Conditions: Small-cell Lung Cancer Brain Metastases
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This is a single arm, multicenter phase II trial for 60 patients with untreated extensive stage (ES) small cell lung cancer (SCLC) with asymptomatic brain metastases. Subjects will receive 4 cycles of induction treatment with Atezolizumab (1200 mg on Day 1) combined with carboplatin (5-6 AUC on Day 1) and etoposide (80-100 mg/m2 on Days 1-3). Each cycle equals 21 days. After 4 cycles of induction treatment, subjects will receive atezolizumab maintenance 1200 mg on Day 1 of each 3-week cycle. Subjects will receive treatment until disease progression, unacceptable drug-related toxicity, or withdrawal from study for any reason.

Detailed description:

Arms:
arm 1: 4 cycles of induction treatment with Atezolizumab (1200 mg on Day 1) combined with carboplatin (5-6 AUC on Day 1) and etoposide (80-100 mg/m2 on Days 1-3). After 4 cycles of induction treatment, subjects will receive atezolizumab maintenance 1200 mg on Day 1 of each 3-week cycle.

Interventions: intervention 1: Carboplatin intervention 2: Etoposide intervention 3: Atezolizumab
Intervention descriptions: intervention 1: Carboplatin 5-6 mg/mL/min AUC will be delivered over 30 - 60 minutes intravenously on Day 1 of each 21 day Cycle after completion of atezolizumab. For 4 cycles. intervention 2: Etoposide 80-100 mg/m2 will be delivered over 60 minutes intravenously on Days 1-3 of each 21 day Cycle after completion of carboplatin (Day 1 only). For 4 cycles. intervention 3: Atezolizumab 1200 mg will be delivered over 60 (± 15) minutes intravenously on Day 1 of each 21 day Cycle for 4 cycles then continue as monotherapy maintenance with the same schedule.

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN LUN19-427 
Chemotherapy and Atezolizumab for Patients with Extensive Stage Small Cell Lung Cancer 
(SCLC) with Untreated, Asymptomatic Brain Metastases 
(HCRN LUN19-427) 
Sponsor Investigator 
Jeffrey Clarke, MD 
Duke University Medical Center 
jeffrey.clarke@duke.edu 
Sub-Investigators 
Scott Antonia, MD, PhD 
Duke University Medical Center 
scott.antonia@duke.edu  
Jeffrey Crawford, MD 
Duke University Medical Center 
jeffrey.crawford@duke.edu 
Neal Ready, MD, PhD 
Duke University Medical Center 
neal.ready@duke.edu 
Thomas Stinchcombe, MD 
Duke University Medical Center 
thomas.stinchcombe@duke.edu 
Katherine Peters, MD, PhD 
Duke University Medical Center 
katherine.peters@duke.edu 
Statisticians 
Lin Gu
Xiaofei Wang, PhD 
Duke University
Duke University 
lin.gu@duke.edu
xiaofei.wang@duke.edu 
Trial Management Provided by 
Hoosier Cancer Research Network, Inc. 
7676 Interactive Way 
Indianapolis, IN 46278 
Trial Supported by 
Genentech, ML#42196 
IND exemption per FDA 8/4/2020 
Initial Protocol Version Date: 04AUG2020 
Protocol Amendment Version Date: 
13MAY2022 
10AUG2022 


Clinical Study Protocol 
HCRN LUN19-427 
PROTOCOL SIGNATURE PAGE 
Chemotherapy and Atezolizumab for Patients with Extensive Stage Small Cell Lung Cancer 
(SCLC) with Untreated Brain Metastases 
(HCRN LUN19-427) 
VERSION DATE: 10AUG2022 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
Signature of Site Investigator
Date 
Site Investigator Name (printed) 
Site Investigator Title 
Name of Facility 
Location of Facility (City and State) 
PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
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Clinical Study Protocol 
HCRN LUN19-427 
SYNOPSIS 
TITLE 
Chemotherapy and Atezolizumab for Patients with Extensive 
Stage Small Cell Lung Cancer (SCLC) with Untreated, 
Asymptomatic Brain Metastases (HCRN LUN19-247) 
SHORT TITLE 
Chemotherapy and Atezolizumab for Untreated SCLC Brain 
Metastases 
PHASE 
II 
OBJECTIVES 
Primary Objective 
1.) Intracranial progression free survival (iPFS) 
Secondary Objectives 
1.) Overall response rate (ORR) 
2.) Extracranial Progression free survival (PFS) 
3.) Overall survival (OS) 
4.) Toxicity of atezolizumab plus carboplatin and etoposide 
Exploratory Objectives 
1.) Explore circulating biomarkers in patients with SCLC brain 
metastases 
2.) Explore patient-reported quality of life (QoL) 
3.) Investigate the immune and genomic landscape of SCLC 
primaries that metastasized to the brain 
STUDY DESIGN 
Single arm, multicenter phase II trial for n=60 patients with 
untreated extensive stage (ES) small cell lung cancer (SCLC) 
and asymptomatic brain metastases. 
KEY ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility criteria) 
•
Histological confirmation of Small Cell Lung Cancer- Stage 
IV/Extensive Stage (SCLC) per Veterans Administration 
Lung Study Group (VALG). 
•
Untreated, asymptomatic brain metastases 
•
No prior systemic therapy for metastatic disease [a single 
cycle of chemotherapy (platinum/etoposide) with or 
without atezolizumab is allowed within 30 days prior to 
enrollment] 
STATISTICAL 
CONSIDERATIONS 
A Kaplan-Meier curve will graphically describe iPFS, PFS, 
and OS among patients treated by at least one cycle of 
Atezolizumab. Median survival, as well as 6-month iPFS and 
PFS, and 12-month OS will be estimated with their 95% 
confidence intervals (CI). The impact of patients’ 
demographics and baseline clinical characteristics on 
survivals will be evaluated in the context of a Cox PH model. 
The ORR, the proportion of treated subjects with a complete 
or partial response, will be calculated with its 95% CI. The 
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Clinical Study Protocol 
HCRN LUN19-427 
association of ORR with patients’ demographics and baseline 
clinical characteristics will be evaluated in a logistic 
regression model. 
The quality of life of treated patients at baseline and during 
treatment will be summarized and the patients’ demographics 
and baseline clinical characteristics on the change of the 
quality of life will be evaluated in a linear regression. 
TOTAL 
NUMBER OF 
SUBJECTS 
N = 63 eligible patients (60 evaluable) 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 22 months from lead site opening to accrual 
ESTIMATED STUDY 
DURATION 
Estimated 40 months 
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Clinical Study Protocol 
HCRN LUN19-427 
TABLE OF CONTENTS 
Schema
6 
1.
Background and Rationale
7 
2.
Study Objectives and Endpoints
 10 
3.
Eligibility Criteria
 11 
4.
Subject Registration
 15 
5.
Treatment Plan
 15 
6.
Toxicities and Dose Delays/Dose Modifications
21 
7.
Study Calendar & Evaluations
26 
8.
Biospecimen Studies and Procedures
29 
9.
Criteria for Disease Evaluation
31 
10 Drug Information
36 
11
Adverse Events
38 
12
Statistical Methods
45 
13
Trial Management
48 
14.
Data Handling and Record Keeping
49 
15 Ethics
50 
16 References
51 
Management Guidelines for Infusion-Related Reactions
64 
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Screening 
Informed Consent 
Examinations 
Lab evaluations 
Brain MRI, Chest CT +/- AP 
Histologically confirmed Stage IV Small Cell Lung Cancer- Extensive Stage (SCLC) 
with untreated, asymptomatic brain metastases. ECOG PS 0-2. 
Induction Treatment 
Atezolizumab + Chemo 
(Cycle = 21 days, 4 cycles) 
Atezolizumab 1200 mg IV (D1) 
Carboplatin 5-6 AUC IV (D1) 
Etoposide 80-100 mg/m
2  IV (D1-D3) 
Maintenance 
(Cycle = 21 days until disease progression or toxicity) 
Atezolizumab 1200 mg IV (D1 each cycle) 
Disease Evaluation 
General and lab evaluations every cycle 
Brain MRI, Check CT +/- AP every other cycle (q6 weeks) 
Follow-up 
(about 30 days after final Atezolizumab treatment) 
General evaluations 
Lab evaluations 
Clinical Study Protocol 
HCRN LUN19-427 
SCHEMA 
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Clinical Study Protocol 
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1.
BACKGROUND AND RATIONALE 
1.1
Extensive Stage Small Cell Lung Cancer (ES SCLC) 
Lung cancer is the most deadly cancer globally, accounting for 12% of diagnoses and 18% of 
cancer-related mortality [1]. An aggressive subtype of lung cancer, small cell lung cancer 
(SCLC), accounts for approximately 15% of lung cancer cases, and is almost always associated 
with smoking [2]. Most patients with SCLC have extensive stage (ES) disease at time of 
diagnosis, where the disease has metastasized (spread) beyond the lung and nearby lymph nodes 
[3]. SCLC appears to have a higher predilection for spreading to the brain, with upwards of 10-
20% of patients with SCLC having brain metastases at initial diagnosis and 40-50% more 
eventually developing brain metastases during the course of disease [4]. 
Historically, in the extensive stage setting, platinum-doublet based chemotherapy has been most 
often utilized as frontline therapy, most commonly using a combination with etoposide. 
Platinum and etoposide typically results in a very high initial response rate (~60-80%) and 
modest progression free survival (~4-6 months), with median overall survival of less than twelve 
months in the majority of patients [5-7]. Despite initial chemosensitivity, a hallmark of SCLC is 
the development recalcitrant behavior to subsequent lines of chemotherapy resulting in dismal 
outcomes in the refractory setting. Prophylactic cranial irradiation (PCI) has been studied and 
utilized extensively over the past several decades to improve outcomes by treating occult 
micrometastatic disease and reducing the incidence of brain metastases. A meta analysis of PCI 
in the limited stage setting, in SCLC demonstrated a marked reduction in brain metastases from 
59% to 33% and improved 3 year survival from 15.3 to 20.7 months [8]. However, in ES SCLC, 
data regarding the role of PCI has been conflicting. The initial phase III EORTC study of 286 
patients randomized PCI or observation following initial 4-6 cycles of chemotherapy [9]. While 
the incidence of symptomatic brain metastases and survival improved in the PCI arm, the results 
were criticized as MRI was not routinely performed prior to PCI and therefore likely included a 
portion of patients with brain metastases. In a separate study from Japan, 224 patients with 
response to chemotherapy were randomized to receive either PCI or observation [10]. All 
patients had a baseline MRI prior to enrollment and every 3 months during follow up. The 
study was stopped early due to futility and a trend was noted with worse survival in patient 
receiving PCI compared with observation. 
In March 2019, the anti-PD-L1 antibody atezolizumab combined with carboplatin and etoposide, 
a topoisomerase II inhibitor, was FDA-approved for first-line treatment of ES SCLC [11]. This 
priority approval was based on the results of the IMpower133 study (NCT02763579), a trial 
which allowed but was not specifically designed for patients with brain metastases. As a result, 
of the 403 patients, only 35 (9%) had brain metastases. Additionally, recent results from the 
CASPIAN study of chemotherapy with or without durvalumab included approximately 10% of 
patients with brain metastases [12]. Thus, limited data exists currently regarding clinical 
outcomes of patients with SCLC and brain metastases at time of diagnosis. 
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1.2
Standard of Care for Small Cell Lung Cancer Brain Metastases 
Given the systemic nature of SCLC, the rate of metastatic spread to the brain and concern for 
micrometastatic disease, whole brain radiotherapy (WBRT) is typically used for the treatment of 
brain metastases in SCLC. Importantly, WBRT is associated commonly with well-documented 
short- and long-term neurotoxicity and reduced quality of life [13-15]. For example, in a pooled 
analysis of over 400 patients receiving PCI for lung cancer resulted in decline in self reported 
cognitive function at 6 and 12 months, while Hopkins Verbal Learning Test assessment declined 
as well [15]. Short term effects typically include fatigue, anorexia, headache, nausea, and hair 
loss [16]. In the EORTC study randomizing patients to receive PCI with ES SCLC, health 
reported quality of life scores were lower in the patients receiving PCI for global health status, 
cognitive function, fatigue within three months of follow up [13]. WBRT is also often partnered 
with systemic therapy, either before or after receipt of radiation, in ES SCLC due to the 
frequently multifocal metastatic nature of the disease. 
Generally, systemic treatment alone with chemotherapy can result in intracranial response in the 
majority of patients with brain metastases. As a result, a common approach clinically is to start 
systemic therapy without WBRT in patients with newly diagnosed ES SCLC and asymptomatic 
brain metastases. However, a limited amount of data exists regarding the outcomes in patients 
with brain metastases treated with systemic therapy alone. In an analysis of 7 studies including 
85 patients with brain metastases treated with chemotherapy, the overall clinical response was 
79%. However, in one of the largest studies, 24 patients with synchronous brain metastases and 
treated with chemotherapy alone were enrolled over 13 years at a single institution [17]. 
Response rate was much lower with 27% having a response to cyclophosphamide, doxorubicin, 
and etoposide and was lower than the response rate of the extracranial disease. This study had 
limitations in that patients only received MRI at baseline, at completion of chemotherapy, and 
upon development of symptoms. Additionally, platinum with etoposide based chemotherapy 
was not used in this study population. 
Given the recent approval of atezolizumab, the current first-line systemic treatment approach for 
patients with ES SCLC is a combination of anti-PD-L1 antibody with a chemotherapy regimen 
of platinum plus etoposide, based on the IMpower133 study (NCT02763579) [18]. The addition 
of atezolizumab, an anti-PD-L1 antibody, to carboplatin and etoposide for first-line treatment of 
ES SCLC improved overall (OS) to 12.3 months, from 10.3 months with placebo, and 
progression-free survival (PFS) to 5.2 months (versus 4.3 months for placebo). While this study 
allowed ES SCLC patients with brain metastases, only 35 patients (n=17-18 per arm, 9%) had 
brain metastases; the study was unpowered to access efficacy in this patient population [18]. 
1.3
Atezolizumab (MPDL3280A) 
Immunotherapies that block checkpoint proteins on immune cells inhibit the negative feedback 
on T cells by these signaling pathways, thereby maintaining activation of the T cells [19]. Two of 
the most predominant clinical checkpoint targets are PD-1 and its ligand PD-L1. Association of 
PD-L1 with PD-1 induces inhibitory signals in T cells that reduce proliferation and cytokine 
production, causing T cell inactivation or exhaustion. Aberrant expression of PD-L1 in tumors 
leads to immune evasion by the tumor, but also provides a therapeutic opportunity. 
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Atezolizumab (MPDL3280A; anti−PD-L1 antibody) is a humanized 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 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 PD-L1 and inhibits 
its interaction with its receptors, PD-1 and B7.1 (CD80, B7-1). Both of these interactions are 
reported to provide inhibitory signals to T cells. 
1.4
Rationale 
The IMpower133 clinical trial evaluated chemotherapy and atezolizumab for first line treatment 
of patients with untreated ES SCLC. The results from the trial led to an FDA approval and 
established this regimen as a new standard of care. However, while patients with brain 
metastases were allowed, prior cranial radiation was required for these patients. Furthermore, 
only 9% of enrolled patients had brain metastases. There remains an urgent need to define 
clinical outcomes for patients treated with chemotherapy and atezolizumab with asymptomatic, 
untreated brain metastases. 
Recent studies with systemic immunotherapy in brain metastases patients have demonstrated that 
outcomes for patients with and without brain metastases are generally similar. The IMpower133 
study demonstrated PFS outcomes of 5.2 months for the atezolizumab arm versus 4.3 months for 
the placebo arm. Thus, we hypothesize that atezolizumab plus chemotherapy (i.e. carboplatin and 
etoposide) will improve intracranial progression free survival (iPFS) in patients with brain 
metastases from SCLC relative to historical controls (≥ 5.2 months vs. 4 months). 
This study will enroll patients with asymptomatic brain metastases and untreated ES SCLC. 
Patients will be treated with combination carboplatin, etoposide, and atezolizumab. Restaging 
radiographic imaging will occur every 6 weeks (approximately every 2 cycles of treatment). At 
time of progression, patients can pursue standard of care treatment and radiation therapy off 
study. Our hypothesis is that the addition of atezolizumab will improve intracranial progression 
free survival in patients with untreated brain metastases. Furthermore, the study will provide 
valuable insight in the clinical outcomes of the patient population with ES SCLC and brain 
metastases. In general, chemotherapy response rates are expected to be high, and immune 
checkpoint therapy is known to have efficacy in other CNS malignancies. We believe treatment 
with systemic therapy alone will 1) delay time to WBRT 2) preserve quality of life longer 3) 
allow a subpopulation of patients to avoid WBRT and 4) be able to avoid a detrimental impact 
on survival given the close radiographic follow up. 
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Clinical Study Protocol 
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2.
STUDY OBJECTIVES AND ENDPOINTS 
2.1
Objectives 
2.1.1 Primary Objective 
•
Estimate intracranial progression free survival (iPFS) for atezolizumab when 
administered with carboplatin and etoposide in subjects with untreated SCLC brain 
metastases 
2.1.2 Secondary Objectives 
•
Estimate the overall response rate (ORR) for atezolizumab when administered with 
carboplatin and etoposide in subjects with untreated SCLC brain metastases 
•
Estimate the extracranial progression free survival (PFS) for atezolizumab when 
administered with carboplatin and etoposide in subjects with untreated SCLC brain 
metastases 
•
Estimate the overall survival (OS) for atezolizumab when administered with carboplatin 
and etoposide in subjects with untreated SCLC brain metastases 
•
Evaluate the toxicity of atezolizumab when administered with carboplatin and etoposide 
in subjects with untreated SCLC brain metastases 
2.1.3 Correlative/Exploratory Objectives 
•
Explore circulating biomarkers in patients with SCLC brain metastases 
•
Explore patient-reported quality of life (QoL) 
•
Investigate the immune and genomic landscape of SCLC primaries that metastasized to 
the brain 
2.2
Endpoints 
2.2.1 Primary Endpoint 
•
Intracranial PFS is defined as the time from Day 1 of treatment until the criteria for 
intracranial  disease progression is met as defined by RANO-BM or death as a result of 
any cause, whichever comes first. 
2.2.2 Secondary Endpoints 
•
ORR will include complete response (CR) + partial response (PR) as determined by 
RECIST 1.1. 
•
Extracranial PFS is defined as the time from Day 1 of treatment until the criteria for 
extracranial disease progression is met as defined by RECIST 1.1 or death as a result of 
any cause, whichever comes first. 
•
OS is defined as the time from Day 1 of treatment until death as a result of any cause. 
•
Toxicity will be graded by Common Toxicity Criteria for Adverse Events (CTCAE V5). 
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2.2.3 Correlative/Exploratory Endpoints 
•
Circulating biomarkers in patients with SCLC brain metastases will be explored in patient 
blood, focusing on circulating immune cells, protein analysis, and cell-free DNA 
•
Patient-reported quality of life (QoL) will be assessed per: 
o
FACT-BR 
o
FACIT-Fatigue 
o
Godin Leisure-Time Exercise Questionnaire 
•
The immune and genomic landscape of SCLC that metastasized to the brain will be 
assessed through analysis of archival paraffin tissue of the primary lesion by 
immunohistochemistry and sequencing 
3.
ELIGIBILITY CRITERIA 
3.1
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
1.
Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE: HIPAA authorization may be included in the 
informed consent or obtained separately. 
2. Age ≥ 18 years with ability and willingness to provide informed consent. 
3.
ECOG Performance Status of 0-2. 
4. Histological confirmation of Small Cell Lung Cancer- Extensive Stage (SCLC) per 
Veterans Administration Lung Study Group (VALG). 
5.
At least one untreated asymptomatic brain metastasis that is measurable by RECIST 1.1 
that has not been previously irradiated. 
6. No prior treatment for metastatic disease. EXCEPTION: A single cycle of 
chemotherapy (platinum/etoposide) with or without atezolizumab is allowed within 30 
days prior to enrollment. 
7.
Treatment-free for at least 6 months since last chemo/radiotherapy, among those treated 
(with curative intent) with prior chemo/radiotherapy for limited-stage SCLC. 
8.
Any prior cancer treatment must be completed at least 6 months prior to registration and 
the subject must have recovered from all reversible acute toxic effects of the regimen 
(other than alopecia) to Grade ≤ 1 or baseline. NOTE: a single cycle of chemotherapy 
(platinum/etoposide) with or without atezolizumab is allowed within 30 days prior to 
enrollment. NOTE: Extracranial radiation is allowed. 
9. A concurrent diagnosis of a separate malignancy is allowed if clinically stable and does 
not require tumor-directed therapy. 
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10. Demonstrate adequate organ function as defined in the table below 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count (ANC) 
2 1.5K/mm
3
 without GCSF 
Hemoglobin (Hgb) 
2 9 g/dL (without transfusion) 
Lymphocyte Count 
2 500/µL 
Platelet Count 
2 100,000/µL without transfusion 
Renal 
Calculated creatinine clearance
1
 
