................... 90 
15.7. 
Financial Disclosure ................................................................................................................ 90 
15.8. 
Protocol Deviations ................................................................................................................. 91 
15.9. 
Retention of Records ............................................................................................................... 91 
16. 
References ....................................................................................................................................... 91 
17. 
Appendices ...................................................................................................................................... 91 
 
  
Appendix 1 
Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula ....... 92 
Appendix 2 
Current National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) ....................................................................................... 93 
Appendix 3 
Response Evaluation Criteria in Solid Tumors (RECIST) ................................ 94 
Appendix 4 
Immune-Related Response Criteria................................................................... 95 
Appendix 5 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale ...... 97 
Appendix 6 
Anaphylaxis Precautions ................................................................................... 98 
Appendix 7 
Safety Reporting Fax Cover Sheet .................................................................... 99 
Appendix 8 
FDA MedWatch 3500 Form ........................................................................... 100 
QoL tool 
Correlative science 
 
 
III. 
List of Tables  
 
Table 1 
Dose Modification Guidelines for Gastrointestinal Toxicity ............................ 61 
Table 2 
Dose Modification Guidelines for Hepatotoxicity ............................................ 62 
Table 3 
Dose Modification Guidelines for Dermatologic Toxicity ............................... 64 
Table 4 
Dose Modification Guidelines for Endocrine Toxicity ..................................... 65 


                                                                                                    
 
 
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Table 5 
Dose Modification Guidelines for Pulmonary Toxicity .................................... 66 
Table 6 
Dose Modification Guidelines for Eye Toxicity ............................................... 67 
 
 
IV. 
Abbreviations and Terms  


                                                                                                    
 
 
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Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
AFT 
Alliance Foundation Trials 
AIDS 
Acquired immunodeficiency syndrome  
anti-HBc 
antibody to hepatitis B core antigen 
anti-TNF 
Anti-tumor necrosis factor 
ATA 
anti-therapeutic antibody 
AUC 
area under the concentration-time curve 
BSA 
body surface area 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CL 
Clearance 
CR 
complete response 
CRF 
Case Report Form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CTMS 
Clinical Trial Management System 
DCR 
Disease control rate 
DLCO 
diffusion capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DVH 
Dose volume histograms 
EBV 
Epstein-Barr virus 
EBNA 
Epstein-Barr nuclear antigen 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
EORTC QLQ C30 
The European Organization for Research and 
Treatment of Cancer QLQ-C30 
FDA 
U.S. Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 


                                                                                                    
 
 
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Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IF 
Immunofluorescence  
IFN 
Interferon 
IHC 
immunohistochemistry 
Ig 
Immunoglobulin 
IL 
Interleukin 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IRF 
independent review facility 
IRR 
infusion-related reaction 
irRC 
immune-related response criteria  
ITF 
internal target volume 
IV 
Intravenous 
LFT 
liver function test 
LPLV 
last patient, last visit 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1  
PES 
Polyethersulfone 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
Package Insert 
PK 
Pharmacokinetic 
PR 
partial response 


                                                                                                    
 
 
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Abbreviation 
Definition 
PRO 
Patient reported outcomes 
PUVA 
psoralen plus ultraviolet A radiation 
PVC 
Polyvinylchloride 
QOL 
Quality of life 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Response rate 
RT 
Radiation Therapy 
SAE 
serious adverse event 
SD 
stable disease 
TNF 
tumor necrosis factor 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
 
1. Background 
 
1.1. Overview of Disease and Patient Population 
 
Lung cancer remains the leading cause of cancer death in the US. While advances in diagnosis and 
treatment have improved survival, these improvements have been gradual and the overall case 
fatality rate remains greater than 80%. Most US patients are diagnosed with locally advanced or 
advanced disease with an estimated more than 40,000 cases per year of stage III NSCLC.   
 
These patients are of particular interest in that they can be treated with curative intent although only 
approximately 25% will be cured by conventional chemoradiotherapy. Their generally better health 
compared to patients with metastatic NSCLC lends this population to an immunologic approach. 
The combination of immune regulation with checkpoint inhibition plus standard treatments that 
deplete T-regulatory cells (radiation and chemotherapy) may create immunologic “space” to 
facilitate clonal expansion of effector T-cells. Further, both chemotherapy and radiation may expose 
otherwise hidden antigens that can present additional targets to the reconstituting immune system 
after chemoradiotherapy.  
 
Immunotherapy has come to the forefront of promising new modalities of care over the past few 
years. Immunotherapies have been successful enough in melanoma that several drugs are now FDA 
approved in this disease.  Similar strategies have shown promise in advanced NSCLC and checkpoint 
inhibitors targeting PD-1 and PD-L1 are FDA approved for NSCLC and are of particular interest 
given their apparently manageable toxicity and the long response durations that have been seen in 
early clinical trials.i, ii 
 
Nivolumab and atezolizumab are approved in second line therapy for metastatic squamous and non-
squamous lung cancer based upon results of the CheckMate Poplar, Birch and Oak Trials.iii 
Pembrolizumab is approved for advanced NSCLC patients whose disease has progressed after 
platinum doublet chemotherapy and whose tumors express PD-L1 and in the first line for stage IV 


                                                                                                    
 
 
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NSCLC patients whose tumors highly express PD-L1 based on the Keynote trials. Other approvals 
for advanced NSCLC are expected. 
 
PD-1 is a T-cell co-receptor found on activated T-cells. Some tumors, including a substantial 
minority of NSCLC, seem to be able to exploit this receptor through expression of the inhibitory 
PD-L1 ligands whose interaction with PD-1 can suppress the antitumor immune response. 
Expression of PD-L1 within lung cancers is thought to contribute to activated T-cell down-regulation 
and to the immunosuppressed state of lung cancer patients. Initial trials in advanced lung cancer 
patients have shown response rates in the 20-30% range but with response durations that can be 
significantly longer than would be expected with chemotherapy.  Most studies suggest that response 
is correlated with degree of PD-L1 expression, but the optimal biomarkers are not known and a few 
non-expressers have responded well. Despite the clinical uncertainties, the approach is promising 
and is particularly attractive in patients with the possibility of cure such as those with stage III 
NSCLC. 
 
An estimated 30-50% of late-stage NSCLC patients may express PD-L1. Preclinical data suggest 
that an even higher percentage of tumors from stage III patients are PD-L1 positive (Genentech 
personal communication) hence these patients are likely to be the best candidates for initial trials of 
checkpoint inhibition. This trial is intended to lead directly into a phase III trial of the combined 
chemoradiotherapy/immunotherapy approach compared to standard chemoradiotherapy. 
 
Radiotherapy can affect the host immune response and impact tumor control and spread.  In 
preclinical studies, Formenti and colleagues demonstrated that the abscopal effect of radiotherapy 
is, in part, immune mediated and that T cells are required for regression of distant metastases after 
radiotherapy.  Lee and Weichselbaum demonstrated that CD-8+ T cells are required for distant 
radiotherapy effects.  Radiation therapy can increase tumor expression of PD-L1, and combined RT 
plus PD-1-pathway targeting results in synergistic reduction of suppressor T-cells, thereby 
promoting anti-tumor immunity.  These pre-clinical data combined with recent case reports of 
immune checkpoint inhibitor mediated abscopal effects form the basis for studying anti-PD-L1 
therapy with atezolizumab in sequence with definitive chemoradiotherapy. 
 
1.2. Study Drug Mechanism of Action 
Atezolizumab is a human immunoglobulin G1 (IgG1) monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese hamster 
ovary cells.  Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid 
substitution (asparagine to alanine) at position 298 on the heavy chain, which results in a non-
glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-effector function at 
expected concentrations in humans.  Atezolizumab targets human programmed death-ligand 1 (PD-
L1) and inhibits its interaction with its receptor, programmed death-1 (PD-1).  Atezolizumab also 
blocks binding of PD-L1 to B7.1, an interaction that is reported to provide additional inhibitory 
signals to T cells. 
 
Atezolizumab (TecentriqTM) is approved in the United States for the treatment of locally advanced 
or metastatic urothelial cancer (UC) and for second line treatment of advanced NSCLC. 
Atezolizumab is being investigated in a wide spectrum of solid tumors and hematologic 
malignancies in humans, please see IB or drug label for approved indications. 
 
1.3. Preclinical Data 


                                                                                                    
 
 
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The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in vivo 
activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an acceptable safety 
profile, and to identify a Phase I starting dose.  Comprehensive pharmacology, PK, and toxicology 
evaluations were thus undertaken with atezolizumab. 
 
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in mice and 
cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the 
appropriate starting dose in humans.  Given the similar binding of atezolizumab for cynomolgus 
monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, pharmacokinetics, and toxicokinetics of 
atezolizumab.  
 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab supported 
entry into clinical studies, including providing adequate safety factors for the proposed Phase I 
starting doses.  The results of the toxicology program were consistent with the anticipated 
pharmacologic activity of down-modulating the PD-L1/PD-1 pathway and supported entry into 
clinical trials in patients. 
 
Refer to the atezolizumab Investigator’s Brochure for details on the nonclinical studies.   
 
1.4. Clinical Pharmacokinetics and Immunogenicity 
On the basis of available preliminary PK data (0.03−20 mg/kg), atezolizumab appeared to show 
linear pharmacokinetics at doses ≥ 1 mg/kg.  For the 1-mg/kg and 20-mg/kg dose groups, the mean 
clearance (CL) and the mean volume at steady state (Vss) had a range of 3.20−4.43 mL/kg and 
48.1−64.1 mL/kg, respectively, which is consistent with the expected profile of an IgG1 antibody in 
humans. 
 
The development of ATAs has been observed in patients in all dose cohorts and was associated with 
changes in pharmacokinetics for some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The 
development of detectable ATAs has not had a significant impact on pharmacokinetics for doses 
from 10−20 mg/kg.  Patients dosed at the 10-, 15-, and 20-mg/kg dose levels have maintained the 
expected target trough levels of drug despite the detection of ATAs.  To date, no clear relationship 
between detection of ATAs and AEs or IRRs has been observed. 
 
1.5. Clinical Data 
 
1.5.1.  Ongoing Clinical Studies 
Current studies of atezolizumab include one ongoing Phase Ia monotherapy study, three 
ongoing combination studies, five Phase II studies, and one Phase III study.  Details of all 
ongoing studies can be found in the Atezolizumab Investigator’s Brochure. 
 
Phase Ia Study PCD4989g 
Study PCD4989g is a multicenter, first-in-human, open-label, dose-escalation study 
evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by IV infusion every 3 weeks to patients with locally advanced 
or metastatic solid malignancies or hematologic malignancies.  Ongoing expansion cohorts 
are studying the efficacy in patients with pancreatic cancer, bladder cancer, breast cancer, 


                                                                                                    
 
 
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esophageal cancer, prostate cancer, small-cell lung cancer, malignant lymphoma, multiple 
myeloma, and other less common tumor types. 
 
Phase Ib Study GP28328 
Ongoing Phase Ib Study GP28328 is evaluating the safety and pharmacology of atezolizumab 
administered with bevacizumab alone (Arm A) or with bevacizumab plus leucovorin, 5-
fluorouracil, and oxaliplatin (FOLFOX; Arm B) in patients with advanced solid tumors.  
Additional cohorts have been included to investigate atezolizumab in combination with 
carboplatin plus paclitaxel, in combination with carboplatin plus pemetrexed, and in 
combination with carboplatin plus nab paclitaxel, pemetrexed, and cisplatin in patients with 
advanced or metastatic non-small cell lung cancer (NSCLC). 
 
Phase Ib Study GP28384 
Ongoing Phase Ib Study GP28384 is evaluating the safety and pharmacology of atezolizumab 
administered in combination with vemurafenib in patients with previously untreated 
BRAFV600-mutation−positive metastatic melanoma. 
 
Phase Ib Study GP28363 
Ongoing Phase Ib Study GP28363 is evaluating the safety and pharmacology of atezolizumab 
administered in combination with cobimetinib (MEK inhibitor) in locally advanced or 
metastatic solid tumors. 
 
Phase II Study GO28625 (FIR) 
Ongoing, single-arm, Phase II Study GO28625 is evaluating the safety and efficacy of 
atezolizumab monotherapy in PD-L1−positive patients with NSCLC.  In particular, this study 
is evaluating whether archival or fresh tumor tissue is more predictive of response to 
atezolizumab.  Safety and efficacy data are not yet available for this study.  
 
Phase II Study GO28753 (POPLAR) 
Study GO28753 is a randomized, open-label, Phase II study in patients with locally advanced 
or metastatic NSCLC who have failed a prior platinum-containing regimen.  Patients in the 
control arm of Study GO28753 will receive docetaxel alone.  Eligible patients will be enrolled 
regardless of PD-L1 status and will be stratified by PD-L1 expression.  The primary endpoint 
is overall survival (OS) for both the PD-L1−positive population and the overall study 
population. 
 
Phase II Study GO28754 (BIRCH) 
Ongoing, single-arm, Phase II Study GO28754 is evaluating the safety and efficacy of 
atezolizumab monotherapy in PD-L1−positive patients with NSCLC.  As of the 1 December 
2015 data cutoff date, 659 patients with NSCLC have been treated with atezolizumab as a 
fixed dose of 1200 mg IV q3w.  In Study GO28754, 93.8% patients experienced at least 
one adverse event, 65% of patients experienced one treatment-related adverse event, and 
12% of patients experienced Grade ≥ 3 treatment-related adverse event.   
 
Phase II Study WO29074 
Ongoing Phase II Study WO29074 is evaluating the safety and efficacy of atezolizumab 
monotherapy or the combination of atezolizumab and bevacizumab versus sunitinib in 
treatment-naïve patients with renal cell carcinoma (RCC).  Safety and efficacy data are not 
yet available for this study. 


                                                                                                    
 
 
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Phase II Study GO29293 
Ongoing Study GO29293 is a single-arm, open label, Phase II study to assess the clinical 
benefit of atezolizumab as a single agent in patients with locally advanced or metastatic UBC.  
The co-primary endpoints of this study are independent review facility (IRF)−assessed 
objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) and investigator-assessed ORR according to modified Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria. 
 
Phase III Study GO28915 (OAK) 
Study GO28915OAK was a randomized, Phase III, open-label study assessing the clinical 
benefit of atezolizumab as a single agent versus docetaxel in PD-L1-unselected patients with 
locally advanced or metastatic NSCLC that has progressed during or following treatment with 
a platinum-containing regimen     
At the primary analysis, there were 850 efficacy-evaluable patients (ITT 
population), 425 in the docetaxel arm and 425 in the atezolizumab arm. Median OS 
in the ITT population was 13.8 months for atezolizumab compared with 9.6 months for 
docetaxel (HR of 0.73; 95% CI:  0.62, 0.87, p=0.0003). OS benefit was seen regardless of 
PD-L1 expression (HR 0.75 in <1% PD-L1 expression population; 0.41 in ≥50% TC or 
≥10% IC expression population) and was consistent across subgroups, including histology 
(HR 0.73 for both), patients with asymptomatic CNS mets (HR 0.54) and never smokers 
(HR 0.71). Atezolizumab was well tolerated with a favorable safety profile compared to 
docetaxel. No new safety signals were identified. The rate of immune-mediated AEs was 
low (Barlesi et al. 2016). 
1.5.2.  Clinical Activity 
 
Single-Agent Clinical Safety in Patients with Non-Small Cell Lung Cancer in Study 
PCD4989g 
 
Study PCD4989g is a Phase Ia dose escalation and expansion study, in which atezolizumab 
is being used as a single agent in patients with locally advanced or metastatic solid tumors 
or hematologic malignancies, and provides significant data (with 629 safety-evaluable 
patients across all cancer types as of the data cutoff date of 15 December 2015) for the 
safety profile of atezolizumab as monotherapy. 
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no 
clear dose-related trends in the incidence of adverse events have been determined. 
The safety profile of atezolizumab as a single agent is observed to be consistent across 
different indications, including small-cell lung cancer, NSCLC, urothelial bladder cancer 
(UBC), renal cell carcinoma (RCC), melanoma, gastric cancer, colorectal cancer, head and 
neck cancer, breast cancer, and sarcoma. 
Of the 629 patients across all cancer types in Study PCD4989g, 619 patients (98.4%) 
experienced at least one adverse event, including 444 patients (70.6%) who experienced 
one treatment-related adverse event.  Commonly reported events (reported in ≥ 10% of all 
patients) included fatigue, nausea, decreased appetite, diarrhea, constipation, dyspnea, 
pyrexia, and cough. 


                                                                                                    
 
 
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A total of 89 safety-evaluable patients with NSCLC received atezolizumab in 
Study PCD4989g.  A total of 88 patients (98.9%) experienced at least one adverse 
event, including 67 patients (75.3%) with treatment-related adverse events, 35 
(39.3%) patients with Grade 3−4 adverse events, 36 patients (40.4%) with serious 
adverse events, 5 patients (5.6%) who discontinued study drug due to an adverse 
event, and 1 death (1.1%). 
The safety profile of the NSCLC cohort was consistent with the overall safety profile 
of all safety-evaluable patients in Study PCD4989g, as well as with the 
safety-evaluable patients with NSCLC who received atezolizumab monotherapy in 
other studies. 
Analyses of tumor-infiltrating immune cells for PD-L1 expression on baseline tumor tissue 
have been performed for Study PCD4989g.  Preliminary results from Study PCD4989g 
suggest that PD-L1 expression in tumor-infiltrating immune cells is likely to be associated 
with response to atezolizumab. 
 
Efficacy in NSCLC Patients 
The POPLAR trial is a randomized, phase II comparison between standard second line 
docetaxel and atezolizumab in good performance status patients with NSCLC that had 
progressed after a platinum based chemotherapy regimen (. The study screened over 500 
patients at 61 centers in 13 countries including the USA and Europe and randomized 144 
patients to atezolizumab and 143 to docetaxel between August 2013 and March 2014. Patients 
had normal organ function and measurable disease and were stratified by PD-L1 status, tumor 
infiltrating immune cells as well as by histology and prior therapy. The primary study 
endpoint was overall survival in the ITT population and the PD-L1 prespecified subgroups.  
Survival was similar to docetaxel in patients lacking PD-L1 expression and improved with 
atezolizumab in both responders and non-responders. 
Overall survival of the participants in the POPLAR study was 12.6 months (95% CI 9.7 – 
16.4) for atezolizumab and 9.7 months (95% CI 8.6 – 12.0) for docetaxel (HR 0.73, p= 0.04). 
Survival improvement with atezolizumab compared to docetaxel was associated with the 
degree of PD-L1 expression. 
Atezolizumab was well tolerated. 11 (8%) patients discontinued treatment due to AEs 
compared to 30 (22%) for docetaxel. 16 (11%) patients in the atezolizumab arm had grade 
3/4 AEs compared to 52 (39%) for docetaxel. There was one treatment related death in the 
atezolizumab group and 3 in the docetaxel group.iv 
For further details, see the atezolizumab Investigator’s Brochure. 
 
