Conditions: Small Cell Lung Cancer ( SCLC )
Keywords: SCLC Small Cell Lung Cancer MPDL3280A atezolizumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is an open-label study with two parts, a Phase I study and a randomized Phase II study. This study will be conducted at approximately ten sites in the United States. Approximately 178 patients will be enrolled in this trial.

Detailed description:
Combining standard chemotherapy with a PD-1/PD-L1 inhibitor holds great appeal in the treatment of SCLC. While this approach may be appropriate for many cancer types, SCLC may be particularly vulnerable to this treatment strategy. Early studies have suggested greater efficacy with agents targeting PD-1/PD-L1 in tumors that are more mutationally complex, such as those associated with tobacco use. SCLC has a strong association with tobacco use and indeed, genome-wide sequencing studies have consistently shown that SCLC carries one of the highest rates of non-synonymous mutations. In addition, MPDL3280A has been safely combined with platinum based chemotherapy doublets in the treatment of NSCLC. Thus, a combination of carboplatin, etoposide and MPDL3280A may significantly improve outcomes in the treatment of SCLC.

Arms:
arm 1: Carboplatin AUC 5 iv on day 1 every 21 days for 4 cycles Etoposide 100mg/m2 iv on days 1-3 every 21 days for 4 cycles arm 2: Carboplatin AUC 5 iv on day 1 every 21 days for 4 cycles Etoposide 100mg/m2 iv on days 1-3 every 21 days for 4 cycles MPDL3280A (Atezolizumab) 1200mg iv on day 1 every 21 days until progression

Interventions: intervention 1: Carboplatin intervention 2: Etoposide intervention 3: MPDL3280A
Intervention descriptions: intervention 1: Standard chemotherapy intervention 2: Standard chemotherapy intervention 3: Experimental biologic

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
 
This is a Georgetown University document that contains confidential information. It is 
intended solely for the recipient clinical investigator(s) and must not be disclosed to 
any other party. This material may be used only for evaluating or conducting clinical 
investigations; any other proposed use requires written consent from Georgetown 
University. 
 
Atezolizumab 
Protocol ML29640, Version 11 
1 
PROTOCOL
TITLE: 
AN OPEN LABEL, RANDOMIZED PHASE I/II TRIAL 
OF CARBOPLATIN PLUS ETOPOSIDE WITH OR 
WITHOUT ATEZOLIZUMAB IN UNTREATED 
EXTENSIVE STAGE SMALL CELL LUNG CANCER  
STUDY NUMBER: 
IND 128613, IRB# 2015-1380, ML29640 
VERSION NUMBER: 
11 
TEST PRODUCTS: 
Atezolizumab 
Carboplatin 
Etoposide 
INVESTIGATORS: 
Giuseppe Giaccone 
3800 Reservoir Road NW, Washington, DC 20007 
Telephone: 202-687-7072 
Fax: 202-687-0313 
E-mail: gg496@georgetown.edu 
 
 
SUB-INVESTIGATORS: 
Stephen V. Liu, Georgetown University 
Deepa Subramaniam, Georgetown University 
Jillian Thompson, Georgetown University 
Leora Horn, Vanderbilt University 
STUDY COORDINATOR: 
Jeanette Crawford 
SUPPORT PROVIDED BY: Genentech, Inc. 
PROTOCOL DATE: 
13 July 2016 
 


Atezolizumab 
Protocol ML29640, Version 11 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................ 10 
1.1 
SMALL CELL LUNG CANCER ...................................................... 10 
1.1.1 
Current Management ............................................................. 10 
1.1.2 
Evidence in Support of Targeting PD-1 and PD-
L1 
10 
1.2 
Background on Atezolizumab ................................................ 11 
1.2.1 
Summary of Nonclinical Experience ...................................... 12 
1.2.1.1  Nonclinical Pharmacology .................................................... 12 
1.2.1.2  Nonclinical Pharmacokinetics ............................................... 13 
1.2.1.3  Nonclinical Toxicology .......................................................... 13 
1.2.1.4  Scientific Rationale ............................................................... 14 
1.2.2 
Clinical Experience with Atezolizumab .................................. 15 
1.2.2.1  Ongoing Clinical Studies ...................................................... 15 
1.2.2.2  Clinical Safety ...................................................................... 17 
1.2.2.3  Clinical Activity ..................................................................... 17 
1.2.2.4  Clinical Pharmacokinetics and Immunogenicity ................... 18 
1.3 
Study Rationale ..................................................................... 18 
2. 
OBJECTIVES .............................................................................................. 19 
2.1 
Primary .................................................................................. 19 
PHASE I ................................................................................................... 19 
PHASE II .................................................................................................. 19 
2.2 
Secondary ............................................................................. 20 
2.3 
EXPLORATORY .................................................................... 20 
3. 
STUDY DESIGN ......................................................................................... 20 
3.1 
Description of the Study ......................................................... 20 
3.1.1 
Phase I .................................................................................. 20 
3.1.2 
Phase II ................................................................................. 21 
3.2 
Rationale for Study Design .................................................... 21 
3.3 
DOSE ESCALATION ............................................................. 22 
3.3.1 
Dose Escalation Rationale ..................................................... 22 
3.3.2 
Phase I Dose Escalation Design ........................................... 22 


TABLE OF CONTENTS (CONT.) 
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Protocol ML29640, Version 11 
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3.3.3 
Dose Levels ........................................................................... 23 
3.3.4 
Definition of Dose-Limiting Toxicity (DLT) .............................. 23 
3.3.5 
Patients Evaluable for Assessment of DLTs .......................... 24 
3.4 
Phase II Dosing ..................................................................... 24 
3.5 
SURVIVAL FOLLOW UP ....................................................... 25 
3.6 
End of Study .......................................................................... 25 
3.7 
Outcome Measures ............................................................... 25 
3.7.1 
Primary Efficacy Outcome Measure (Phase II) ...................... 25 
3.7.2 
Secondary Efficacy Outcome Measures ................................ 25 
3.7.3 
Safety Outcome Measures .................................................... 25 
3.7.4 
Exploratory Measures ............................................................ 25 
4. 
MATERIALS AND METHODS .................................................................... 26 
4.1 
Study Population ................................................................... 26 
4.1.1 
Inclusion Criteria .................................................................... 26 
4.1.2 
Exclusion Criteria ................................................................... 27 
4.2 
Study Treatment .................................................................... 30 
4.2.1 
Method of Treatment Assignment .......................................... 30 
4.2.2 
Study Drug: Atezolizumab ..................................................... 30 
4.2.2.1  Formulation .......................................................................... 30 
4.2.2.2  Dosage, Administration, and Storage ................................... 31 
4.2.3 
Carboplatin and Etoposide .................................................... 32 
4.2.3.1  Formulation and Storage ...................................................... 32 
4.2.3.2  Etoposide Dosing ................................................................. 32 
4.2.3.3  Carboplatin Dosing ............................................................... 32 
4.3 
Concomitant and Excluded Therapies ................................... 33 
4.3.1 
Concomitant Therapy ............................................................ 33 
4.3.2 
Excluded Therapy .................................................................. 34 
4.4 
General Plan to Manage Safety Concerns ............................ 35 
4.4.1 
Management of Specific Safety Concerns with 
Atezolizumab ........................................................................................... 36 
4.4.2 
Guidelines for Dosage Modification and 
Treatment Interruption or Discontinuation ................................................ 36 


TABLE OF CONTENTS (CONT.) 
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Protocol ML29640, Version 11 
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4.4.2.1  Dose Modifications of Carboplatin and 
Etoposide ........................................................................................... 38 
4.4.2.2  Gastrointestinal Toxicity ....................................................... 40 
4.4.2.3  Hepatotoxicity ....................................................................... 41 
4.4.2.4  Dermatologic Toxicity ........................................................... 42 
4.4.2.5  Endocrine Toxicity ................................................................ 43 
4.4.2.6  Pulmonary Toxicity ............................................................... 44 
4.4.2.7  Pericardial and Pleural Effusions ......................................... 45 
4.4.2.8  Potential Pancreatic Toxicity ................................................ 45 
4.4.2.9  Potential Eye Toxicity ........................................................... 46 
4.5 
Patient Discontinuation .......................................................... 46 
4.6 
Study Treatment Discontinuation ........................................... 47 
4.7 
Study and Site Discontinuation .............................................. 47 
4.8 
Clinical and Laboratory Evaluations ...................................... 48 
4.8.1 
Study Assessments ............................................................... 48 
4.8.1.1  Medical History and Demographic Data ............................... 48 
4.8.1.2  Vital Signs ............................................................................ 48 
4.8.1.3  Physical Examination ........................................................... 49 
4.8.1.4  Tumor and Response Evaluation ......................................... 49 
4.8.1.5  Laboratory Assessments ...................................................... 50 
4.8.1.6  Cardiac Function Tests ........................................................ 50 
4.8.2 
Treatment Discontinuation Visit ............................................. 51 
4.8.3 
Follow-Up Assessments ........................................................ 51 
4.8.4 
Post-Treatment Evaluations .................................................. 52 
5. 
STATISTICAL CONSIDERATIONS ............................................................ 52 
5.1 
Safety Analyses: Adverse Events, Laboratory 
Tests, ECGs, and Vital Signs ................................................ 53 
5.2 
Anti-Tumor Activity Analyses ................................................. 53 
5.3 
Determination of Sample Size for Phase I ............................. 53 
5.4 
Determination of Sample Size and Data Analysis 
for Phase II ............................................................................ 54 
5.5 
Data Quality Assurance ......................................................... 56 
6. 
ASSESSMENT OF SAFETY ....................................................................... 56 


TABLE OF CONTENTS (CONT.) 
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Protocol ML29640, Version 11 
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6.1 
Risks Associated with atezolizumab ...................................... 57 
6.2 
Risks associated with carboplatin .......................................... 59 
6.3 
Risks associated with etoposide ............................................ 59 
6.4 
potential overlapping toxicities ............................................... 59 
6.5 
Safety Parameters and Definitions ........................................ 60 
6.5.1 
Overview ................................................................................ 60 
6.5.2 
Adverse Events ..................................................................... 60 
6.5.3 
Serious Adverse Events ........................................................ 60 
6.5.4 
Dose-Limiting Toxicities ......................................................... 61 
6.6 
Methods and Timing for Assessing and 
Recording Safety Variables ................................................... 61 
6.6.1 
Adverse Event Reporting Period ........................................... 61 
6.6.2 
Assessment of Adverse Events ............................................. 62 
6.7 
Procedures for Eliciting, Recording, and 
Reporting Adverse Events ..................................................... 62 
6.7.1 
Eliciting Adverse Events ........................................................ 62 
6.7.2 
Specific Instructions for Recording Adverse 
Events 
62 
6.7.2.1  Diagnosis versus Signs and Symptoms ............................... 63 
6.7.2.2  Deaths .................................................................................. 63 
6.7.2.3  Preexisting Medical Conditions ............................................ 63 
6.7.2.4  Hospitalizations for Medical or Surgical 
Procedures ......................................................................................... 63 
6.7.2.5  Pregnancies in Female Patients ........................................... 63 
6.7.2.6  Pregnancies in Female Partners of Male 
Patients 64 
6.7.2.7  Abortions .............................................................................. 64 
6.7.2.8  Congenital Anomalies/Birth Defects ..................................... 64 
6.7.2.9  Post-Study Adverse Events .................................................. 64 
6.7.2.10  Safety Reconciliation .......................................................... 65 
6.7.2.11  Adverse Events of Special Interest..................................... 65 
6.7.2.12  Adverse Event Reporting ................................................... 66 
6.7.3 
Additional Reporting Requirements for IND ........................... 68 
6.7.4 
IND Annual Reports ............................................................... 69 