2 50 cc/min 
OR 
Serum Cr 
< 1.5 x institutional ULN 
Hepatic 
Bilirubin
2
 
< 1.5 × upper limit of normal (ULN) 
Aspartate aminotransferase (AST) 
< 2 × ULN without liver metastasis 
< 5 × ULN with liver metastasis 
Alanine aminotransferase (ALT) 
< 2 × ULN without liver metastasis 
< 5 × ULN with liver metastasis 
1 Cockcroft-Gault formula will be used to calculate creatinine clearance 
2 Patients with known Gilbert disease who have serum bilirubin level < 3x ULN may be 
enrolled 
11. Females of childbearing potential must have a negative serum pregnancy test within 3 
days (72 hours) prior to enrollment. NOTE: Females are considered of childbearing 
potential unless they are surgically sterile (have undergone a hysterectomy or bilateral 
oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. 
12. Females of childbearing potential and males must be willing to abstain from heterosexual 
activity or to use 2 forms of effective methods of contraception, including at least one 
method with a failure rate of < 1% per year, from the time of informed consent until 150 
days (5 months) after treatment discontinuation. 
13. Negative hepatitis B surface antigen (HBsAg) test, negative total hepatitis B core 
antibody (HBcAb) test, or positive total HBcAb test followed by a negative hepatitis B 
virus (HBV) DNA test. The HBV DNA test will be performed only for patients who have 
a positive total HBcAb test. Testing required at screening only if results are not known. 
14. Negative hepatitis C virus (HCV) antibody test, or positive HCV antibody test followed 
by a negative HCV RNA test. The HCV RNA test will be performed only for patients 
who have a positive HCV antibody test. A positive HCV RNA test is sufficient to 
diagnose active HCV infection in the absence of an HCV antibody test. 
15. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures. 
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3.2
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
1. Known active CNS metastases which are symptomatic. CNS metastases are considered 
asymptomatic if the patient does not require high dose or escalating corticosteroids or 
anticonvulsant therapy. Steroid dose must be equivalent to 2 mg of dexamethasone or less 
daily. 
•
Prior steroid use as part of an anti-emetic regimen with chemotherapy is allowed. 
•
Patients must be on a stable dose of corticosteroid. No tapering or decreasing dose 
within 7 days of enrollment. 
2.
Leptomeningeal disease. Discrete dural-based metastases will be allowed without 
evidence of leptomeningeal disease. 
3.
Radiation therapy within 14 days prior to Day 1 of Cycle 1 Day 1. NOTE: Extracranial 
radiation is allowed. 
4.
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 
12 mg/dL or corrected serum calcium > ULN) 
5.
Known auto-immune conditions requiring systemic immune suppression therapy other 
than prednisone ≤ 10 mg daily (or equivalent). 
6. History of interstitial pneumonitis from any cause. 
7.
Concurrent severe and/or uncontrolled medical conditions which may compromise 
participation in the study as assessed by site investigator. 
8.
Current active infectious disease requiring systemic antibiotics, antifungal, or antiviral 
treatment on Cycle 1 Day 1. Patients receiving prophylactic antibiotics (e.g., for 
prevention of urinary tract infection or chronic obstructive pulmonary disease) are 
eligible. NOTE: Subjects with active tuberculosis are NOT eligible. 
9. Current use of medications specified by the protocol as prohibited for administration in 
combination with the study drugs. This includes patients with a condition requiring 
systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or 
other immunosuppressive medications within 14 days prior to Cycle 1 Day 1. Inhaled or 
topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are 
permitted in the absence of active autoimmune disease. Patients who are receiving 
denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate 
instead. 
10. History of myocardial infarction, NYHA class II or greater congestive heart failure, or 
unstable angina, cardiac or other vascular stenting, angioplasty, or surgery within 6 
months prior to study enrollment. 
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11. Known history of HIV seropositivity or known acquired immunodeficiency syndrome 
(AIDS), Testing not required at screening. 
12. Requirement for ongoing anticoagulation with heparin, low molecular weight heparin, or 
other oral anticoagulant (coumadin, DOAC). 
13. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently). NOTE: Patients with indwelling catheters 
(e.g., PleurX®) are allowed. 
14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins. 
15. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster 
ovary cells or any component of the atezolizumab formulation. 
16. History of allergic reactions to carboplatin or etoposide. 
17. Intolerance of atezolizumab or other PD-1/PD-L1 axis drug(s), or any other antibody or 
drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, 
including prior therapy with anti-tumor vaccines or other immune-stimulatory anti-tumor 
agents. 
18. Active or history of autoimmune disease or immune deficiency, including, but not limited 
to, myasthenia gravis, myositis, autoimmune hepatitis, inflammatory bowel disease, 
antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, 
Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: 
•
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
•
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
•
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
o
Rash must cover < 10% of body surface area 
o
Disease is well controlled at baseline and requires only low-potency 
topical corticosteroids 
o
There has been no occurrence of acute exacerbations of the underlying 
condition requiring psoralen plus ultraviolet A radiation, methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors 
19. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab. 
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20. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study). 
21. Treatment with any investigational drug within 28 days prior to Cycle 1 Day 1. 
4.
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. A subject 
is considered registered when an “On Study” date is entered into the EDC system. Subjects must 
be registered prior to starting protocol therapy. 
5.
TREATMENT PLAN 
This is a single arm, multicenter phase II trial for 60 patients with untreated extensive stage (ES) 
small cell lung cancer (SCLC) with asymptomatic brain metastases. Subjects will receive 4 
cycles of induction treatment with Atezolizumab (1200 mg on Day 1) combined with carboplatin 
(5-6 AUC on Day 1) and etoposide (80-100 mg/m
2
 on Days 1-3). Each cycle equals 21 days. 
After 4 cycles of induction treatment, subjects will receive atezolizumab maintenance 1200 mg 
on Day 1 of each 3-week cycle. Subjects will receive treatment until disease progression, 
unacceptable drug-related toxicity, or withdrawal from study for any reason. 
5.1
Study Treatment 
5.1.1 ACE (Atezolizumab-Carboplatin-Etoposide) Induction 
Drug 
Dose
1
 
Route 
Schedule
2
 
Cycle 
Length 
Total # of 
Cycles 
Atezolizuma 
b 
1200 mg 
Intravenously (IV) 
over 60 minutes 
before 
carboplatin 
Day 1 
3 weeks 
(21 days) 
4 
Carboplatin 
5-6 
mg/mL/min 
AUC 
IV over 30-60 min 
after completion 
of atezolizumab 
Day 1 
Etoposide 
80-100 
mg/m
2
 
IV over 60 min 
after completion 
of carboplatin 
Days 1, 2, 3 
1 Dosing calculations should be based on actual body weight where applicable. Institutional 
standards for recalculating the dose based on weight changes should be used. All doses 
should be rounded up or to the nearest milligram per institutional standard. 
2 A window of ±3 days may be applied to all study visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. Date and time of each drug administration 
should be clearly documented in subject’s chart and electronic case report forms (eCRFs). 
5.1.2 Atezolizumab Maintenance 
Drug 
Dose 
Route 
Schedule
1
 
Cycle Length 
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Atezolizumab 
1200 mg 
IV over 60 minutes 
Day 1 
3 weeks 
(21 days) 
1 A window of ± 7 days may be applied to all study visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. Date and time of each drug administration 
should be clearly documented in subject’s chart and electronic case report forms (eCRFs). 
 