1.6. Clinical Safety  
 
The presented safety data for atezolizumab have been derived mainly from the treatment of patients 
in Phase Ia Study PCD4989g.  As of 10 May 2014, atezolizumab has been administered to 
approximately 775 patients with solid and hematologic malignancies.  No dose-limiting toxicities 
(DLTs) have been observed at any dose level, and no maximum tolerated dose (MTD) was 
established.  Fatigue was the most frequently reported adverse event (AE).  


                                                                                                    
 
 
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Adverse Events 
The following safety data are from PCD4989g, in which atezolizumab is being used as single-agent 
therapy in patients with locally advanced or metastatic solid tumors or hematologic malignancies.  
In 412 treated patients, 97.1% reported an AE while on study.  Of these AEs, 48.8% were Grade 1 
or 2 in maximum severity on the basis of National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  The most frequently observed AEs (occurring 
in ≥ 10% of treated patients) included fatigue, nausea, decreased appetite, pyrexia, dyspnea, 
diarrhea, constipation, cough, headache, back pain, vomiting, anemia, arthralgia, rash, insomnia, 
asthenia, abdominal pain, chills, pruritus, and upper respiratory tract infection.   
 
Grade ≥ 3 AEs were reported by 199 of 412 patients (48.3%). There were 51 patients (12.4%) who 
reported Grade ≥ 3 AEs that were assessed as related to study drug by the investigators.  The most 
frequently reported related Grade ≥ 3 AEs included fatigue (5 patients [1.2%]), increased ALT and 
increased AST (each reported in 4 patients [1.0%]); and asthenia, autoimmune hepatitis, and hypoxia 
(each reported in 3 patients [0.7%]).  
 
Immune-Related Adverse Events 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated AEs have been closely monitored during the atezolizumab clinical program.  
These include potential dermatologic, hepatic, endocrine, and respiratory events as well as events of 
hepatitis/elevated liver function tests (LFTs) and influenza-like illness.  Expected adverse drug 
reactions associated with atezolizumab include the following:  hepatitis/transaminitis, 
hypothyroidism, infusion-related reactions (IRRs), pneumonitis, influenza-like illness, and 
dermatologic reactions.  Potential adverse drug reactions include the following:  anti-therapeutic 
antibodies (ATAs), colitis, endocrine disorders, hypersensitivity, neurologic disorders, and 
pericardial effusion.   
 
For further details, see the Atezolizumab Package Insertv. 
 
1.7. Study Design Rationale and Significance 
 
1.7.1.  Study Design 
 
This phase II pilot trial will combine neoadjuvant immunotherapy with atezolizumab q 21 
days for 12 weeks with standard chemoradiotherapy with curative intent for good PS patients 
with unresectable stage IIIA/B NSCLC. Because of the consequences of progression in this 
curative-intent population, restaging CT scans will be carried out after the first 2 cycles of 
neoadjuvant therapy. Non progressing patients will complete a total of one year of anti-PDL1 
therapy with an interruption during chemoradiotherapy. Patients with evidence of progression 
at the first restaging evaluation will proceed immediately to chemoradiotherapy if still eligible 
for curative intent therapy. 
  
Assumptions include a DCR of at least 70% to neoadjuvant immunotherapy, that 85% of the 
study population will complete radiation, and that 60% of the study population will complete 
the entire treatment course including consolidation chemotherapy and adjuvant 
immunotherapy with atezolizumab. If the pilot study reaches its preplanned endpoints, a 
randomized phase III trial is planned in which patients will be randomized 2:1 to  induction 


                                                                                                    
 
 
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immunotherapy followed by chemoradiotherapy with immunotherapy and adjuvant 
immunotherapy vs standard conventional chemoradiotherapy followed by immunotherapy.  
 
A key component of the successful completion of this study will be quality assurance of the 
radiotherapy delivery. Augmentation of the immune system by immune checkpoint inhibition 
has the potential to increase risk of pneumonitis.  To date, there are limited data on the use of 
PD-1/PD-L1 pathway agents in sequence with radiotherapy.  Out of 129 patients with NSCLC 
on a phase I, dose-escalation, cohort expansion trial for the PD-1 inhibitor nivolumab, 75 
(58%) had previously received RT.  Without knowing the precise details of radiotherapy 
treatment, out of the 129 NSCLC cases, there were 9 cases of pneumonitis (7.0%) and 3 cases 
of grade 3-4 pneumonitis (2.3%), suggesting that the incidence of radiation mediated toxicity 
was not increased by the immunotherapy in that small cohort.  There is some suggestion that 
the risk of pneumonitis will be less with atezolizumab than previously seen with nivolumab.  
Recent trials of the anti-PD-L1 BMS agent 936559 reported no cases of pneumonitis.  
However, given the possibility that the immune mediated risk of pneumonitis could be higher 
in a lung cancer population being treated with definitive thoracic RT, tight quality control 
through the cooperative group process will be critical.  In multiple datasets, the quality of 
radiotherapy has been integral to the outcome in combined modality therapy trials. Reports 
of immune mediated myocarditis have been occasional but reports of fatal myocarditis 
surfaced in 2016. This complication appears very rare and more common in patients treated 
with combined immunotherapy with an anti-CTLA4 agent plus a checkpoint inhibitor. 
Cardiac function will be followed with echocardiography and all care will be taken to 
minimize heart dose in the radiation fieldvi. 
 
1.7.2.  Rationale for Study and Patient Population 
 
Lung cancer remains the leading cause of cancer death in the US. While advances in diagnosis 
and treatment have improved survival, these improvements have been gradual and the overall 
case fatality rate remains greater than 80%. Most US patients are diagnosed with locally 
advanced or advanced disease with an estimated more than 40,000 cases per year of stage III 
NSCLC.   
 
Stage III NSCLC patients are of particular interest in that they can be treated with curative 
intent with chemoradiotherapy although only approximately 25% will be cured. Their 
generally better health compared to patients with metastatic NSCLC lends this population to 
an immunologic approach. The combination of checkpoint inhibition immunotherapy with 
standard treatments that deplete T-regulatory cells (radiation and chemotherapy) may create 
immunologic “space” to facilitate clonal expansion of effector T-cells. Further, both 
chemotherapy and radiation may expose otherwise hidden antigens that can present additional 
targets to the recovering immune system.  
 
PD-1 is a T-cell co-receptor found on activated T-cells. Some tumors, including a substantial 
minority of NSCLC, seem to be able to exploit this receptor through expression of the 
inhibitory PD-L1 ligands whose interaction with PD-1 can suppress the antitumor immune 
response. Expression of PD-L1 within lung cancers is thought to contribute to activated T-
cell down-regulation and to the immunosuppressed state of lung cancer patients. Initial trials 
in advanced lung cancer patients report response rates in the 20-30% range but with response 
durations that can be significantly longer than would be expected with chemotherapy.  Most 
studies suggest that response correlates with the degree of PDL1 expression, but the optimal 
biomarkers are not known and a few non-expressers have responded well. Despite the clinical 


                                                                                                    
 
 
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uncertainties, the approach is promising and is particularly attractive in patients with the 
possibility of long term survival such as those with stage III NSCLC in whom the curative 
fraction may be increased by this strategy. 
 
An estimated 30-50% of late-stage NSCLC patients may express PD-L1. Preclinical data 
suggest that an even higher percentage of tumors from stage III patients are PD-L1 positive 
(Genentech personal communication) hence these patients are likely to be the best candidates 
for induction trials of checkpoint inhibition. This trial is intended to lead directly into a phase 
III trial of combined chemoradiotherapy/immunotherapy compared to standard 
chemoradiotherapy. 
 
1.7.3.  Trial Significance 
 
Patients with stage III lung adenocarcinoma are treated with chemoradiotherapy with curative 
intent, but the vast majority of patients will relapse and die of disease. This patient population 
is healthier and more likely to have an intact immune system than patients with more 
advanced disease and with heavy cytotoxic pretreatment. The opportunity to add immune 
modulation with checkpoint inhibitors neoadjuvantly and adjuvantly in this patient population 
would be expected to improve overall survival significantly and may increase the proportion 
of patients who can be cured. 
 
1.7.4.  Rationale for Dose Selection and Duration of Treatment 
 
Chemoradiotherapy will be the Alliance standard carboplatin + paclitaxel concurrent with RT 
as most recently used in the 0617 clinical trial. This regimen has shown the best survival 
statistics to date with a weekly low dose carboplatin and paclitaxel chemotherapy backbone 
and a radiation dose of 60 Gy. The duration of atezolizumab therapy of one year with an 
interruption during chemoradiotherapy is based on previous trials with the agent. 
 
1.7.5.  Rationale for Endpoints 
 
1.7.5.1 Primary - Induction immunotherapy may not produce early tumor shrinkage so the 
traditional tumor response measurement method, such as RECIST, may not accurately 
capture the immunotherapy efficacy. In this trial, we elected to use disease control rate as 
the primary endpoint, rather than response rate (CR+PR) defined in RECIST 1.1. The 
decision was intended to better capture the immunotherapy effect among those patients who 
may respond to immunotherapy without early tumor shrinkage.vii  
 
1.7.5.2 Secondary - The secondary endpoints of PFS, OS, RR and safety are standard. The 
proportion of patients completing induction chemoradiation and consolidation chemotherapy 
is of particular importance in a stage III NSCLC population. - The denominator will be the 
total number of patients who register to the trial and start the induction immunotherapy. The 
numerator will be the number of the patients who complete induction immunotherapy, 
chemoradiation therapy and consolidation chemotherapy.  These data are vital to compare the 
study therapy with recent multimodality trials in stage III NSCLC patients without the 
immunotherapy component. 
 
1.7.5.3 Translational Research. The primary correlative analysis for this trial will be the 
correlation of PD-L1 expression in tumor specimens with changes in immune system 


                                                                                                    
 
 
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function and response to atezolizumab.  Please refer to the correlative sciences manual for 
the study for additional detail. 
 
1.7.5.4 Correlative biomarkers 
Please refer to specimen management manual for additional information and to Appendix 
11 for correlative science objectives. 
 
1.7.5.5 Patient reported outcomes/QoL 
Questionnaires will be collected at the following time points: on Cycle 1 Day One of 
Induction Therapy, Day 1 of Concurrent Therapy, Cycle 1 Day of Consolidation Therapy 
and at 3 month intervals throughout adjuvant therapy.   The EORTC QLQ-C30 is a well-
validated cancer-specific measure73. It is comprised of six functional scales (physical, role, 
emotional, cognitive, social, and global health status/quality of life); three symptom scales 
(fatigue, pain, and nausea and vomiting); and six single items (appetite loss, constipation, 
diarrhea, dyspnea, sleep disturbance, and economic consequences of the disease and 
treatment). Functional and symptom scales/items are combined into a newly developed 
single health-related QOL (HRQL) summary measure. The summary score and all scales 
and single items range from 0-100. A high score for the summary measure and all 
functional scales indicates a high/better level of QOL or functioning, whereas a high score 
on a symptom scale/item represents a higher level of symptoms/problems. 
 
2. Objectives 
 
2.1. Primary Objective  
 
The primary objective of this single arm phase II trial is to determine whether neoadjuvant and 
adjuvant anti-PD-L1 therapy bracketing standard chemoradiation therapy and consolidation therapy 
is worthy of further investigation in NSCLC  patients treated with curative intent for stage IIIA and 
IIIB disease (AJCC 7th edition). The primary endpoint will be the disease control rate (DCR) after 
12 weeks induction immunotherapy.  
 
2.2. Secondary Objectives 
 
Secondary endpoints include objective response rate (ORR), progression free survival (PFS), overall 
survival (OS) and the proportion of patients who complete induction immunotherapy, chemoradiation 
therapy and consolidation chemotherapy. Toxicity including immune related adverse events will be 
assessed for all patients receiving any study therapy.  
 
2.3. Translational Science Principal Objective 
 
Assess the utility of PD-L1 as a biomarker for DCR, ORR, PFS, OS in the study population. 
 
2.4. Translational Science Additional Objectives 
 
Study the association of biomarkers, including immunologic signatures, and clinical outcomes. 
Analyses may include, but are not limited to, multipanel immunohistochemistry, gene expression 
profiling by Nanostring, RNAseq or RT-PCR, whole exome and T cell receptor sequencing, 
cytokine/chemokine analysis, flow cytometry, and T cell function. Specimens will include blood and 
FFPE tissue. Time-points are: at baseline, after atezolizumab induction, after chemoradiotherapy, 


                                                                                                    
 
 
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during adjuvant atezolizumab monotherapy, at treatment completion, and during follow-up. Please 
see appendix 11 for detailed correlative science description and procedures. 
 
2.5. Other Correlative Science Objectives 
Quality of life endpoints will be measured by the EORTC QLQ-30 assessed during induction, during 
chemoradiotherapy, during adjuvant atezolizumab at 3 month intervals. 
 
2.6. Study Design 
 
Single arm phase II trial of induction immunotherapy with anti-PD-L1 for patients with 
unresectable stage III NSCLC and PS 0-1. 
 
The phase II trial will register a total 63 patients. Assuming 5% ineligibility and cancelation, 60 
eligible patients are expected to receive at least one cycle of the experimental agent. PD-L1 status 
will be determined by Ventana assay (TC/IC). Of 60 patients, we expect approximately 40 and 20 
patients are PD-L1 positive (≥1% expression in tumor cells or tumor-infiltrating immune cells) and 
PD-L1 negative (otherwise), respectively. The DCR in PD-L1 negative patients in particular is a 
topic of great interest and will be assessed in real time by study staff in order to avoid harm to this 
particular population. 
 
2.7. Sample Size 
 
The disease control rate (DCR) is assumed the same for PD-L1 positives and negatives. With 60 
eligible and treated patients, the study has approximately 90% power to detect H0:P</=0.50  versus 
H1: P>/= 0.67, where p is the disease control rate (DCR) after 12 weeks neoadjuvant anti-PD-L1 
therapy, with a one-sided binomial test at a significance level of 0.10. In particular, if 35 or fewer 
of these patients remain disease controlled, it will be concluded that the treatment regimen is not 
worthy of further investigation. Otherwise, it will be concluded that the treatment regimen has 
sufficient efficacy to warrant further investigation. Under the design, the probability of erroneously 
concluding that the treatment regimen is worthy of further investigation when the DCR is truly 
50% or less is 0.0775. The probability of erroneously concluding that the treatment regimen is NOT 
worthy of further investigation when the true DCR is 67% or greater is 0.0999. 
 
2.8. Accrual Rate and Accrual Duration 
 
A total of 63 patients will be registered to the trial. The trial will be open for patient enrollment in 
15 Alliance institutions selected for their experience and prior good enrollment in clinical trials of 
chemoradiotherapy for NSCLC. We expect approximately 4 unresectable stage III NSCLC patients 
who meet the eligibility criteria will be enrolled per month. It will take approximately 16 months to 
reach the target accrual. Follow up of at least 18 months will be required for all patients for 
progression free survival and overall survival.  
 
2.9. Primary Endpoint Completion Date  
 
Approximately two years after the first enrollment. 
 
2.10. Data Safety Monitoring 
 
If 5 or more of the first 20 treated patients experience grade 4/5 non-hematologic adverse events 
that are probably, possibly, or definitely related to study treatments, OR if the rate of treatment-


                                                                                                    
 
 
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related deaths within the first 60 days exceeds 4 among the first 20 patients at any time, accrual to 
the study will be suspended to allow for investigation. If the true rate of grade 4/5 non-hematologic 
AEs is 10%, 20%, 30%, 33%, 40%, 50%, the corresponding probability of accrual suspension is 
0.043, 0.370, 0.762, 0.848, 0.949, 0.994, respectively. The safety stopping rule will allow trial 
suspension with considerable probability when excessive AE events occur in an initial cohort of 
treated patients, e.g. >84.8% if the true SAE is ≥30%. After consideration by the study team, a 
decision will be made as to whether accrual can be resumed, potentially with modifications to entry 
criteria and/or study conduct. 
 
2.11. Analytic Methods 
 
The analysis cohort will be the patients who meet eligibility criteria and receive at least one cycle of 
the experimental agent.  
 
The primary endpoint is disease control rate (DCR), which is defined as the proportion of patients who 
reach complete/partial response and stable disease after 12 weeks of neoadjuvant atezolizumab 
therapy. Binomial exact test will be used for testing. The 90% exact confidence interval for DCR will 
be provided.   
 
For the analysis of secondary endpoints, the primary analysis cohort will be used. Objective response 
rate (ORR) is the rate of best overall response (complete or partial response) after 12 weeks of 
neoadjuvant atezolizumab therapy. ORR and its 95% confidence interval will be estimated.  
Progression-free survival (PFS) is defined as the time from the start of neoadjuvant therapy to disease 
progression or recurrence (first disease recurrence or death, whichever comes first). The Kaplan-Meier 
estimator will be used to estimate median PFS, PFS at 12 months, and their confidence intervals. 
Similar analysis will be conducted to estimate median overall survival (OS) and OS at 12 and 18 
months.  The frequencies of metastases by site will be tabulated.  
 
The proportion of patients who complete induction immunotherapy, chemoradiation therapy and 
consolidation chemotherapy will be estimated. Its 95% confidence interval will be provided.  
 
Overall treatment-related adverse events will be summarized by phase of protocol treatment (Induction 
immunotherapy, Chemoradiotherapy, Consolidation chemotherapy, Adjuvant immunotherapy), type 
and grade for all patients who received at least one cycle of atezolizumab therapy.  
 
Blood based biomarkers will be evaluated before and after the protocol treatment. The association of 
the baseline value and the changes of these biomarkers with clinical outcomes, such as objective 
response, overall survival and progression free survival, will be evaluated using logistic regression and 
Cox models.  
 
QoL will be measured by the EORTC QLQ-30. The QoL scores, including mean, standard 
deviation, range, for each scale will be summarized at the following time points: induction at 6 & 
12 weeks, chemoradiotherapy at completion of concurrent phase + after consolidation, during 
adjuvant atezolizumab at 3 month intervals.  
 