TABLE OF CONTENTS (CONT.) 
Atezolizumab 
Protocol ML29640, Version 11 
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6.8 
Study Close-Out .................................................................... 69 
7. 
ETHICAL CONSIDERATIONS .................................................................... 69 
7.1 
Compliance with Laws and Regulations ................................ 69 
7.2 
Informed Consent .................................................................. 69 
7.3 
Institutional Review Board or Ethics Committee 
Approval ................................................................................ 70 
7.4 
Confidentiality ........................................................................ 70 
8. 
STUDY MEDICAL MONITORING REQUIREMENTS ................................. 70 
8.1 
investigator requirements ...................................................... 71 
8.1.1 
Study Initiation ....................................................................... 71 
8.1.2 
Study Completion .................................................................. 71 
8.1.3 
Informed Consent Form ......................................................... 72 
8.1.4 
Communication with Institutional Review Board .................... 73 
8.1.5 
Amendments to the Protocol ................................................. 73 
8.1.6 
Study Monitoring Requirements ............................................ 73 
8.1.7 
Electronic Case Report Forms ............................................... 73 
8.1.8 
Source Data Documentation .................................................. 74 
8.1.9 
Use of Computerized Systems .............................................. 74 
8.1.10 
Study Medication Accountability ............................................ 74 
8.1.11 
Data Management and Monitoring ........................................ 75 
8.1.12 
Adherence to the Protocol ..................................................... 76 
8.1.13 
Emergency Modifications ....................................................... 76 
8.1.14 
Single Patient/Subject Exceptions ......................................... 76 
8.1.15 
Other Protocol Deviations/Violations ..................................... 76 
8.1.15 
Disclosure of Data ................................................................. 77 
8.1.16 
Retention of Records ............................................................. 77 
8.1.17 
Obligations of Investigators ................................................... 78 
8.2 
Study Medication Accountability ............................................ 78 
8.3 
Data Collection ...................................................................... 78 
8.4 
MULTI-INSTITUTION STUDY COORDINATION .................. 79 
8.5 
 Retention of Records ............................................................ 80 
9. 
CORRELATIVE STUDIES .......................................................................... 80 
 


TABLE OF CONTENTS (CONT.) 
Atezolizumab 
Protocol ML29640, Version 11 
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LIST OF TABLES 
 
Table 1. 
Outcomes with Standard Therapy in SCLC…………………….......9 
Table 2. 
Dose Levels……………………......................................................22 
Table 3. 
Dose Modification Guidelines for Hematologic Toxicity …............37 
Table 4. 
Dose Modification Guidelines for Non-Hematologic Toxicity........38 
Table 5. 
Dose Modification Guidelines for Gastrointestinal Toxicity ......... 41 
Table 6. 
Dose Modification Guidelines for Hepatotoxicity ......................... 42 
Table 7. 
Dose Modification Guidelines for Dermatologic Toxicity ............. 43 
Table 8. 
Dose Modification Guidelines for Endocrine Toxicity .................. 44 
Table 9. 
Dose Modification Guidelines for Pulmonary Toxicity ................. 45 
Table 10. 
Dose Modification Guidelines for Ocular / Eye Toxicity ............... 46 
Table 11. 
DLT Probabilities...........................................................................52 
 
 
LIST OF APPENDICES 
Appendix 1 
Study Flowchart .......................................................................... A1 
Appendix 2 
Calculation of Creatinine Clearance Using the Cockcroft-
Gault Formula ............................................................................. A3 
Appendix 3 
Safety Reporting Fax Cover Sheet ............................................. A4 
Appendix 4 
FDA MedWatch 3500 Form ........................................................ A5 
Appendix 5 
Current NCI Common Terminology Criteria for Adverse 
Events (CTCAE) ......................................................................... A6 
Appendix 6 
Response Evaluation Criteria in Solid Tumors (RECIST) ........... A7 
Appendix 7 
Immune-Related Response Criteria .......................................... A17 
Appendix 8 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale .............................................................................. A19 
Appendix 9 
Anaphylaxis Precautions ........................................................... A20 
Appendix 10 
References ................................................................................ A21 


 
Atezolizumab 
Protocol ML29640, Version 11 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
antibody to hepatitis B core antigen 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibody 
AUC 
area under the concentration-time curve 
BSA 
body surface area 
Cmax 
maximum serum concentration  
Cmin 
minimum serum concentration  
CBC 
complete blood count 
CMP 
complete metabolic panel 
CNS 
central nervous system 
CR 
complete responses 
CRC 
colorectal cancer 
CRF 
Case Reporting Form 
CT 
computed tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
diffusion capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DSMB 
Data Safety and Monitoring Board 
EBNA 
Epstein-Barr nuclear antigen 
EC50 
50% effective concentrations  
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
U.S. Food and Drug Administration 
G-CSF 
granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
IC50 
50% inhibitory concentration  
ICH 
International Conference on Harmonisation 
IFN 
interferon 


 
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Protocol ML29640, Version 11 
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Abbreviation 
Definition 
IHC 
immunohistochemistry 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
irRC 
immune-related response criteria  
irSAE 
immune-related serious adverse event 
IV 
intravenous 
LFT 
liver function test 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI  
National Cancer Institute  
NOAEL 
no observed adverse effect level 
NSCLC 
nonsmall cell lung cancer 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCI 
prophylactic cranial irradiation 
PD 
progressive disease 
PD-1 
programmed death1 
PD-L1 
programmed deathligand 1  
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetic 
PR 
partial response 
PS  
performance status 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
response rate 
SAE 
serious adverse event 
SCLC 
small cell lung cancer 
SD 
stable disease 
TBNK 
T, B, and natural killer [cells] 
TNF 
tumor necrosis factor 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cells 
WBRT 
whole brain radiation therapy 


 
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Protocol ML29640, Version 11 
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1. 
INTRODUCTION 
1.1 
SMALL CELL LUNG CANCER 
Lung cancer remains the most lethal cancer in the United States, responsible for nearly 
160,000 deaths per year [1]. Small cell lung cancer (SCLC), which comprises 
approximately 13% of these cases, is a particularly lethal subtype characterized by rapid 
growth and dissemination [2]. Patients with early, limited-stage SCLC can be treated 
with chemoradiation with the potential for long-term survival [3]. However, the majority of 
patients with SCLC (~70%) will present with extensive-stage disease (ED-SCLC) where 
efforts are palliative in nature.  
1.1.1 
Current Management 
The current standard treatment for patients with ED-SCLC is platinum-based 
chemotherapy [4]. The combination of cisplatin plus etoposide emerged as an 
efficacious regimen in the early 1980s. While this regimen is still employed today, 
carboplatin has demonstrated equal efficacy with a more favorable toxicity profile [5]. 
Multiple trials employing these platinum doublets (at various doses) have shown fairly 
consistent outcomes (Table 1). Overall response rates (ORR) are high, on the order of 
60-70%, but the benefit from treatment is transient. Progression free survival (PFS) is 
approximately 6 months and median overall survival (OS) with standard treatment 
remains under a year.  
 
 
Platinum Dosing
Etoposide Dosing
RR 
PFS (m)
OS (m)
Roth , 1992 [4] 
Cisplatin 20 mg/m2 days 1-5 
80 mg/m2 days 1-5 
61% 
4.3 
8.6 
Pujol, 2001 [6] 
Cisplatin 100 mg/m2 day 2 
100 mg/m2 days 1-3 
61% 
6.3 
9.3 
Noda, 2002 [7] 
Cisplatin 80 mg/m2 day 1 
100 mg/m2 days 1-3 
68% 
4.8 
9.4 
Eckardt, 2006 [8] 
Cisplatin 80 mg/m2 day 1 
100 mg/m2 days 1-3 
69% 
6.3 
10.1 
Hanna, 2006 [9] 
Cisplatin 60 mg/m2 day 1 
120 mg/m2 days 1-3 
44% 
4.6 
10.2 
Okamoto, 2007 [10] 
Cisplatin 25 mg/m2 days 1-3 
80 mg/m2 days 1-3 
73% 
4.7 
9.9 
Okamoto, 2007 [10] 
Carboplatin AUC 5 day 1 
80 mg/m2 days 1-3 
73% 
5.2 
10.6 
Socinski, 2009 [11] 
Carboplatin AUC 5 day 1 
100 mg/m2 days 1-3 
52% 
5.4 
10.6 
Rudin, 2008 [12] 
Carboplatin AUC 5 day 1 
80 mg/m2 days 1-3 
60% 
7.6 
10.6 
Nagel, 2011 [13] 
Carboplatin AUC 6 day 1 
120 mg/m2 days 1-3 
67% 
7.0 
11.0 
Schmittel, 2011 [14] 
Carboplatin AUC 5 day 1 
140 mg/m2 days 1-3 
52% 
6.0 
9.0 
Table 1. Representative results from randomized trials using platinum-based chemotherapy for SCLC. 
 
There have been many unsuccessful efforts to improve the durability of response to 
chemotherapy in SCLC. While identification of actionable driver mutations has led to 
more effective treatment algorithms in non-small cell lung cancer (NSCLC), genomic 
analyses of SCLC have not revealed consistent actionable targets. Novel therapeutic 
strategies for SCLC remain an unmet need. 
1.1.2 
Evidence in Support of Targeting PD-1 and PD-L1 
One of the more promising paradigms to emerge in the treatment of advanced cancer is 
the use of agents targeting programmed death-1 (PD-1) and its ligands (PD-L1, PD-L2). 
Encouraging clinical data emerging in the field of tumor immunotherapy have 


 
Atezolizumab 
Protocol ML29640, Version 11 
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demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced cancer [15].  
PD-L1 is one of two ligands that binds PD-1, an inhibitory receptor expressed on T cells 
following T-cell activation, which is sustained in states of chronic stimulation such as 
chronic infection or cancer [16]. Ligation of PD-1 with PD-L1 inhibits T-cell proliferation, 
cytokine production, and cytolytic activity, leading to the functional inactivation or 
exhaustion of T cells. Aberrant expression of PD-L1 on tumor cells has been reported to 
impede anti-tumor immunity, resulting in immune evasion [17]. Therefore, interruption of 
the PD-1/PD-L1 pathway represents an attractive strategy to re-invigorate tumor-specific 
T-cell immunity. PD-L1 expression is prevalent in many human tumors (e.g., lung, 
ovarian, melanoma, and colon carcinoma), and elevated PD-L1 expression is often 
associated with a worse prognosis. Furthermore, in murine tumor models, interruption of 
the interaction between PD-1 and PD-L1 resulted in anti-tumor effects [18, 19]. 
Early clinical data demonstrated efficacy of PD-1 antibodies in the treatment of different 
epithelial carcinomas. Two of these agents have been approved for the treatment of 
advanced NSCLC. Nivolumab, an anti-PD-1 antibody, was compared to docetaxel in 
patients with pretreated, advanced squamous NSCLC [20]. Patients randomized to 
receive nivolumab experienced an improvement in median overall survival (9.2 vs. 6.0 
months). A similar outcome was seen in non-squamous NSCLC [21], where nivolumab 
again improved survival as compared to docetaxel (12.2 vs. 9.4 months). Nivolumab has 
also been associated with durable tumor regression in patients with advanced 
melanoma and renal cell carcinoma [22]. Pembrolizumab is another anti-PD-1 antibody 
now approved for treatment in melanoma [23] and NSCLC. In patients whose tumors 
express PD-L1, the response rate of pemetrexed was over 45% [24]. MEDI4736, which 
targets PD-L1, has shown activity in various cancers, including NSCLC, melanoma, 
head and neck squamous cell carcinoma (SCC), gastroesophageal cancer, breast 
cancer and pancreatic cancer [25, 26]. 
This strategy also shows promise in SCLC. The CheckMate 032 study explored an 
immunotherapy strategy in SCLC [27]. This phase I/II trial explored the activity of 
nivolumab with or without ipilimumab in patients with refractory small cell lung cancer. In 
the 40 patients who received nivolumab 3mg/kg every 2 weeks, the disease control rate 
was 38% with an acceptable toxicity profile. In addition, there were many patients who 
achieved a durable response. 
1.2 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab (MPDL3280A) is a human immunoglobulin (Ig) G1 monoclonal antibody 
consisting of two heavy chains (448 amino acids) and two light chains (214 amino acids) 
and is produced in Chinese hamster ovary cells. Atezolizumab was engineered to 
eliminate Fc-effector function via a single amino acid substitution (asparagine to alanine) 
at position 298 on the heavy chain, which results in a non-glycosylated antibody that has 
minimal binding to Fc receptors and prevents Fc-effector function at expected 