5.2 
Chemotherapy 
Institutional standards may be used for the infusion of carboplatin and etoposide. This includes 
pre-medications, infusion windows and treatment of side effects. Because the effects of 
corticosteroids on T-cell proliferation have the potential to attenuate atezolizumab-mediated anti-
tumor immune activity, premedication with corticosteroids should be minimized to the extent 
that is clinically feasible. The current package insert should be referenced for additional 
information regarding these medications. Both medications will be used in the commercially 
available formulation. 
5.2.1 Carboplatin 
Carboplatin 5-6 mg/mL/min AUC will be delivered over 30 - 60 minutes intravenously on Day 1 
of each 21 day Cycle after completion of atezolizumab. Institutional standards may be used for 
dose calculation. 
5.2.2 Etoposide 
Etoposide 80-100 mg/m
2
 will be delivered over 60 minutes intravenously on Days 1-3 of each 21 
day Cycle after completion of carboplatin (Day 1 only). Institutional standards may be used for 
dose calculation. 
5.3
Atezolizumab 
Atezolizumab 1200 mg will be delivered over 60 (± 15) minutes intravenously on Day 1 of each 
21 day Cycle. Institutional standards may be used regarding all aspects of the infusion. The 
investigator’s brochure should be utilized for additional details regarding this medication. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. Atezolizumab infusions instructions outlined in the Table below. 
First Infusion 
Subsequent Infusions 
● 
● 
● 
● 
No premedication is allowed. 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before starting 
infusion. 
Infuse atezolizumab (1200 mg in a 250 mL 
0.9% NaCl intravenous infusion bag) over 60 
(± 15) minutes. 
If clinically indicated, record patient’s vital 
signs (heart rate, respiratory rate, blood 
pressure, and temperature) during the infusion 
at 15, 30, 45, and 60 minutes 
● 
● 
● 
If the patient experienced an infusion-related 
reaction during any previous infusion, 
premedication with antihistamines may be 
administered for Cycles ≥ 2 at the discretion 
of the treating physician. 
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) within 60 minutes before starting 
infusion. 
If the patient tolerated the first infusion well, 
without infusion-associated adverse events, 
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●
(± 5-minute windows are allowed for all time 
points). 
●
If clinically indicated, record patient’s vital 
signs (heart rate, respiratory rate, blood 
pressure, and temperature) at 30 (± 10) 
minutes after the infusion. 
●
Patients will be informed about the possibility 
of delayed post-infusion symptoms and 
instructed to contact their study physician if 
they develop such symptoms.  
the second infusion may be administered over 
30 (± 10) minutes. 
●
If no reaction occurs, subsequent infusions 
may be administered over 30 (± 10) minutes. 
o
Continue to record vital signs within 60 
minutes before starting infusion and 
during and after the infusion, if clinically 
indicated. 
●
If the patient had an infusion-related reaction 
during the previous infusion, the subsequent 
infusion must be administered over 60 (± 15) 
minutes. 
o
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) during the infusion if 
clinically indicated or if patient 
experienced symptoms during the 
previous infusion. 
o
Record patient’s vital signs (heart rate, 
respiratory rate, blood pressure, and 
temperature) 30 (± 10) minutes after the 
infusion if clinically indicated or if patient 
experienced symptoms during previous 
infusion. 
5.3.1 Infusion -Related Reactions with Atezolizumab 
No premedication is indicated for the administration of Cycle 1 of atezolizumab. However, 
patients who experience an infusion-related reaction (IRR) with Cycle 1 of atezolizumab may 
receive premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions. Metamizole (dipyrone) is prohibited in treating atezolizumab-associated 
IRRs because of its potential for causing agranulocytosis. Guidelines for medical management of 
IRRs during Cycle 1 are provided in the Table below. For subsequent cycles, IRRs should be 
managed according to institutional guidelines. 
5.3.2 Management Guidelines for Infusion-Related Reactions 
Event 
Management 
IRR, Grade 1 
• 
Reduce infusion rate to half the rate being given at the time of event onset. 
• 
After the event has resolved, the investigator should wait for 30 minutes while 
delivering the infusion at the reduced rate. 
• 
If the infusion is tolerated at the reduced rate for 30 minutes after symptoms 
have resolved, the infusion rate may be increased to the original rate. 
• 
Monitor vital signs as clinically indicated 
IRR, Grade 2 
• 
Interrupt atezolizumab infusion. 
• 
Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, 
anti-pyretic medication, glucocorticoids, epinephrine, bronchodilators, 
oxygen). 
• 
After symptoms have resolved to baseline, resume infusion at half the rate 
being given at the time of event onset. 
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• 
• 
• 
For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics and monitor closely for IRRs. 
Monitor vital signs as clinically indicated 
Consider permanent discontinuation of atezolizumab treatment if Grade 2 
infusion reaction occurs despite adequate premedication 
IRR, Grade 3 or 4 • 
• 
• 
• 
• 
Stop infusion. 
Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, 
anti-pyretic, glucocorticoids, epinephrine, bronchodilators, oxygen). 
Monitor vital signs as clinically indicated 
Hospitalization indicated for clinical sequelae (examples: renal impairment, 
pulmonary infiltrates) 
Permanently discontinue atezolizumab. 
a
 
IRR = infusion-related reaction. 
a  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). See Appendix I 
for additional information. 
5.4
Concomitant Medications 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs or 
homeopathic remedies, nutritional supplements) used by a patient from 7 days prior to screening 
until the treatment discontinuation visit. Steroid medication use  should be reported to the 
investigator and recorded on the Concomitant Medications eCRF. 
5.4.1 Allowed Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
The following therapies may continue while patients are in the study: 
•
Oral contraceptives 
•
Hormone-replacement therapy 
•
Prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin or warfarin at a stable dose level) 
•
If palliative radiotherapy is required, it should be discussed with HCRN and the sponsor-
investigator. 
•
Inactive influenza vaccinations 
•
Megestrol administered as an appetite stimulant 
•
Inhaled corticosteroids for chronic obstructive pulmonary disease 
•
Mineralocorticoids (e.g., fludrocortisone) 
•
Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency 
In general, investigators should manage a patient’s care with supportive therapies as clinically 
indicated per local standards. Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or 
another H2 receptor antagonist per standard practice (for sites outside the United States, 
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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. 
All concomitant steroid medications must be recorded on the appropriate Concomitant 
Medications eCRF. 
5.4.2 Cautionary Therapy for Atezolizumab-Treated Patients 
Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab. Therefore, in situations where systemic corticosteroids or 
TNF- α inhibitors would be routinely administered, alternatives, including antihistamines, should 
be considered first by the treating physician. If the alternatives are not clinically appropriate, 
systemic corticosteroids and TNF- α inhibitors may be administered at the discretion of the 
treating physician except in the case of patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance). 
Systemic corticosteroids are recommended, with caution, at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with atezolizumab 
therapy. 
Refer to the Atezolizumab Investigator’s Brochure for additional information on the 
management of immune-mediated adverse events. 
5.4.3 Prohibited Concomitant Medications with Atezolizumab 
Any concomitant therapy intended for the treatment of cancer, whether health authority-
approved or experimental, is prohibited for various time periods prior to starting study treatment, 
depending on the anti-cancer agent, and during study treatment until disease progression is 
documented and the patient has discontinued study treatment. This includes, but is not limited to 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, non-approved experimental 
agents, or herbal therapy (unless otherwise noted). 
The following medications are prohibited while in the study, unless otherwise noted: 
•
Denosumab; patients who are receiving denosumab prior to enrollment must be willing 
and eligible to receive a bisphosphonate instead 
•
Any live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior enrollment, during 
treatment, and for 5 months following the last dose of atezolizumab 
•
Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in such 
patients, non-contrast CT scans of the chest and non-contrast CT scans or MRIs of the 
abdomen and pelvis should be performed 
The concomitant use of herbal therapies is not recommended because their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown. However, their use 
for patients in the study is allowed at the discretion of the investigator, provided that there are no 
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known interactions with any study treatment. As noted above, herbal therapies intended for the 
treatment of cancer are prohibited. 
5.5
Supportive Care 
In general, investigators should manage a patient’s care with supportive therapies as clinically 
indicated per local standards. Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or 
another H2 receptor antagonist 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. 
All concomitant steroid medications must be recorded on the appropriate Concomitant 
Medications eCRF. 
5.6
Reproductive Information 
Negative pregnancy test done ≤ 72 hours (or per institutional policy) prior to treatment, for 
women of childbearing potential only. Female subjects should be using highly effective 
contraceptive measures, and must have a negative pregnancy test or must have evidence of non-
child-bearing potential by fulfilling one of the following criteria at screening: 
•
Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 
months following cessation of all exogenous hormonal treatments. 
•
Women under 50 years old would be consider postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and with LH and FSH levels in the post-menopausal range for the institution 
•
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation 
Men and women of childbearing potential must agree to use highly effective methods of 
contraception, including at least one method with a failure rate of < 1% per year, during the 
course of the study and for 5 months after the last dose of study drug, even if oral contraceptives 
are also used. All subjects of reproductive potential must agree to use both a barrier method and 
a second method of birth control during the course of study and for 5 months after the last dose 
of study drug. 
5.6.1 Contraception Options 
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly are described in the table below. 
Note that some contraception methods are not considered highly effective (e.g. male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action; and triphasic 
combined oral contraceptive pills). Abstaining from heterosexual intercourse is considered an 
effective method of contraception. 
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Highly Effective Methods of Contraception (<1% Failure Rate) 
Barrier/Intrauterine methods
Hormonal Methods 
•
Copper T intrauterine device 
•
Levonorgestrel-releasing intrauterine 
system (e.g., Mirena®)
a
 