3. Patient Selection 
 
3.1. Inclusion Criteria 
Patients must meet the following criteria for study entry: 


                                                                                                    
 
 
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1) Newly diagnosed stage IIIA/B (per AJCC 7) NSCLC, PS 0-1. 
2) No active autoimmune disease or uncontrolled infection, normal bone marrow, renal, 
hepatic function, FEV1 ≥ 1.2L, no significant underlying heart or lung disease. 
3) Pathologically proven diagnosis of NSCLC. 
4) Measurable Stage IIIA or IIIB disease per AJCC 7. 
5) Patients must be considered unresectable or inoperable. Patients with nodal recurrence 
after surgery for early-stage NSCLC are eligible if the following criteria are met: 
• 
No prior chemotherapy or radiation for this lung cancer 
• 
Prior curative-intent surgery at least 3 months prior to the nodal recurrence 
6) Stage III A or B disease (per AJCC 7) with minimum diagnostic evaluation within 6 
weeks to include: 
• 
History/physical examination 
• 
Contrast enhanced CT of the chest and upper abdomen  
• 
MRI of the brain with contrast (or CT with contrast if MRI is medically 
contraindicated) 
• 
PET/CT 
7)  If pleural fluid is visible on CT scan, thoracentesis to exclude malignancy should be 
obtained. Patients with effusions that are too small to tap are eligible. 
8) Patients must be at least 4 weeks from major surgery and must be fully recovered. 
9) Age ≥ 18 years. 
10) Availability of representative formalin-fixed paraffin-embedded (FFPE) tumor 
specimens in paraffin blocks (blocks are preferred) or at least 4 (preferably 20) unstained 
slides, with an associated pathology report, for central testing of tumor PD-L1 
expression. 
• 
If an archived tumor block exists, then either the block (preferred) or at least 4 
(preferably 20) unstained slides from the block should be submitted. Tumor tissue 
should be of good quality based on total and viable tumor content, i.e. at least 50 
viable tumor cells and intact tissue architecture.  Fine-needle aspiration, brushing, 
and lavage samples are not acceptable.  If the block is tissue from a core-needle 
biopsy, then the block should contain tissue from at least three cores to be sufficient 
for evaluation.   
• 
Patients who do not have existing (archived) tissue specimens meeting eligibility 
requirements may undergo a biopsy during the screening period.  Acceptable 
samples include core-needle biopsies for deep tumor tissue (minimum of three 
cores) or excisional, or forceps biopsies for endobronchial or nodal lesions. The 
tissue should be fixed in formalin and embedded on site and sent as a block. 


                                                                                                    
 
 
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11) Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1; if repeat 
labs are obtained on or prior to C1D1 must re-meet eligibility criteria to treat the subject): 
• 
ANC ≥ 1500 cells/µL 
• 
WBC counts > 2500/µL 
• 
Lymphocyte count ≥ 300/µL 
• 
Platelet count ≥ 100,000/µL  
• 
Hemoglobin ≥ 10.0 g/dL 
• 
Total bilirubin ≤ 1.5 × upper limit of normal (ULN) with the following exception:  
­ 
Patients with known Gilbert disease who have serum bilirubin 
level ≤ 3 × ULN may be enrolled. 
• 
AST and ALT ≤ 3.0 × ULN  
• 
Alkaline phosphatase ≤ 2.5 × ULN  
• 
Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the basis of 
the Cockcroft-Gault glomerular filtration rate estimation: 
­ 
(140 − age) × (weight 
in 
kg) × (0.85 
if 
 
female) 
72 × (serum creatinine in mg/dL) 
12) Measurable disease per RECIST v1.1 (see Appendix 3). 
13) For female patients of childbearing potential and male patients with partners 
of childbearing potential, agreement (by patient and/or partner) to use highly effective 
form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when 
used consistently and correctly, such as hormonal or barrier method of birth control, or 
abstinence) and to continue its use for 150 days after the last dose of atezolizumab. 
14) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
(see Appendix 5). 
3.2. Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from study entry. 
General Exclusion Criteria: 
1) Active autoimmune disease. 
2) Greater than minimal, exudative, or cytologically positive pleural effusions. 
3) Involved contralateral hilar nodes. 
4) 10% weight loss within the past month. 
5) Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free 
for a minimum of 3 years; non-invasive conditions such as carcinoma in situ of the breast, 
localized prostate cancer or thyroid nodules, carcinoma in situ of the oral cavity or cervix 
are all permissible. 


                                                                                                    
 
 
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6) Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a 
different cancer is allowable. 
7) Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields. 
8) Prior severe infusion reaction to a monoclonal antibody. 
9) Severe, active co-morbidity, defined as follows: 
10) Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, 
unstable angina, myocardial infarction within the last 6 months, uncontrolled congestive 
heart failure, and cardiomyopathy with decreased ejection fraction. 
11) Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration or within 2 weeks of cycle 1 day 1. 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy within 30 days before registration. 
12) Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects. 
13) Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; 
note, HIV testing is required for entry into this protocol due to the immunologic basis for 
induction treatment.  
14) Pregnancy, lactation, or inability or unwillingness to use medically acceptable forms of 
contraception if pregnancy is a risk. 
15) Any history of allergic reaction to paclitaxel or other taxanes, or to carboplatin. 
16) Uncontrolled neuropathy grade 2 or greater regardless of cause. 
17) Any approved anticancer therapy, including chemotherapy, hormonal therapy, 
or radiotherapy, within 3 weeks prior to initiation of study treatment; however, 
the following are allowed: 
i. Hormone-replacement therapy or oral contraceptives 
ii. Herbal therapy > 1 week prior to Cycle 1, Day 1 (herbal therapy intended 
as anticancer therapy must be discontinued at least 1 week prior to Cycle 
1, Day 1) 
18) Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis; cirrhosis; fatty liver; and inherited liver disease. 
19) Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis 
B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core 
antigen] antibody test) are eligible. 
20) Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA. 
21) Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies. 
22) Inability to comply with study and follow-up procedures. 


                                                                                                    
 
 
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23) History of active autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune 
thyroid disease, vasculitis, or glomerulonephritis. 
24) Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
25) Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible. 
26) Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular 
manifestations. 
Rash must cover less than 10% of body surface area (BSA). 
Disease is well controlled at baseline and only requiring low potency topical steroids 
(e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 
0.05%, alclometasone dipropionate 0.05%). 
No acute exacerbations of underlying condition within the last 6 months (not requiring 
psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors; high potency or oral steroids). 
27) History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) 
scan. 
28) Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation of 
the results or render the patient at high risk from treatment complications. 
29) Active tuberculosis. 
30) Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need 
for a major surgical procedure during the course of the study. 
31) Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 
or anticipation that such a live, attenuated vaccine will be required during the study. 
32) Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 
weeks prior to Cycle 1, Day 1 or at any time during the study. 
 
Medication-Related Exclusion Criteria: 
33) Prior 
treatment 
with 
anti−PD-1, 
or 
anti−PD-L1 
therapeutic 
antibody 
or pathway-targeting agents. 


                                                                                                    
 
 
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34) Treatment with systemic immunostimulatory agents (including but not limited to 
interferon [IFN]-α or interleukin [IL]-2) within 6 weeks or five half-lives of the drug 
(whichever is shorter) prior to Cycle 1, Day 1. 
35) Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within 
five half-lives of the investigational product, whichever is longer). 
36) Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, or anti-tumor 
necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1. 
37) Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled. 
38) The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
39) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric 
or humanized antibodies or fusion proteins. 
40) Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation. 
 
4. Patient Enrollment 
 
4.1. Site Enrollment Requirements 
 
 
Site must submit all required essential documents including: 
• 
IRB/Regulatory Approval  
• 
Investigator 1572(s) 
• 
Institutional informed consent form 
• 
Following regulatory and ethical approval for each participating site, it is the responsibility 
of the Sponsor to formally activate sites according to local obligations. Sites will only be 
able to enroll patients once formal site activation has been performed by the Sponsor.  
 
4.2. Patient Enrollment Procedures 
 
Informed consent: The patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental nature of 
the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human 
protection committee approval of this protocol and a consent form is required prior to patient consent 
and enrollment. 
 
Patient enrollment will be facilitated using the AFT web-based RAVE EDC (electronic data capture) 
system.  
 
Patients must be enrolled prior to submission of biospecimens. After written informed consent has 
been obtained, the study site will obtain a unique patient identifier which will stay the same 
throughout the entire study.  Patients enrolled but not treated for any reason have to be documented 
as a Screening Failure in IRT. 
 
Prior to accessing AFT EDC, site staff should verify the following: 


                                                                                                    
 
 
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• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization form. 
 
. 
 
 
 
 


                                                                                                    
 
 
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5. Schedule of Assessments 
 
Assessment 
Screening 
Registration 
Induction Immunotherapy 
(Cycle=21 Days) 
Concurrent Therapy 
 (weekly during radiation): 
Consolidation  
(1 cycle = 21 
days, 2 cycles 
total) 
Adjuvant 
Immuno-
therapy 
(Q21days 
to complete 
1 Year) 
Treatment 
Completion/
ET Visite 
Follow-up visit 
(months after the 
termination of 
treatment) 
3 
6 
12 
Day 
-60 -42 -28 -16 
0 C1D1 C2D1 C3D1 C4D1 D1 D8 D15 D22 D29 D36 C1D1 C2D1 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General med history & 
baseline conditions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsa 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical examination 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematologyb 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chemistryc 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
TSH 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Toxicity Assessment 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
CT Scan for Tumor 
Measurementh 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X – q 3 
months 
X 
X 
X 
X 
PET/CT Scan 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Brain MRI (CT if MRI 
is contraindicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Test 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                                                                                                    
 
 
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Assessment 
Screening 
Registration 
Induction Immunotherapy 
(Cycle=21 Days) 
Concurrent Therapy 
 (weekly during radiation): 
Consolidation  
(1 cycle = 21 
days, 2 cycles 
total) 
Adjuvant 
Immuno-
therapy 
(Q21days 
to complete 
1 Year) 
Treatment 
Completion/
ET Visite 
Follow-up visit 
(months after the 
termination of 
treatment) 
3 
6 
12 
Day 
-60 -42 -28 -16 
0 C1D1 C2D1 C3D1 C4D1 D1 D8 D15 D22 D29 D36 C1D1 C2D1 
 
 
 
 
 
Other laboratory testsk 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Response assessmenti 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X – q 3 
months 
X 
X 
X 
X 
Concomitant 
medications 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse events 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECG 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Echocardiogramj 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (prior to 
first 
infusion) 
X 
 
 
 
PFTsd 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
QoL Assessmentsi 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X – q 3 
months 
 
 
 
 
Tumor Tissuef 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACD and heparin tubes 
for correlative 
researchg 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X – q 3 
months 
X 
 
 
 
Whole Blood Streckg 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X – q3 
months 
X 
X 
X 
X 
Abbreviation: ECG= electrocardiogram; ET= Early termination; PFT= pulmonary function tests; QoL= quality of life; 
a Heart rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 


                                                                                                    
 
 
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b Hemoglobin, hematocrit, platelet count, WBC count, percent and absolute differential count. If obtained during screening within 7 days of C1D1, need not be 
repeated on C1D1. 
c Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, total bilirubin, total protein, albumin, ALT, AST, LDH, alkaline phosphatase. If 
obtained during screening within 7 days of C1D1, need not be repeated on C1D1. 
d    Pulmonary Function Tests will be completed at the following time intervals and shall include spirometry and diffusion capacity testing: Prior to enrollment as 
pre-screening, between completion of induction immunotherapy and start of chemoradiotherapy, at 12 months after study entry 
e    Treatment completion refers to a subject’s completion of 12 months of study treatment, or early discontinuation of study treatment. For those who complete 
study treatment, the treatment completion visit should occur within 21 days of the last dose. 
f    FFPE blocks (preferred) or slides, see section 3.1.11. 
g   10 ml in two Streck tubes, 5 ml in two ACD tubes and 10 ml in two heparin tubes. C1D1 draw may be performed any time after registration and prior to study 
drug infusion. Samples should only be drawn M-Th per shipment requirements. 
h   CT scan for tumor measurements – This will be a CT of the chest with IV contrast (unless contra-indicated).  These scans will occur within 28 days prior to 
registration, after completion of the second cycle of induction immunotherapy but prior to the third cycle starting, and at least seven days after the completion 
of the last cycle of induction immunotherapy but no later than Day 1 of concurrent chemoradiotherapy.  CT of the entire chest with IV contrast obtained for 
radiotherapy simulation may serve as the third scan provided it is of diagnostic quality and read by a radiologist.  The CT scan at the after the completion of 
concurrent chemoradiotherapy will occur at least 14 days after the completion of chemoradiotherapy but no later than Day 1 of the consolidative 
chemotherapy.  During adjuvant immunotherapy, CT scans will be completed every 3 months, starting 3 months after the prior scan. 
i These assessments during adjuvant immunotherapy should be performed in the same timeframe as the CT scans. 
j Echocardiogram –   Required at screening, otherwise as clinically indicated at other timepoints. 
k Thyroid function testing (free T3 and free T4), Epstein-Barr virus (EBV) serology (EBNA IgG), hepatitis B virus (HBV) serology (HBsAg, antibodies against 
HBsAg, hepatitis B core antigen), and HCV serology (anti-HCV) as clinically indicated. HBV DNA test is required for patients who have known positive 
serology for anti HBc. HCV RNA test is required for patients who have known positive serology for anti HCV.


 
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6. Study Assessments and Procedures  
 
The flowchart of scheduled study assessments is provided in Section 5.  Patients will be closely 
monitored for safety and tolerability throughout the study.  All assessments must be performed and 
documented for each patient. 
 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable. 
 
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend that 
precludes the visit, the visit should be scheduled on the nearest following feasible date, with 
subsequent visits rescheduled accordingly. Systemic therapy visits with be within 3 days except 
within 1 day for the concurrent chemoradiotherapy portion. 
 
6.1. Medical History  
 
Medical history includes clinically significant diseases within the previous 5 years, smoking 
history, cancer history (including tumor characteristics such as hormone receptor status), 
prior cancer therapies and procedures, and all medications used by the patient within 7 days 
before the screening visit (including prescription, over-the-counter, and herbal/homeopathic 
remedies and therapies). 
 
6.2. Physical Examination and Vital Signs 
 
A complete physical examination will be performed at screening and at the treatment 
discontinuation visit and should include the evaluation of head, eye, ear, nose, and throat 
and cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems. 
 
A limited physical examination will be performed at other visits to assess changes from 
baseline abnormalities and any new abnormalities and to evaluate patient-reported 
symptoms.  New or worsened abnormalities should be recorded as AEs if appropriate. 
 
 
All patients should be monitored for symptoms of brain metastases.  Symptoms suggestive 
of new or worsening CNS metastases should prompt a full neurological examination.  A CT 
or magnetic resonance imaging (MRI) scan of the head should be done as clinically indicated 
to confirm or refute new or worsening brain involvement. 
 
Vital signs will include measurements of heart rate, systolic and diastolic blood pressures 
while the patient is in a seated position, and temperature. 
 
For the first infusion, the patient’s vital signs (heart rate, blood pressure, and temperature) 
should be determined within 60 minutes before, during (every 15 [± 5] minutes), and 
30 (± 10) minutes after the infusion.  For subsequent infusions, vital signs will be collected 
within 60 minutes before and within 30 minutes after the infusion.  Vital signs should be 
collected during the infusion only if clinically indicated.  Patients will be informed about 
the possibility of delayed post-infusion symptoms and instructed to contact their study 
physician if they develop such symptoms. 


 
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6.3. Laboratory Assessments  
 
Samples for hematology, serum chemistries, coagulation, urinalysis, and the pregnancy test 
will be analyzed at the study site’s local laboratory. Analysis of biomarkers on tumor and 
blood samples will be performed at a central laboratory. 
 
Local laboratory assessments will include the following: 
• 
Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential, and platelet count) 
• 
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, chloride, 
bicarbonate, calcium, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total 
protein, and albumin) 
• 
TSHHIV test 
• 
Pregnancy test, either serum or urine (for women of childbearing potential, including 
women who have had a tubal ligation) 
• 
Thyroid function testing (free T3, and free T4), Epstein-Barr virus (EBV) serology 
(EBNA IgG), hepatitis B virus (HBV) serology (HBsAg, antibodies against HBsAg, 
hepatitis B core antigen), and HCV serology (anti-HCV) as clinically indicated 
HBV DNA test is required for patients who have known positive serology for anti-HBc  
HCV RNA test is required for patients who have known positive serology for anti-HCV 
• 
Echocardiograms: 
o Echocardiograms will be obtained at the following time intervals: 
­ 
Prior to enrollment as pre-screening (required) 
­ 
Between completion of chemoradiotherapy and start of adjuvant 
immunotherapy (as clinically indicated) 
­ 
At study completion (as clinically indicated) 
• 
Pulmonary Function Testing: 
o Pulmonary Function tests will be completed at the following time intervals and 
shall include spirometry and diffusion capacity testing: 
­ 
Prior to enrollment as pre-screening 
­ 
Between completion of induction immunotherapy and start of 
chemoradiotherapy 
­ 
At 12 months after start of study therapy. 
 
7. Data and Specimen Submission 
 
7.1. Data Collection and Submission 
 


 
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Data collection for this study will be done through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application 
to all persons with the appropriate roles assigned in AFT CTMS System.  See Study Manual 
of Operations/Data Entry Guidelines for additional instructions. 
 
7.2. Biospecimen Collection, Shipping and Processing 
 
  
Tissue from a formalin-fixed biopsy of a tumor lesion not previously irradiated must be 
collected for integrated correlative PD-L1 biomarker analysis.  A fine needle aspirate or 
cytologic specimen will not be accepted. Core needle or excisional biopsies, or resected 
tissue is required. For core needle biopsies, 3 full cores are required to be submitted. Only 
patients with an adequate tissue biopsy submission are eligible for enrollment (see section 
3.1.9). 
 
7.3. Biospecimen Collection Schemas  
 
 
7.4. Biospecimen Logging and Tracking (AFT BioMS) 
 
Use of the AFT Biospecimen Management System (AFT.BioMS) is mandatory and all 
specimens must be logged and shipped via this system. AFT BioMS is a web-based system 
for logging and tracking all biospecimens collected on AFT trials. Authorized individuals 
may access AFT.BioMS through the AFT single sign on portal, using most standard web 
browsers (Safari, Firefox, Internet Explorer). For information on using the AFT.BioMS 
system, please refer to the ‘Help’ links on the BioMS webpage to access the on-line user 
manual, FAQs, and training videos.  
 
 
 
  Staff 


 
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members should familiarize themselves with the AFT.BioMS system and confirm that they 
are able to log into the system, prior to registering patients to the trial. 
 
After logging collected specimens in AFT.BioMS, the system will create a shipping 
manifest.  This shipping manifest must be printed and placed in the shipment container with 
the specimens. 
 