 
Atezolizumab 
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concentrations in humans. Atezolizumab targets human PD-L1 and inhibits its interaction 
with its receptor, PD-1. Atezolizumab also blocks the binding of PD-L1 to B7.1, an 
interaction that is reported to provide additional inhibitory signals to T cells. 
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans. Atezolizumab has been approved for locally 
advanced or metastatic urothelial carcinoma who have disease progression during or 
following platinum-based chemotherapy. 
1.2.1 
Summary of Nonclinical Experience 
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in 
vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an 
acceptable safety profile, and to identify a Phase I starting dose. Comprehensive 
pharmacology, PK, and toxicology evaluations were thus undertaken with atezolizumab. 
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in 
mice and cynomolgus monkeys to support intravenous (IV) administration and to aid in 
projecting the appropriate starting dose in humans. Given the similar binding of 
atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab.  
Refer to the atezolizumab (MPDL3280A) Investigator’s Brochure for details on the 
nonclinical studies. A brief summary is provided below. 
1.2.1.1 
Nonclinical Pharmacology 
Several in vitro studies have been conducted to characterize the binding of atezolizumab 
to its target PD-L1, as well as its ability to block the binding of this glycoprotein to its 
known receptors PD-1 and B7-1. 
In more detail, equilibrium binding analysis demonstrated that atezolizumab binds to 
human and murine PD-L1 expressed on transfected 293 cells with sub-nanomolar 
affinities (Kd  0.433 nM and 0.134 nM, respectively). These high affinities were 
confirmed in flow cytometry experiments with use of human T cells and murine 
PD-L1expressing 293 cells, showing 50% effective concentrations (EC50) of 
0.395  0.030 nM and 0.519  0.025 nM for human and mouse, respectively. 
A comparable affinity to PD-L1 was determined in cynomolgus monkey T cells 
(EC50  0.704  0.084 nM). 
Furthermore, atezolizumab blocked binding of human recombinant PD-L1 to its target 
receptor PD-1 (50% inhibitory concentration [IC50]  82.8  40.3 pM) and to B7-1 
(IC50  48.4  25.9 pM), as measured by an enzyme-linked immunosorbent assay 
(ELISA). 


 
Atezolizumab 
Protocol ML29640, Version 11 
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Finally, atezolizumab-dependent cytokine release from human peripheral blood 
mononuclear cells (PBMCs) was not detected following in vitro culture with immobilized 
or soluble atezolizumab at concentrations approximately 750-fold above the expected 
maximum observed concentration at the proposed starting dose, suggesting that the risk 
for exaggerated cytokine release associated with atezolizumab administration is low. 
1.2.1.2 
Nonclinical Pharmacokinetics 
The pharmacokinetics of atezolizumab were characterized following a single IV dose of 
0.5, 5, and 20 mg/kg in cynomolgus monkeys (Study 08-0598). The PK properties of 
atezolizumab were typical for IgG1 antibodies in cynomolgus monkeys. The mean 
plasma clearance (CL) was 3.70 mL/day/kg, the mean volume at steady state (Vss) was 
similar to that of the plasma volume (59.8 mL/kg), and the mean beta-phase half-life was 
11.5 days. 
The toxicokinetics of atezolizumab were characterized in the repeat-dose toxicology 
study in cynomolgus monkeys following multiple IV doses with a range of 550 mg/kg 
given weekly for a total of nine doses (Study 08-1148). Linear dose-dependent systemic 
exposures were observed up to Day 7 in all dosed groups.  
Human PK parameters were projected using the species invariant-time method [28], 
incorporating results from the single-dose PK study in cynomolgus monkeys (Study 08-
0598). The estimated mean CL value in humans was 1.98 mL/day/kg (range, 1.922.09 
mL/day/kg). The estimated mean elimination half-life in humans was 21.5 days (range, 
20.323.1 days). These parameters were used in calculating safety factors to support 
the starting dose in humans. 
The proposed starting dose of atezolizumab in humans was 0.01 mg/kg administered 
intravenously. This dose was adequately supported by the 8-week, nonclinical toxicology 
study in cynomolgus monkeys (Study 08-1148). With use of the no observed adverse 
effect level (NOAEL) of 5 mg/kg and a human CL value of 1.98 mL/day/kg, the exposure 
(area under the concentration-time curve [AUC])-based safety factor is 268-fold. The 
single-dose, body weight-normalized, dose-based safety factor at the proposed Phase I 
starting dose of 0.01 mg/kg is 500-fold, and the safety factor based on the body surface 
area (BSA)-normalized dose is approximately 160-fold. These safety factors were 
considered adequate to support the proposed Phase I starting dose of 0.01 mg/kg. 
The pharmacokinetics and toxicokinetics of atezolizumab were characterized in 
cynomolgus monkeys. Overall, the nonclinical pharmacokinetics observed for 
atezolizumab support the proposed Phase I study, including providing adequate safety 
factors for the Phase I doses. 
1.2.1.3 
Nonclinical Toxicology 
The toxicology program was designed to support IV administration of atezolizumab to 
patients up to every week for at least 2 months. The program included an 8-week, 


 
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repeat-dose study in cynomolgus monkeys, a 15-day exploratory study in mice, 
an in vitro hemolytic potential evaluation, and a tissue cross-reactivity analysis of human 
and cynomolgus monkey tissues. 
Atezolizumab was well tolerated in cynomolgus monkeys following IV doses of up to 
50 mg/kg for 8 weeks (total of nine doses). Minimal-to-mild arteritis/periarteritis was 
observed in 1 of 12 and 3 of 12 cynomolgus monkeys following administration of 15 and 
50 mg/kg atezolizumab, respectively. These findings were not present on Day 141, 
indicating apparent resolution during the recovery period. Spontaneous, sporadic 
arteritis/periarteritis has been observed in cynomolgus monkeys, suggesting that the 
monkeys may be predisposed to this form of autoimmune disorder [29]. 
Atezolizumab did not cause hemolysis of human or cynomolgus monkey erythrocytes 
at in vitro concentrations of up to 125 mg/mL (the highest testable concentration). 
In human tissues, biotin- atezolizumabspecific staining was detected in the placenta, 
lymph 
node, 
tonsil, 
and 
thymus. 
In 
cynomolgus 
monkey 
tissues, 
biotin-atezolizumabspecific staining was detected only in the lymph node. This staining 
is consistent with the reported expression of PD-L1 on lymphoid and nonlymphoid 
tissues [30, 31]. 
Taken together, the results of the toxicology program were consistent with the 
anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway and 
support entry into this Phase I trial in patients with locally advanced or metastatic solid 
tumors or hematologic malignancies. 
1.2.1.4 
Scientific Rationale 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with stage IV cancer [15, 32]. Therefore, 
immunomodulation represents a promising new strategy for cancer therapy resulting in 
improved anti-tumor activity. 
PD-L1 expression is prevalent in many human tumors (e.g., lung, ovarian, melanoma, 
glioblastoma multiforme, malignant lymphoma, multiple myeloma, and colon carcinoma), 
and elevated PD-L1 expression is often associated with a worse prognosis in patients 
with several cancers including renal cell carcinoma (RCC), melanoma, colorectal cancer 
(CRC), lung cancer, ovarian cancer, and others. Furthermore, in mouse tumor models, 
interruption of the interaction between PD-1 and PD-L1 resulted in anti-tumor effects [18, 
19]: single-agent activity of PD-L1 blockade in the syngeneic CRC model MC-38, 
expressing the foreign antigen ovalbumin, resulted in complete responses (CRs) in all 
animals tested in fewer than 2 weeks of treatment (unpublished Genentech data). 
Finally, reports from three Phase I clinical trials testing cancer therapies targeting the 
PD-L1/PD-1 
pathway 
have 
demonstrated 
activity 
in 
late-stage, 
standard-of-


 
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carerefractory patients with cancer. In a Phase I dose-escalation study of 207 patients 
treated with BMS-936559, an IgG4 antiPD-L1 monoclonal antibody, Brahmer et al. [33] 
observed a response rate of approximately 17% in patients with melanoma, 12% in 
patients with RCC, 10% in patients with nonsmall cell lung cancer (NSCLC), and 6% in 
patients with ovarian cancer. A Phase I dose-escalation study of 296 patients treated 
with nivolumab, an IgG4 antiPD-1 monoclonal antibody, reported a response rate of 
approximately 28% in patients with melanoma, 27% in patients with RCC, and 18% in 
patients with NSCLC [34]. In a Phase I study in which 17 patients were treated with 
CT-011, a humanized antibody interacting with PD-1, clinical benefit was observed in 
33% of patients, with one CR (non-Hodgkin’s lymphoma) and one major response (acute 
myelogenous leukemia) [35]. 
Atezolizumab targets PD-L1, thus inhibiting its interaction with the PD-1 receptor. 
In multiple mouse tumor models, comparable efficacy has been observed with the 
blocking of either the PD-1 receptor or the PD-L1 ligand. Atezolizumab was designed 
with an amino acid substitution that may reduce the incidence and severity of toxicities 
and potentially provide a greater therapeutic index. 
Collectively, these data provide a compelling rationale to test whether inhibition of the 
PD-L1/PD-1 pathway with a human antiPD-L1 IgG1 antibody with diminished effector 
function will result in an enhanced clinical benefit in patients with cancer. 
1.2.2 
Clinical Experience with Atezolizumab 
1.2.2.1 
Ongoing Clinical Studies 
Current studies of atezolizumab include an ongoing Phase Ia monotherapy study, three 
ongoing combination studies, and three Phase II studies in patients with solid tumors. 
Details of all ongoing studies may be found in the atezolizumab (MPDL3280A) 
Investigator’s Brochure. 
Phase Ia Study PCD4989g 
Study PCD4989g is a multicenter, first-in-human, open-label, dose-escalation study 
evaluating the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by IV infusion every 3 weeks to patients with locally 
advanced or metastatic solid malignancies or hematologic malignancies. Ongoing 
expansion cohorts are studying the efficacy in patients with pancreatic cancer, bladder 
cancer, breast cancer, esophageal cancer, prostate cancer, SCLC, malignant 
lymphoma, multiple myeloma, and other less common tumor types. 
Phase Ib Study GP28328 
Ongoing Phase Ib Study GP28328 is evaluating the safety and pharmacology of 
atezolizumab administered with bevacizumab alone (Arm A) or with bevacizumab plus 
leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX; Arm B) in patients with advanced 
solid tumors. Additional cohorts have been included to investigate atezolizumab in 