•
Etonogestrel implants: e.g. Implanon 
•
Intravaginal device: e.g. ethinylestradiol and 
etonogestrel 
•
Medroxyprogesterone injection: e.g. Depo-
Provera 
•
Normal and low dose combined oral 
contraceptive pill 
•
Norelgestromin/ethinylestradiol transdermal 
system 
a
This is also considered a hormonal method 
6.
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v5 will be used to grade 
adverse events. Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study as specified 
in Study Calendar & Evaluations. Subjects will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption or discontinuation as 
specified in Study Calendar & Evaluations. 
6.1
Dose Delays/Dose Modifications 
Reasons for dose modifications including dose delays, the supportive measures taken, and the 
outcomes will be documented in the patient's chart and recorded on the eCRF. The severity of 
adverse events will be graded according to the NCI CTCAE v5 grading system. 
•
When several toxicities with different grades of severity occur at the same time, the dose 
modifications should be according to the highest grade observed. 
•
If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
component of the study treatment and the dose or administration of that component is 
delayed or modified, the dose or administration of the other study treatment components 
do not require modification and may be administered if there is no contraindication. 
•
When treatment is temporarily interrupted because of toxicity caused by atezolizumab, 
carboplatin, or etoposide, the treatment cycles should be restarted such that the 
atezolizumab infusions remain synchronized and aligned with the chemotherapy 
schedule. 
•
If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
chemotherapy drug, the dose of the other chemotherapy drug does not require 
modification. 
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The investigator may use discretion in modifying or accelerating the dose modification 
guidelines described below depending on the severity of toxicity and an assessment of the risk 
versus benefit for the patient, with the goal of maximizing patient compliance and access to 
supportive care. 
6.2
Atezolizumab Dose Modification 
There will be no dose modifications for Atezolizumab. Adverse events will be managed as 
described in detail in Appendix “Management of Atezolizumab-Specific Adverse Events”. 
If a dose of atezolizumab is withheld for toxicity, then subjects may resume dosing with 
atezolizumab if that is appropriate at their next scheduled appointment or when toxicity has 
improved as described in the Appendix “Management of Atezolizumab-Specific Adverse 
Events”. 
Atezolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as below and as listed in appendix. 
Subjects who require corticosteroids to manage atezolizumab-related AEs must be at an 
equivalent dose of ≤ 10 mg per day of prednisone to resume dosing with atezolizumab. 
Furthermore, an inability to reduce the corticosteroid dose for managing a drug-related adverse 
event to the equivalent of ≤ 10 mg prednisone per day within 12 weeks of the last atezolizumab 
dose should prompt discussion between the site investigator and sponsor-investigator regarding 
the subject’s ability to continue on treatment with atezolizumab the study. With site investigator 
and sponsor-investigator agreement, subjects with a laboratory adverse event still at Grade 2 
after 12 weeks may continue treatment in the study only if asymptomatic and controlled. 
In subjects who continue on atezolizumab having experienced a Grade 3, Grade 4, or persistent 
(> 4 weeks) Grade 2 atezolizumab-related AE, dosing should be held until the AE resolves to 
Grade 0-1 or baseline. 
However, in subjects who experience Grade 3 or 4 pneumonitis, or recurrent persistent (> 4 
weeks) Grade 2 drug-related pneumonitis after re-challenge from a prior episode of persistent (> 
4 weeks) Grade 2 drug-related pneumonitis, atezolizumab must be permanently discontinued. 
For subjects Hepatotoxicity events of Grade 3-4, patients are to permanently discontinue 
Atezolizumab, with the exception of patients with liver metastasis who began treatment with 
Grade 2 AST or ALT; if AST or ALT increases by greater than or equal to 50% relative to 
baseline and lasts for at least 1 week then subjects should be discontinued. 
Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at 
physician discretion. Permanently discontinue study drug for persistent Grade 2 adverse 
reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 
within 12 weeks of the last dose. 
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Refer to the Atezolizumab Investigator’s Brochure for more detailed information regarding dose 
modification. 
6.3
Chemotherapy Dose Modification 
Dose modifications for carboplatin and etoposide are permitted for toxicity according to the 
prescribing information and local standard-of-care. Dose modification guidelines are provided 
below. Once reduced, the dose cannot be increased back to 100%. 
Treatment with carboplatin or etoposide should be discontinued if a patient experiences any 
hematologic or non-hematologic Grade 3 or Grade 4 toxicity after two dose reductions or 
treatment is delayed for more than 63 days due to toxicities. 
6.3.1 Criteria for start of Cycle 
Prior to the start of each Cycle the following is required: 
•
ANC ≥1500/uL 
•
Platelet count ≥ 100,000/uL 
6.3.2 Hematologic Toxicity 
Treatment may be delayed for up to 63 days to allow sufficient time for recovery. Growth factors 
may be used in accordance with American Society of Clinical Oncology (ASCO) and NCCN 
guidelines (Smith et al. 2006; NCCN 2015). Upon recovery, dose adjustments at the start of a 
subsequent cycle will be made on the basis of the lowest platelet and neutrophil values from the 
previous cycle. See the Table below. 
In the event that dose adjustments are needed for both ANC and platelets, patients are to receive 
the lower dose. 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, infection, 
or febrile neutropenia so that these complications can be promptly and appropriately managed. 
Patients should be made aware of these signs and encouraged to seek medical attention at the 
earliest opportunity. 
If chemotherapy is withheld because of hematologic toxicity, full blood counts (including 
differential WBC) should be obtained weekly until the counts reach the lower limits for 
treatment as outlined. The treatment can then be resumed. 
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No dose reductions are recommended for anemia. Patients should be supported per the 
investigator’s institution’s guidelines. 
6.3.3 Non-Hematologic Toxicity 
For a non-hematologic toxicity, treatment may be delayed for up to 63 days until resolution to 
less than or equal to the patient’s baseline value (or Grade ≤ 1 if the patient did not have that 
toxicity at baseline). Dose reductions at the start of the subsequent cycle should be made on the 
basis of non-hematologic toxicities from the dose administered in the preceding cycle. 
Recommended dose modifications for non-hematologic toxicities are in Table below. 
Diarrhea should be controlled with adequate anti-diarrhea medication. Nausea and/or vomiting 
may be controlled with adequate anti-emetics. For Grade 3 or 4 neurotoxicity chemotherapy 
should be resumed at 50% of the previous dose upon improvement or discontinued immediately 
(based on investigator’s clinical judgment). 
Suggested recommendations for dose modification of etoposide for renal impairment are 
provided below. 
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6.4
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined above, a subject will 
also be discontinued from protocol therapy and followed per protocol under the following 
circumstances outlined below. The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF) 
•
Documented disease progression based on RECIST 1.1 
•
Site investigator determines a change of therapy would be in the best interest of the 
subject 
•
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
•
Female subject becomes pregnant 
•
Protocol therapy is interrupted for ≥ 63 days. 
6.5
Protocol Discontinuation 
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
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7.
STUDY CALENDAR & EVALUATIONS 
Study Evaluation 
Cycle = 21 days 
Screening 
On Treatment Cycles 1-4 
Maintenance 
Cycles 5+ 
Safety follow up 
visit
10
 
Long-term 
Follow up
11
 
-28 days 
Day 1 
± 2 days 
Day 2 
Day 3 
Day 1 
± 2 days 
30 days post last 
dose 
+ 7 days 
Every 3 months 
(±14 days) 
REQUIRED ASSESSMENTS 
Informed Consent 
X 
Medical History
1
 
X 
Physical Exam
2
 
X 
X 
X 
X 
Vital signs and ECOG Performance Status
2
 
X 
X 
X 
X 
Quality of Life Questionnaires
3
 
X 3 
X 3 
X 3 
AEs & concomitant medications 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC) 
X 
X 9 
X 
X 
Comprehensive Metabolic Profile (CMP) 
X 
X 9 
X 
X 
PT/INR and aPTT 
X 
Thyroid Function Testing
4
 