7.5. Biospecimen Shipping 
 
Biospecimen shipping kits will be available for collecting and shipping biospecimens at 
baseline and follow up collection time points.  Kits must be requested using the AFT.BioMS 
application. Instructions for using the AFT.BioMS kit request system may be found on the 
AFT.BioMS web site. 
 
Please note that: 
1. Tumor tissue for PD-L1 biomarker analysis MUST be submitted within 14 days 
of registration. 
2. A formalin fixed tissue block is preferred, but if a block cannot be sent then 
unstained tissue section slides may be sent as a substitute. 
3. If the tumor tissue (either newly obtained or from a previous diagnostic procedure) 
consists of needle core biopsy specimens, the block or slides submitted should 
contain at least three independent needle cores to ensure sufficient tumor and 
tumor representation for biomarker analysis. 
4. Whole blood collected in heparin and ACD tubes must be shipped within 24 hours 
of collection. Also note that blood in Heparin and ACD tubes will be shipped to 
an independent location (Ohio State University) and NOT the AFT biorepository 
at Washington University in St. Louis.  Proper use of the AFT.BioMS system will 
guide the user to ensure that the correct samples are shipped to the correct location. 
5. Whole blood collected in BCT (Streck) tubes must be shipped within 72 hours of 
collection. 
All submitted biospecimens must be physically labeled with the AFT patient number, 
patient’s initials and date of specimen collected.  A copy of the Shipment Packing Slip 
produced by BioMS must be printed and placed in the shipment with the specimens.  A 
printed, de-identified copy of the institutional surgical pathology report should also be 
included with the shipment of surgical pathology tissue samples.  Please be sure to use a 
method of shipping that is secure and traceable.  Ship specimens on Monday through 
Thursday only. Shipping by overnight service to assure receipt is required. Do not ship 
specimens on Fridays or Saturdays.  All specimens should be sent as directed by the address 
printed on each AFT.BioMS shipment manifest. 
 
7.6. Biospecimen Collection 
Specific instructions for biospecimen collection can be found in the correlative sciences 
manual. 
 
Screening/Registration 
 
The following biospecimens will be collected at screening: 
 
A.  MANDATORY- Slides for PD-L1 staining.  Four 4 micron, unstained tumor tissue 
sections from a formalin fixed / paraffin embedded (FFPE) tissue block containing tumor 


 
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tissue should be serially cut and mounted onto positively charged glass slides, with at least 
50 viable tumor cells. Slides must not be older than 60 days (freshly cut) although the FFPE 
blocks from which they originate may be older. Slides should be labeled with the patient 
study ID, institutional surgical pathology number, and serial cut number, i.e. 1-4. These 
must be submitted within 14 days of registration. 
 
B.  REQUIRED- Tumor tissue for additional correlative studies.  
 
C.  REQUIRED (if available)- For recurrent cases, tumor tissue from the primary case.  
If the patient is presenting with a recurrent tumor, and a tumor tissue block is available 
from the primary presentation case, a representative tumor tissue block from the original 
case or 1 H/E stained slide and tissue curls from that block should be submitted for 
correlative, comparative genomic studies.  The total number of tissue curls to submit will 
depend upon the cross sectional area of the tissue face. Slide, block, or tissue curls should 
be labeled with the patient study ID and institutional surgical pathology number.  
 
D.  REQUIRED- Whole blood in two ACD yellow tubes (10 ml).  Collect 5 mL of whole 
blood by standard venous phlebotomy into each of two ACD yellow tubes provided.  Tube 
should be labeled with patient study number, patient initials, and date / time of collection.  
After collection, invert the tube 10 times to ensure adequate mixing and anticoagulation.  
ACD tubes must be shipped within 24 hours of collection.  
 
E.  REQUIRED- Whole blood in two cell stabilization (Streck) tubes (20 ml).  Collect 
10 mL of whole blood by standard venous phlebotomy into each of two BCT (Streck) tubes 
provided.  Tube should be labeled with patient study number, patient initials, and date / 
time of collection.  After collection invert the tube 10 times to ensure adequate mixing and 
preservation.  Store tube at room temperature until ready for shipment. Whole blood 
collected in BCT (Streck) tubes must be shipped within 72 hours of collection. 
 
F.  REQUIRED- Whole blood in two heparin tubes (20 ml).  Collect 10 mL whole blood 
in each of two heparin tubes. Tube should be labeled with patient study number, patient 
initials, and date / time of collection.  After collection invert the tube 10 times to ensure 
adequate mixing and preservation.  Store tube at room temperature until ready for 
shipment.  Heparin tubes must be shipped within 24 hours of collection.   
 
Whole blood biospecimens will be collected at each of these 9 time points:  
Baseline (pre-treatment on C1D1 of induction immunotherapy) / D1 of concurrent 
chemoradiation therapy / D1 of consolidation chemotherapy / 3 months after consolidation 
chemotherapy during adjuvant immunotherapy / 6 months after consolidation 
chemotherapy during adjuvant immunotherapy / end of study 
Streck tubes only during follow-up: 3 months after end of treatment / 6 months after end of 
treatment / 12 months after end of treatment 
 
8. Study Treatment 
 
8.1. Treatment Plan 
 
Protocol treatment is to begin within 21 days of registration. Questions regarding treatment 
should be directed to the ALLIANCE Study Chair. 
 


 
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Protocol therapy will consist of induction (neoadjuvant) atezolizumab 1200 mg IV every 21 
days for 4 cycles followed by radiotherapy given with concurrent chemotherapy for six 
weeks. Consolidative chemotherapy will be given for two cycles after the completion of 
concurrent therapy.  Adjuvant atezolizumab will be administered as in the neoadjuvant 
portion of the trial every 21 days to complete a total of one year of therapy.  
 
Concurrent Therapy (1 cycle = 36 days):  
Concurrent Chemoradiotherapy will begin 21 to 28 days after completion of the last dose of 
induction immunotherapy. Chemotherapy and radiotherapy should be started within 1 day 
of each other. 
Patients will receive paclitaxel 50 mg/m2 by IV over 1 hour weekly with standard 
premedication followed by carboplatin AUC 2 by IV over 30-60 minutes for 6 weeks (days 
1,8,15,22,29,36). 
 
Consolidation (1 cycle = 21 days): 3-5 weeks following the end of radiotherapy, patients 
will receive paclitaxel 200 mg/m2 by IV over 3 hours followed by carboplatin AUC 6 by IV 
over 30-60 minutes on day 1 of each 21 day cycle for a total of 2 cycles (days 1 and 22).  
 
8.2. Radiotherapy  
 
All patients will receive a radiotherapy course using single daily fractions of 2 Gy for a total 
dose of 60 Gy. Conformal 3-dimensional or IMRT treatment planning will be utilized. CT 
scans for radiotherapy simulation should be performed within 16 days of start of 
radiotherapy. All treatment plans must be reviewed by the IROC Rhode Island Quality 
Assurance Review Center (QARC) prior to initiating therapy.  NOTE: Digital submission 
of treatment plans is required on this study. 
 
8.2.1. Target Volume Definitions 
 
The nomenclature and definitions of ICRU Reports 50 and 62 shall be followed in 
this study. 
 
The GTV will be the volume of tumor visible on CT or PET imaging or biopsy proven 
sites.  This will in general include lymph nodes within the mediastinum ≥ 1.0 cm in 
short diameter and/or PET positive lymph nodes. Information from PET imaging 
should be used to determine occult nodal areas as well as to accurately contour gross 
disease within areas of atelectasis. For areas within or near inflated lung tissue, lung 
window settings will be utilized for contouring.  For disease within or abutting the 
mediastinum, soft tissue window settings will be used.  
 
The GTV will be expanded based on motion assessment imaging to account for target 
motion and thus an internal target volume (ITV) will be created.   
 
A 0.5 cm (CTV) expansion of the ITV will be utilized to account for potential occult 
tumor involvement.  This can be edited back from areas were extension cannot occur 
(blood vessels, bone, chest wall, etc.) unless there is imaging evidence that inclusion 
would be logical.  Elective nodal irradiation of lymph nodes is not allowed on this 
study.  Only areas of gross disease as determined by contrast enhanced CT and PET 
imaging will be targeted. 
 


 
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The CTV will be expanded an additional uniform 5mm minimum to create a planning 
target volume (PTV) to which the radiotherapy dose will be prescribed.  This can be 
adjusted to no more than 1.0 cm if patient specific uncertainty requires additional 
planning margin. 
 
If patients have a complete response (CR) to induction immunotherapy, the target 
volume will be modified such that a CTV will be delineated to include the pre-
immunotherapy nodal stations in the hilum and mediastinum and as best as possible, 
the location of the original primary tumor.  The size of this CTV should take into 
account anatomic changes as a result of the response to therapy, i.e. diminishment in 
mediastinal width due to response.  This CTV will be expanded by 5mm to create a 
PTV. 
 
8.2.2. Treatment Techniques 
 
3D Conformal Planning or IMRT is required on this protocol.  Both planar and non-
coplanar field arrangements are acceptable.  If IMRT is used, patient specific IMRT 
QA will be required prior to treatment with the IMRT plan.   
• 
Patient Position  
A custom immobilization cast is encouraged but not required. All components 
of immobilization must, in conjunction with the image guidance being used, 
ensure that both interfraction set-up uncertainty and unaccounted for 
intrafraction motion be limited to less than 5mm (PTV margin).  Patients must 
be treated in the supine position.   
• 
Inhibition of effects of internal organ motion:   
Motion management with respiratory gating, active breathing control (ABC), 
or breath hold and monitoring techniques will be encouraged.  IMRT will be 
restricted to patients with less than 1cm of tumor motion on 4D imaging or 
utilizing of gating, ABC, or breath hold methods.  Abdominal compression as 
a method of minimizing respiratory motion is allowed.  The Motion 
Management Reporting Form shall be submitted to document the method used. 
 
• 
Image Guidance:  
A reliable method of daily image guidance will be utilized.  This can include 
but is not limited to daily conebeam imaging, fiducial marker tracking systems, 
kV – kV matching.   
 
8.2.3. Equipment 
 
• 
Modality - 3D Conformal or IMRT Radiotherapy  
• 
Energy - Megavoltage quality radiation will be used with a nominal energy of 
4-12 MV.  C0-60 treatment is not allowed on this protocol.  Proton therapy is 
not allowed on this protocol. 
• 
Geometry - The distance from the radiation source to the isocenter should not 
be less than 100 cm. 
3.3.1 
Target Dose 
• 
Prescribed Dose: 60 Gy in 30 fractions of 2.0 Gy per fraction given once daily. 


 
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• 
Dose Uniformity: The prescribed isodose volume will cover at least 95% of the 
PTV. The minimum PTV dose must not fall below 95% of the prescription 
dose. The maximum dose must not exceed a value that is 125% of the prescribed 
dose.  The minimum and maximum doses will be defined as the dose to a 0.1cc 
volume of the PTV.   
• 
Acceptable and Unacceptable Variations: Deviations from the above target 
coverage are not desirable, but are acceptable for treatment situations in which 
the target to critical structure geometry is challenging.  Variations Acceptable 
include: The prescribed dose can cover as little as 90% of the PTV.  The 
minimum dose to the PTV can likewise fall to 90% of the prescribed dose.  The 
maximum dose cannot exceed 130% of the prescribed dose. Unacceptable 
deviations occur if the variation acceptable limits are exceeded. Additionally, a 
deviation unacceptable is assigned if more than 1 cc of tissue outside the PTV 
receives > 120% of the prescribed dose. 
• 
Tissue Heterogeneity: All dose calculations will account for the density 
differences within the irradiated volume.   
• 
Approved Dose Algorithms: Planning must be performed using an approved 
dose calculation algorithm. Approved algorithms include: convolution 
superposition, collapsed cone convolution, and Monte Carlo. Contact QARC 
 for information regarding approved dose algorithms.  
• 
Additionally, the treatment planning system PlanUNC, which uses a 
Clarkson’s-integration with a 2-source model and modified Batho correction 
dose algorithm, will be allowed as part of this protocol based on successful 
irradiation of the standardized lung phantom in 2009. 
8.2.4. Imaging Requirements 
 
Computed tomography will be the primary image platform for targeting and 
treatment planning. The planning CT scans are encouraged to be done with IV 
contrast unless the patient has allergic problems with contrast or has renal 
insufficiency. Contrast will allow better distinction between tumor and adjacent 
normal tissue or atelectasis. Axial acquisitions with gantry 0 degrees will be required 
with spacing ≤ 3.0 mm between scans in the region of the tumor. Images will be 
transferred to the treatment planning computers via direct lines, disc, or tape. 
• 
The additional exception to the use of IV contrast with the CT planning scan 
will be if the restaging diagnostic CT of the chest at the completion of the 
induction immunotherapy occurs within 10 days (before or after) of the 
planning CT in such a way that it can be timely incorporated into the planning 
process and that the patient can start on time.  This will minimize the 
possibility of close-proximity contrast injections. 
 
Four-dimensional CT (4D-CT) is permitted and encouraged for the study. There are 
many valid approaches to defining target volumes and margins using multiple 
datasets representing different phases of the breathing cycle. These include but not 
limited to: 
a. the ITV (Internal Target Volume) concept from ICRU 62 with an appropriate 
margin accounting for geometric uncertainties (uniform 5 mm recommended) 
to define the PTV; this method is preferred for purposes of this protocol. 


 
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b. the mean target position with an appropriate margin to account for target motion 
and geometric uncertainties to define the PTV; 
c. two helical scans, one scan with the patient at inhale breath-hold and the second 
scan with patient at exhale breath-hold. 
Options B and C have inherently more uncertainty and the PTV margin will be a 
minimum of 7 mm with a maximum of 1 cm based on discretion of treating 
physician. The following will be required in terms of documenting target motion: 
1. For particular method of target motion suppression (abdominal compression, 
breath hold, etc.), keep a tally of target motion range for each patient treated. 
Describe clearly the method utilized in the measurement of range of target 
motion and provide estimated error of measurement. Justify the estimation of 
error. 
2. It is preferable to have information on range of motion along each axis of the 
patient’s body (sup-inf, ap-pa, lt-rt). In case such information is not available, 
provide range of motion in 1 or 2 directions with clear indication of the 
orientation of the axis along which the motion range is evaluated. 
3. In case of multiple measurements of ranges of motion (at simulations and/or at 
treatments, possibly pre- and post-treatments) provide information about the 
day and time when the data have been collected. 
4. When data for some patients/treatment fractions is not collected the record of 
the missing measurement has to be kept and reported. If there is a clinical reason 
for not collecting data, it needs to be reported as well. 
5. The reported range of motion has to be separated from setup errors. 
 
A treatment planning FDG PET/CT scan (or FDG-PET alone) with the patient in 
the treatment position may be utilized to aid in treatment planning.  If no dedicated 
treatment planning PET imaging is available then the staging PET imaging must be 
reviewed by the treating physician in order to accurately contour the target areas. 
 
8.2.5. Time-dose Considerations 
 
Treatment will be delivered in single daily fractions, 5 fractions per week.   
 
Adjustments for Treatment Interruptions: There are no planned radiotherapy rests. 
Treatment interruptions are strongly discouraged. The Study Chair should be notified 
for treatment interruptions > 3 days not including weekends and traditional holidays. 
 
8.2.6. Contouring of Normal Tissue Structures  
 
Spinal Cord  
The spinal cord will be contoured based on the bony limits of the spinal canal. The 
spinal cord should be contoured starting at the level of the cricoid cartilage and 
extending to the level of the GE junction. In short, this should include the same 
contouring range as that for the esophagus. 
 
Esophagus  


 
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The esophagus will be contoured using mediastinal windowing on CT to 
correspond to the mucosal, submucosa, and all muscular layers out to the fatty 
adventitia. The esophagus should be contoured starting at the cricoid cartilage and 
extend inferiorly to the level of the GE junction.  
 
Brachial Plexus  
The defined ipsilateral brachial plexus originates from the spinal nerves exiting the 
neuroforamina on the involved side from C5 to T2. The brachial plexus will consist 
of the actual roots and trunks of the brachial plexus without including the surrogate 
vasculature.  The plexus will be outlined starting from the C5 nerve root and ending 
at the sublavian neurovascular bundle.  Please refer to Kong et al IJROBP 2010 
thoracic radiotherapy contouring atlas for description of contouring techniques.36 
 
Heart  
The heart will be contoured along with the pericardial sac. The superior aspect (or 
base) for purposes of contouring will begin at the level of the root of the great vessels 
and extend inferiorly to the apex of the heart.  
 
Whole Lung  
Both the right and left lungs should be contoured as one structure. Contouring should 
be carried out using pulmonary windows. All inflated and collapsed lung should be 
contoured; however, gross tumor (GTV) and trachea/ipsilateral bronchus when 
contouring structure should not be included in this structure.  
 
Chest Wall 
Although no specific dose constraints will be used, the dose to the chest wall is of 
interested and will be required.  The chest wall is defined as 3cm thick expansion of 
the lung contour toward the periphery of the patient subtracting the lung and 
mediastinal contents.  
 
Bronchial Tree 
The dose to the proximal bronchial tree will not be restricted but recorded for this 
protocol in order to potentially learn some dose constraint for hypofractionated 
therapy with regard to this organ.  The bronchial tree will be defined as the distal 2 
cm of trachea and include the mainstem bronchi, and lobar bronchi to the level of the 
segmental bronchi.  Please refer to Kong et al IJROBP thoracic contouring atlas for 
detailed descriptions.36 
 
8.2.7. Normal Tissue Sparing 
 
The following dose constraints will be followed: 
Lung  
V20 > 35% will be a minor deviation, V20 > 40% will be a major deviation.  
Mean Lung Dose will be recorded and in general should be kept below 20 Gy 


 
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although the V20 constraints will be utilized as the dose limitations for 
purposes of this protocol. 
Heart 
The heart will be treated with the following limits: V50 < 25% and mean heart 
dose < 20 Gy. 
Spinal Cord 
The maximum cumulative dose to any contiguous volume ≥ 0.03 cc in the 
spinal cord will be: 50.0 Gy. 
Esophagus 
The esophagus is in general located in close proximity to nodal areas involved 
in stage 3 NSCLC and therefore is challenging to limit the total dose without 
sacrificing tumor coverage.  In general < 30% of the contoured esophagus 
will be allowed to receive a dose > 55 Gy.  This is also not an absolute 
requirement but maximum dose to a contiguous 5cc of the esophagus will be 
limited to ≤ 105% of the prescription dose when feasible. 
Brachial Plexus 
The maximum cumulative dose to any contiguous volume ≥ 0.03 cc in the 
brachial plexus will be:  62.1 Gy. 
 