 
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combination with carboplatin plus paclitaxel, in combination with carboplatin plus 
pemetrexed, and in combination with carboplatin plus nab paclitaxel, pemetrexed, and 
cisplatin in patients with advanced or metastatic NSCLC. 
Phase Ib Study GP28384 
Ongoing Phase Ib Study GP28384 is evaluating the safety and pharmacology of 
atezolizumab administered in combination with vemurafenib in patients with previously 
untreated BRAFV600mutation positive metastatic melanoma. 
Phase Ib Study GP28363 
Ongoing Phase Ib Study GP28363 is evaluating the safety and pharmacology of 
atezolizumab administered in combination with cobimetinib (MEK inhibitor) in locally 
advanced or metastatic solid tumors. 
Phase II Study GO28625 (FIR) 
Ongoing, single-arm, Phase II Study GO28625 is evaluating the safety and efficacy of 
atezolizumab monotherapy in PD-L1positive patients with NSCLC. In particular, this 
study is evaluating whether archival or fresh tumor tissue is more predictive of response 
to atezolizumab. Safety and efficacy data are not yet available for this study.  
Phase II Study GO28753 (POPLAR) 
Study GO28753 is a randomized, open-label, Phase II study in patients with locally 
advanced or metastatic NSCLC who have failed a prior platinum-containing regimen. 
Patients in the control arm of Study GO28753 will receive docetaxel alone. Eligible 
patients will be enrolled regardless of PD-L1 status and will be stratified by PD-L1 
expression. The primary endpoint is OS for both the PD-L1positive population and the 
overall study population. 
Phase II Study GO28754 (BIRCH) 
Ongoing, single-arm, Phase II Study GO28754 is evaluating the safety and efficacy of 
atezolizumab monotherapy in PD-L1positive patients with NSCLC. Safety and efficacy 
data are not yet available for this study. 
Phase III Study GO28915 (OAK) 
Study GO28915 is a randomized, open-label, Phase III study in patients with locally 
advanced or metastatic NSCLC who have failed a prior platinum-containing regimen. 
Patients in the control arm of Study GO28915 will receive docetaxel alone. Eligible 
patients will be enrolled regardless of PD-L1 status and will be stratified by PD-L1 
expression. The primary endpoint is OS for both the PD-L1positive population and the 
overall study population. 
Phase II Study WO29074 
Ongoing Phase II Study WO29074 is evaluating the safety and efficacy of atezolizumab 
monotherapy or the combination of atezolizumab and bevacizumab versus sunitinib in 


 
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treatment-naïve patients with RCC. Safety and efficacy data are not yet available for this 
study. 
1.2.2.2 
Clinical Safety 
The presented safety data for atezolizumab have been derived mainly from the 
treatment of patients in Phase Ia Study PCD4989g. As of 10 May 2014, atezolizumab 
has been administered to approximately 775 patients with solid and hematologic 
malignancies. No dose-limiting toxicities (DLTs) have been observed at any dose level 
and no maximum tolerated dose (MTD) was established. Fatigue was the most 
frequently reported adverse event.  
Adverse Events 
The following safety data are from PCD4989g, in which atezolizumab is being used as 
single-agent therapy in patients with locally advanced or metastatic solid tumors or 
hematologic malignancies. In 412 treated patients, 97.1% reported an AE while on 
study. Of these AEs, 48.8% were Grade 1 or 2 in maximum severity on the basis of 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 
(NCI CTCAE v4.0). The most frequently observed AEs (occurring in  10% of treated 
patients) included fatigue, nausea, decreased appetite, pyrexia, dyspnea, diarrhea, 
constipation, cough, headache, back pain, vomiting, anemia, arthralgia, rash, insomnia, 
asthenia, abdominal pain, chills, pruritus, and upper respiratory tract infection.  
Grade  3 AEs were reported by 199 of 412 patients (48.3%). There were 51 patients 
(12.4%) who reported Grade  3 AEs that were assessed as related to study drug by the 
investigators. The most frequently reported related Grade  3 AEs included fatigue (5 
patients [1.2%]), increased alanine aminotransferase and increased aspartate 
aminotransferase (each reported in 4 patients [1.0%]), and asthenia, autoimmune 
hepatitis and hypoxia (each reported in 3 patients [0.7%]).  
Immune-Related Adverse Events 
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events have been closely monitored during the 
atezolizumab clinical program. These include potential dermatologic, hepatic, endocrine, 
and respiratory events as well as events of hepatitis/elevated liver function tests and 
influenza-like illness, which are considered potential adverse drug reactions associated 
with atezolizumab.  
For further details, see the atezolizumab (MPDL3280A) Investigator’s Brochure. 
1.2.2.3 
Clinical Activity  
As of the data cutoff of 19 September 2013 (dosing cutoff 8 August 2013), efficacy data 
are available for 301 patients treated in Phase Ia Study PCD4989g. Patients with 
multiple tumor types were included in the study, with the largest cohorts consisting of 
patients with NSCLC, RCC, and melanoma. In the overall efficacy-evaluable population, 


 
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the overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) was 19.3%. Objective responses with atezolizumab 
monotherapy were observed in a broad range of malignancies, including NSCLC, RCC, 
melanoma, bladder cancer, breast cancer, colorectal cancer, head and neck cancer, 
gastric cancer, and sarcoma. The majority of responses have been durable, with 78% of 
responses still ongoing. Overall, a total of 58 responders were identified with a median 
duration of response of 73.9 weeks.  
Preliminary results from Study PCD4989g suggest that PD-L1 expression in 
tumor-infiltrating immune cells is likely to be associated with response to atezolizumab. 
PD-L1 positivity is currently defined as discernible PD-L1 staining of any intensity in 
tumor-infiltrating immune cells covering  5% of the tumor, which is defined as an 
immunohistochemistry (IHC) score of 2 or higher (i.e., IHC 2 or IHC 3). The prototype 
diagnostic IHC assay used in Study PCD4989g was analytically validated at this 
threshold. In the overall cohort of efficacy-evaluable patients with a variety of tumor 
types in Study PCD4989g, patients with IHC 2 or IHC 3 had a higher ORR at 24.8% 
compared with 14.8% in patients with IHC 0 or IHC 1. 
For further details, see the atezolizumab (MPDL3280A) Investigator’s Brochure. 
1.2.2.4 
Clinical Pharmacokinetics and Immunogenicity 
On the basis of available preliminary PK data (0.03−20 mg/kg), atezolizumab appeared 
to show linear pharmacokinetics at doses ≥ 1 mg/kg. For the 1-mg/kg and 20-mg/kg 
dose groups, the mean apparent clearance (CL) and the mean volume of distribution at 
steady state (Vss) had a range of 3.20 to 4.44 mL/day/kg and 48.1 to 65.7 mL/kg, 
respectively, which is consistent with the expected PK profile of an IgG1 antibody in 
humans. The development of anti-therapeutic antibodies (ATAs) has been observed in 
patients in all dose cohorts and was associated with changes in pharmacokinetics for 
some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg). The development of 
detectable ATAs has not had a significant impact on pharmacokinetics for doses from 10 
to 20 mg/kg. Patients dosed at the 10, 15, and 20 mg/kg dose levels have maintained 
the expected target trough levels of drug despite the detection of ATAs. To date, no 
clear relationship between detection of ATAs and adverse events or infusion reactions 
has been observed. 
1.3 
STUDY RATIONALE 
Platinum-based chemotherapy such as carboplatin plus etoposide remains the current 
standard for advanced SCLC but the benefit from this therapy has reached a plateau 
(Table 1). While initial response rates are high, new strategies to maintain the response 
and prolong survival are needed. Tumor cell death after cytotoxic chemotherapy can 
reasonably be expected to expose the immune system to high levels of tumor antigens. 
Invigorating tumor-specific T-cell immunity in this setting by inhibiting PD-1/PD-L1 
signaling may result in deeper and more durable responses compared to standard 
chemotherapy alone.  


 
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Early efforts incorporating checkpoint inhibition in SCLC have been promising. A 
randomized Phase II trial compared six cycles of standard chemotherapy (carboplatin 
and paclitaxel) with two different schedules of ipilimumab, a CTLA-4 inhibitor in 103 
patients with SCLC. In the concurrent schedule, ipilimumab was given with cycle 1 to 4 
of chemotherapy followed by two doses of placebo; in the phased schedule, placebo 
was given with the first two cycles of chemotherapy and ipilimumab was added with 
cycle 3 to 6. Eligible patients were given maintenance ipilimumab or placebo every 12 
weeks until progression. The primary endpoint was immune relate progression free 
survival (irPFS). This trial noted an improvement in irPFS in patients treated with the 
phased ipilimumab schedule compared to chemotherapy alone (6.4 vs. 5.3 months, HR 
0.64, P=0.03) with a non-significant trend towards improvement in RR (57% vs. 49%) 
and OS (12.9 vs. 9.9 months) [36]. The CheckMate 032 explored an immunotherapy 
strategy in SCLC [27]. This phase I/II trial explored the activity of nivolumab with or 
without ipilimumab in patients with refractory small cell lung cancer. In the 40 patients 
who received nivolumab 3mg/kg every 2 weeks, the disease control rate was 38% with 
an acceptable toxicity profile. In addition, there were many patients who achieved a 
durable response. 
Combining standard chemotherapy with a PD-1/PD-L1 inhibitor holds great appeal in the 
treatment of SCLC. While this approach may be appropriate for many cancer types, 
SCLC may be particularly vulnerable to this treatment strategy. Early studies have 
suggested greater efficacy with agents targeting PD-1/PD-L1 in tumors that are more 
mutationally complex, such as those associated with tobacco use. SCLC has a strong 
association with tobacco use and indeed, genome-wide sequencing studies have 
consistently shown that SCLC carries one of the highest rates of non-synonymous 
mutations [37, 38]. In addition, atezolizumab has been safely combined with platinum 
based chemotherapy doublets in the treatment of NSCLC [39]. Thus, a combination of 
carboplatin, etoposide and atezolizumab may significantly improve outcomes in the 
treatment of SCLC. 
2. 
OBJECTIVES 
2.1 
PRIMARY 
 
PHASE I  
To evaluate the safety and tolerability of atezolizumab administered 
with carboplatin and etoposide. 
 
PHASE II 
To evaluate the hazard ratio (HR) for PFS according to modified RECIST 
v1.1 in patients receiving first-line carboplatin, etoposide and 
atezolizumab for ED-SCLC compared with patients receiving 
carboplatin and etoposide alone. 
 


 
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2.2 
SECONDARY 
 
To evaluate PFS with carboplatin, etoposide and atezolizumab compared to 
chemotherapy alone according to RECIST v1.1  
 
To evaluate the complete response rate with carboplatin, etoposide and 
atezolizumab compared to chemotherapy alone according to RECIST v1.1 
 
To evaluate ORR with carboplatin, etoposide and atezolizumab compared 
to chemotherapy alone according to RECIST v1.1  
 
To evaluate the HR for OS in patients receiving first-line carboplatin, 
etoposide and atezolizumab for ED-SCLC compared with patients receiving 
carboplatin and etoposide alone 
 
To evaluate the safety and tolerability of atezolizumab when given with 
carboplatin plus etoposide 
 
To evaluate the 6 month and 12 month survival with carboplatin, etoposide 
and atezolizumab compare to chemotherapy alone  
 
2.3 
EXPLORATORY 
 
To evaluate the ORR and PFS with atezolizumab alone in patients with ED-
SCLC who progress after initial therapy with carboplatin plus etoposide 
 
To evaluate the relationship between tumor biomarkers (including but not 
limited to PD-L1, PD-1 and others) as defined by IHC or quantitative 
reverse-transcriptase polymerase chain reaction (qRT-PCR) and efficacy 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label study with two parts, a Phase I study and a randomized Phase II 
study. This study will be conducted at approximately ten sites in the United States. 
Approximately 178 patients will be enrolled in this trial. 
3.1.1 Phase I 
The Phase I portion will assess the safety and tolerability of atezolizumab with 
carboplatin and etoposide. The first dose-level will employ carboplatin plus etoposide at 
standard doses with the recommended Phase II dose of atezolizumab determined for 
single agent use. Standard 3+3 rules will apply. If there are 0-1 DLTs, the cohort will be 
expanded to 6 patients. If 0-1 out of 6 patients experience a DLT, this will be the dose 
used in the randomized Phase II portion. If 2 or more patients develop a DLT from the 
first cohort, the dose of atezolizumab will be reduced. If there are 0-1 DLTs in this 
second cohort, the cohort will be expanded to 6 patients. If 0-1 out of these 6 patients 
experiences a DLT, this will be the dose used in the randomized Phase II portion. If 2 or 
more patients in this cohort develop a DLT, the combination will be deemed intolerable 
without further modification to the protocol. Carboplatin plus etoposide will be given for 4 
cycles and atezolizumab will be continued as long as patients are experiencing clinical 
benefit in the opinion of the investigator (i.e., in the absence of unacceptable toxicity or 
symptomatic deterioration attributed to disease progression) after an integrated 
assessment of radiographic data, biopsy results (if available), and clinical status. 