X 
C3D1 
X 4 
X 
Hepatitis Testing
4
 
X 
Pregnancy test (serum or urine) (WOCBP)
4
 
X 
X 4 
X 4 
DISEASE ASSESSMENT 
CT of chest
5
 
X 5 
C3D1 
X 5 
X 5 
CT or MRI of abdomen and pelvis
5
 
X 5 
C3D1 
X 5 
X 5 
MRI Brain
5
 
X 5 
C3D1 
X 5 
X 5 
TREATMENT EXPOSURE 
Atezolizumab
6
 
D1 
X 6 
Carboplatin
6
 
D1 
Etoposide
6
 
D1-D3 
SPECIMEN COLLECTION 
Archival Tumor Tissue
7
 
X 7 
Blood Samples
8
 
X 8 
X 8 
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X 
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1: Medical History; other data to obtained during this assessment includes a smoking history questionnaire and trial awareness question. In 
addition, prior anti-cancer treatment should be documented including medications (chemotherapy, checkpoint inhibitors, etc) radiation or surgery. 
In addition, diagnosis and staging to include pathology report and TNM staging documentation. Histological confirmation per VALG of Stage IV 
Stage Small Cell Lung Cancer (SCLC)- extensive stage. Prior genomic testing (ie NGS) and PD-L1 results are required if available. 
2: Physical exam to include a complete neurological exam. Vital signs to include temperature, pulse, respirations, blood pressure weight, and 
height (screening only) and ECOG performance status. 
3: Quality of life evaluations include FACT-Br, FACIT-Fatigue, and Godin Leisure-Time Exercise Questionnaire. Questionnaires to be completed 
Cycle 1 Day 1 then every other Cycle of treatment (6 weeks; ±1 week) and at the D30 Safety Visit. 
4: CBC with platelet and differential (white blood cell count, absolute neutrophil count, hemoglobin and platelet count). Serum chemistries 
(creatinine, glucose, total bilirubin, aspartate transaminase [AST] and alanine transaminase [ALT] and calcium). Thyroid Function testing should 
be performed at screening then every 6 weeks (i.e. every other cycle). TSH will be obtained. T4 and T3 including free versus total testing is at the 
discretion of the site investigator. Hepatitis testing to be performed at screening if results as described in the inclusion criteria are not known. For 
women of childbearing potential (WOCBP): urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. Testing is required within 24 hours prior to initiation of study treatment. During 
treatment, testing should be performed every 3 weeks (on Day 1 of each cycle prior to administering treatment). 
5: Tumor response assessment will consist of evaluation by MRI scan of the brain and CT scans of chest +/- abdomen and pelvis. If unable to 
perform MRI due to medical reasons, CT with contrast is acceptable. Brain MRI used to diagnose brain metastases allowed or a CT with contrast 
is acceptable. The abdomen/pelvis may be scanned at follow-up timepoints only if positive disease was detected at baseline. Radiology imaging to 
be performed at screening (within 6 weeks prior to C1D1), then every 6 weeks (prior to Cycle 3 Day 1 and Cycle 6 Day 1) then every 9 weeks 
(prior to Cycle 9 and so on). Imaging needs to occur every time point regardless of any delay in treatment. Tumor imaging to be done in the 
follow up period is at discretion of site investigator. If tumor assessments are available for subjects who have not yet experienced progressive 
disease (PD) at the time treatment is discontinued, the follow-up tumor evaluations will be documented in the eCRF until PD or death is 
confirmed, or until another treatment is initiated. 
6: Induction treatment will consist of 4 cycles of Atezolizumab (1200 mg on Day 1) combined with carboplatin (5-6 AUC on Day 1) and etoposide 
(80-100 mg/m2 on Days 1-3). After 4 cycles of induction treatment, subjects will receive atezolizumab maintenance 1200 mg on Day 1 of each 3-
week cycle. Subjects will receive treatment until disease progression, unacceptable drug-related toxicity, or withdrawal from study for any reason. 
7: Archival tissue is required if available. Archival tissue should be identified and requested at screening and shipped by Cycle 2 Day 1, if 
available. If archival tissue is not available, the subject may still be eligible for the trial. See CLM for collection, labeling, and shipping 
instructions. Subjects will also be consented for optional storage of any remaining tissue samples after protocol-specified studies are complete. 
These samples will be stored for future unspecified cancer-related research and are considered “banking samples”. 
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8: Blood (whole blood for PBMCs, plasma and buffy coat for germline DNA) for correlative analysis will be drawn prior to treatment on Cycle 1 
Day1, Cycle 3 Day 1 and at the D30 safety visit/progression. Additional details regarding correlatives can be found in Section 8 and the CLM. 
9: If screening (baseline) CBC and Chemistry (CMP) were performed within 7 days of Day 1 of treatment, these do not need to be repeated. All 
laboratory assessments should be done prior to treatment. 
10: Safety Follow Up: The safety follow-up visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, 
progression, or other reason) and should be performed 30 days (+ 7 days) after the last dose of treatment. Subjects who have an ongoing Grade ≥ 2 
or serious AE (SAE) at this visit will continue to be monitored by a member of the study team until the event is resolved, stabilized, determined to 
be irreversible by the site investigator or a new anti-cancer treatment starts, whichever occurs earlier. 
11: Long Term Follow Up: For subjects who discontinue for reasons other than progressive disease, radiographic disease assessment should be 
performed every 9 weeks until progression, initiating a new cancer treatment, withdrawing consent or becoming lost to follow-up. The scan 
interval may be reset if scans were done sooner for clinical reasons and the type of scan may be left to discretion of the site investigator. This 
imaging may be done locally. Once disease progression is documented, subjects will be followed for survival every 3 months for 1 year from 
documented progression. Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. A window of ± 14 days will 
be applied to follow up. 
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8.
BIOSPECIMEN STUDIES AND PROCEDURES 
The correlative research proposed below represents ideas based upon the state of the field to 
date. However, the exact correlative research that will be done may be modified based upon the 
sample availability and best science at the time these assays are ready to be performed. The 
correlative laboratory manual (CLM) will contain detailed instructions regarding correlatives. 
8.1
Archival Tissue 
Archival tissue is required if available. If archival tissue is not available, the subject may still be 
eligible for the trial. Archival tissue should be identified and requested at screening and shipped 
by Cycle 2 Day 1, if available. 
8.3.2 Tumor Immune Infiltrates by Immunohistochemistry (IHC) 
Tumor samples may be tested by IHC for expression of proteins that may be associated with 
sensitivity or resistance to atezolizumab, including but not limited to immune cell populations 
including CD3, CD4, CD8, Treg, Th17 T-cells and monocyte/macrophage and neutrophil 
populations, as well as immune and tumor cell expression of PD-1, and PD-L1 and PD-L2, 
respectively. Multiplex IHC opportunities could be performed by Genentech or other laboratory 
upon receipt of adequate funding. 
8.1.2 Tumor Immune/Inflammatory Analysis by Gene Expression 
RNASeq may be conducted in order to assess gene expression of the tumor. Analyses could be 
conducted by Genentech or other laboratory upon receipt of adequate funding. 
8.1.3 Characterization of genomic alterations by whole exome sequencing 
Whole exome sequencing or specific targeted DNA panels may be conducted. Analyses could 
be conducted by Genentech or other laboratory upon receipt of adequate funding. 
8.2
Peripheral Blood Samples 
Blood (whole blood for PBMCs, plasma and buffy coat) for correlative analysis will be drawn 
prior to treatment on Cycle 1 Day1, Cycle 3 Day 1 and at the D30 safety visit/progression. 
8.2.1 Circulating Immune Cell Analysis 
Immune cell correlates using flow-based assays may be performed in collaboration with the 
Duke Immune Profiling Core (DIPC) laboratory. Changes in the immune cell subtypes that are 
expected to be altered by treatment will be analyzed. Other technologies approaches may also be 
considered. The lymphoid panel focuses on T-cell activation, maturation, regulation, and 
exhaustion. The myeloid panel focuses on myeloid derived suppressor cells (MDSC), M1/M2 
polarization, and dendritic cells (DC, pDC). 
8.2.2 Circulating Protein Analysis 
Analyses may include immune proteins, inflammatory cytokines and tumor growth factors upon 
receipt of adequate funding. Analyte levels, and changes in analyte levels, will be correlated 
with clinical outcome (PFS, OS). Plasma may be evaluated for protein markers that may be 
associated with sensitivity or resistance to atezolizumab. These may include CRP and other 
markers of inflammation, including but not limited to IFNγ, IL1β, IL4, IL6, IL7, IL10, IL12, 
IL17A, IL17E, and IL23. 
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8.2.3 Cell-free DNA for mutational analysis 
Tumor-derived cfDNA (ctDNA) has become the focus of intensive investigation in the search for 
genomic biomarkers that can be used to monitor the presence or absence of disease, disease 
progression, or the development of resistance mechanisms during the course of treatment. The 
promise of cfDNA is that it may provide a sensitive and non-invasive means of monitoring the 
genetic composition of a patient’s disease both during treatment and as a means of monitoring 
response or resistance. ctDNA analysis may be performed upon receipt of adequate funding. The 
final gene panel will be decided at the time of analysis, allowing for coverage of the most 
relevant point mutations, amplifications, and gene fusions. 
8.2.4 Buffy Coat for Germline DNA 
Buffy coat will be collected for germline DNA samples. These samples may be used as a 
somatic baseline comparison when analyzing ctDNA and/or tumor mutations. 
8.2.5 Exosome Analysis 
Exosomes are composed of numerous RNA, proteins, lipids and have great biomarker 
potential, as they transport molecular contents of cells from which they originate. Additional 
analysis of exosomes may also be performed upon receipt of adequate funding. 
8.3 Genetic Testing 
Participants will be given information as part of the informed consent process that samples will 
be used for research purposes that will include genetic testing. The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may 
or may not already be aware. In the case where an incidental genetic finding is identified, the 
sponsor investigator of this project will be notified. Possible decisions for handling incidental 
findings may include notification of the participant (and provider); recommendation for genetic 
counseling, which may or may not include genetic testing (e.g., if the finding was not done in a 
CLIA certified laboratory); or, neither. In general, a member of the participant’s treating team 
will be given the information to help with notification. In all cases, the current policy of Duke 
University Medical Center and local/participating site IRBs, as applicable, will be followed. Any 
additional approvals that may be required prior to participant notification will be secured in 
advance. 
8.4 Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples collected for study-specific 
correlative research. Hoosier Cancer Research Network (HCRN) will manage the banked 
samples. Samples will be coded and banked indefinitely in the Hoosier Cancer Research 
Network Biorepository and used for future unspecified cancer-related research. 
8.5
Confidentiality of Biospecimens 
Samples will be identified by the subject’s study number assigned at the time of registration to 
the trial. Any material issued to collaborating researchers will be anonymized and only identified 
by the subject’s study number. 
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8.6
Quality of Life Assessment 
8.6.1 Patient Reported Outcomes 
Quality of life evaluations include FACT-Br, FACIT-Fatigue, and Godin Leisure-Time Exercise 
Questionnaire. These questionnaires are to be completed Cycle 1 Day 1 then every other Cycle 
of treatment (6 weeks; ±1 week). 
Patient-reported Quality of Life (QoL) outcomes will be assessed using the following 
standardized and validated questionnaires: 
•
Functional Assessment of Cancer Therapy-Brain (FACT-BR) scale (version 4) [26], 
which contains subscales for physical (7-items), functional (7-items), emotional (6-
items), and social/family (7-items) well-being, as well as a 23-item brain cancer subscale 
(BCS) that assesses symptoms commonly reported by brain cancer patients 
•
Functional Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) subscale (version 4) 
[27] 
•
Godin Leisure-Time Exercise Questionnaire Short Scale [28, 29], a simple questionnaire 
to assess patterns of exercise behavior during a subject’s leisure time 
9.
CRITERIA FOR DISEASE EVALUATION 
9.1
Definitions for Response Evaluation – RECIST 1.1 
9.1.1 Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters  (or decimal 
fractions of centimeters). 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
9.1.2 Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. NOTE: Cystic lesions that meet the criteria for 
radiographically defined simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ 
thought to represent cystic metastases can be considered as measurable lesions, if they meet the 
definition of measurability described above. However, if non-cystic lesions are present in the 
same subject, these are preferred for selection as target lesions. 
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9.1.3 Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
9.1.4 Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
9.1.5 Evaluation of Target Lesions 
NOTE: In addition to the information below, also see the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 
45;2009:228-247) for special notes on the assessment of target lesions. 
Complete Response 
(CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study 
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9.1.6 Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (<10 mm short axis). NOTE: If 
tumor markers are initially above the upper normal limit, 
they must normalize for a subject to be considered in 
complete clinical response. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
Unequivocal progression should not normally trump target 
lesion status. It must be representative of overall disease 
status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
9.1.7 Evaluation of Best Overall Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
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9.2
Definitions for Response Evaluation – RANO -BM 
MRI scan of head at screening and every other treatment cycle (i.e. 6 weeks) through week 48, 
then every 9 weeks (i.e. every 3 cycles) until documented disease progression starting after 
treatment initiation with Cycle 1. Given that imaging following immunotherapy differs greatly 
from what is typically seen following chemoradiation treatment or treatment with anti-
angiogenic compounds, evaluation of response using Macdonald criteria or Response 
Assessment in Neuro-Oncology (RANO) criteria is not appropriate in this trial. Due to 
differences in the nature of primary brain tumors and brain metastases, a modified version of 
RANO called RANO-BM will be used. 
9.2.1 Measurable disease 
Measurable disease is defined as a contrast-enhancing lesion that can be accurately measured in 
at least one dimension, with a minimum size of 10 mm, and is visible on two or more axial slices 
that are preferably 5 mm or less apart with 0 mm skip (and ideally ≤1·5 mm apart with 0 mm 
skip). Additionally, although the longest diameter in the plane of measurement is to be recorded, 
the diameter perpendicular to the longest diameter in the plane of measurement should be at least 
5 mm for the lesion to be considered measurable. Cystic lesions or surgical cavities should 
generally be considered non-measurable unless there is a nodular component that measures 
10mm or more in longest diameter and 5mm or more in the perpendicular plane. The cystic or 
surgical cavity should not be measured for the determination of a response. 
Non-measurable lesions 
Non-measurable disease includes all other lesions, including lesions with longest dimension less 
than 10 mm, lesions with borders that cannot be reproducibly measured, dural metastases, bony 
skull metastases, cystic-only lesions, and leptomeningeal disease. 
9.2.2 Tumor response assessment 
Assignment of CNS response is independent of systemic disease response. All baseline 
assessments should be done as close as possible to the treatment start and no more than 4 weeks 
before the beginning of treatment. When more than one measurable lesion in the CNS is present 
at baseline, all lesions up to a maximum of five CNS lesions should be identified as target lesions 
and will be recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (longest diameter) and as those that can be measured reproducibly. A sum of the 
diameters for all target lesions will be calculated and reported as the baseline sum of longest 
diameters. All other CNS lesions should be identified as non-target lesions and should also be 
recorded at baseline. 
9.2.3 Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all CNS target lesions sustained for at least 4 
weeks; with no new lesions, no use of corticosteroids, and 
patient is stable or improved clinically. 
Partial Response (PR) 
At least a 30% decrease in the sum longest diameter of CNS 
target lesions, taking as reference the baseline sum longest 
diameter sustained for at least 4 weeks; no new lesions; stable 
to decreased corticosteroid dose; stable or improved clinically. 
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Progressive Disease (PD) 
At least a 20% increase in the sum longest diameter of CNS 
target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, at least one lesion 
must increase by an absolute value of 5 mm or more to be 
considered progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for progressive disease, taking as 
reference the smallest sum longest diameter while on study. 
9.2.4 Evaluation of non-target lesions 
Complete Response (CR) 
Requires all of the following: disappearance of all enhancing 
CNS non-target lesions, no new CNS lesions. 
Non-CR/ Non-PD 
Persistence of one or more non-target CNS lesion or lesions. 
Progressive Disease (PD) 
Any of the following: unequivocal progression of existing 
enhancing non-target CNS lesions, new lesion(s) (except while 
on immunotherapy-based treatment), or unequivocal progression 
of existing tumor-related non-enhancing (T2/FLAIR) CNS 
lesions. In the case of immunotherapy-based treatment, new 
lesions alone may not constitute progressive disease. 
9.2.5 Evaluation of best overall CNS response 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions** 
Corticosteroids 
Clinical 
status 
Overall 
Response 
None 
None 
None 
None 
Stable or 
improved 
CR 
≥30% decrease 
in sum longest 
distance relative 
to baseline 
Stable or 
improved 
None 
Stable or 
decreased 
Stable or 
improved 
PR 
<30% decrease 
relative to 
baseline but 
<20% increase 
in sum longest 
distance relative 
to nadir 
Stable or 
improved 
None 
Stable or 
decreased 
Stable or 
improved 
SD 
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*Progression occurs when any of these criteria are met. If ≤ 6 months from initiation of 
immunotherapy, radiographic progression (including new lesions) with no new or 
significantly worsened neurologic deficits not due to co-morbid event or concurrent 
medication should be confirmed on follow-up imaging 3 months after initial radiographic 
progression (if progression confirmed, the date of actual progression should be back-dated 
to the date of initial radiographic progression). **A new lesion is one that is not present on 
prior scans and is visible in minimum two projections. If a new lesion is equivocal, for example 
because of its small size, continued therapy can be considered, and follow-up assessment will 
clarify if the new lesion is new disease. If repeat scans confirm there is definitely a new lesion, 
progression should be declared using the date of the initial scan showing the new lesion. 
≥20% increase 
in sum longest 
distance relative 
to nadir* 
Unequivocal 
progressive 
disease* 
Present* 
N/A 
Worse* 
PD 
Clinical Study Protocol 
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10
DRUG INFORMATION 
All drugs used in this clinical trial will be standard of care. Please refer to the latest version of 
the prescribing information that can be found at 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/,  and/or  each manufacturer’s website. 
10.1 
Atezolizumab 
PD-L1 may be expressed on tumor cells and/or tumor infiltrating immune cells and can 
contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. 
Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells 
suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production. Atezolizumab 
(TECENTRIQ®) is a monoclonal antibody that binds to PD-L1 and blocks its interactions with 
both PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of the immune 
response, including activation of the anti-tumor immune response without inducing antibody 
dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity 
resulted in decreased tumor growth. 
Please refer to the current version of the Investigator’s Brochure (IB) for additional information 
regarding this drug. 
10.1.1 Supplier/How Supplied 
GNE will supply atezolizumab at no charge to subjects participating in this clinical trial. 
Atezolizumab Injection, 1200 mg/20 mL (60 mg/mL). Atezolizumab is provided in a single-use, 
glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid 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 a solution containing 
histidine acetate, sucrose, and polysorbate 20 at pH 5.8. 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
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10.1.2 Preparation 
Visually inspect drug product for particulate matter and discoloration prior to administration, 
whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or 
visible particles are observed. Do not shake the vial. Prepare the solution for infusion as follows: 
•
Select the appropriate vial(s) based on the prescribed dose. 
•
Withdraw the required volume of atezolizumab from the vial(s). 
•
Dilute into a 250 mL polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) 
infusion bag containing 0.9% Sodium Chloride Injection, USP. 
•
Dilute with only 0.9% Sodium Chloride Injection, USP. 
•
Mix diluted solution by gentle inversion. Do not shake. 
10.1.3 Storage and Stability 
Storage of Infusion Solution: This product does not contain a preservative. Administer 
immediately once prepared. If diluted Atezolizumab infusion solution is not used immediately, 
store solution either: 
•
At room temperature for no more than 6 hours from the time of preparation. This includes 
room temperature storage of the infusion in the infusion bag and time for administration 
of the infusion, or 
•
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from time of 
preparation. 
•
Do not freeze or shake 
10.1.4 Dispensing 
Atezolizumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Atezolizumab should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects. 
10.1.5 Adverse Events 
Please refer to the latest version of the prescribing information that can be found at 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/,  and/or  on the manufacturer’s website. 
10.2 
Carboplatin and Etoposide 
Carboplatin and etoposide will be used as standard of care in the study and sourced 
commercially. 
For information regarding these medications, please refer to the latest version of the prescribing 
information that can be found at  http://www.accessdata.fda.gov/scripts/cder/drugsatfda/,  and/or 
on the manufacturer’s website. 
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11
ADVERSE EVENTS 
11.1 
Definitions 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs: 
•
Unintended or unfavorable sign or symptom (including an abnormal laboratory finding) 
•
A disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution 
•
An intercurrent illness or injury that impairs the well-being of the subject 
•
AEs not previously observed in the subject that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with extensive stage 
Small Cell Lung Cancer (SCLC) with untreated asymptomatic brain metastases that 
were not present prior to the AE reporting period. 
•
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
•
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
•
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE. 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
•
Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
•
Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
•
Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
•
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
•
Results in a congenital anomaly or birth defect in a neonatal/infant born to a mother 
exposed to IMP. 
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•
Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
11.1.3 Adverse Events of Special Interest (AESI) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to 
the product, for which ongoing monitoring and rapid communication by the site investigator 
to Hoosier Cancer Research Network who will then report to GNE is required. Such an event 
might require further investigation in order to characterize and understand it. Depending on 
the nature of the event, rapid communication by the trial Sponsor to other parties (e.g., 
Regulatory Authorities) may also be warranted. 
The following AEs are considered of special interest: 