8.2.8. Quality Assurance Documentation 
 
Digital Submission: 
Submission of treatment plans in digital format as 
DICOM RT is required. Digital data must include CT scans, structures, plan and 
dose files. Submission may be either by SFTP or CD. Instructions for data 
submission are on the QARC web site at 
Any items on the list 
below that are not part of the digital submission may be submitted as screen 
captures along with the digital data. 
Prior to the start of radiotherapy, the following data should be submitted for 
pre-treatment review: 
Treatment Planning System Output 
• 
RT treatment plan including CT, structures, dose, and plan files.  These 
items are included in the digital plan. 
• 
Dose volume histograms (DVH) of the GTV, spinal cord, chest wall, heart, 
esophagus, and liver.  When using IMRT, a DVH shall be submitted for a 
category of tissue called “unspecified tissue.”  This is defined as tissue 
contained within the skin, but which is not otherwise identified by 
containment within any other structure.  DVH’s are included in the digital 
plan. 
• 
Digitally reconstructed radiographs (DRR) for each treatment field.  DRR's 
are not required for IMRT. 
• 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of 
interest dose statistics. 
Supportive Data 


 
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• 
Copies and reports of CT scans, PET scans, and other diagnostic materials 
used for planning target volumes. 
• 
Prescription Sheet for Entire Treatment  
• 
If the recommended doses to the organs at risk are exceeded, an explanation 
should be included for review by QARC and the radiation oncology 
reviewers. 
Forms 
• 
RT-1 Dosimetry Summary Form 
• 
Motion Management Reporting Form 
Within one week of the completion of radiotherapy the following data shall be 
submitted.   
• 
The RT-2 Radiotherapy Total Dose Record form. 
• 
A copy of the patient’s radiotherapy record including prescription, and the 
daily and cumulative doses to all required areas, critical organ and reference 
points 
• 
Documentation listed above showing any modifications from original 
submission. 
 
Supportive Data and Forms may be included with the transmission of the digital RT data 
via sFTP or submitted separately via e-mail.  
 
 
 
 
 
 
 
 
 
 
 
Questions regarding the dose calculations or documentation should be directed to: 
 
 
 
 
 
 
 
8.2.9.  Definitions of Deviations in Protocol Performance 
Prescription Dose 
• 
 Variation Acceptable: The dose to the prescription isodose surface 
differs from that in the protocol by between 6% and 10%. 
• 
 Deviation Unacceptable: The dose to the prescription isodose surface 
differs from that in the protocol by more than 10%. 


 
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Dose Uniformity 
• 
 Variation Acceptable: The prescribed dose covers between 90% and 
95% of the PTV or the minimum dose to 1 cc of the PTV is between 90% 
and 95% of the prescribed dose or the maximum dose to 1 cc of the PTV 
exceeds 130% of the prescribed dose. 
• 
 Deviation Unacceptable: The prescribed dose covers less than 90% of 
the PTV or the minimum dose to 1 cc of the PTV is less than 90% of the 
prescribed dose or the maximum dose to 1 cc of tissue outside the PTV 
exceeds 120% of the prescribed dose. 
Volume 
• 
 Variation Acceptable: Margins less than specified, or field(s) excessively 
large as deemed by the study chair. 
• 
 Deviation Unacceptable: GTV incorrectly defined resulting in fields that 
transect tumor. 
Critical Organ 
• 
 Variation Acceptable: The lung V20 exceeds 35%; the dose to the heart, 
esophagus, or brachial exceeds the limits specified in Section 9.2.8. 
• 
 Deviation Unacceptable: The maximum dose to the spinal cord exceeds 
the limits specified in Section 9.2.8 or the lung V20 exceeds 40%. 
 
8.3. Chemotherapy and immunotherapy 
Patients will receive induction and adjuvant immunotherapy as well as concurrent 
chemoradiotherapy followed by consolidation chemotherapy (cycles 1 and 2).  
 
Induction immunotherapy: Atezolizumab 1200 mg IV every 21 days for 4 cycles 
following the manufacturer’s instructions for mixing and administration. 
 
8.3.1. Concurrent Chemoradiotherapy (1 cycle = 36 days) 
 
Paclitaxel* at 50 mg/m2 by IV over 1 hour on days 1, 8, 15, 22.29, 36 
Carboplatin** AUC 2 by IV over 30 minutes on days 1, 8, 15, 22.29, 36 following 
the paclitaxel administration 
*Premedications for Paclitaxel and carboplatin should be given as per institutional 
standards of the treating institution 
1.  
** The Calvert equation (Dose = AUC X [GFR + 25]) will be used to calculate 
carboplatin dose. The GFR will be estimated by the Crockoft-Gault formula as 
follows: 
 
A maximum calculated GFR of 125 ml/min will be used for both men and women. 
Institutional standard may be used for paclitaxel and carboplatin dosing 
calculations. 


 
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8.3.2.  Consolidation Chemotherapy (1 cycle = 21 days, 2 cycles to be administered) 
Consolidation chemotherapy will begin 3-5 weeks after completion of radiotherapy. 
If the patient is unable to begin chemotherapy by the 5 week time point following 
radiotherapy, the chemotherapy may be delayed up to an additional 4 weeks.  If the 
chemotherapy cannot be given during this time interval, the patient will be 
considered off protocol treatment. Patients will be required to have ANC ≥ 
1,500/mm3 and platelet count ≥100,000 mm3 to start consolidation chemotherapy. 
Paclitaxel* at 200 mg/m2 by IV over 3 hours on day 1 of each 21 day cycle 
Carboplatin** AUC 6 by IV over 30-60 minutes on day 1 of each 21 day cycle, 
following the paclitaxel administration 
*Premedications for Paclitaxel and carboplatin should be given as per institutional 
standards of the treating institution 
** The Calvert equation (Dose = AUC X [GFR + 25]) will be used to calculate carboplatin 
dose. The GFR will be estimated by the Crockoft-Gault formula as follows: 
 
A maximum calculated creatinine clearance of 125 ml will be used for both men 
and women. Serum CR 0.7 minimum for calculating. 
At the treating physician’s discretion, institutional standard dosing for carboplatin 
and paclitaxel may be used, using actual body weight in the calculation of drug 
doses. 
 
8.3.3.  Adjuvant Immunotherapy 
 
Adjuvant atezolizumab will be administered as in the neoadjuvant portion of the 
trial every 21 days to complete a total of one year of therapy. 
 
8.4. Study drug - Investigational Product (IP) 
 
8.4.1.  Study Drug:  Atezolizumab 
 
8.4.2. Once marketing authorization is received commercial atezolizumab will be used 
and will not be provided by Genentech for “on-label” studies.  For studies done 
before marketing authorization and/or "out of label", atezolizumab will be provided 
free of charge by Genentech but switched to commercial drug once marketing 
authorization is received.  Genentech will replace any atezolizumab drug that is not 
reimbursed.  For studies done “out of label,” atezolizumab will be provided free of 
charge by Genentech. The Sponsor-investigator of the study will ensure 
maintenance of complete and accurate records of the receipt, dispensation, and 
disposal or return of all study drug in accordance with 21 Code of Federal 
Regulations (CFR), Part 312.57 and 312.62, and Genentech requirements.  
Formulation 
 
The atezolizumab drug product is provided in a single-use, 20-cc USP/Ph. Eur. Type 
1 glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid 


 
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solution intended for IV administration.  The vial is designed to deliver 20 mL (1200 
mg) of atezolizumab solution but may contain more than the stated volume to enable 
delivery of the entire 20 mL volume.  The atezolizumab drug product is formulated 
as 60 mg/mL atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% 
polysorbate 20, pH 5.8. 
Atezolizumab must be refrigerated at 2°C - 8°C (36°F - 46°F) upon receipt until 
use.  Atezolizumab vials should not be used beyond the expiration date provided by 
the manufacturer.  No preservative is used in the atezolizumab drug product; 
therefore, each vial is intended for single use only.  Discard any unused portion of 
drug left in a vial.  Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
For further details, see the Atezolizumab Investigator’s Brochure. 
8.4.3.  Dosage, Administration, and Storage 
 
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an 
average body weight−based dose of 15 mg/kg) administered by IV infusion 
every 3 weeks (21 [± 2] days).  Atezolizumab will be delivered in infusion bags with 
IV infusion lines that have product contacting surfaces of polyvinyl chloride (PVC) 
or polyolefin and 0.2 µm in-line filters (filter membrane of polyethersulfone [PES]).  
No incompatibilities have been observed between ATEZOLIZUMAB and PVC or 
polyolefin infusion materials (bags or infusion lines).  
Administration of atezolizumab will be performed in a setting with emergency 
medical facilities and staff who are trained to monitor for and respond to medical 
emergencies. 
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes.  If the 
first infusion is tolerated without infusion-associated AEs, the second infusion may 
be delivered over 30 (± 10) minutes.  If the 30-minute infusion is well tolerated, 
all subsequent infusions may be delivered over 30 (± 10) minutes.  For the first 
infusion, the patient’s vital signs (heart rate, blood pressure, and temperature) should 
be determined within 60 minutes before, during (every 15 [± 5] minutes), and 
30 (± 10) minutes after the infusion.  For subsequent infusions, vital signs will be 
collected within 60 minutes before and within 30 minutes after the infusion.  Vital 
signs should be collected during the infusion only if clinically indicated.  Patients 
will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms. 
No premedication will be allowed for the first dose of atezolizumab.  Premedication 
may be administered for Cycles ≥ 2 at the discretion of the treating physician.  The 
management of IRRs will be according to severity as follows: 
a. In the event that a patient experiences a mild (NCI CTCAE Grade 1) 
IRR, the infusion rate should be reduced to half the rate being given at 
the time of event onset.  Once the event has resolved, the investigator 
should wait for 30 minutes while delivering the infusion at the reduced 


 
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rate.  If tolerated, the infusion rate may then be increased to the original 
rate. 
b. In the event that a patient experiences a moderate IRR (NCI CTCAE 
Grade 2) or flushing, fever, or throat pain, the infusion should be 
immediately interrupted and the patient should receive aggressive 
symptomatic treatment.  The infusion should be restarted only after the 
symptoms have adequately resolved to baseline grade.  The infusion rate 
at restart should be half of the infusion rate that was in progress at the 
time of the onset of the IRR. 
c. For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the 
infusion should be stopped immediately, and aggressive resuscitation 
and supportive measures should be initiated.  Patients experiencing 
severe or life-threatening IRRs will not receive further infusion and will 
be further managed as clinically indicated until the event resolves. 
For anaphylaxis precautions, see Appendix  6. 
 
Guidelines for dosage modification, treatment interruption, or discontinuation and the 
management of specific adverse events are provided in Section 12 and Section 9, 
respectively. 
8.5. Non-Investigational Product (Non IP) 
 
Carboplatin, paclitaxel and all routine pre-medications will be obtained from standard 
commercial sources and administered according to the manufacturers’ and institutional 
guidelines. 
 
8.6. Dose and Treatment Modifications 
 
8.6.1.  General Guidelines  
 
Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious AEs, defined and graded according to NCI CTCAE v4.0.  Patients will 
be assessed for safety (including laboratory values) according to the schedule in 
Protocol Section 5.  Patients will be followed for safety for 90 days following the last 
dose of study treatment or until receipt of another anticancer therapy, whichever 
comes first.   
General safety assessments will include serial interval histories, physical 
examinations, and specific laboratory studies, including serum chemistries and blood 
counts (see Protocol Section 5for the list and timing of study assessments).  
All serious adverse events (SAEs) and protocol-defined events of special interest 
(see Section 12.3.2.10) will be reported in an expedited fashion (see Section 
12.3.3.3).  In addition, the investigators will review and evaluate observed AEs on a 
regular basis. 
Patients who have an ongoing study treatment−related AE upon study completion    
or at discontinuation from the study will be followed until the event has resolved to 


 
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baseline grade, the event is assessed by the investigator as stable, new anticancer 
treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, 
or until it has been determined that study treatment or participation is not the cause 
of the AE. 
8.6.1.1. 
Management of Specific Safety Concerns with Atezolizumab 
 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as 
autoimmune serology or biopsies, may be used to determine a possible 
immunogenic etiology. 
Although most immune-related adverse events (irAEs) observed with 
immunomodulatory agents have been mild and self-limiting, such events should 
be recognized early and treated promptly to avoid potential major complications.  
Discontinuation of atezolizumab may not have an immediate therapeutic effect 
and, in severe cases, immune-related toxicities may require acute management 
with topical corticosteroids, systemic corticosteroids, mycophenolate, or TNFα 
inhibitors. 
The primary approach to Grade 1 to 2 irAEs is supportive and symptomatic care 
with continued treatment with atezolizumab; for higher-grade irAEs, 
Atezolizumab should be withheld and oral and/or parenteral steroids administered.  
Recurrent Grade 2 irAEs may also mandate withholding atezolizumab or the use 
of steroids.  Assessment of the benefit-risk balance should be made by the 
investigator, with consideration of the totality of information as it pertains to the 
nature of the toxicity and the degree of clinical benefit a given patient may be 
experiencing prior to further administration of atezolizumab.  Atezolizumab 
should be permanently discontinued in patients with life-threatening irAEs. 
Please refer to the IB for management of specific irAEs and guidelines for dose 
modifications in specific circumstances. 
8.6.2.  Dose Modifications 
 
Atezolizumab treatment will be given as long as the patient continues to experience 
clinical benefit in the opinion of the investigator until the earlier of unacceptable 
toxicity, symptomatic deterioration attributed to disease progression, or any of the 
other reasons for treatment discontinuation listed in Section 9. 
There will be no dose reduction for atezolizumab in this study.  Patients may 
temporarily suspend study treatment for up to 84 days beyond the scheduled date of 
delayed infusion if study drug-related toxicity requiring dose suspension is 
experienced.  If atezolizumab is held because of AEs for > 84 days beyond the 
scheduled date of infusion, the patient will be discontinued from atezolizumab and 
will be followed for safety and efficacy as specified in Section 12.1. 
If a patient must be tapered off steroids used to treat AEs, atezolizumab may be held 
for additional time beyond 84 days from the scheduled dose until steroids are 
discontinued or reduced to a prednisone dose (or dose equivalent) of ≤ 10 mg/day.  
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Dose holds do not affect dosing or assessment schedules. 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may 
be allowed.  The acceptable length of interruption will be at the discretion of the 
Sponsor. 
Any toxicities associated or possibly associated with atezolizumab treatment should 
be managed according to standard medical practice.  Additional tests, such as 
autoimmune serology or biopsies, may be used to determine a possible immunogenic 
etiology.  Although most irAEs observed with immunomodulatory agents have been 
mild and self-limiting, such events should be recognized early and treated promptly 
to avoid potential major complications.  Discontinuation of atezolizumab may not 
have an immediate therapeutic effect, and there is no available antidote for 
atezolizumab.  In severe cases, immune-related toxicities may be acutely managed 
with topical corticosteroids, systemic corticosteroids, mycophenolate, or TNFα 
inhibitors. 
Patients should be assessed clinically (including review of laboratory values) for 
toxicity prior to, during, and after each infusion.  If unmanageable toxicity due to 
atezolizumab occurs at any time during the study, treatment with atezolizumab 
should be discontinued. 
Management of hepatitis/transaminitis, colitis, rash, and hypothyroidism are 
presented in this section as they have been observed in this study and are potentially 
immune related.  See appendix 4 for guidelines for the management of IRRs (see 
Appendix 6 for precautions for anaphylaxis). 
8.6.2.1. 
Gastrointestinal Toxicity 
 
Immune-mediated colitis has been associated with the administration of 
atezolizumab. 
 
Patients should be advised to inform the investigator if any diarrhea occurs, even 
if it is mild. 
 
If the event is of significant duration or magnitude, or is associated with signs of 
systemic inflammation or acute phase reactants (e.g., increased CRP or platelet 
count or bandemia), it is recommended that sigmoidoscopy (or colonoscopy, if 
appropriate) with colonic biopsy with three to five specimens for standard paraffin 
block be performed.  If possible, one or two biopsy specimens should be snap 
frozen and stored.     
Treatment may be restarted following the resolution of colitis.  In addition, if the 
patient is being managed with corticosteroids, treatment should not be restarted 
until the steroids have been tapered down to a prednisone dose ≤ 10 mg/day.  
Patients who resume treatment should be monitored closely for signs of renewed 
diarrhea.  Table 1 provides a summary of dose modification guidelines for 
gastrointestinal toxicities. 
 


 
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Table 1 
Dose Modification Guidelines for Gastrointestinal Toxicity 
Toxicity 
Description 
Management 
Diarrhea 
Grade 2 (4−6 stools per day 
over baseline) < 5 days 
Hold atezolizumab and 
discontinue NSAIDS (or other 
medications known to 
exacerbate colitis). 
Investigate for etiology.  
Restart atezolizumab once at 
baseline stool frequency. 
Grade 2 (4−6 stools per day 
over baseline) > 5 days 
Hold atezolizumab and 
discontinue NSAIDS (or other 
medications known to 
exacerbate colitis) while 
etiology is being investigated.  
Consider referral to a 
gastroenterologist. 
Administer anti-diarrheal 
agent (e.g., Imodium). 
Consider oral budesonide, 
mesalamine, or 10 mg oral 
prednisone equivalent per day.   
Restart atezolizumab once at 
baseline stool frequency. 
Abdominal pain 
 
Blood or mucus in stool 
 
OR 
 
Grade ≥ 3 (≥ 7 stools/day 
over baseline) with peritoneal 
signs, ileus, or fever 
Hold atezolizumab and 
discontinue NSAIDS (or other 
medications known to 
exacerbate colitis). 
Rule out bowel perforation.  
Consider administering 
prednisone 60 mg/day or 1-2 
mg/kg/day or equivalent.  
Taper steroids over 1 month.  
Restart atezolizumab if 
diarrhea is resolved and 
systemic steroid dose is ≤ 10 
mg oral prednisone equivalent 
per day. 
Permanently discontinue 
atezolizumab for 
life-threatening, 
immune-related diarrhea or 
colitis. 
NSAID = nonsteroidal anti-inflammatory drug. 
  
8.6.2.2. 
Hepatotoxicity 
 
Immune-mediated hepatitis has been associated with the administration of 
atezolizumab. 


 
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While in this study, patients presenting with right upper-quadrant abdominal pain 
and/or unexplained nausea or vomiting should have LFTs performed immediately, 
and LFTs should be reviewed before administration of the next dose of study drug. 
 
If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic 
etiologies should be considered and addressed, as appropriate.  Imaging of the 
liver, gall bladder, and biliary tree should be performed to rule out neoplastic or 
other causes of increased LFTs.  Anti-nuclear antibody, perinuclear anti-neutrophil 
cytoplasmic antibody, anti-liver kidney microsomal, and anti-smooth muscle 
antibody tests should be performed if an autoimmune etiology is considered. 
 