 
Atezolizumab 
Protocol ML29640, Version 11 
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3.1.2 Phase II 
The Phase II portion will assess the efficacy of carboplatin and etoposide with 
atezolizumab as compared to carboplatin and etoposide alone. The dose of carboplatin 
and etoposide given with atezolizumab will be established by the Phase I portion. 
Patients will be randomized in a 1:1 fashion to receive chemotherapy alone or with 
atezolizumab; there will be no placebo. Carboplatin plus etoposide will be given for 4 
cycles either alone or with atezolizumab and then patients in the experimental arm will 
receive atezolizumab alone until progression. At the time of progression, patients in the 
standard arm may receive atezolizumab alone until progression provided certain 
eligibility criteria are met. 
All patients will return to the clinic for an end of treatment visit within 30 days after the 
last dose of study treatment. All AEs will be recorded until 60 days after the last dose of 
study treatment or until initiation of another anti-cancer therapy, whichever occurs first. 
After this period, only ongoing serious AEs determined by the investigator to be 
treatment related will be recorded. Additionally, patients with unresolved AEs or 
abnormal laboratory values deemed to be related to study treatment may be contacted 
by telephone for follow up of these events. AEs will be graded according to NCI CTCAE 
v4.0. Patients who discontinue study treatment for reasons other than disease 
progression (e.g., toxicity) should continue to undergo scheduled tumor assessments 
approximately every 12 weeks until the patient dies, experiences disease progression, or 
initiates further systemic cancer therapy, whichever occurs first. Following completion 
and/or discontinuation of study treatment, all patients will be followed for survival. 
3.2 
RATIONALE FOR STUDY DESIGN 
The starting dose of atezolizumab in this study will be 1200 mg administered once every 
3 weeks (q3w). No DLTs have been encountered at this dose in ongoing studies. 
Simulations do not suggest any clinically meaningful differences in exposure following 
fixed dose or dose adjusted for weight [40]. 
Given that nonclinical and available Phase IA and IB data for atezolizumab have shown 
minimal overlap with the well defined safety profiles of cytotoxic chemotherapy agents 
including carboplatin, it is anticipated that a dose level at the single-agent MTD is an 
appropriate starting dose to evaluate the proposed treatment combination. Because 
standard therapy is effective, at least initially, carboplatin and etoposide will be 
administered at standard, published doses: carboplatin AUC 5 plus etoposide 100 mg/m2 
given intravenously on day 1 and days 1-3, respectively, q3w [11]. If this initial dose is 
not well tolerated, de-escalation of atezolizumab will commence. 
The ethical conduct of a study of cancer therapy requires that a patient has the 
opportunity to continue study treatment for as long as such treatment is effective and 
tolerable. Therefore, patients who comply with the requirements of the protocol, are 
tolerating study treatment, and have not developed progressive disease per modified 


 
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(during Phase II) RECIST v1.1 criteria will be offered dosing beyond the DLT 
assessment window, as described in Section 3.3. 
Based on prior combination studies, there is no expectation that atezolizumab will 
significantly alter the pharmacokinetics of carboplatin or etoposide. 
Development of a predictive diagnostic assay that enables prospective identification of 
patients with SCLC who are likely to respond to treatment with atezolizumab in 
combination with carboplatin plus etoposide may allow for preselection of patients likely 
to benefit from treatment with these regimens in future clinical studies. Preliminary 
results suggest that tumor expression of PD-L1 correlates with response to anti-PD-1 
therapy [41]. Archival paraffin-embedded tumor tissue will be used to assess PD-L1 
expression by IHC and qPCR assays. In addition, other potential predictive and 
prognostic markers that are related to PD-L1 activity, tumor immune biology, and type of 
disease may be analyzed. Patients who cannot provide a specimen may still be eligible, 
upon discussion with the Principal Investigator. Analysis of these specimens may help 
determine which marker is more predictive of potential response to atezolizumab. 
3.3 
DOSE ESCALATION 
3.3.1 Dose Escalation Rationale 
 
There will be no dose adjustments of atezolizumab, which will be given at a dose of 
1200 mg every 3 weeks, as dose reductions would not be expected to reduce toxicity.  
Ongoing studies of atezolizumab with platinum-based chemotherapy in patients with 
NSCLC have demonstrated tolerability with no overlapping toxicities. Because 
chemotherapy is effective in patients with SCLC, and because we expect the 
combination to be well tolerated, treatment will start with standard chemotherapy dosing. 
If this combination is poorly tolerated, we will de-escalate the doses of chemotherapy. 
Asymptomatic neutropenia or grade 3 neutropenic fever are often encountered with 
standard chemotherapy and can be prevented with the use of myeloid growth factors. 
These specific toxicities should not limit the dose of this regimen. Thus, if the DLTs at 
dose level 1 are related to asymptomatic neutropenia that resolves or grade 3 
neutropenic fever (with no other non-neutropenia related DLTs), patients will be enrolled 
to a cohort employing the same doses but mandating the use of G-CSF or pegylated G-
CSF.  
3.3.2 Phase I Dose Escalation Design 
Atezolizumab is planned to be tested at a flat dose of 1200 mg. Carboplatin will be given 
at a dose of AUC 5 and etoposide will be given at a dose of 100 mg/m2. Dose reduction 
of atezolizumab is not permitted. Dose de-escalation of carboplatin and etoposide, if 
necessary, will occur in accordance with the following rules: 


 
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 
A minimum of 3 patients will be initially enrolled in the first cohort. 
 
If 0-1 of the first 3 patients enrolled in the first cohort experiences a DLT, 3 additional 
patients (for a total of 6 evaluable patients) may be enrolled in that cohort. 
 
If fewer than one-third of the evaluable patients in the first cohort experiences a DLT 
(i.e., DLT in 0-1 of the 6 patients), the Phase I portion will be complete and this dose 
level will be used for the Phase II portion. 
 
If a DLT is observed in one-third or more of the patients in the first cohort (i.e., 2 or 
more of the 6 patients), the MTD will have been exceeded and dose de-escalation 
will commence. 
 
For dose level -1 and -2, evaluation will proceed in the same fashion as above. If 
dose level -2 exceeds the MTD, alternate dosing or schedules may be evaluated 
after consultation with the Principal Investigator and creation of a study amendment. 
Intra-patient dose escalation or re-escalation will not be allowed in this study. Patients 
will receive 4 cycles of chemotherapy plus atezolizumab followed by atezolizumab 
therapy until progression. In the event of intolerable toxicity, the investigator will have the 
option of discontinuing chemotherapy before cycle 4 and continuing treatment with 
atezolizumab alone, if the investigator feels the patient is deriving clinical benefit. 
3.3.3 Dose Levels 
Dose Schedule for Cohorts 
 
Dose 
 
Atezolizumab 
Carboplatin 
Etoposide 
Level 1 
1200 mg 
AUC 5 
100 mg/m2 
Level 1A* 
1200 mg 
AUC 5 
100 mg/m2 
Level -1 
1200 mg 
AUC 5 
80 mg/m2 
Level -2 
1200 mg 
AUC 4 
80 mg/m2 
Table 2. Dose schedules. Atezolizumab will be given on day 1, carboplatin will be 
given on day 1, etoposide will be given on days 1-3, and cycle length is 21 days. 
 
* If there are 2 or more patients with DLTs in Level 1 and at least one of the 
patient’s only DLTs were related to asymptomatic neutropenia or grade 3 
neutropenic fever, patients will then be enrolled to dose level 1A, where dosing is 
the same as in Level 1 but the use of G-CSF or pegylated G-CSF is mandated. If 
other DLTs are responsible for de-escalation, patients will be enrolled to level -1. 
Use of myeloid growth factors will stop once carboplatin and etoposide are 
complete (i.e., no myeloid growth factors will be mandated with atezolizumab 
alone). 
3.3.4 Definition of Dose-Limiting Toxicity (DLT) 
DLT is defined as one of the following toxicities occurring during the DLT assessment 
window (Days 1-21 of Cycle 1) that is at least possibly related to atezolizumab (see 
Section 6.6.2). Dose reductions or delays of carboplatin or etoposide will not, in 
themselves, constitute DLTs. 


 
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 
Grade > 4 neutropenia (ANC < 500/L) lasting > 7 days 
 
Grade > 3 febrile neutropenia 
 
Grade > 3 thrombocytopenia associated with acute hemorrhage 
 
Grade > 4 thrombocytopenia lasting > 7 days 
 
Any Grade > 3 non-hematologic or non-hepatic major organ adverse event, with the 
following exceptions: 
o Grade 3 nausea, vomiting, or diarrhea that resolves to Grade < 1 within 7 days of 
implementing maximal supportive care 
o Grade 3 skin rash that resolves to Grade < 2 within 7 days with appropriate 
supportive care 
o Grade 3 laboratory abnormality that is asymptomatic and also deemed by the 
investigator not to be clinically significant 
 
Grade > 3 hepatic toxicity lasting for > 48 hours with the following exception: For 
patients with Grade 2 AST, ALT, and/or alkaline phosphatase abnormalities at 
baseline, only an increase to > 8x the upper limit of normal (ULN) lasting > 48 hours 
will be considered a DLT. 
 
Any toxicity leading to a delay in treatment for > 3 weeks 
 
3.3.5 Patients Evaluable for Assessment of DLTs 
For patients enrolled in the dose-finding stage (the Phase I portion), DLTs will be 
assessed during the DLT assessment window (Days 1-21 of Cycle 1). Patients who 
withdraw or are withdrawn from the study prior to completing the DLT assessment 
window for any reason other than a DLT will not be considered evaluable for DLTs and 
will be replaced. 
3.4 
PHASE II DOSING 
Dosing for the Phase II portion will be determined by results from the Phase I dose 
escalation. 
In the experimental arm, patients will receive 4 cycles of chemotherapy plus 
atezolizumab followed by atezolizumab therapy alone as long as patients are 
experiencing clinical benefit. In the event of intolerable toxicity, the investigator will have 
the option of discontinuing chemotherapy before cycle 4 and continuing treatment with 
atezolizumab alone, if the investigator feels the patient is deriving clinical benefit. 
In the standard arm, patients will receive 4 cycles of chemotherapy alone and enter 
observation. At the time of progression, patients may receive atezolizumab, provided 
they continue to meet the eligibility criteria with respect to hematologic and end organ 
function, general exclusions, and exclusion criteria related to medications. Patients 
approved for treatment may receive atezolizumab as long as patients are experiencing 
clinical benefit. Patients must re-sign the main informed consent to acknowledge 
deferring standard treatment options that may exist in favor of initiating atezolizumab. 