•
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: 
o
Treatment-emergent ALT or AST > 3 × ULN (or > 3 × baseline value in disease 
states where LFTs may be elevated at baseline) in combination with total 
bilirubin > 2 × ULN (of which ? 35% is direct bilirubin) 
o
Treatment-emergent ALT or AST > 3 × ULN (or > 3 × baseline value in disease 
states where LFTs may be elevated at baseline) in combination with clinical 
jaundice 
•
Data related to a 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. 
•
Systemic lupus erythematosus 
•
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, macrophage activating syndrome and hemophagocytic lymphohistiocytosis 
•
Nephritis 
•
Ocular toxicities (e.g. uveitis, retinitis, optic neuritis) 
•
Grade ? 2 cardiac disorders (e.g. atrial fibrillation, myocarditis, pericarditis) 
•
Vasculitis 
•
Autoimmune hemolytic anemia 
•
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
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11.2 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, 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 duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the 
atezolizumab, carboplatin and etoposide (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
11.2.1 Relatedness 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. AEs will be categorized according to the likelihood that they are 
related to the study drug(s). Specifically, they will be categorized using the following terms: 
Unrelated 
Adverse Event is not related to the study drug(s) 
Unlikely 
Adverse Event is doubtfully related to the study drug(s) 
Possible 
Adverse Event may be related to the study drug(s) 
Probable 
Adverse Event is likely related to the study drug(s) 
Definite 
Adverse Event is clearly related to the study drug(s) 
Yes (Definite/Probable/Possible/Unlikely) 
There is a plausible temporal relationship between the onset of the AE and administration of 
atezolizumab, carboplatin or etoposide and the AE cannot be readily explained by the subject’s 
clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known 
pattern of response to atezolizumab, carboplatin or etoposide or with similar treatments; and/or 
the AE abates or resolves upon discontinuation of the atezolizumab, carboplatin or etoposide 
or dose reduction and, if applicable, reappears upon re- challenge. 
No (Unrelated) 
Evidence exists that the AE has an etiology other than the atezolizumab, carboplatin or 
etoposide (e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
atezolizumab, carboplatin or etoposide administration (e.g., cancer diagnosed 2 days after first 
dose of study drug). 
11.2.2 Assessment of Adverse Events (Expectedness) 
Expected Adverse Events 
For atezolizumab, expected adverse events are those adverse events that are listed or 
characterized in the current Investigator Brochure (I.B). For carboplatin and etoposide, expected 
adverse events are those adverse events that are listed or characterized in the Package Insert (P.I). 
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Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current I3 , prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the I3 as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
11.2.3 Procedures for Eliciting, Recording and Reporting Adverse Events 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points 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?” 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
Diagnosis vs. 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 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. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period, 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” 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting 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 preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
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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 subject 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 subject 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 preexisting 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 
11.2.4 Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0 Update current versions) will 
be used for assessing adverse event severity. Below Table should be used for assessing severity 
for adverse events that are not specifically listed in the NCI CTCAE. 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE  
Grade
Severity 
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
2
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age-appropriate instrumental activities of daily living a 
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
or limiting self-care activities of daily living b,c 
4
Life-threatening consequences or urgent intervention indicated d 
5
Death related to adverse event d 
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NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
NOTE: Based on the most recent version of NCI CTCAE (v 5.0), which can be found 
at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as performed 
by patients who are not bedridden. 
c. If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event 
d. Grade 4 and 5 events must be reported as serious adverse events 
11.2 
Reporting 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. 
in accordance with CFR 312.32 (IND Safety Reports). 
11.2.1 Adverse Events 
•
AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first. 
•
AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s). 
•
All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
11.2.2 Serious Adverse Events (SAEs) 
11.2.2.1 
Site Requirements for Reporting SAEs and AESIs to HCRN 
•
SAEs will be reported from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first. 
•
SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event. 
•
SAEs include events related and unrelated to the study drug(s). 
•
All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form will be submitted to HCRN electronically to 
safety@hoosiercancer.org.  The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements. 
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The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
Once the SAE has resolved (see resolution guidelines listed above), sites must submit a follow-
up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org. 
11.2.2.2 
HCRN Requirements for Reporting SAEs and AESIs to Genentech 
HCRN will report all SAEs and AESIs to Genentech within 1 business day of receipt of the 
SAE Submission Form from a site. Follow-up information will be provided to Genentech as it is 
received from site. Genentech Drug Safety: Fax: 650-238-6067 or Email:  usds_aereporting-
d@gene.com  
11.3 
Other Reportable Events 
11.3.1 Pregnancy reports 
If a female subject or a female partner of a male subject becomes pregnant while receiving the 
study drug or within 5 months after the last dose of study drug, an SAE submission form will be 
completed. The site should report the event within 1 business day of discovery of the event to 
HCRN and HCRN will report the event to Genentech within 1 business day of receipt of the 
SAE submission form. Follow-up to obtain the outcome of the pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as serious, 
and reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a 
female subject exposed to the study drug should be reported as an SAE. 
If after the 30 day safety visit, the investigator should become aware of a congenital anomaly in a 
subsequently conceived offspring of a female subject, including pregnancy occurring in the 
partner of a male study subject, who participated in the study, this should be reported as an SAE 
from the site to HCRN who will report to Genentech drug Safety. 
11.3.2 Post-Study Adverse Events 
SAEs occurring after discontinuation of study drugs will be reported as outlined in section 11.2.2 
if attributed to prior atezolizumab, carboplatin or etoposide exposure. 
11.3.3 Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations 
Reports should be collected even in the absence of an Adverse Event and transmitted to HCRN 
from the site and HCRN to GNE within thirty (30) calendar days. 
•
Data related to the Product usage during breastfeeding 
•
Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors) 
•
In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population 
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11.3.4 Product Complaints 
All Product Complaints (with or without an AE) shall be forwarded to HCRN from the site and 
HCRN to GNE within fifteen (15) calendar days of the awareness date. A Product Complaint 
is defined as any written or oral information received from a complainant that alleges 
deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 
All Product Complaints without  an AE should be reported via call at: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
11.4 
Sponsor-Investigator Responsibilities 
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site. The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness. 
11.5 
HCRN Responsibilities to FDA 
For protocols exempt from the requirements of an IND, the above stated requirements are not 
applicable. HCRN will continue to facilitate compliance of applicable requirements for the 
sponsor-investigator in relation to this study. This includes but is not limited to 21 CFR 50.20 
informed consent, 21 CFR Part 56 IRB, and pertinent sections of the Public Health Service Act 
and FDAAA. 
11.6 
IND Safety Reports Unrelated to this Trial 
Genentech will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines. HCRN will forward safety reports to the sponsor-investigator who 
will review these reports and determine if revisions are needed to the protocol or consent. HCRN 
will forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review. Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required). All IND safety reports will 
also be made available to sites via the EDC system. 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
12
STATISTICAL METHODS 
12.1 
Study Design 
This is a multicenter, single arm, open label phase II trial to evaluate the safety and efficacy of 
atezolizumab in combination with carboplatin and etoposide in patients with untreated extended 
stage small cell lung cancer (ES-SCLC) brain metastases. 
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12.2 
Endpoints 
The primary endpoint of the trial is intracranial progression free survival (iPFS). 
The secondary endpoints include overall response rate (ORR), intracranial or extracranial 
progression free survival (PFS), overall survival (OS), and the grade and type of toxicity of 
atezolizumab in combination with carboplatin and etoposide. 
12.2.1 Definition of Primary Endpoint 
The primary endpoint of the study is intracranial progression free survival (iPFS), which is 
defined as the time from Day 1 of protocol treatment until the criteria for iPFS is met as defined 
by RANO-BM or death from any cause, whichever comes first. 
12.2.2 Definition of Secondary Endpoints 
ORR is the proportion of patients whose best response to protocol treatment are either complete 
response (CR) or partial response (PR) by the investigator using RECIST 1.1. Patients not 
meeting these criteria, including patients without any post-baseline tumor assessment, will be 
considered non-responders. 
PFS is defined as the time from Day 1 of protocol treatment until the criteria for disease 
progression (intracranial or extracranial) is met as defined by RECIST 1.1 and RANO-BM, or 
death from any cause, whichever comes first. Subjects who have not progressed will be right-
censored at the date of the last disease evaluation. If progression occurs in either intracranial or 
extrancranial or both compartments, the criteria for progression-free survival will have been met 
per RANO-BM. 
OS is defined as the time from Day 1 of protocol treatment until death from any cause. 
CTCAE V5 will be utilized to define the grade and type of toxicities and adverse events. 
12.3 
Sample Size and Accrual 
The study will enroll 63 eligible patients who receive at least one dose of the study agent. 
The sample size of the study is determined by the analysis of iPFS. To detect an improvement of 
median iPFS = 5.2 months from 4.0 months in historical control (IMpower 133) (HR = 0.77) 
using a logrank test, 60 treated patients will be required to achieve approximately 81% power at 
a one-sided significance level of 0.15. Patients are accrued for a period of 22 months. Follow-up 
continues for 12 months after the last patient is enrolled. The probability that a patient 
experiences an event during the study is 0.9707. The expected number of events during the study 
is 58. It is assumed that the survival time is exponentially distributed. The sample size 
calculation above is conducted in PASS v16.0.2. Assuming a 5% rate of dropout prior to 
protocol treatment, a total of 63 eligible patients will be treated by at least one doses of the study 
agent. 
The sample size calculation is determined to have adequate power to reject the null hypothesis 
when the alternative hypothesis is true for the primary endpoint iPFS. Whether it has sufficient 
power for addressing secondary endpoints or exploratory analysis is not of concern. 
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12.4 
Assessment of Safety 
All subjects that have received one dose of study treatment will be evaluable for safety. Adverse 
events will be continuously monitored. Safety assessments using the NCI-CTCAE version 5 will 
be performed as outlined in Section 7 of the Study Calendar. 
12.5 
Assessment of Efficacy 
All subjects with measurable disease who have received at least one cycle of treatment and have 
their disease re-evaluated will be evaluable for assessment of iPFS, PFS, ORR, OS, and HRQol. 
12.6 
Data Analysis Plans 
12.6.1 Analysis Plans for Primary Objective 
Median iPFS and 6-month iPFS rate along with their 95% conference intervals (CIs) will be 
estimated using Kaplan-Meier (KM) approach. KM curve will be used to characterize iPFS. 
Cox proportional hazard models will evaluate the relationship between iPFS with the patients’ 
baseline characteristics, including age at enrollment, gender, race, and ECOG Performance 
Status and the estimated HRs and their 95% Cis will be provided. 
12.6.2 Analysis Plans for Secondary Objectives 
ORR and its 95% CI will be estimated. 
Median PFS and OS and their 95% CIs will be estimated using Kaplan-Meier approach. KM 
curves will be used to characterize PFS and OS. Six-month PFS and 12-month OS rates and their 
95% CIs will also be estimated. Cox proportional hazard models will evaluate the relationship 
between PFS or OS with the patients’ baseline characteristics, including age at enrollment, 
gender, race, and ECOG Performance Status and the estimated HRs and their 95% Cis will be 
provided. 
The types and frequencies of toxicities will be summarized by the severities. 
12.6.3 Analysis Plans for Exploratory Objectives 
The summary statistics (mean, standard deviation, median, Q1, Q3, and range) of subscale and 
overall scores derived from FACT-BR questionnaires will be calculated. 
12.6.4 Other Planned Analyses 
Patients’ baseline characteristics will be summarized. Mean, SD, median and range for 
continuous variables (age at enrollment), and frequencies and percentages for categorical 
variables (sex, race, ethnicity, performance status) will be calculated. 
12.7 
Interim Analysis/Criteria for Stopping Study 
One interim analysis for futility will be conducted at half of the required events for the final 
analysis (approximately 29 events) based on the Wieand rule [30]. If the one-sided p-value of the 
logrank test exceeds 0.50, the trial will be terminated for futility, declaring the probability of 
rejecting the null hypothesis is very low. The Wieand rule to futility monitoring negligibly 
reduces the power of the trial, usually less than 2% and offers a 50% chance of early stopping 
accrual to an ineffective therapy. 
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13
TRIAL MANAGEMENT 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted with guidance from the Duke University Cancer Center’s DSMP. 
HCRN oversight activities include: 
•
Review and process all adverse events requiring expedited reporting as defined in the 
protocol. 
•
Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator. 
•
Submit data summary reports to the lead institution Data Safety Monitoring Committee. 
13.2 
Data Safety Monitoring Board 
This study will have a Data and Safety Monitoring Board (DSMB). The DSMB is chaired by an 
independent medical oncologist external to this trial. The DSMB will provide a recommendation 
to the sponsor-investigator after all information is reviewed. This information will also be 
provided to HCRN who will distribute to the site investigator/participating sites for submission 
to their respective IRB according to the local IRB’s policies and procedures. 
The DSMB review will include but is not limited to: 
•
Adverse event summary report 
•
Audit results if applicable 
•
Data related to stopping/decision rules described in study design 
•
Study accrual patterns 
•
Protocol deviations 
The DSMB will review study data at least semi-annually while subjects are on study treatment.. 
Issues of immediate concern by the DSMB will be brought to the attention of the sponsor-
investigator and other regulatory bodies as appropriate. The sponsor-investigator will work with 
HCRN to address the DSMB’s concerns. 
13.3 
Data Quality Oversight Activities by HCRN 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel. 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause audits may be performed as necessary. During onsite 
monitoring visits, source documents will be reviewed for verification of agreement with data 
entered into the EDC system. It is important for the site investigator and their relevant personnel 
to be available for a sufficient amount of time during the monitoring visits or audit, if applicable. 
The site investigator and institution guarantee access to source documents by HCRN or its 
designee. 
The trial site may also be subject to quality assurance audit by Genentech or its designee as well 
as inspection by appropriate regulatory agencies. 
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13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank,  http://www.clinicaltrials.gov.  All 
results of primary and secondary objectives must be posted to CT.gov  within a year of 
completion. The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information. 
14.
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform (EDC system), a system compliant with Good 
Clinical Practices and Federal Rules and Regulations. HCRN personnel will coordinate and 
manage data for quality control assurance and integrity. Select data will be collected and entered 
into the EDC system by study site personnel from participating institutions. 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives. 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN. No records 
will be destroyed until HCRN confirms destruction is permitted. 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel. 
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Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Genentech, IRB, or government agencies, like the FDA, 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
15
ETHICS 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study. 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require. 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki. Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject. 
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Slotman, B.J., et al., Prophylactic cranial irradiation in extensive disease small-cell lung 
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Brown, P.D., et al., Postoperative stereotactic radiosurgery compared with whole brain 
radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3). a 
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1060. 
15.
Gondi, V., et al., Decline in tested and self-reported cognitive functioning after 
prophylactic cranial irradiation for lung cancer. pooled secondary analysis of Radiation 
Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol 
Phys, 2013. 86(4): p. 656-64. 
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16.
Brown, P.D., et al., Whole-Brain Radiotherapy for Brain Metastases. Evolution or 
Revolution? J Clin Oncol, 2018. 36(5): p. 483-491. 
17.
Seute, T., et al., Response of asymptomatic brain metastases from small-cell lung cancer 
to systemic first-line chemotherapy. J Clin Oncol, 2006. 24(13): p. 2079-83. 
18.
Horn, L., et al., First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-
Cell Lung Cancer. N Engl J Med, 2018. 379(23): p. 2220-2229. 
19.
Lorger, M., et al., Immune Checkpoint Blockade - How Does It Work in Brain 
Metastases? Front Mol Neurosci, 2019. 12: p. 282. 
20.
Blank, C., T.F. Gajewski, and A. Mackensen, Interaction of PD-L1 on tumor cells with 
PD-1 on tumor-specific T cells as a mechanism of immune evasion. implications for 
tumor immunotherapy. Cancer Immunol Immunother, 2005. 54(4): p. 307-14. 
21.
Blank, C. and A. Mackensen, Contribution of the PD-L1/PD-1 pathway to T-cell 
exhaustion. an  update on implications for chronic infections and tumor evasion. Cancer 
Immunol Immunother, 2007. 56(5): p. 739-45. 
22.
Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with 
advanced cancer. N Engl J Med, 2012. 366(26): p. 2455-65. 
23.
Keir, M.E., et al., PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 
2008. 26: p. 677-704. 
24.
Chan, C., et al., Statistical mixture modeling for cell subtype identification in flow 
cytometry. Cytometry A, 2008. 73(8): p. 693-701. 
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Frelinger, J., et al., Modeling flow cytometry data for cancer vaccine immune monitoring. 
Cancer Immunol Immunother, 2010. 59(9): p. 1435-41. 
26.
Weitzner, M.A., et al., The Functional Assessment of Cancer Therapy (FACT) scale. 
Development of a brain subscale and revalidation of the general version (FACT-G) in 
patients with primary brain tumors. Cancer, 1995. 75(5): p. 1151-61. 
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Van Belle, S., et al., Comparison of proposed diagnostic criteria with FACT-F and VAS 
for cancer-related fatigue. proposal for use as a screening tool. Support Care Cancer, 
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community. Can J Appl Sport Sci, 1985. 10(3): p. 141-6. 
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Jones, L.W., et al., Assessment of physical functioning in recurrent glioma. preliminary 
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30.
Wieand, S., G. Schroeder, and J.R. O'Fallon, Stopping when the experimental regimen 
does not appear to help. Stat Med, 1994. 13(13-14): p. 1453-8. 
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APPENDIX I: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE EVENTS 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology. 
PULMONARY EVENTS  
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab. Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will also have computed tomography (CT) scans of the chest 
performed at every tumor assessment. All pulmonary events should be thoroughly evaluated for 
other commonly reported etiologies such as pneumonia or other infection, lymphangitic 
carcinomatosis, pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension. 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary event, 
• Continue atezolizumab and monitor closely. 
Grade 1 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
• Consider withholding atezolizumab 
Pulmonary event, 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
Grade 2 
• Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL. 
• Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
• For recurrent events, or events with no improvement after 48-72 
hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary event, 
• Permanently discontinue atezolizumab and contact HCRN. c 
Grade 3 or 4 
• Bronchoscopy or BAL is recommended. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
BAL = bronchoscopic alveolar lavage. 
a
 Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be based on assessment of benefit-risk by the investigator and in 
alignment with the protocol requirement for duration of treatment and documented by the investigator. 
Sponor-Investigator is available to advise as needed. 
b
 If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c
 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
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Sponsor-Investigator is available to advise as needed 
HEPATIC EVENTS  
Immune-mediated hepatitis has been associated with the administration of atezolizumab. 
Eligible patients must have adequate liver function, as manifested by measurements of total 
bilirubin and hepatic transaminases, and liver function will be monitored throughout study 
treatment. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of 
the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
•
Continue atezolizumab. 
•
Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2 
All events: 
•
Monitor LFTs more frequently until return to baseline values. 
Events of > 5 days’ duration: 
•
Withhold atezolizumab for up to 12 weeks after event onset. a 
•
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
•
If event resolves to Grade 1 or better, resume atezolizumab. b 
•
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Hepatic event, 
Grade 3 or 4 
•
Permanently discontinue atezolizumab. c 
•
Consider patient referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury. 
•
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
•
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
•
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
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Event 
Management 
In patients with HCC 