Patients with LFT abnormalities should be managed according to the guidelines 
in Table 2. 
 
Table 2 
Dose Modification Guidelines for Hepatotoxicity 
Toxicity 
Description 
Management 
LFT abnormalities 
AST/ALT (> ULN to 
3 × ULN) with total 
bilirubin < 2 × ULN 
Continue with the standard monitoring 
plan (i.e., LFTs every 3 weeks before 
dosing). 
AST/ALT (> 3 × ULN to  
< 10 × ULN) with total 
bilirubin < 2 × ULN 
Continue atezolizumab.   
Monitor LFTs at least weekly.   
Consider referral to a hepatologist. 
AST/ALT > 10 × ULN 
Hold atezolizumab.   
Consider administering IV steroids for 
24−48 hours (prednisone 60 mg/day or 1-
2 mg/kg/day or equivalent) followed by 
an oral prednisone (or equivalent) taper 
over 2−4 weeks.  If LFT results do not 
decrease within 48 hours after initiation 
of systemic steroids, addition of an 
alternative immunosuppressive agent 
(e.g., mycophenolate or TNFα 
antagonist) to the corticosteroid regimen 
may be considered.  Monitor LFTs every 
48−72 hours until decreasing and then 
follow weekly.   
Restart atezolizumab if AST/ALT 
≤ 3 × ULN with bilirubin < 2 × ULN and 
steroid dose is ≤ 10 mg oral prednisone 
equivalent per day. 
Permanently discontinue atezolizumab 
for life-threatening, immune-related 
hepatic events. 
 


 
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Table 2 
Dose Modification Guidelines for Hepatotoxicity (cont.) 
Toxicity 
Description 
Management 
LFT abnormalities  
(cont.) 
AST/ALT ≥ 3 × ULN with 
bilirubin > 2 × ULN 
Hold atezolizumab.   
Consult a hepatologist.   
Consider administering IV steroids for 
24−48 hours (prednisone 60 mg/day or 1-
2 mg/kg/day or equivalent) followed by 
oral taper over 1 month.  If LFTs results 
do not decrease within 48 hours after 
initiation of systemic steroids, addition of 
an alternative immunosuppressive agent 
(e.g., mycophenolate or TNFα antagonist) 
to the corticosteroid regimen may be 
considered.  Monitor LFTs every 
48−72 hours until decreasing and then 
follow weekly.  Restart atezolizumab if 
AST/ALT ≤ 3 × ULN with bilirubin 
< 2 × ULN and steroid dose is ≤ 10 mg 
oral prednisone equivalent per day. 
IV = intravenous; LFT = liver function test; TNFα = tumor necrosis factor alpha; ULN = upper 
limit of normal. 
  
8.6.2.3. 
Dermatologic Toxicity 
 
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self-limited, with or without pruritus. 
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be performed unless contraindicated.  Low-grade rash and pruritus irAEs 
have been treated with symptomatic therapy (e.g., antihistamines).  Topical or 
parenteral corticosteroids may be required for more severe symptoms. 
 
Dermatologic toxicity and rash should be managed according to the guidelines in 
Table 3. 


 
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Table 3 
Dose Modification Guidelines for Dermatologic Toxicity 
Toxicity 
Description 
Management 
Dermatologic toxicity/rash 
(e.g., maculopapular or 
purpura) 
Grade 1:  Mild 
< 10% BSA 
Continue atezolizumab 
symptomatic therapy with 
antihistamine PRN. 
Consider topical steroids 
and/or other symptomatic 
therapy (e.g., antihistamines). 
Grade 2:  Moderate  
10%−30% BSA 
Continue atezolizumab.  
Consider dermatologist 
referral. 
Administer topical steroids. 
Consider higher potency 
topical steroids if rash is 
unresolved. 
Grade 3:  Severe  
> 30% BSA 
Hold atezolizumab.   
Consult dermatologist.  
Administer oral prednisone 
10 mg or equivalent.  If the 
rash is unresolved after 48−72 
hours, administer oral 
prednisone 60 mg or 1-2 
mg/kg/day or equivalent. 
Restart atezolizumab if rash is 
resolved and systemic dose is 
≤ 10 mg oral prednisone 
equivalent per day. 
Permanently discontinue 
atezolizumab for 
life-threatening, 
immune-related dermatologic 
toxicity. 
BSA = body surface area; PRN = as needed. 
  
8.6.2.4. 
Endocrine Toxicity 
 
Hypothyroidism has been associated with the administration of atezolizumab. 
 
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental 
status changes, or constipation should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies, as well as for hyponatremia or 
hyperkalemia.  An endocrinologist should be consulted if an endocrinopathy is 
suspected.  Thyroid-stimulating hormone (TSH) and free T4 levels should be 
obtained to determine whether thyroid abnormalities are present.  TSH, prolactin, 
and a morning cortisol level will help to differentiate primary adrenal insufficiency 
from primary pituitary insufficiency. 
 
Hypothyroidism should be managed according to the guidelines in Table 4. 


 
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Table 4 
Dose Modification Guidelines for Endocrine Toxicity 
Toxicity 
Description 
Management 
Hypothyroidism 
TSH elevated, asymptomatic 
Continue atezolizumab.   
Start thyroid-replacement 
hormone.   
Monitor TSH weekly. 
TSH elevated, symptomatic 
Hold atezolizumab.   
Consider referral to an 
endocrinologist.    
Restart atezolizumab when 
symptoms are controlled by 
thyroid replacement and TSH 
levels are decreasing.  
TSH = thyroid-stimulating hormone. 
  
8.6.2.5. 
Pulmonary Toxicity 
 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have 
been associated with the administration of atezolizumab and have primarily been 
observed in patients with underlying NSCLC. 
 
Mild-to-moderate events of pneumonitis have been reported with atezolizumab.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease (COPD), or 
pulmonary hypertension and the following should be performed: 
a. Measurement of oxygen saturation (i.e., arterial blood gas) 
b. High-resolution CT scan of the chest 
c. Bronchoscopy with bronchoalveolar lavage and biopsy 
d. Pulmonary function tests (with diffusion capacity of the lung for carbon 
monoxide [DLCO]) 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study.  
Patients will also have CT scans of the chest at every tumor assessment 
(see Section 10.3.2). 
Pulmonary toxicity should be managed according to the guidelines in Table 5. 


 
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Table 5 
Dose Modification Guidelines for Pulmonary Toxicity 
Toxicity 
Description 
Management 
Pulmonary toxicity 
GGO or non-infectious 
infiltrate in absence of 
hypoxia, or dyspnea 
Hold treatment with 
atezolizumab.   
Re-evaluate after 1 week. 
If no worsening in 
GGO/infiltrates and patient 
still asymptomatic, resume 
treatment with atezolizumab. 
If GGO/infiltrates worsen and 
patient is still asymptomatic, 
continue to hold atezolizumab 
and refer for bronchoscopy.  
Consider starting low-dose 
oral prednisone 10 mg or 
equivalent.   
Re-evaluate after 1 week.  
Resume atezolizumab if 
GGO/infiltrates improving.  
Hypoxia or dyspnea in 
presence of GGO or infiltrate 
without alternative etiology 
Hold atezolizumab.   
Consult a pulmonologist.  
Investigate for other etiologies 
and consider bronchoscopy.  
If bronchoscopy is consistent 
with immune-related etiology, 
start 60 mg or 1-2 mg/kg 
prednisone equivalent per day 
followed by taper over 
2 weeks.  
Restart atezolizumab if 
symptomatically improved, 
infiltrates are resolved, and 
steroid use is ≤ 10 mg 
prednisone equivalent per day. 
Permanently discontinue 
atezolizumab for 
life-threatening, 
immune-related pulmonary 
events. 
GGO = ground glass opacities. 
  
8.6.2.6. 
Pericardial and Pleural Effusions 
 
 
Pericardial and pleural involvement with associated effusions is common in 
patients with cancer and has the theoretical potential to be exacerbated by 
inflammation associated with anti-tumor immunity following PD-L1 blockade.  
Patients presenting with dyspnea, chest pain, or unexplained tachycardia should be 
evaluated for the presence of a pericardial effusion.  Patients with pre-existing 
pericardial effusion should be followed closely for pericardial fluid volume 
measurements and impact on cardiac function.  When intervention is required for 


 
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pericardial or pleural effusions, appropriate workup includes cytology, LDH, 
glucose, cholesterol, protein concentrations (with pleural effusions), and cell count.  
For patients with a pericardial effusion causing end-diastolic right ventricular 
collapse, treatment may be restarted following the placement of a pericardial 
window, demonstration of hemodynamic stability, and resolution of right 
ventricular dysfunction. 
 
8.6.2.7. 
Potential Pancreatic Toxicity 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with administration of other 
immunomodulatory agents.  The differential diagnosis of acute abdominal pain 
should include pancreatitis.  Appropriate workup should include an evaluation for 
obstruction, as well as serum amylase and lipase tests (see also Section 8.6.2.4). 
8.6.2.8. 
Potential Eye Toxicity 
 
An ophthalmologist should evaluate visual complaints.  Uveitis or episcleritis may 
be treated with topical corticosteroid eye drops.  Atezolizumab should be 
permanently discontinued for immune-mediated ocular disease that is 
unresponsive to local immunosuppressive therapy. 
Ocular toxicity should be managed according to the guidelines in Table 6. 
Table 6 
Dose Modification Guidelines for Eye Toxicity 
Toxicity 
Description 
Management 
Eye toxicity (autoimmune 
uveitis, iritis, or episcleritis) 
Symptomatic 
Hold atezolizumab.   
Consult ophthalmologist and 
start topical corticosteroid eye 
drops.   
Atezolizumab may be 
restarted following resolution 
of the events. 
Permanently discontinue 
atezolizumab for 
immune-mediated ocular 
disease that is unresponsive to 
local immunosuppressive 
therapy. 
 
8.7. Concomitant Medications 
8.7.1.  Concomitant Therapy 
 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation 
and the treatment discontinuation visit. 
 
Patients who experience infusion-associated symptoms may be treated 
symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or 


 
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cimetidine or another H2 receptor antagonist, as per standard practice (for sites 
outside the United States, equivalent medications may be substituted per local 
practice).  Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and β2-adrenergic agonists; see Appendix ). 
 
Systemic corticosteroids and TNFα inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician.  If feasible, alternatives to corticosteroids should 
be considered.  Premedication may be administered for Cycles ≥ 2 at the discretion 
of the treating physician.  The use of inhaled corticosteroids and mineralocorticoids 
(e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical 
insufficiency is allowed.  Megastrol administered as appetite stimulant is acceptable 
while the patient is enrolled in the study.   
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low-molecular-weight heparin or 
warfarin at a stable dose level), or other allowed maintenance therapy should continue 
their use.  Males and females of reproductive potential should use highly effective 
means of contraception.  
8.7.2.  Excluded Therapy 
 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited.  This includes but is not limited to 
the following: 
• 
Chemotherapy, 
hormonal 
therapy, 
immunotherapy, 
radiotherapy, 
investigational agents, or herbal therapy 
 
It is strongly recommended that:  
• 
Traditional herbal medicines not be administered because the ingredients 
of many herbal medicines are not fully studied and their use may result in 
unanticipated drug-drug interactions that may cause, or confound 
assessment of, toxicity 
• 
The use of a RANKL inhibitor (denosumab) be discontinued during the 
study; this agent could potentially alter the activity and the safety of 
atezolizumab 
 
Initiation or increased dose of granulocyte colony-stimulating factors 
(e.g., granulocyte 
colony-stimulating 
factor, 
granulocyte/macrophage 
colony-stimulating factor, and/or pegfilgrastim) is prohibited for patients with 
solid malignancies.   
 
Patients are not allowed to receive immunostimulatory agents, including but not 
limited to IFN-α, IFN-γ, or IL-2, during the entire study.  These agents, in 


 
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combination with atezolizumab, could potentially increase the risk for autoimmune 
conditions. 
 
Patients should also not be receiving immunosuppressive medications, including 
but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide.  
These agents could potentially alter the activity and the safety of atezolizumab.  
Systemic corticosteroids and anti-TNFα agents may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at 
the discretion of the treating physician.  If feasible, alternatives to these agents 
should be considered. 
In addition, all patients (including those who discontinue the study early) should 
not receive other immunostimulatory agents for 10 weeks after the last dose of 
atezolizumab. 
9. Dose Modifications and Management of Toxicity 
 
9.1. Dose Modifications During Concurrent Chemoradiotherapy 
 
9.1.1. Hematologic Toxicities 
 
• 
For ANC <1,000 or platelets <75,000 on day of treatment, delay carboplatin 
and paclitaxel until ANC ≥1,000 and platelets ≥75,000, then resume at the 
previous doses. If treatment is delayed for ≥ 3 weeks, discontinue the drugs for 
the duration of concurrent therapy. 
• 
For febrile neutropenia occurring at any time during a cycle, hold therapy. 
• 
Doses that are missed will not be made up. 
• 
Radiation therapy will be held for grade 4 hematologic toxicity. 
 
9.1.2. Non-hematologic Toxicities 
 
Radiation therapy should continue to be delivered for ≤ grade 3 non-hematologic 
toxicities in or outside the radiation treatment field. RT should be held for all Grade 
4 non-hematologic toxicity in or outside the treatment field and resumed only when 
toxicity ≤ grade 2. 
Neurotoxicity: 
• 
Grade 2: Hold paclitaxel until ≤ Grade1, then resume at full dose. If paclitaxel 
is held ≥ 3 weeks, discontinue paclitaxel permanently. Continue carboplatin at 
full dose. 
• 
Grade 3:  Discontinue palictaxel permanently, continue carboplatin. 
 
Renal Toxicity: A ≥10% change in the serum creatinine, based on weekly 
calculated creatinine clearance, will require a recalculation of the carboplatin dose. 
Ototoxicity: For ≥ grade 3 toxicity discontinue carboplatin permanently. 
Hypersensitivity: For grade 3 reactions, in the subsequent cycle, use double dose 
steroids pretreatment and decrease the paclitaxel infusion rate for the first 1/3 of the 


 
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infusion. For the last 2/3 of the infusion, double the rate of the infusion. For 
documented Grade 4 hypersensitivity reactions to paclitaxel, discontinue paclitaxel. 
Cardiotoxicity: If a patient develops chest pain, hypotension, or arrhythmia other 
than asymptomatic sinus brachycardia, the paclitaxel infusion should be stopped 
and patients should not receive further paclitaxel. For asymptomatic sinus 
brachycardia, the infusion need not be stopped, but the patient should be followed 
carefully. 
Hepatic Dysfunction: Give the following % of full dose for paclitaxel: 
AST 
 
Bilirubin 
Paclitaxel 
<2.0 x ULN 
and 
<1.5 mg/dl 
100% 
2.0-5.0 x ULN 
and 
<1.5 mg/dl 
50% 
>5.0 x ULN 
or 
≥1.5 mg/dl 
0* 
* Hold paclitaxel for one week (radiation therapy may continue), repeat labs, and 
evaluate for etiology. If progressive disease is found, take the patient off 
protocol treatment. If disease progression is not found and labs return to normal 
(AST <2.0 x ULN and Bili<1.5 mg/dl) within three weeks, reinstitute paclitaxel 
at 100%. IF AST >5.0 x ULN or bilirubin >1.5 mg/dl after three weeks, 
discontinue paclitaxel for all subsequent cycles but continue treatment with 
carboplatin. 
Other toxicities: For all other toxicities that exceed grade 3 (except alopecia, 
nausea, vomiting, fatigue and anorexia), hold carboplatin and paclitaxel until 
toxicity resolves to ≤ grade 2. 
 
9.1.3. Radiotherapy Related Toxicity 
Esophagus/pharynx 
• 
Grade 3: If day of chemotherapy hold until ≤ grade 2. Hold radiotherapy ≤ 5 
days. 
• 
Grade 4: Hold radiation and chemotherapy until toxicity has resolved to ≤ 
grade 2, then resume therapy at previous dose. 
• 
If IV support is needed insertion of a feeding tube should be considered. 
• 
If treatment is interrupted ≥ 3 weeks discontinue all protocol therapy. 
 
 


 
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Pulmonary Toxicity 
• 
Grade 3: Hold treatment with carboplatin, paclitaxel and radiation therapy. 
Once toxicity has resolved to < grade 2 restart chemotherapy and radiotherapy 
at previous dose. 
• 
Grade 4: Discontinue all further radiotherapy. Hold treatment with 
carboplatin and paclitaxel until toxicity resolves to ≤ grade 2. 
• 
If treatment is interrupted ≥ 3 weeks discontinue all protocol therapy. 
 
9.2. Dose Modifications During Consolidation Chemotherapy 
 
• 
If more than one of the dose modifications apply, use the most stringent (i.e., the 
greatest dose reduction). 
• 
The following dose levels are used for dose modifications. If dose reduction below 
level -1 is required, discontinue the drug causing the toxicity, and continue the other 
drug.  
• 
If treatment is delayed for ≥ 3 weeks, discontinue all protocol treatment. 
Dose Level 
Carboplatin 
Paclitaxel 
0 
AUC = 6 
200 mg/m2 
-1 
AUC = 4.5 
150 mg/m2 
 
9.2.1. Hematologic Toxicity 
• 
For ANC <1,500 or platelets <100,000 on day 1, delay treatment with 
carboplatin and paclitaxel until ANC ≥1,500 and platelets ≥100,000, then 
resume at the previous doses if fully recovered in 1 week. If not, decrease by 
1 dose level when recovered.  
• 
For ANC <500 or platelets <25,000, hold therapy then decrease carboplatin 
and paclitaxel by one dose level for all subsequent doses once ANC ≥1,500 
and platelets ≥100,000.  
 
9.2.2. Non-hematologic Toxicities 
 
Neurotoxicity: 
• 
Grade 2: Hold paclitaxel until ≤ Grade1, then resume at full dose. If paclitaxel 
is held ≥ 3 weeks, discontinue paclitaxel permanently. Continue carboplatin at 
full dose. 
• 
Grade 3:  Discontinue paclitaxel permanently, continue carboplatin. 
 
Renal Toxicity: A ≥10% change in the serum creatinine, based on weekly 
calculated creatinine clearance, will require a recalculation of the carboplatin dose. 
 
Ototoxicity: For ≥ grade 3 toxicity discontinue carboplatin permanently. 
 