 
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3.5 
SURVIVAL FOLLOW UP 
Following early discontinuation or completion of treatment, all patients will be followed 
for survival every 3 months via telephone calls, patient medical records, and/or clinical 
visits until death, loss to follow-up, or study termination by the Sponsor. 
3.6 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for statistical analysis (i.e., progression) 
or safety follow-up is received from the last patient, whichever occurs later. LPLV is 
expected to occur within 12 months after the last patient is enrolled.  
3.7 
OUTCOME MEASURES 
3.7.1 
Primary Efficacy Outcome Measure (Phase II) 
 
Progression-free survival (PFS), defined as the time from the first study treatment to 
the first occurrence of progression using RECIST v1.1 or death, whichever occurs 
first 
3.7.2 
Secondary Efficacy Outcome Measures 
 
Overall survival (OS), defined as the time from the first study treatment to death 
 
Survival at 6 months and 12 months  
 
Objective response, defined as a complete or partial response using RECIST v1.1 
 
3.7.3 
Safety Outcome Measures 
The safety and tolerability of atezolizumab administered in combination with carboplatin 
plus etoposide will be assessed using the following primary safety outcome measures: 
 
Incidence and nature of DLTs  
 
Incidence, nature, and severity of AEs and laboratory abnormalities graded per NCI 
CTCAE v4.0 
 
Additional safety outcome measures will include the number of cycles and the dose 
intensity of each component of the treatment regimen, as well as changes in vital signs 
and clinical laboratory test results during and following atezolizumab administration in 
combination with carboplatin and etoposide. 
3.7.4 
Exploratory Measures 
The following exploratory biomarker endpoints will be assessed when appropriate: 
 
Status of PD-L1 (and other exploratory markers) in tumor tissue 


 
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4. 
MATERIALS AND METHODS 
4.1 
STUDY POPULATION 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form (ICF) 
 
Ability and willingness to comply with the requirements of the study protocol 
 
Age  18 years. 
 
Histological or cytological diagnosis of ES-SCLC (Note: Extensive-stage disease is 
defined as disease beyond the ipsilateral hemithorax, mediastinum and ipsilateral 
supraclavicular area and including malignant pleural or pericardial effusion or 
hematogenous metastases) 
o Patients with mixed histology SCLC and NSCLC are permitted 
 
Representative tumor specimens in paraffin blocks (preferred) or at least 
10 unstained slides, with an associated pathology report, requested at any time 
prior to study entry. Tissue from core needle, punch, or excisional biopsy sample 
collection is preferred but slides from fine-needle aspiration, brushing, and lavage 
samples are acceptable. Patients without available tissue may still be eligible if 
permitted by the study PI. 
 
Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1): 
– 
ANC  1000 cells/L 
– 
WBC counts  2500/L 
– 
Lymphocyte count  500/L 
– 
Platelet count  100,000/L  
– 
Hemoglobin  9.0 g/dL (transfusion to meet this criterion is permitted) 
– 
Serum sodium > 120 mmol/L 
– 
Total bilirubin  1.5  ULN with the following exception:  
Patients with known Gilbert disease who have serum bilirubin 
level  3  ULN may be enrolled. 
– 
AST and ALT  3.0  ULN with the following exception: 
Patients with liver involvement: AST and/or ALT  5  ULN 
– 
Alkaline phosphatase  2.5  ULN with the following exception: 
Patients with liver or bone involvement: alkaline phosphatase  5  ULN 
– 
Serum creatinine  1.5  ULN or creatinine clearance  50 mL/min on the basis 
of the Cockcroft-Gault glomerular filtration rate estimation: 
(140  age)  (weight in kg)  (0.85 if female) 
72  (serum creatinine in mg/dL) 


 
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Protocol ML29640, Version 11 
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 
Measurable disease per RECIST v1.1 (see Appendix 6)  
 
Patients with asymptomatic CNS metastases are allowed 
 
For female patients of childbearing potential and male patients with partners 
of childbearing potential, agreement (by patient and/or partner) to use highly 
effective form(s) of contraception (i.e., one that results in a low failure rate [ 1% per 
year] when used consistently and correctly) and to continue its use for 6 months 
after the last dose of atezolizumab 
 
ECOG performance status of 0 or 1 (see Appendix 8) 
– 
Patients with ECOG performance status of 2, secondary to the underlying 
disease, may be enrolled in the Phase II portion of the study 
 
INR and aPTT  1.5  ULN 
– 
This applies only to patients who do not receive therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation (such as lowmolecular weight 
heparin or warfarin) should be on a stable dose. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry. 
 
Inability to comply with study and follow-up procedures 
 
Limited stage SCLC appropriate for definitive treatment with chemoradiation 
 
Prior systemic anti-cancer therapy for small cell lung cancer 
 
Prior palliative radiation therapy < 2 weeks prior to administration of study treatment 
or prior whole brain radiation therapy (WBRT) < 4 weeks prior to study treatment 
 
Symptomatic brain metastases (patients with asymptomatic brain metastases may 
be eligible provided other criteria are met) 
 
Leptomeningeal disease or carcinomatous meningitis 
 
Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL) or 
symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or 
denosumab (patients receiving bisphosphonate therapy or denosumab to prevent 
skeletal events and who do not have a history of clinically significant hypercalcemia 
are eligible, though patients receiving denosumab must be willing and eligible to 
receive bisphosphonates instead) 
 
Malignancies other than SCLC within 2 years prior to administration of study 
treatment with the exception of those with a negligible risk of metastases or death 
treated with expected curative outcome (such as adequately treated carcinoma in 
situ of the cervix or breast, basal or squamous cell skin cancer, or localized prostate 
cancer treated definitively) 
 
Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, fatty liver, and inherited liver disease 
 
Pregnancy, lactation, or breastfeeding 


 
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Protocol ML29640, Version 11 
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 
History or risk of autoimmune disease, including but not limited to systemic lupus 
erythematosus, 
rheumatoid 
arthritis, 
inflammatory 
bowel 
disease, 
vascular thrombosis 
associated 
with 
antiphospholipid 
syndrome, 
Wegener’s granulomatosis, 
Sjögren’s 
syndrome, 
Bell’s 
palsy, 
Guillain-Barré 
syndrome, 
multiple 
sclerosis, 
autoimmune 
thyroid 
disease, 
vasculitis, 
or 
glomerulonephritis 
– 
Patients with a history of autoimmune hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible. 
– 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen 
may be eligible. 
– 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
– 
Patients with psoriasis must have a baseline ophthalmologic exam to rule out 
ocular manifestations 
o Rash must cover less than 10% of body surface area (BSA) 
o Disease is well controlled at baseline and only requiring low potency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) 
o No acute exacerbations of underlying condition in the last 12 months (not 
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, 
retinoids, biologics, oral calcineurin inhibitors, high potency oral steroids) 
 
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing 
pneumonia 
(i.e., 
bronchiolitis 
obliterans, 
cryptogenic 
organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan 
– 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection 
– 
Patients with past or resolved hepatitis B infection (defined as having a 
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc 
[antibody to hepatitis B core antigen] antibody test) are eligible. 
– 
Patients positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV RNA. 
 
Active, clinically serious infections of NCI CTCAE v4.0 Grade 2 or higher within 
4 weeks prior to Cycle 1, Day 1  
 
Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction within the previous 3 months, 
unstable arrhythmias, or unstable angina. Patient with known coronary artery 
disease, congestive heart failure not meeting the above criteria, or known left 
ventricular ejection fraction less than 50% must be on a stable medical regimen that 
is optimized in the opinion of the treating physician 


 
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 
Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation 
of need for a major surgical procedure during the course of the study 
 
History of stroke or transient ischemic attack (TIA) within 6 months prior to Cycle 1, 
Day 1 
 
Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 
or anticipation that such a live attenuated vaccine will be required during the study 
– 
Influenza vaccination should be given during influenza season only 
(approximately October to March). Patients must not receive live, attenuated 
influenza vaccine (e.g., FluMist) within 4 weeks prior to Cycle 1, Day 1 or at 
any time during the study. 
 
 
Treatment with systemic immunostimulatory agents (including but not limited to 
IFN-, IL-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to 
Cycle 1, Day 1 
 
Prior treatment with antiPD-1, or antiPD-L1 therapeutic antibody or pathway 
targeting agents 
– 
Patients who have received prior treatment with antiCTLA-4 may be enrolled, 
provided the following requirements are met: 
 
Minimum of 12 weeks from the first dose of antiCTLA-4 and  6 weeks from 
the last dose 
 
No history of severe immune-related adverse effects from antiCTLA-4 
(CTCAE Grade 3 and 4) 
 
Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within 
five half-lives of the investigational product, whichever is longer) 
 
Treatment with systemic immunosuppressive medications (including but not limited 
to 
prednisone, 
cyclophosphamide, 
azathioprine, 
methotrexate, 
thalidomide, 
and antitumor necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1, Day 1 
– 
Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be 
enrolled. 
– 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) 
for patients with orthostatic hypotension or adrenocortical insufficiency is 
allowed. 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric 
or humanized antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies 
 
Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation 
 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 


 
Atezolizumab 
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contraindicates the use of an investigational drug or that may affect the interpretation 
of the results or render the patient at high risk from treatment complications 
 
4.2 
STUDY TREATMENT 
4.2.1 
Method of Treatment Assignment 
This is an open-label study with two parts, a Phase I study and a randomized Phase II 
study. 
For the Phase I portion, patients will be assigned to dose levels in the order in which 
they were enrolled. Upon completion of all screening evaluations, the site eligibility 
packet reviewed by the study coordinator. Upon approval, a patient number, cohort, and 
dose will be assigned for patients in the Phase I portion. 
For the Phase II portion, patients will be assigned to the standard arm (carboplatin plus 
etoposide) or the experimental arm (carboplatin, etoposide, plus atezolizumab) by 
stratified randomization via via Georgetown Lombardi Comprehensive Cancer Center 
Department of Biostatisics.  
4.2.2 
Study Drug: Atezolizumab 
Once marketing authorization is received commercial atezolizumab will be used and will 
not be provided by Genentech for “on label” studies. For studies done before marketing 
authorization and/or "out of label", atezolizumab will be provided free of charge by 
Genentech but switched to commercial drug once marketing authorization is received. 
Genentech will replace any atezolizumab drug that is not reimbursed. For studies done 
“out of label,” atezolizumab will be provided free of charge by Genentech. (This may also 
apply to other chemotherapeutic agents if the trial is a combination therapy trial. The 
Sponsor Investigator should discuss with other corporate sponsors.) The Sponsor 
Investigator of the study will ensure maintenance of complete and accurate records of 
the receipt, dispensation, and disposal or return of all study drug in accordance with 21 
Code of Federal Regulations (CFR), Part 312.57 and 312.62 and Genentech 
requirements. 
4.2.2.1 
Formulation 
Atezolizumab is provided in a single-use, 20-cc USP/Ph. Eur. Type 1 glass vial as a 
colorless-to-slightly-yellow, sterile, preservative-free, clear liquid solution intended for IV 
administration. The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution 
but may contain more than the stated volume to enable delivery of the entire 20 mL 
volume. The atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 
mM histidine acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8 (Phase III 
formulation). 
 
For further details, see the atezolizumab (MPDL3280A) Investigator’s Brochure. 