AST/ALT is within 
normal limits at baseline 
and increases to 
> 3×ULN to ≤ 10×ULN 
or 
AST/ALT is > ULN to 
≤ 3×ULN at baseline and 
increases to 
> 5×ULN to ≤ 10× ULN 
or 
AST/ALT is > 3×ULN to 
≤ 5×ULN at baseline and 
increases to 
> 8×ULN to ≤ 10×ULN 
•
Monitor LFTs more frequently until return to baseline values. 
•
Withhold atezolizumab for up to 12 weeks after event onset. a 
Events of > 5 days' duration: 
•
Consider initiating treatment with corticosteroids equivalent to 
1−2 mg/kg/day oral prednisone. 
•
If event resolves to baseline or to Grade 1 or better, resume 
atezolizumab. b 
•
If event does not resolve to baseline or to Grade 1 or better 
while withholding atezolizumab, permanently discontinue 
atezolizumab and contact Sponsor-Investigator. c 
AST or ALT increases to 
>10×ULN or 
total bilirubin increases 
to > 3×ULN 
•
Permanently discontinue atezolizumab and contact Sponsor-
Investigator. c 
•
Consider patient referral to GI specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury. 
•
Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day oral prednisone. 
•
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
•
If event resolves to baseline, taper corticosteroids over ≥ 1 month. 
LFT = liver function tests. 
a
 Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length 
of the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment 
with the protocol requirement for duration of treatment and documented by the investigator. Sponsor-
Investigator is available to advise as needed. 
b
 If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c
 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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GASTROINTESTINAL EVENTS  
Immune-mediated colitis has been associated with the administration of atezolizumab. All 
events of diarrhea or colitis should be thoroughly evaluated for other more common etiologies. 
For events of significant duration or magnitude or associated with signs of systemic 
inflammation or acute-phase reactants (e.g., increased C-reactive protein, platelet count, or 
bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with 
three to five specimens for standard paraffin block to check for inflammation and lymphocytic 
infiltrates to confirm colitis diagnosis. 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
• Continue atezolizumab. 
colitis, Grade 1 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for > 7 days. 
• Monitor closely. 
Diarrhea or 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
colitis, Grade 2 
• Initiate symptomatic treatment. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist >5 days, initiate treatment 
with 1−2 mg/kg/day oral prednisone or equivalent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Diarrhea or 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
colitis, Grade 3 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab c 
Diarrhea or 
• Permanently discontinue atezolizumab. c 
colitis, Grade 4 
• Refer patient to GI specialist for evaluation and confirmation biopsy. 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
GI = gastrointestinal. 
a
 Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length 
of the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment 
with the protocol requirement for duration of treatment and documented by the investigator. Sponsor-
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investigator is available to advise as needed. 
b
 If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c
 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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ENDOCRINE EVENTS  
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies. The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected. Thyroid-stimulating hormone (TSH) and free triiodothyronine and 
thyroxine levels should be measured to determine whether thyroid abnormalities are present. 
Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, 
follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] 
levels, and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with 
detailed pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency. 
Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 
•
Continue atezolizumab. 
•
Initiate treatment with thyroid replacement hormone. 
•
Monitor TSH closely. 
Symptomatic 
hypothyroidism 
•
Withhold atezolizumab. 
•
Initiate treatment with thyroid replacement hormone. 
•
Monitor TSH closely. 
•
Consider patient referral to endocrinologist. 
•
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Asymptomatic 
hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
•
Continue atezolizumab. 
•
Monitor TSH every 4 weeks. 
•
Consider patient referral to endocrinologist. 
TSH < 0.1 mU/L: 
•
Follow guidelines for symptomatic hyperthyroidism. 
•
Consider patient referral to endocrinologist. 
Symptomatic 
hyperthyroidism 
•
Withhold atezolizumab. 
•
Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
•
Consider patient referral to endocrinologist. 
•
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
•
Permanently discontinue atezolizumab. c 
Symptomatic 
adrenal 
insufficiency, 
Grade 2−4 
•
Withhold atezolizumab for up to 12 weeks after event onset. a 
•
Refer patient to endocrinologist. 
•
Perform appropriate imaging. 
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• 
• 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Hyperglycemia, 
• Continue atezolizumab. 
Grade 1 or 2 
• Investigate for diabetes. If patient has Type 1 diabetes, treat 
as a Grade 3 event. If patient does not have Type 1 diabetes, 
treat as per institutional guidelines. 
• Monitor for glucose control. 
Hyperglycemia, 
• Withhold atezolizumab. 
Grade 3 or 4 
• Initiate treatment with insulin. 
•
Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 
• 
• Monitor for glucose control. 
• Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
Hypophysitis (pan- 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
hypopituitarism), 
• Refer patient to endocrinologist. 
Grade 2 or 3 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan- 
• Permanently discontinue atezolizumab c 
hypopituitarism), 
• Refer patient to endocrinologist. 
Grade 4 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
a
 Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be based on assessment of benefit-risk by the investigator and in 
alignment with the protocol requirement for duration of treatment and documented by the investigator. 
Sponsor-investigator is available to advise as needed. 
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b
 If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c
 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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OCULAR EVENTS  
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, Grade 1 
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset.
a
 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab c 
Ocular event, Grade 3 or 
• Permanently discontinue atezolizumab. c 
4 
• Refer patient to ophthalmologist. 
• Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
a  Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of 
the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment with 
the protocol requirement for duration of treatment and documented by the investigator. Sponsor-investigator is 
available to advise as needed. 
b  If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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IMMUNE-MEDIATED MYOCARDITIS  
Immune-mediated myocarditis has been associated with the administration of atezolizumab. 
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope. Myocarditis may also be a 
clinical manifestation of myositis and should be managed accordingly. Immune-related 
myocarditis needs to be distinguished from myocarditis resulting from infection (commonly 
viral, e.g., in a patient who reports a recent history of GI illness), ischemic events, underlying 
arrhythmias, exacerbation of preexisting cardiac conditions, or progression of malignancy. 
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines below. 
Management Guidelines for Immune-Related Myocarditis 
Event 
Management 
Immune-mediated 
myocarditis, Grade 2, 
3 or 4 
• 
• 
• 
• 
• 
• 
Permanently discontinue atezolizumab. a 
Refer patient to cardiologist. 
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. a,b 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device 
a  Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of 
the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment with 
the protocol requirement for duration of treatment and documented by the investigator. Sponsor-investigator is 
available to advise as needed. 
b  If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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Infusion-Related Reactions and Cytokine-Release Syndrome 
No premedication is indicated for the administration of Cycle 1 of atezolizumab. However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) 
with atezolizumab may receive premedication with antihistamines, antipyretics, and/or 
analgesics (e.g., acetaminophen) for subsequent infusions. Metamizole (dipyrone) is prohibited 
in treating atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab. These reactions, which are thought to be due to release of cytokines 
and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells. Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction  (Lee et al. 2019).  CRS has 
been well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell 
engager antibody therapies but has also been reported with immunotherapies that target PD-1 or 
PD-L1  (Rotz et al. 2017; Adashek and Feldman 2019),  including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided below. 
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) involving 
the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-
 (Merad and Martin 
2020). If a patient develops suspected CRS during the study, a differential diagnosis should 
include COVID-19, which should be confirmed or refuted through assessment of exposure 
history, appropriate laboratory testing, and clinical or radiologic evaluations per investigator 
judgment. If a diagnosis of COVID-19 is confirmed, the disease should be managed as per local 
or institutional guidelines. 
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Management Guidelines for Infusion-Related Reactions 
Event 
Management 
Grade 1 a 
• Immediately interrupt infusion. 
fever 
b
 with or 
• Upon symptom resolution, wait for 30 minutes and then 
without 
restart infusion at half the rate being given at the time of 
constitutional 
event onset. 
symptoms 
• If the infusion is tolerated at the reduced rate for 30 minutes, 
the infusion rate may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment, 
c
 including maintenance 
of IV fluids for hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2. 
• For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
Grade 2 a 
• Immediately interrupt infusion. 
fever 
b
 with 
• Upon symptom resolution, wait for 30 minutes and then 
hypotension not 
restart infusion at half the rate being given at the time of 
requiring 
event onset. 
vasopressors 
• If symptoms recur, discontinue infusion of this dose. 
and/or 
• Administer symptomatic treatment. c 
hypoxia requiring 
• For hypotension, administer IV fluid bolus as needed. 
low-flow oxygen d 
• Monitor cardiopulmonary and other organ function closely 
by nasal cannula or 
(in the ICU, if appropriate). Administer IV fluids as 
blow-by 
clinically indicated and manage constitutional symptoms and 
organ toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis). If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS. 
• Consider IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. e 
• Consider hospitalization until complete resolution of 
symptoms. If no improvement within 24 hours, manage as 
per Grade 3, that is, hospitalize patient (monitoring in the 
ICU is recommended), permanently discontinue 
atezolizumab, and contact Sponsor-investigator. 
• If symptoms resolve to Grade 1 or better for 3 consecutive 
days, next dose of atezolizumab may be administered. For 
subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 
3 consecutive days, contact Sponsor-investigator. 
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Event 
Management 
Grade 3 a 
• Permanently discontinue atezolizumab and contact Sponsor 
fever 
b
 with 
Investigator. e 
hypotension 
• Administer symptomatic treatment. c 
requiring a 
• For hypotension, administer IV fluid bolus and vasopressor as 
vasopressor (with or 
needed. 
without vasopressin) • Monitor cardiopulmonary and other organ function closely; 
and/or 
monitoring in the ICU is recommended. Administer IV fluids as 
hypoxia requiring 
clinically indicated, and manage constitutional symptoms and 
high-flow oxygen d 
organ toxicities as per institutional practice. 
by nasal cannula, 
face mask, 
non-rebreather mask, 
or venturi mask 
• 
• 
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis). If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS. 
Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. e 
• Hospitalize patient until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 4, that 
is, admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed; for patients who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of 
the investigator and in consultation with the Sponsor-
investigator. 
Grade 4 a 
• Permanently discontinue atezolizumab and contact Sponsor-
fever 
b
 with 
investigator. e 
hypotension 
• Administer symptomatic treatment. c 
requiring multiple 
vasopressors 
• Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
(excluding 
needed. Monitor other organ function closely. Manage 
vasopressin) 
constitutional symptoms and organ toxicities as per institutional 
and/or 
practice. 
hypoxia requiring 
• Rule out other inflammatory conditions that can mimic CRS 
oxygen by positive 
(e.g., sepsis). If no improvement within 24 hours, initiate 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
• 
workup and assess for signs and symptoms of HLH or MAS. 
Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
mechanical 
• Consider anti-cytokine therapy. For patients who are refractory to 
ventilation) 
anti-cytokine therapy, experimental treatments
f
 may be 
considered at the discretion of the investigator and in consultation 
with the Sponsor-Investigator. 
• Hospitalize patient until complete resolution of symptoms. 
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ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level positive airway pressure; 
CAR = chimeric antigen receptor; CPAP = continuous positive airway pressure; CRS = cytokine-release syndrome; 
CTCAE = Common Terminology Criteria for Adverse Events; eCRF = electronic Case Report Form; 
HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; IRR = infusion-related reaction; 
IV=intraveous; MAS = macrophage activation syndrome; NCCN = National Cancer Comprehensive Network; 
NCI = National Cancer Institute. 
Note: These management guidelines have been adapted from the NCCN guidelines for the management of CAR T-
cell−related toxicities (Version 2.2019). 
a
 Grading system for these management guidelines is based on ASTCT consensus grading for CRS. NCI CTCAE 
(version as specified in the protocol) should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF. Organ toxicities associated with CRS should not influence 
overall CRS grading. 
b
 Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop CRS and 
who then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer required when 
subsequently determining event severity (grade). In this case, the grade is driven by the presence of hypotension 
and/or hypoxia. 
c
 Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, bronchodilators, and/or 
oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per institutional 
practice. 
d
 Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered at > 6 L/min. 
e
 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-mediated event. The decision to rechallenge patients with atezolizumab should be 
based on investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate 
delegate). Sponsor-investigator is available to advise as needed. For subsequent infusions, administer oral 
premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS. 
Premedication with corticosteroids and extending the infusion time may also be considered after assessing the 
benefit−risk ratio. 
f
 Refer to  Riegler et al. (2019) 
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PANCREATIC EVENTS  
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should include pancreatitis. Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests. 
Management Guidelines for Pancreatic Events, Including Pancreatitis 
Event 
Management 
Amylase and/or 
lipase elevation, 
Grade 2 
Amylase and/or lipase > 1.5−2.0 × ULN: 
•
Continue atezolizumab. 
•
Monitor amylase and lipase weekly. 
•
For prolonged elevation (e.g., > 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0−5.0 × ULN: 
•
Treat as a Grade 3 event. 
Amylase and/or 
lipase elevation, 
Grade 3 or 4 
•
Withhold atezolizumab for up to 12 weeks after event onset. a 
•
Refer patient to GI specialist. 
•
Monitor amylase and lipase every other day. 
•
If no improvement, consider treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
•
If event resolves to Grade 1 or better, resume atezolizumab. b 
•
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
•
For recurrent events, permanently discontinue atezolizumab. c 
Immune-related 
pancreatitis, Grade 
2 or 3 
•
Withhold atezolizumab for up to 12 weeks after event onset. a 
•
Refer patient to GI specialist. 
•
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
•
If event resolves to Grade 1 or better, resume atezolizumab. b 
•
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
•
For recurrent events, permanently discontinue atezolizumab. c 
Immune-related 
pancreatitis, Grade 
4 
•
Permanently discontinue atezolizumab. c 
•
Refer patient to GI specialist. 
•
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
•
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
•
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
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a  Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of 
the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment with 
the protocol requirement for duration of treatment and documented by the investigator. Sponsor-investigator is 
available to advise as needed. 
b  If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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DERMATOLOGIC EVENTS  
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. Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab. A dermatologist should evaluate persistent 
and/or severe rash or pruritus. A biopsy should be considered unless contraindicated. 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, Grade 1 
• 
• 
Continue atezolizumab. 
Consider treatment with topical corticosteroids and/or 
other symptomatic therapy (e.g., antihistamines). 
Dermatologic event, Grade 2 
• 
• 
• 
Continue atezolizumab. 
Consider patient referral to dermatologist for evaluation 
and, if indicated, biopsy. 
Initiate treatment with topical corticosteroids. 
• Consider treatment with higher-potency topical 
corticosteroids if event does not improve. 
• If unresponsive to topical corticosteroids, consider oral 
prednisone 0.5 mg/kg/day. 
Dermatologic event, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event 
onset. a 
• Refer patient to dermatologist for evaluation and, if 
indicated, biopsy. 
• Initiate treatment with 10 mg/day oral prednisone or 
equivalent, increasing dose to 1−2 mg/kg/day if event does 
not improve within 48−72 hours. 
• If event resolves to Grade 1 or better, resume 
atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Sponsor- Investigator. c 
Dermatologic event, Grade 4 
• Permanently discontinue atezolizumab and contact 
Sponsor-Investigator. c 
Stevens Johnson syndrome or • Additional guidance for Stevens Johnson syndrome or 
toxic epidermal necrolysis 
toxic epidermal necrolysis: 
(any grade) 
• Withhold atezolizumab for suspected Stevens Johnson 
syndrome or toxic epidermal necrolysis. 
• Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist, or urologist as relevant) 
for evaluation and, if indicated, biopsy. 
• Follow the applicable treatment and management 
guidelines above. 
• If Stevens Johnson syndrome or toxic epidermal necrolysis 
is confirmed, permanently discontinue atezolizumab. 
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a  Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of 
the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment with 
the protocol requirement for duration of treatment and documented by the investigator. Sponsor-investigator is 
available to advise as needed. 
b  If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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NEUROLOGIC DISORDERS  
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies. 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-related 
• Continue atezolizumab. 
neuropathy, Grade 1 
• Investigate etiology. 
Immune-related 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
neuropathy, Grade 2 
• Investigate etiology and refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
Immune-related 
• Permanently discontinue atezolizumab. c 
neuropathy, Grade 3 or 4 
• Refer patient to neurologist 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
• Permanently discontinue atezolizumab. c 
Guillain-Barré syndrome 
• Refer patient to neurologist. 
(any grade) 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of 1−2 mg/kg/day oral or IV prednisone 
or equivalent. 
a  Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of 
the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment with 
the protocol requirement for duration of treatment and documented by the investigator. Sponsor-investigator is 
available to advise as needed. 
b  If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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IMMUNE-MEDIATED MENINGOENCEPHALITIS  
Immune-mediated meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-mediated meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. 
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression 
of malignancy, or secondary to a paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines below. 
Management Guidelines for Immune-Mediated Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, all 
grades 
• 
• 
• 
• 
• 
Permanently discontinue atezolizumab. a 
Refer patient to neurologist. 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
a
 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. The decision to rechallenge patients with atezolizumab should be 
based on investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate 
delegate). Sponsor-Investigator is available to advise as needed. 
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RENAL EVENTS  
Immune-mediated nephritis has been associated with the administration of atezolizumab. 
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment. Patients with abnormal renal 
function should be evaluated and treated for other more common etiologies (including prerenal 
and postrenal causes, and concomitant medications such as nonsteroidal anti-inflammatory 
drugs). Refer the patient to a renal specialist if clinically indicated. A renal biopsy may be 
required to enable a definitive diagnosis and appropriate treatment. If no alternative cause of 
acute kidney injury is identified, patients with signs and symptoms of acute kidney injury, in the 
absence of an identified alternate etiology, should be treated according to the management 
guidelines for immune-related renal events in the table below. 
Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
• 
• 
Continue atezolizumab. 
Monitor kidney function closely, including creatinine and 
urine protein, until values resolve to within normal limits 
or to baseline values. 
Renal event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event 
onset. a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume 
atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
Renal event, 
Grade 3 or 4 
• 
• 
Permanently discontinue atezolizumab. 
Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
a  Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of 
the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment with 
the protocol requirement for duration of treatment and documented by the investigator. Sponsor-investigator is 
available to advise as needed. 
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b  If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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IMMUNE-MEDIATED MYOSITIS  
Immune-mediated myositis has been associated with the administration of atezolizumab. 
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are amongst the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatinine-kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle-biopsy. 
Patients with possible myositis should be referred to a rheumatologist or neurologist. Patients 
with possible myositis should be monitored for signs of myocarditis. 
Management Guidelines for Immune-Related Myositis 
Event 
Management 
Immune-related myositis, Grade 
• 
Continue atezolizumab 
1 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines 
Immune-related myositis, Grade 
• 
Withhold atezolizumab for up to 12 weeks after event onset
a
 and contact 
2 
site investigator. 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines 
• 
Consider treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If corticosteroids are initiated and event does not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent 
• 
If event resolves to Grade 1 or better, resume atezolizumab.
b
 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
sponsor-investigator. 
c
 