 
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Hypersensitivity: For grade 3 reactions, in the subsequent cycle, use double dose 
steroids pretreatment and decrease the paclitaxel infusion rate for the first 1/3 of the 
infusion. For the last 2/3 of the infusion, double the rate of the infusion. For 
documented Grade 4 hypersensitivity reactions to paclitaxel, discontinue paclitaxel. 
 
Cardiotoxicity: If a patient develops chest pain, hypotension, or arrhythmia other 
than asymptomatic sinus brachycardia, the paclitaxel infusion should be stopped 
and patients should not receive further paclitaxel. For asymptomatic sinus 
brachycardia, the infusion need not be stopped, but the patient should be followed 
carefully. 
 
Hepatic Dysfunction: Give the following % of full dose for paclitaxel: 
 
 AST 
 
Bilirubin 
Paclitaxel 
<2.0 x ULN 
and 
<1.5 mg/dl 
100% 
2.0-5.0 x ULN 
and 
<1.5 mg/dl 
50% 
>5.0 x ULN 
or 
≥1.5 mg/dl 
0* 
* Hold paclitaxel for one week, repeat labs, and evaluate for etiology. If 
progressive disease is found, take the patient off protocol treatment. If disease 
progression is not found and labs return to normal (AST <2.0 x ULN and 
Bili<1.5 mg/dl) within three weeks, reinstitute paclitaxel at 100%. IF AST >5.0 
x ULN or bilirubin >1.5 mg/dl after three weeks, discontinue paclitaxel for all 
subsequent cycles but continue treatment with carboplatin. 
 
Other toxicities: For all other toxicities that exceed grade 3 (except alopecia, 
nausea, vomiting, fatigue and anorexia), hold carboplatin and paclitaxel until 
toxicity resolves to ≤ grade 2. 
 
9.2.3. Failure to Complete Consolidation Chemotherapy 
 
Based on available data of consolidation chemotherapy (34-35), it is expected that 
not all patients will either start or complete the consolidation chemotherapy portion 
of the trial. These patients will still be evaluable for toxicity and outcome 
endpoints. Toxicities will be scored as outlined above. Not completing 
consolidation therapy will not in and of itself constitute a dose limiting toxicity. 
For purposes of follow-up assessment, imaging will be timed to start as outlined 
in the calendar based on the anticipated Cycle 5 Day 1 date. 
 
Patients with contraindications to consolidation therapy may be allowed to proceed 
directly to adjuvant atezolizumab, only with prior approval from the sponsor. 
 
9.3. Dosing for Obese Patients 
There is no clearly documented adverse impact of treatment in obese patients when 
actual body weight is used to calculate doses which are defined in terms of body surface 
area (BSA) considerations. Accordingly, paclitaxel dosing, defined on the basis of BSA, 
will be calculated on the basis of the patient's actual body weight. This will eliminate 
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administration. Failure to use actual body weight in the calculation of drug dosages will 
be considered a major protocol violation.  
AUC dosing will be used to determine carboplatin dosing. The protocol permits use of 
the Cockcroft-Gault formula to estimate creatinine clearance. However, in markedly 
obese patients, the Cockcroft-Gault formula will tend to overestimate the creatinine 
clearance. (Adipose tissue tends to contribute little creatinine requiring renal clearance). 
The actual body weight (in kilograms) will be utilized in the Cockcroft-Gault formula. 
However, if the calculated creatinine clearance exceeds an upper limit for creatinine 
clearance, as specified below, then this ceiling value for creatinine clearance, rather than 
the calculated creatinine clearance, will be used in the Calvert formula to calculate the 
dose of carboplatin.  
 
At the treating physician’s discretion, institutional standard dosing for carboplatin and 
paclitaxel may be used, using actual body weight in the calculation of drug doses. 
 
The maximum CrCl that can be used in this calculation, for both women and men, 
is 125 mL/min.  
Alternatively, at the treating physician's discretion, a measured 24 hour creatinine 
clearance can be obtained. In this case, the measured creatinine clearance can be used 
to calculate the carboplatin dose in the Calvert formula. 
 
10. Measurement of Effect 
Any evaluable or measurable disease must be documented at screening and reassessed at each 
subsequent tumor evaluation.  For solid malignancy patients with measurable disease, response will 
be assessed by the investigator per RECIST v1.1 (see Appendix ) and immune-related response 
criteria (irRC; see Appendix ).  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1).  Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the short axis measurements in the case of lymph nodes are used in the RECIST guidelineviii. 
 
10.1. Schedule of Evaluations: 
 
For the purposes of this study, patients should be reevaluated for response and survival every 
6 weeks during induction immunotherapy, 3 weeks after completion of concurrent combined 
modality therapy, 3 weeks after completion of consolidation chemotherapy and every 3 
months during adjuvant immunotherapy. 
 
10.2. Definitions of Measurable and Non-Measurable Disease 
 
10.2.1. Measurable Disease 
 
A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT 
component of a PET/CT, or MRI.  
 


 
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A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in 
diameter as assessed using calipers (e.g. skin nodules) or imaging.  In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
 
A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). 
 
10.2.2. Non-Measurable Disease 
 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥ 1.0 to < 1.5 cm).   
 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.  In addition, lymph nodes that have a short axis < 
1.0 cm are considered non-pathological (i.e., normal) and should not be recorded 
or followed. 
 
10.3. Guidelines for Evaluation of Measurable Disease 
 
10.3.1. Measurement Methods 
 
• 
All measurements should be recorded in metric notation (i.e., decimal fractions 
of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment.  
 
10.3.2. Acceptable Modalities for Measurable Disease 
 
• 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or 
less. If CT scans have slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be twice the slice thickness. 
• 
As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  The lesions should be measured on the same pulse sequence.  Ideally, 
the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  Body scans should be 
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• 
PET-CT:  If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.   
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid with 
an update greater than twice that of the surrounding tissue on the attenuation 
corrected image; otherwise, an FDG-PET scanned lesion is considered 
‘negative.’  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm: 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:   
1) If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.   
2) If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT at the same evaluation, additional follow-up CT scans 
(i.e., additional follow-up scans at least 4 weeks later) are needed to 
determine if there is truly progression occurring at that site. In this 
situation, the date of PD will be the date of the initial abnormal PDG-
PET scan.   
3) If the positive FDG-PET at follow-up corresponds to a pre-existing site 
of disease on CT that is not progressing on the basis of the anatomic 
images, it is not classified as PD. 
 
10.3.3. Measurement at Follow-up Evaluation   
 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
10.4. Measurement of Treatment/Intervention Effect 
 
10.4.1. Target Lesions & Target Lymph Nodes 
• 
Measurable lesions up to a maximum of 5 lesions, representative of all involved 
organs, should be identified as “Target Lesions” and recorded and measured at 
baseline.  These lesions can be non-nodal or nodal, where no more than 2 lesions 
are from the same organ and no more than 2 malignant nodal lesions are 
selected.  


 
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Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.   
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be 
the case that, on occasion, the largest lesion (or malignant lymph node) does not 
lend itself to reproducible measurements in which circumstance the next largest 
lesion (or malignant lymph node) which can be measured reproducibly should 
be selected.   
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD).  The BSD 
will be used as reference to further characterize any objective tumor response 
in the measurable dimension of the disease.   
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph nodes 
will be calculated and reported as the post-baseline sum of dimensions (PBSD).  
If the radiologist is able to provide an actual measure for the target lesion (or 
target lymph node), that should be recorded, even if it is below 0.5 cm.  If the 
target lesion (or target lymph node) is believed to be present and is faintly seen 
but too small to measure, a default value of 0.5 cm should be assigned.  If it is 
the opinion of the radiologist that the target lesion or target lymph node has 
likely disappeared, the measurement should be recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
10.4.2. Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 12.2.2) are classified as non- target lesions 
or non-target lymph nodes and should also be recorded at  baseline.  These lesions 
and lymph nodes should be followed in accord with 12.4.3.3. 
 
10.4.3. Response Criteria 
 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT must be 
measured on re-evaluation at evaluation times specified in Section 11.1.  Specifically, 
a change in objective status to either a PR or CR cannot be done without re-
measuring target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be evaluated at each  
assessment, especially in the case of first response or confirmation of response.  In  
selected circumstances, certain non-target organs may be evaluated less frequently.   
For example, bone scans may need to be repeated only when complete response is  
identified in target disease or when progression in bone is suspected. 
 
10.4.3.1. 
Evaluation of Target Lesions 


 
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• 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to < 1.0 
cm. 
• 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis of all 
the target lymph nodes at current evaluation) taking as reference the BSD 
(see Section 11.4.1). 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and increased 
to ≥ 1.0 cm short axis during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference the MSD (Section 
11.4.1).  In addition, the PBSD must also demonstrate an absolute 
increase of at least 0.5 cm from the MSD.  
c. See Section 11.3.2 for details in regards to the requirements for PD 
via FDG-PET imaging. 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
 
10.4.3.2. 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
• 
Complete Response (CR): 
All of the following must be true: 
a. Disappearance of all non-target lesions.  
b. Each non-target lymph node must have a reduction in short axis to 
<1.0 cm. 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions or non-
target lymph nodes. 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and increased 
to ≥ 1.0 cm short axis during follow-up.   
b. Unequivocal progression of existing non-target lesions and non-
target lymph nodes.  (NOTE:  Unequivocal progression should not 
normally trump target lesion and target lymph node status.  It must 
be representative of overall disease status change.)  
c. See Section 11.3.2 for details in regards to the requirements for PD 
via FDG-PET imaging. 
 
10.4.4. Overall Objective Status 
 


 
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The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-target 
lymph nodes, and new disease as defined in the following tables:  
 
For Patients with Measurable Disease  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
 
10.4.5. Symptomatic Deterioration 
Patients with global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time, and not 
either related to study treatment or other medical conditions, should be reported as 
PD due to “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment due to 
symptomatic deterioration. 
 
11. End of Treatment and Follow-up 
11.1. Duration of Treatment 
 
11.1.1. CR, PR, or SD  
Patients who are in CR, PR or SD will continue on therapy for a total of 12 months.  
After treatment is discontinued, patients will be followed per the study calendar in 
Section 5.0 and 6.0. 
11.1.2. Disease Progression 
 


 
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Remove from protocol therapy any patient with disease progression. Document 
details, including tumor measurements, on data forms. 
 
After disease progression, patients should be followed for survival per the study 
calendar (Section 5.0 and 6.0). 
 
11.2. Managing ineligible patients and registered patients who never receive protocol 
intervention 
Definition of ineligible patients: A study participant who is registered to the trial but does 
not meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed 
ineligible may continue protocol treatment, provided the treating physician, study chair, and 
executive officer agree there are no safety concerns if the patient continues protocol 
treatment. All scans, tests, and data submission are to continue as if the patient were eligible. 
Notification of the local IRB may be necessary per local IRB policies. 
 
Study participants who are registered to the trial but never receive study intervention (for a 
reason other than because they were deemed ineligible) must still complete follow-up 
requirements as specified below.  
 
11.3. Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health 
and/or the patient no longer wishes to continue protocol therapy, protocol therapy shall 
be discontinued. In this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
11.4. Follow-up  
After the end of treatment visit, patients will be required to attend follow-up visits. These visits 
will occur 3, 6 and 12 months after the end of treatment visit. Patients will have tumor response 
evaluation by RECIST and imaging. Blood samples will be collected for assessment of 
circulating tumor cells as well (See Section 5 for details).  
 
12. Safety Instructions and Guidance  
12.1. Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of any study procedures and ends 30 days following the 
last administration of study treatment or study discontinuation/termination, whichever is 
earlier.  After this period, investigators should only report SAEs that are attributed to prior 
study treatment. 
12.2. Assessment of Adverse Events 
 
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means, will be reported appropriately.  Each reported AE or SAE will be described by its 


 
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duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the study drug (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration 
of atezolizumab, and the AE cannot be readily explained by the patient’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to atezolizumab; and/or the AE abates or resolves upon discontinuation of 
atezolizumab or dose reduction and, if applicable, reappears upon re-challenge. 
     No 
 
Evidence exists that the AE has an etiology other than atezolizumab (e.g., pre-existing 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to atezolizumab administration (e.g., 
cancer diagnosed 2 days after first dose of study drug). 
 
Expected AEs are those AEs that are listed or characterized in the Package Insert (PI) or 
current Investigator’s Brochure.  
Unexpected AEs are those not listed in the PI or current Investigator’s Brochure or not 
identified.  This includes AEs for which the specificity or severity is not consistent with 
the description in the PI or Investigator’s Brochure.  For example, under this definition, 
hepatic necrosis would be unexpected if the PI or Investigator’s Brochure only referred to 
elevated hepatic enzymes or hepatitis. 
12.3. Procedures for Eliciting, Recording, and Reporting Adverse Events 
12.3.1. Eliciting Adverse Events 
 
A consistent methodology for eliciting AEs at all patient evaluation timepoints 
should be adopted.  Examples of non-directive questions include:  
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last 
here?” 
 
12.3.2. Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs 
or SAEs.  Avoid colloquialisms and abbreviations. 
12.3.2.1. 
Diagnosis versus Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a 


 
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single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available.  If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
12.3.2.2. 
Deaths 
 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 12.1), regardless of attribution, will be reported to the appropriate 
parties.  When recording a death, the event or condition that caused or 
contributed to the fatal outcome should be reported as the single medical 
concept.  If the cause of death is unknown and cannot be ascertained at the time 
of reporting, report “Unexplained Death.”  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 12.1) that are 
attributed by the investigator solely to progression of disease should be 
recorded only in the study eCRF. 
12.3.2.3. 
Pre-existing Medical Conditions 
 
A pre-existing medical condition is one that is present at the start of the 
study.  Such conditions should be reported as medical and surgical history.  A 
pre-existing medical condition should be re-assessed throughout the trial and 
reported as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When reporting such events, it is important 
to convey the concept that the pre-existing condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
 
12.3.2.4. 
Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE.  If a patient is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE.  For 
example, if a patient is hospitalized to undergo coronary bypass surgery, record 
the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for pre-existing conditions, 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study, or 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of 
the target disease of the study. 
 
12.3.2.5. 
Pregnancies in Female Patients 
 
Female patients of childbearing potential will be instructed to immediately 
inform the investigator if they become pregnant during the study or within 90 
days after the last dose of study drug.  A Pregnancy Report CRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after 


 
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learning of the pregnancy) and submitted via fax.  A pregnancy report will 
automatically be generated and sent to Genentech Drug Safety.  Pregnancy 
should not be recorded on the Adverse Event CRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient 
should continue until conclusion of the pregnancy.  Any SAEs associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after 
the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event CRF. 
A Clinical Trial Pregnancy Reporting Form should be completed in the AFT-
EDC (Rave) system within 24 hours after learning of the pregnancy. AFT will 
forward to Genentech Drug Safety within 24 hours of receipt. 
12.3.2.6. 
Pregnancies in Partners of Male Patients 
 
Male patients will be instructed through the ICF to immediately inform the 
investigator if their partner becomes pregnant during the study or within 
90 days after completing treatment with Atezolizumab.  Male patients who 
received study treatment should not attempt to father a child until end of study.  
A Pregnancy Report CRF should be completed by the investigator immediately 
(i.e., no more than 24 hours after learning of the pregnancy) in the AFT-EDC 
(Rave) system. AFT will forward to Genentech Drug Safety within 24 hours of 
receipt. 
Attempts should be made to collect and report details of the course and outcome 
of any pregnancy in the partner of a male patient exposed to study drug.  The 
pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  Once 
the authorization has been signed, the investigator will update the Pregnancy 
Report with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible 
effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
12.3.2.7. 
Abnormal Liver Functions Tests Reported as Hy’s Law 
 
Investigators must report as a serious adverse event the occurrence of either of 
the following: 
 
• 
Treatment-emergent ALT or AST (>3 x ULN) in combination with 
total bilirubin (>2 x ULN) 
• 
Treatment-emergent ALT or AST (>3 x ULN) in combination with 
clinical jaundice 
 
The finding of an elevated ALT or AST (>3 x ULN) in combination with 
either an elevated total bilirubin (>2 x ULN) or clinical jaundice in the 
absence of cholestasis or other causes of hyperbilirubinemia is considered to 
be an indicator of severe liver injury. 
 


 
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The most appropriate diagnosis or (if a diagnosis cannot be established) the 
abnormal laboratory values should be recorded on the Adverse Event eCRF 
and reported to the safety department of AFT (US sites) or ABCSG (Non-US 
sites) immediately (i.e., no more than 24 hours after learning of the event) 
using the study specific SAE reporting way. 
12.3.2.8. 
Abortions 
 
Any spontaneous abortion should be classified as an SAE (as the Sponsors 
consider spontaneous abortions to be medically significant events), recorded on 
the Adverse Event eCRF, and reported to AFT immediately (i.e., no more than 
24 hours after learning of the event; see Section 12.3). AFT will forward to 
Genentech Drug Safety within 24 hours of receipt. 
12.3.2.9. 
Congenital Anomalies/Birth Defects 
 
Any congenital anomaly/birth defect in a child born to a female patient or 
female partner of a male patient exposed to study drug should be classified as 
an SAE, recorded on the Adverse Event CRF, and reported to AFT immediately 
(i.e., no more than 24 hours after learning of the event). AFT will forward to 
Genentech within 24 hours of receipt. 
12.3.2.10. Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring after a patient 
has completed or discontinued study participation if attributed to prior 
atezolizumab exposure.  If the investigator should become aware of the 
development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female patient who participated in the study, this should be 
reported as an SAE.  
12.3.2.11. Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are defined as a potential safety 
problem, identified as a result of safety monitoring of the IMP. 
Adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event) via the AFT-EDC (Rave) system. 
The following AEs are considered of special interest and must be reported to 
the Genentech Drug Safety expeditiously, irrespective of regulatory 
seriousness criteria: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT 
or AST in combination with either an elevated bilirubin or clinical 
jaundice, as defined by Hy's Law and based on the following 
observations: 


 
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o Treatment-emergent ALT or AST ≥ 3 × baseline value in 
combination with total bilirubin ≥ 2 × ULN (of which > 35% is 
direct bilirubin) 
o Treatment-emergent ALT or AST ≥ 3 × baseline value in 
combination with clinical jaundice 
• 
Suspected transmission of an infectious agent by the study treatment, as 
defined below 
o Any organism, virus, or infectious particle (e.g., prion protein 
transmitting transmissible   spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected 
from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term 
applies only when a contamination of study treatment is 
suspected 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism and hypophysitis 
• 
Hepatitis, including AST or ALT > 10 x ULN 
• 
Systemic lupus erythematosus 
• 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome 
or myasthenia gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, 
cytokine release syndrome, influenza-like illness, systemic inflammatory 
response syndrome and systemic immune activation 
• 
Nephritis 
• 
Ocular toxicities (e.g. uveitis, retinitis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Grade >2 cardiac disorders (e.g. atrial fibrillation, myocarditis, 
pericarditis) 
 
12.3.3. Adverse Events Reporting 
 
The prompt reporting of adverse events is the responsibility of each investigator 
engaged in clinical research, as required by Federal Regulations. Adverse events 
must be described and graded using the terminology and grading categories defined 
in the NCI’s Common Terminology Criteria for Adverse Events (CTCAE), Version 
4.0. The CTCAE is available at 
Attribution 


 
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to protocol treatment for each adverse event must be determined by the investigator 
and reported on the required forms, using the codes provided. 
 