 
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4.2.2.2 
Dosage, Administration, and Storage 
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an 
average body weightbased dose of 15 mg/kg) administered by IV infusion q3w (21 [ 2] 
days). Atezolizumab will be delivered in infusion bags with IV infusion lines that have 
product contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 m in-line 
filters (filter membrane of polyethersulfone [PES]). No incompatibilities have been 
observed between atezolizumab and PVC or polyolefin infusion materials (bags or 
infusion lines).  
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. 
The initial dose of atezolizumab will be delivered over 60 ( 15) minutes. If the 
first infusion is tolerated without infusion-associated adverse events, the second infusion 
may be delivered over 30 ( 10) minutes. If the 30-minute infusion is well tolerated, 
all subsequent infusions may be delivered over 30 ( 10) minutes. For the first infusion, 
the patient’s vital signs (heart rate, respiratory rate, blood pressure, and temperature) 
should be determined within 60 minutes before, during (every 15 [ 5] minutes), and 
30 ( 10) minutes after the infusion. For subsequent infusions, vital signs will be collected 
within 60 minutes before and within 30 minutes after the infusion. Vital signs should be 
collected during the infusion only if clinically indicated. Patients will be informed about 
the possibility of delayed post-infusion symptoms and instructed to contact their study 
physician if they develop such symptoms. 
No steroid premedication will be allowed for the first dose of atezolizumab. 
Premedication may be administered for Cycles    2 at the discretion of the treating 
physician. The management of infusion-related reactions will be according to severity as 
follows: 
 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) infusion-related 
event, the infusion rate should be reduced to half the rate being given at the time of 
event onset. Once the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate. If tolerated, the infusion 
rate may then be increased to the original rate. 
 
In the event that a patient experiences a moderate infusion-related event 
(NCI CTCAE Grade 2) or flushing, fever, or throat pain, the infusion should be 
immediately interrupted and the patient should receive aggressive symptomatic 
treatment. The infusion should be restarted only after the symptoms have 
adequately resolved to baseline grade. The infusion rate at restart should be half of 
the infusion rate that was in progress at the time of the onset of the infusion-related 
event. 
 
For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), 
the infusion should be stopped immediately, and aggressive resuscitation and 
supportive measures should be initiated. Patients experiencing severe or 


 
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life-threatening infusion-related events will not receive further infusion and will be 
further managed as clinically indicated until the event resolves. 
 
For anaphylaxis precautions, see Appendix 9. 
Atezolizumab must be refrigerated at 2C  8°C (36F  46F) upon receipt until use. 
Atezolizumab vials should not be used beyond the expiration date provided by the 
manufacturer. No preservative is used in the atezolizumab drug product; therefore, each 
vial is intended for single use only. Vial contents should not be frozen or shaken and 
should be protected from direct sunlight. 
4.2.3 
Carboplatin and Etoposide 
4.2.3.1 
Formulation and Storage 
Please refer to the carboplatin (PARAPLATIN) and etoposide (ETOPOPHOS) Package 
Inserts for details on respective formulations and storage. Carboplatin and etoposide will 
be sourced commercially by individual study sites. Anti-emetic premedication with a 
5HT3 antagonist (such as ondansetron) 30 minutes prior to administration of 
chemotherapy is recommended, though sites should follow their institutional standard of 
care. The use of dexamethasone as a premedication is prohibited in Cycle 1. Use 
in subsequent cycles is strongly discouraged but may be permitted after discussion with 
the Principal Investigator. 
4.2.3.2 
Etoposide Dosing 
Etoposide will be dosed according to Table 1 for the Phase I portion and the dose for the 
Phase II portion will be determined by the Phase I study. Sites may follow their own 
institutional practice for determining the etoposide dose for obese patients and for dose 
adjustments in the event of patient weight changes. 
4.2.3.3 
Carboplatin Dosing 
Carboplatin will be dosed according to Table 1 for the Phase I portion and the dose for 
the Phase II portion will be determined by the Phase I study. The Calvert formula will be 
used to calculate the dose. Creatinine clearance will be capped at 125 ml/min when 
calculating carboplatin doses using the Calvert formula. 
4.2.4 
Administration 
The induction phase of the study will consist of four cycles of atezolizumab plus 
chemotherapy, with each cycle being 21 days in duration. On Day 1 of each cycle, all 
eligible patients will receive drug infusions in the following order: 
 
  
Atezolizumab → carboplatin → etoposide 
 
For Cycle 1, premedication administered for atezolizumab/placebo is not permitted. 
Patients should receive anti-emetics and IV hydration for platinum-based treatments 
according to the local standard of care and manufacturer’s instruction. However, 


 
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because of the immunomodulatory effects of steroids, premedication with steroids is not 
permitted with cycle 1. 
 
On Day 1 of scheduled infusions of atezolizumab, carboplatin and etoposide (Cycles 
1−4), study treatment should be administered in the following manner: 
 
1. Atezolizumab (omitted for patients in the Phase II portion randomized to 
chemotherapy alone) administered intravenously over 60 (± 15) minutes (for the 
first infusion, shortening to 30 [± 10] minutes for subsequent infusions) followed by 
 
2. Carboplatin administered intravenously over 30−60 minutes to achieve an initial 
target area under the concentration−time curve (AUC) of 5 mg/mL/min (Calvert 
formula dosing), followed by 
 
3. Etoposide (100 mg/m2) administered intravenously over 60 minutes. On Days 2 
and 3 of Cycles 1−4, etoposide (100 mg/m2) will be administered intravenously 
over 60 minutes. 
 
Chemotherapy may be administered in accordance with local standard of care in lieu of 
the suggested infusion times. If there is a significant difference between the protocol 
guidelines and institutional standard of care, contact the study PI. 
 
4.3 
CONCOMITANT AND EXCLUDED THERAPIES 
4.3.1 
Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation 
and the treatment discontinuation visit. 
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another 
H2 receptor antagonist, as per standard practice (for sites outside the United States, 
equivalent 
medications 
may 
be 
substituted 
per 
local 
practice). 
Serious 
infusion-associated 
events 
manifested 
by 
dyspnea, 
hypotension, 
wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 9). 
Systemic corticosteroids and TNF inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician. If feasible, alternatives to corticosteroids should be 
considered. Premedication may be administered for Cycles  2 at the discretion of the 
treating physician. The use of inhaled corticosteroids and mineralocorticoids (e.g., 
fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is 


 
Atezolizumab 
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allowed. Megestrol administered as appetite stimulant is acceptable while the patient is 
enrolled in the study.  
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as lowmolecular weight heparin or warfarin at 
a stable dose level), or other allowed maintenance therapy (see Section 4.1.2) should 
continue their use. Males and females of reproductive potential should use highly 
effective means of contraception.  
Prophylactic Cranial Irradiation (PCI) 
PCI is permitted but not mandated for patients. For patients in the phase II portion who 
are randomized to the experimental arm, PCI can be administered within 8 weeks of 
completion of chemotherapy at a total dose of 25 - 30 Gy in 10 fractions. Atezolizumab 
will continue every 21 days as scheduled but will be held for PCI. PCI should not begin 
within 2 weeks of atezolizumab administration. Upon completion of PCI, atezolizumab 
will resume at least 14 days after the last day of radiation. Patients will discontinue study 
treatment if there is evidence of CNS metastasis. 
4.3.2 
Excluded Therapy 
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited. This includes but is not limited to the 
following: 
 
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy (except for maintenance therapies outlined in 
Section 4.1.2 and Section 4.3.1 and except for PCI as outlined in Section 4.3.1) 
After Cycle 1, certain forms of radiotherapy may be considered for pain palliation 
if patients are deriving benefit (e.g., treatment of known bony metastases); 
atezolizumab administration may be suspended during radiotherapy. 
Patients experiencing a mixed response requiring local therapy (e.g., surgery, 
stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for control of 
three or fewer lesions may still be eligible to continue study treatment after 
discussion with the PI.  
 
It is strongly recommended that:  
 
Traditional herbal medicines not be administered because the ingredients of many 
herbal medicines are not fully studied and their use may result in unanticipated 
drug-drug interactions that may cause, or confound assessment of, toxicity 
 
The use of a RANKL inhibitor (denosumab) be discontinued during the study; 
this agent could potentially alter the activity and the safety of atezolizumab 
 


 
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Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte 
colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or 
pegfilgrastim) is prohibited with Cycle 1 except for patients enrolled on dose level 1A.  
Patients are not allowed to receive immunostimulatory agents, including but not limited 
to IFN-, IFN-, or IL-2, during the entire study. These agents, in combination with 
atezolizumab, could potentially increase the risk for autoimmune conditions. 
Patients should also not be receiving immunosuppressive medications, including but not 
limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide. These agents 
could potentially alter the activity and the safety of atezolizumab. Systemic 
corticosteroids and antiTNF agents may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab but may be administered at the discretion of the 
treating physician. If feasible, alternatives to these agents should be considered. 
In addition, all patients (including those who discontinue the study early) should not 
receive other immunostimulatory agents for 10 weeks after the last dose of 
atezolizumab. 
4.4 
GENERAL PLAN TO MANAGE SAFETY CONCERNS 
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (see Section 4.1.1 and Section 4.1.2) 
and close monitoring (as indicated below and in Section 4.8.1). See Section 6.7 for 
complete details regarding safety reporting for this study.  
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this trial (see 
Section 4.1.2). Results from the nonclinical toxicology studies with atezolizumab as well 
as the nonclinical/clinical data from other PD-L1/PD-1 inhibitors were taken into account. 
Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious AEs, defined and graded according to NCI CTCAE v4.0. Patients will be 
assessed for safety (including laboratory values) according to the schedule in 
Appendix 1. Patients will be followed for safety for 90 days following the last dose of 
study treatment or until receipt of another anticancer therapy, whichever comes first.  
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts (see 
Appendix 1 for the list and timing of study assessments). All SAEs and protocol-defined 
events of special interest (see Section 6.5.3 and Section 6.7.2.11) will be reported in an 
expedited fashion (see Section 6.7). In addition, investigators will review and evaluate 
observed AEs on a regular basis. 


 
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Patients who have an ongoing study treatmentrelated adverse event upon study 
completion or at discontinuation from the study will be followed until the event has 
resolved to baseline grade, the event is assessed by the investigator as stable, new 
anticancer treatment is initiated, the patient is lost to follow-up, the patient withdraws 
consent, or until it has been determined that study treatment or participation is not the 
cause of the AE. 
4.4.1 
Management of Specific Safety Concerns with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, may be used to determine a possible immunogenic etiology. 
Although most irAEs observed with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid 
potential major complications. Discontinuation of atezolizumab may not have an 
immediate therapeutic effect and, in severe cases, immune-related toxicities may require 
acute 
management 
with 
topical 
corticosteroids, 
systemic 
corticosteroids, 
mycophenolate, or TNF inhibitors. 
The primary approach to Grade 1 to 2 irAEs is supportive and symptomatic care with 
continued treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be 
withheld and oral and/or parenteral steroids administered. Recurrent Grade 2 irAEs may 
also mandate withholding atezolizumab or the use of steroids. Assessment of the 
benefit-risk balance should be made by the investigator, with consideration of the totality 
of information as it pertains to the nature of the toxicity and the degree of clinical benefit 
a given patient may be experiencing prior to further administration of atezolizumab. 
Atezolizumab should be permanently discontinued in patients with life-threatening irAEs. 
4.4.2 
Guidelines for Dosage Modification and Treatment Interruption 
or Discontinuation 
Reasons for dose modifications or delays, the supportive measures taken, and the 
outcome will be documented in the patient's chart and recorded on the eCRF. The 
severity of AEs will be graded according to the NCI CTCAE v4.0 grading system. 
 
For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator 
feels it is appropriate. For example, if a patient has Grade 1 asthenia at baseline that 
increases to Grade 2 during treatment, this will be considered a shift of one grade 
and treated as Grade 1 toxicity for dose-modification purposes. 
 