Immune-related myositis, Grade 
• 
Withhold atezolizumab for up to 12 weeks after event onset
a
 and contact 
3 
site investigator. 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines 
• 
Respiratory support may be required in more severe cases 
• 
Initiate treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher dose bolus if subject is severely 
compromised (eg, cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1-2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, resume atezolizumab.
b
 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
HCRN. 
c
 
• 
For recurrent events, treat as a Grade 4 event 
Immune-related myositis, Grade 
• 
Permanently discontinue atezolizumab and contact site investigator.
c
 
4 
• 
Refer subject to rheumatologist or neurologist 
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•
Initiate treatment as per institutional guidelines. 
•
Respiratory support may be required in more severe cases 
•
Initiate treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher dose bolus if subject is severely 
compromised (eg, cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1-2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
•
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
•
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
a  Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of 
the extended period of time must be based on assessment of benefit-risk by the investigator and in alignment with 
the protocol requirement for duration of treatment and documented by the investigator. Sponsor-investigator is 
available to advise as needed. 
b  If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c  Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge patients with atezolizumab should be based on 
investigator’s assessment of benefit-risk and documented by the investigator (or an appropriate delegate). 
Sponsor-Investigator is available to advise as needed 
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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE  
ACTIVATION SYNDROME  
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are considered 
to be potential risks for atezolizumab. Clinical and laboratory features of severe CRS overlap 
with HLH, and HLH should be considered when CRS presentation is atypical or prolonged. 
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014). A patient should be classified as having HLH if five of the following eight 
criteria are met: 
•
Fever ≥ 38.5°C 
•
Splenomegaly 
•
Peripheral blood cytopenia consisting of at least two of the following: 
–
Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
–
Platelet count < 100 × 10
9
/L (100,000/µL) 
–
ANC < 1.0 × 10
9
/L (1000/µL) 
•
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L (150 mg/dL) 
•
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
•
Low or absent natural killer cell activity 
•
Ferritin > 500 mg/L (500 ng/mL) 
•
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard deviations above 
age-adjusted laboratory-specific norms 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016). A febrile patient should be classified as 
having MAS if the following criteria are met: 
•
Ferritin > 684 mg/L (684 ng/mL) 
•
At least two of the following: 
–
Platelet count ≤ 181 × 10
9
/L (181,000/µL) 
–
AST ≥ 48 U/L 
–
Triglycerides > 1.761 mmol/L (156 mg/dL) 
–
Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
Patients with suspected HLH or MAS should be treated according to the guidelines below 
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Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
• 
• 
• 
• 
• 
• 
Permanently discontinue atezolizumab and contact Sponosr-
Investigator. 
Consider patient referral to hematologist. 
Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent. 
If event does not respond to treatment within 24 hours, contact 
Sponsor-Investigator and initiate treatment as appropriate according 
to published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
If event resolves to Grade 1 or better, taper corticosteroids over 
 1 
month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
IMMUNE-MEDIATED PERICARDIAL DISORDERS  
The following recommendations will be included in the updated atezolizumab Investigator’s 
Brochure (IB) and study protocols for immune-mediated pericardial disorders: 
•
The diagnosis of immune-mediated pericarditis should be considered in all patients 
presenting with chest pain. 
•
The diagnosis of immune-mediated pericardial effusion and cardiac tamponade should be 
considered in all patients presenting with chest pain associated with dyspnea or 
hemodynamic instability. 
•
Cardiac tamponade should be treated as a medical emergency and consultation with a 
cardiologist should be sought for further management. 
•
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
•
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
•
Atezolizumab should be withheld for patients with suspected immune-mediated 
pericardial disorders. 
•
Atezolizumab should be permanently withdrawn for any grade confirmed immune-
mediated pericardial disorders. 
•
Caution should be used when considering the use of atezolizumab in a patient 
experienced a pericardial disorder on prior treatment with other immune-stimulatory 
anticancer agents. 
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References  
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti−programmed death-1 
antibody: raising awareness among community oncologist. J Oncol Practice 
2019;15:502−4. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc 
Hematol Educ Protram 2015;1:190−6. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic 
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