12.3.3.1. 
  Routine Adverse Event Reporting 
 
Adverse event data collection and reporting, which are required as part of 
every clinical trial are done to ensure the safety of patients enrolled in the 
studies as well as those who will enroll in future studies using similar agents. 
Adverse events will be recorded after informed consent is obtained and 
initiation of any study procedures through 30 days following cessation of 
treatment.  Adverse events are reported in a routine manner at scheduled times 
according to the study calendar in Section 6. All adverse events are entered 
into the Adverse Event eCRF in Rave. 
 
12.3.3.2. 
Expedited Adverse Event Reporting 
 
Investigators are required by Federal Regulations to report serious adverse 
events as defined in the table below. Investigators are required to notify the 
AFT and their Institutional Review Board if a patient has a reportable serious 
adverse event. The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4 
will be utilized for AE reporting.  The CTCAE is identified and located on 
the 
CTEP 
website 
at: 
 
All 
appropriate treatment areas should have access to a copy of the CTCAE. All 
reactions determined to be “reportable” in an expedited manner must be 
reported via the Adverse Event eCRF in the Rave. 
 
Note:  All deaths on study require both routine and expedited reporting 
via the AFT-EDC (Rave) system, regardless of causality.  Attribution to 
treatment or other cause should be provided. 
 
12.3.3.3. 
Serious Adverse Event (SAE) 
 
Investigators MUST immediately report to the sponsor (AFT) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 


 
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Table 7. Serious Adverse Event Reporting Requirements 
 
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS  
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
7) Or is a new cancer (that is not a condition of the study). 
8) Or is associated with an overdoes 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to AFT via 
the AFT-EDC (Rave) system. 
Hospitalization 
Grade 
1 
Timeframes 
Grade 
2 
Timeframes 
Grade 
3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization > 24 hrs 
Enter into AFT-EDC (Rave) as an SAE within 24 hours of the site’s 
awareness of the event 
 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required to enter as an SAE in 
AFT-EDC (Rave). 
Enter into AFT-SRS as an SAE 
within 24 hours of the site’s 
awareness of the event 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via AFT-EDC (Rave)  ≤ 24 
hours of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of 
the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 calendar 
days of learning of the AE. 
 All serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite or any SAE that occurs through 90 
days following cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the investigational product, require reporting into AFT-EDC (Rave) within 24 hours 
of awareness of the event.  
NOTE: Deaths occurring outside of the serious adverse event reporting period that are clearly due to 
progressive disease should NOT be reported as an SAE, but rather should be reported via routine 
reporting methods in the AFT-EDC (Rave) system.  For deaths occurring within the reporting window, 
even if considered to be related to disease progression, the cause of death should be reported as an 
SAE within the AFT-EDC (Rave) system with death noted as the outcome of the event. 


 
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13. Statistical Considerations and Methodology 
 
13.1. Overview of the Study Design 
 
This phase II pilot trial will combine neoadjuvant immunotherapy with atezolizumab q 21 
days for 12 weeks with standard chemoradiotherapy with curative intent for good PS patients 
with unresectable stage IIIA/B NSCLC. Because of the consequences of progression in this 
curative-intent population, restaging CT scans will be carried out after the first 2 cycles of 
neoadjuvant therapy. Responding patients will complete a total of one year of anti-PDL1 
therapy with an interruption during chemoradiotherapy and consolidation chemotherapy. 
Patients with evidence of progression at the first restaging evaluation will proceed 
immediately to chemoradiotherapy if still eligible. 
  
Assumptions include a DCR of at least 70% to neoadjuvant immunotherapy, that 85% of 
the study population will complete radiation, and that 60% of the study population will 
complete the entire treatment course including consolidation chemotherapy and adjuvant 
immunotherapy with atezolizumab. 
 
13.2. Endpoints 
 
13.3. Primary Objective  
 
The primary objective of this single arm phase II trial is to determine whether neoadjuvant 
and adjuvant anti-PD-L1 therapy bracketing standard chemoradiation therapy and 
consolidation therapy is worthy of further investigation. The primary endpoint will be the 
disease control rate (DCR) after 12 weeks induction immunotherapy.  
 
13.4. Secondary Objectives 
 
Secondary endpoints are objective response rate (ORR), progression free survival (PFS) and 
overall survival (OS), the proportion of patients who complete induction immunotherapy, 
chemoradiation therapy and consolidation chemotherapy. Toxicity including immune 
related adverse events will be assessed for all patients receiving any study therapy.  
 
13.5. Translational Science Principal Objective 
 
Assess the utility of PD-L1 as a biomarker for DCR, ORR, PFS, OS in the study 
population. 
 
13.6. Translational Science Additional Objectives 
 
Examine the role of immunologic signatures for positive and negative predictive value and 
to identify selective biomarkers. Multi-panel immunohistochemistry, NanoString/RNA-
Seq/RT-PCR expression profiling, whole exome and T cell receptor sequencing, flow 
cytometry, and cytokine and chemokine markers will be assessed in blood and in FFPE 
tissue. Additionally, whole blood and serum will be obtained at study entry and at crucial 
time-points for additional evaluation of circulating tumor DNA (ctDNA). Whole blood 
will be obtained at 3 crucial timepoints (at baseline, after induction atezolizumab, after 
chemoradiotherapy. 
 


 
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13.7. Other Correlative Science Objectives (e.g., QoL, PRO, etc) 
 
Quality of life endpoints will be assessed during induction, during chemoradiotherapy, 
during adjuvant atezolizumab at 3 month intervals and will be measured by the EORTC 
QLQ-30. 
 
13.8. Sample Size, Accrual time, and Study Duration 
 
13.8.1. Sample Size 
 
The disease control rate (DCR) is assumed the same for PD-L1 positives and 
negatives. With 60 eligible and treated patients, the study has approximately 90%  
power to detect H0: p≤0.50 versus H1: p≥0.67, where p is the disease control rate  
(DCR) after 12 weeks neoadjuvant anti-PD-L1 therapy, with a one-sided binomial  
test at a significance level of 0.10. In particular, if 35 or fewer of these patients  
remain disease controlled, it will be concluded that the treatment regimen is not  
worthy of further investigation. Otherwise, it will be concluded that the treatment  
regimen has sufficient efficacy to warrant further investigation. Under the design,  
the probability of erroneously concluding that the treatment regimen is worthy of  
further investigation when the DCR is truly 50% or less is 0.0775. The probability  
of erroneously concluding that the treatment regimen is NOT worthy of further  
investigation when the true DCR is 67% or greater is 0.0999. 
 
13.8.2. Accrual Rate and Accrual Duration 
 
The phase II trial will register a total 63 patients. Assuming 5% ineligibility and 
cancelation, 60 eligible patients are expected to receive at least one cycle of the 
experimental agent. PD-L1 status will be determined by Ventana assay (TC/IC). Of 
them, we expect approximately 40 and 20 patients are PD-L1 positive (≥1% 
expression) and PD-L1 negative (otherwise), respectively. 
 
A total of 63 patients will be registered to the trial. The trial will be open for patient 
enrollment in 15 Alliance institutions selected for their experience and prior good 
enrollment in clinical trials of chemoradiotherapy for NSCLC. We expect 
approximately 4 unresectable stage III NSCLC patients who meet the eligibility 
criteria will be enrolled per month. It will take approximately 16 months to reach the 
target accrual. Follow up of at least 18 months will be required for all patients for 
progression free survival and overall survival.  
 
13.9. Study Team - Safety Monitoring 
 
In addition to the collection of the treatment-related toxicity forms (radiotherapy and 
chemotherapy), the status of patients will be monitored by the study chairs via telephone 
conversations with the treating sites. The monitoring will occur at least twice monthly during 
therapy and monthly after treatment.  The goal is for real time understanding of potential 
toxicity issues, treatment delivery challenges, accrual barriers, and study retention. 
 
14. Correlative Sciences 
 
See Appendix 11. 


 
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15. General Regulatory and Other considerations   
 
15.1. 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 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.  
Information posted will allow patients to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information. 
 
15.2. Regulatory and ethical compliance 
 
By signing the Protocol the investigator agrees to treat all of the information that is provided 
with the strictest confidentiality and to require the same of his personnel as well as the IRB. 
Study documents (protocols, investigator`s brochures, eCRFs, etc.) provided by the AFT 
will be stored in an appropriate manner in order to ensure confidentiality. The information 
provided to the investigator by AFT must not be made available to other parties without a 
direct written authorization by the aforesaid parties, with the exception of the extent to which 
disclosure is necessary in order to obtain informed consent from the patients who wish to 
participate in the study. 
 
15.3. Ethics and Good Clinical Practice 
 
This study will be conducted in compliance with the study protocol, subsequent 
amendment(s) and with the study-specific manuals/guidelines, if applicable. These 
documents ensure that the ICH E6 guideline for Good Clinical Practice is maintained as well 
as compliance with the principles of the Declaration of Helsinki (World Medical 
Association), or the laws and regulations of the country in which the research is conducted, 
whichever afford the greater protection to the individual. The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting). 
 
Studies conducted in the United States or under a U.S. Investigational New Drug (IND) 
application will comply with U.S. FDA regulation and applicable local, state and federal 
laws. 
 
By signing the study protocol the investigator agrees to comply with the instructions and 
procedures described therein and thus to adhere to the principles of good clinical practice, 
which these instructions and procedures reflect. 
 
15.4. Confidentiality 
 
Patient medical information both, associated with biologic specimens or not, is confidential 
and may only be disclosed to third parties as permitted by the ICF (or separate authorization 
for use and disclosure of personal health information) which has been signed by the patient, 
unless permitted or required by law. Data derived from biologic specimen analysis on 


 
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individual patients will in generally not be provided to study investigators unless a request 
for research use is granted. The overall results of any research conducted using biologic 
specimens will be available in accordance with the effective AFT policy on study data 
publication. 
 
15.5. Protocol Amendments  
 
Any modifications to the protocol or the Informed Consent Form which may impact on the 
conduct of the study, potential benefit of the study, or may affect patient safety, including 
changes of study objectives, study design, patient population, sample sizes, study 
procedures, or significant administrative aspects will require a formal amendment to the 
protocol. Such amendment will be released by AFT, agreed by the investigator(s) and 
approved by relevant IRBs prior to implementation. A signed and dated statement that the 
protocol, any subsequent relevant amended documents and the Informed Consent Form have 
been approved by relevant IRBs must be provided to AFT before the study is initiated.  
 
Administrative changes of the protocol are minor corrections and/or clarifications that have 
no effect on the way the study is to be conducted. These administrative changes will be 
released by the AFT, agreed by the investigator(s) and notified to the IRB.  
 
15.6. Informed Consent 
 
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable by local regulations), to obtain written Informed Consent from each patient 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study. This information must be provided to the patient 
prior to undertaking any trial-related procedure which is not part of the routine clinical 
management of the patient (i.e. would not be indicated outside the study).  
 
For patients not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative. In the case where both the patients and 
his/her legally acceptable representative are unable to read, an impartial witness should be 
present during the entire informed consent discussion. After the patient and representative 
have orally consented to participation in the trial, the witness’ signature on the form will 
attest that the information in the consent form was accurately explained and understood. The 
Investigator or designee must also explain that the patients are completely free to refuse to 
enter the study or to withdraw from it at any time, for any reason.  
 
Furthermore, it is the investigator’s responsibility to obtain the signed Informed Consent 
Form, and a signature from the person conducting the informed consent discussion, prior to 
undertaking any trial-related procedure. The proposed Informed Consent Form must 
accomplish with the ICH GCP guideline and regulatory requirements.  
 
15.7. Financial Disclosure 
Investigators will provide AFT with adequate and accurate financial information in 
accordance with local regulations and laws in order to allow AFT to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing updated information on financial interests during 
the course of the study as well as for 1 year after completion of the study. 


 
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15.8. Protocol Deviations 
 
 
The investigator is responsible to document and explain any deviations from the approved 
protocol. The investigator should promptly report any deviations that might impact patient 
safety and data integrity to AFT and if locally applicable, to the respective IRB in 
accordance with local IRB policies and procedures. Deviations should also be recorded in 
the AFT-EDC (Rave). 
 
15.9. Retention of Records 
 
Any records and documents relating to the conduct of this study and the distribution of 
investigational drug, including ICFs, eCRFs, PRO data, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator until 
notification by AFT, or for the length of time required by relevant national or local health 
authorities, whichever is longer. After that period of time, the documents may be destroyed, 
subject to local regulations. No records may be disposed of without the written approval of 
AFT. Written notification should be provided to AFT prior to transferring any records to 
another party or moving them to another location. 
 
16. References 
 
Attached as endnotes. 
 
17. Appendices 


 
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Appendix 1  Calculation of Creatinine Clearance Using the 
Cockcroft-Gault Formula 
 
Creatinine Clearance (men) = (140-Age) × Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL) × 72 
 
Creatinine Clearance (women) = 0.85 × (140-Age) × Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL) × 72 
Reference: 
Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted 
serum creatinine (editorial). Nephron 1992;62:249. 
 


 
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Appendix 2  Current National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) 
 
P
 
 


 
Appendix 3  Response Evaluation Criteria in Solid Tumors (RECIST) 
 
 
 
 
 


 
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Appendix 4  Immune-Related Response Criteria 
 
INTRODUCTION 
Increasing clinical experience indicates that traditional response criteria (e.g., Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization 
[WHO]) may not be sufficient to characterize fully activity in the new era of target therapies 
and/or biologics.  In studies with cytokines, cancer vaccines, and monoclonal antibodies, 
complete response, partial response, or stable disease has been shown to occur after an increase in 
tumor burden as characterized by progressive disease by traditional response criteria.  Therefore, 
conventional response criteria may not adequately assess the activity of immunotherapeutic 
agents because progressive disease (by initial radiographic evaluation) does not necessarily 
reflect therapeutic failure.  Long-term effect on the target disease must also be captured.  The 
immune-related response criteria1 (irRC) are criteria that attempt to do that by enhancing 
characterization of new response patterns that have been observed with immunotherapeutic 
agents (i.e., ipilimumab).  (Note:  The irRC only index and measurable new lesions are taken 
into account.) 
GLOSSARY 
Term 
Definition 
SPD 
sum of the products of the two largest perpendicular diameters 
Tumor burden SPDindex lesions + SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irBOR 
immune-related best overall response 
 
BASELINE ASSESSMENT USING irRC 
Step 1. Identify the index lesions (five lesions per organ, up to ten visceral lesions and 
five cutaneous lesions).   
Step 2. Calculate the SPD of all of these index lesions: 
SPD = 
(Largest diameter of lesion i) × (Second largest diameter of lesion i). 
 
                                                     
1  Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Can Res. 2009;15:7412−20. 
∑
i


 
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Appendix 4  Immune-Related Response Criteria (cont.) 
 
POST-BASELINE ASSESSMENTS USING irRC 
Step 1. Calculate the SPD of the index lesions.   
Step 2. Identify new, measurable lesions (≥ 5 × 5 mm; up to five new lesions per organ:  five new 
cutaneous lesions and ten visceral lesions).   
Step 3. Calculate the SPD of the new, measurable lesions. 
Step 4. Calculate the tumor burden: 
Tumor burden =  SPDindex lesions + SPDnew, measurable lesions 
Step 5. Calculate the change in tumor burden relative to baseline and the change in tumor burden 
relative to nadir. 
Step 6. Derive the overall response using the table below. 
Overall Response Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or not, and no 
new lesions) confirmed by a repeat, consecutive assessment ≥ 4 weeks 
from the date first documented 
irPR 
Decrease in tumor burden ≥ 50% relative to baseline confirmed by a 
consecutive assessment ≥ 4 weeks from the date first documented 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require 
confirmation 
irPD 
Increase in tumor burden ≥ 25% relative to nadir confirmed by a 
consecutive assessment ≥ 4 weeks from the date first documented 
irCR = immune-related complete response; irPD = immune-related progressive disease; 
irPR = immune-related partial response; irSD = immune-related stable disease. 
 
DETERMINATION OF irBOR 
Once a patient has completed all tumor assessments, his/her irBOR may be determined: 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR = immune-related best overall response; irCR = immune-related complete response; 
irPD = immune-related progressive disease; irPR = immune-related partial response; 
irSD = immune-related stable disease. 
 


 
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Appendix 5  Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale 
 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 
 


 
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Appendix 6  Anaphylaxis Precautions 
 
EQUIPMENT NEEDED 
i. 
Tourniquet 
j. 
Oxygen 
k. Epinephrine for subcutaneous, intravenous, and/or endotracheal use in 
accordance with standard practice  
l. 
Antihistamines 
m. Corticosteroids 
n. Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study drug infusion, the following procedures 
should be performed: 
1. 
Stop the study drug infusion. 
2. 
Apply a tourniquet proximal to the injection site to slow systemic absorption of study drug.  Do not 
obstruct arterial flow in the limb. 
3. 
Maintain an adequate airway. 
4. 
Administer antihistamines, epinephrine, or other medications as required by patient status and 
directed by the physician in charge. 
5. 
Continue to observe the patient and document observation. 
 


 
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Appendix 7  Safety Reporting Fax Cover Sheet 
 
 
GENENTECH SUPPORTED RESEARCH 
 
 
 
 
Page 1 of ___ 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
Initial Report Date 
 
 
/ 
/ 
 
 
dd / mmm / yyyy 
Follow-up Report Date 
 
 
/ 
/ 
 
 
dd / mmm / yyyy 
Patient Initials 
(Please enter a dash if the patient has no 
middle name) 
____ - ____ -____ 
 
 
      
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET. 


 
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Appendix 8  FDA MedWatch 3500 Form 
 
This form is included in the study start-up zip file to be sent to sites via email, and can also be found on 
the FDA website. 
 
 


 
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Appendix 9  Carboplatin Package Insert 
 


 
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Appendix 10  Paclitaxel Package Insert 
 
 


 
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Appendix 11 Correlative Sciences 
 
Correlative Sciences information to be maintained in a separate correlative sciences manual, 
housed outside of the study protocol. 
 
 


 
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