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 (i.e., atezolizumab, carboplatin or etoposide) and 
the dose of that component is delayed or modified in accordance with the guidelines 


 
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below, other components may be administered if there is no contraindication. If 
chemotherapy is being delayed, atezolizumab should be delayed to allow concurrent 
administration for patients in the experimental arm.  
 
When treatment is temporarily interrupted because of toxicity caused by 
atezolizumab, carboplatin and/or etoposide, the treatment cycles will be restarted 
such that the atezolizumab and carboplatin plus etoposide infusions remain 
synchronized. 
 
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. 
 
In the event of intolerable toxicity, the investigator will have the option of 
discontinuing chemotherapy before cycle 4 and continuing treatment with 
atezolizumab alone, if the investigator feels the patient is deriving clinical benefit. 
 
The treating physician 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. 
Modification of the atezolizumab dose will not be permitted. Patients may temporarily 
suspend study treatment for up to 84 days beyond the scheduled date of delayed 
infusion if study drugrelated toxicity requiring dose suspension is experienced. If 
atezolizumab is held because of AEs for  84 days beyond the scheduled date of 
infusion, then the patient will be discontinued from atezolizumab and will be followed for 
safety and efficacy as specified in Section 6.6.1. 
Atezolizumab treatment will be given as long as the patient continues to experience 
clinical benefit in the opinion of the investigator until the earlier of unacceptable toxicity, 
symptomatic deterioration attributed to disease progression, or any of the other reasons 
for treatment discontinuation listed in Section 4.5. 
Any toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, may be used to determine a possible immunogenic etiology. 
Although most irAEs observed with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid 
potential major complications. Discontinuation of atezolizumab may not have an 
immediate therapeutic effect, and there is no available antidote for atezolizumab. 
In severe cases, immune-related toxicities may be acutely managed with topical 
corticosteroids, systemic corticosteroids, mycophenolate, or TNF inhibitors. 
Patients should be assessed clinically (including review of laboratory values) for toxicity 
prior to, during, and after each infusion. If unmanageable toxicity due to atezolizumab 


 
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occurs at any time during the study, treatment with atezolizumab should be 
discontinued. 
If a patient must be tapered off steroids used to treat adverse events, atezolizumab 
may be held for additional time beyond 84 days from the scheduled dose until steroids 
are discontinued or reduced to a prednisone dose (or dose equivalent)of  10 mg/day. 
The acceptable length of interruption will be at the discretion of the investigator. 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be 
allowed. The acceptable length of interruption will be at the discretion of the investigator. 
Management of hepatitis/transaminitis, colitis, rash, and hypothyroidism are presented 
later in this section as they have been observed in this study and are potentially immune 
related. See Section 4.3.1 for guidelines for the management of infusion-related 
reactions (see Appendix 9 for precautions for anaphylaxis). 
4.4.2.1 
Dose Modifications of Carboplatin and Etoposide 
Dose modifications of carboplatin and etoposide are allowed as described below. 
Patients should not begin a new cycle of treatment unless the ANC is > 1000 cells/mm3 
and the platelet count is > 100,000 cells/mm3. Patients who permanently discontinue 
combination carboplatin/etoposide chemotherapy for toxicity may still be considered for 
maintenance atezolizumab, depending on the nature of the toxicity and after discussion 
with the Principal Investigator. 


 
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Hematologic Toxicity 
Table 2 summarizes dose modifications for carboplatin and etoposide based on ANC 
and platelets. 
Table 3. Carboplatin and Etoposide Dosing Based on Hematologic Toxicity 
 
Etoposide dose 
(mg/m2/day) 
Carboplatin dose (AUC) 
Febrile neutropenia  
75% of previous dose 
Decrease previous AUC by 1.5
ANC < 1.0 
Hold chemotherapy until 
ANC ≥ 1.5 then resume at 
75% of previous dose if 
recurs then reduce to 50% 
of initial dose 
Hold chemotherapy until ANC 
≥ 1.5 and then decrease 
previous AUC by 1.5 
Nadir platelets < 
50,000/mm3 without 
bleeding 
Hold until platelets > 
100,000/ m3 then reduce to 
75% of previous dose 
Hold until platelets > 100,000/ 
m3 then decrease previous 
AUC by 1.5 
Nadir platelets < 
50,000/mm3 with 
bleeding 
Hold until platelets > 
100,000/ m3 then reduce to 
50% of previous dose 
Hold until platelets > 100,000/ 
m3 then decrease previous 
AUC by 1.5 
* Patients experiencing neutropenia-related toxicities as defined above will receive 
myeloid growth factor (G-CSF or pegylated G-CSF) on day 4 or 5 of the subsequent 
cycle and maintain the original doses. If any neutropenia-related toxicities recur with 
subsequent cycles, the dose reductions listed above will be employed. Use of myeloid 
growth factors will stop once carboplatin and etoposide are complete (i.e., no myeloid 
growth factors will be mandated with atezolizumab alone). If patients are receiving 
treatment on dose level 1A, which mandates G-CSF use, dose reductions above 
should be immediately employed. 
Dose reductions for neutropenia and/or thrombocytopenia are permanent. Patients who 
require a third dose reduction will permanently discontinue combination (carboplatin and 
etoposide) chemotherapy. Combination chemotherapy should also be discontinued if 
ANC and platelets do not recover to > 1000/L and > 100,000/mm3, respectively, after 
treatment is delayed by 3 weeks. For the Phase II portion, patients experiencing 
neutropenia-related toxicities as defined above will receive myeloid growth factor (G-
CSF or pegylated G-CSF) on day 4 or 5 of the subsequent cycle. If any neutropenia-
related toxicities recur with subsequent cycles, the dose reductions listed above will be 
employed. Use of myeloid growth factors will stop once carboplatin and etoposide are 
complete (i.e., no myeloid growth factors will be used with atezolizumab alone). 
In cases of anemia, no dose reductions are required. The investigator may use 
supportive transfusions, other measures or dose delays as deemed appropriate.  


 
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Non-Hematologic Toxicity 
If patients develop non-hematologic toxicities Grade > 3, treatment should be withheld 
until resolution to Grade < 2. Exclusions include alopecia and nausea and/or emesis 
controlled on adequate anti-emetic therapy. 
Table 4. Carboplatin and Etoposide Dosing Based on Non-Hematologic 
Toxicity  
 
NCIC-CTCAE v4.0 
Chemotherapy 
Grade < 2  
No dose adjustment required 
Grade 3 
Delay until grade < 2 then reduce by 1 dose level 
Grade 4 
Delay until grade < 2 then reduce by 1 dose level, 
consider permanent discontinuation of chemotherapy 
Dose reductions for Grade 3 or 4 non-hematologic toxicities are permanent. Patients 
who require a third dose reduction will permanently discontinue combination 
(carboplatin and etoposide) chemotherapy.  
 
4.4.2.2 
Gastrointestinal Toxicity 
Immune-mediated colitis has been associated with the administration of atezolizumab. 
Patients should be advised to inform the investigator if any diarrhea occurs, even if it is 
mild. 
If the event is of significant duration or magnitude or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased CRP or platelet count or 
bandemia), it is recommended that sigmoidoscopy (or colonoscopy, if appropriate) with 
colonic biopsy with three to five specimens for standard paraffin block be performed. If 
possible, one or two biopsy specimens should be snap frozen and stored.  
Treatment may be restarted following the resolution of colitis In addition, if the patient is 
being managed with corticosteroids, treatment should not be restarted until the steroids 
have been tapered down to a prednisone dose  10 mg/day. Patients who resume 
treatment should be monitored closely for signs of renewed diarrhea. Table  provides a 
summary of dose modification guidelines for gastrointestinal toxicities. 


 
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Table 5. Dose Modification Guidelines for Gastrointestinal Toxicity 
Toxicity 
Description 
Management 
Diarrhea 
Grade 2 (46 stools per 
day over baseline)  5 
days 
Hold atezolizumab and discontinue NSAIDS (or other 
medications known to exacerbate colitis). 
Investigate for etiology. Restart atezolizumab once at 
baseline stool frequency. 
Grade 2 (46 stools per 
day over baseline)  5 
days 
Hold atezolizumab and discontinue NSAIDS (or other 
medications known to exacerbate colitis) while 
etiology is being investigated. Consider referral to a 
gastroenterologist. 
Administer anti-diarrheal agent (e.g., Imodium). 
Consider oral budesonide, mesalamine, or 10 mg oral 
prednisone equivalent per day.  
Restart atezolizumab once at baseline stool 
frequency. 
Abdominal pain 
 
Blood or mucus in stool 
 
OR 
 
Grade  3 ( 7 stools/day 
over baseline) with 
peritoneal signs, ileus, or 
fever 
Hold atezolizumab and discontinue NSAIDS (or other 
medications known to exacerbate colitis). 
Rule out bowel perforation. Consider administering 
prednisone 60 mg/day or equivalent.  
Taper steroids over 1 month. Restart atezolizumab if 
diarrhea is resolved and systemic steroid dose is 
 10mg oral prednisone equivalent per day. 
 
Permanently discontinue atezolizumab for 
life-threatening immune-related diarrhea or colitis. 
TNF  tumor necrosis factor. 
  
4.4.2.3 
Hepatotoxicity 
Immune-mediated 
hepatitis 
has 
been 
associated 
with 
the 
administration 
of 
atezolizumab. 
While on this study, patients presenting with right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should have LFTs performed immediately and reviewed 
before administration of the next dose of study drug. 
If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies 
should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, 
and biliary tree should be performed to rule out neoplastic or other causes for the 
increased LFTs. Anti-nuclear antibody, perinuclear anti-neutrophil cytoplasmic antibody, 
anti-liver kidney microsomal, and antismooth muscle antibody tests should be 
performed if an autoimmune etiology is considered. 
Patients with LFT abnormalities should be managed according to the guidelines in 
Table . 


 
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Table 6. Dose Modification Guidelines for Hepatotoxicity 
Toxicity 
Description 
Management 
LFT abnormalities 
AST/ALT ( ULN to 
3  ULN) with total 
bilirubin  2  ULN 
Continue with the standard monitoring plan (i.e., 
LFTs every 3 weeks before dosing). 
AST/ALT ( 3  ULN to 
 10  ULN) with total 
bilirubin  2  ULN 
Continue atezolizumab. Monitor LFTs at least 
weekly. Consider referral to a hepatologist. 
AST/ALT  10  ULN 
Hold atezolizumab. Consider administering IV 
steroids for 2448 hours (prednisone 60 mg/day 
equivalent) followed by oral prednisone (or 
equivalent) taper over 24 weeks. If LFT results do 
not decrease within 48 hours after initiation of 
systemic steroids, addition of an alternative 
immunosuppressive agent (e.g., mycophenolate or 
TNF antagonist) to the corticosteroid regimen 
may be considered. Monitor LFTs every 4872 
hours until decreasing, and then follow weekly. 
Restart atezolizumab if AST/ALT  3  ULN with 
bilirubin  2  ULN and steroid dose is  10mg oral 
prednisone equivalent per day 
 
Permanently discontinue atezolizumab for life-
threatening immune-related hepatic events. 
 
AST/ALT  3  ULN 
with bilirubin 
 2  ULN 
Hold atezolizumab. Consult hepatologist. Consider 
administering IV steroids for 2448 hours 
(prednisone 60 mg/day equivalent) followed by oral 
taper over 1 month. If LFTs results do not decrease 
within 48 hours after initiation of systemic steroids, 
addition of an alternative immunosuppressive agent 
(e.g., mycophenolate or TNF antagonist) to the 
corticosteroid regimen may be considered. Monitor 
LFTs every 4872 hours until decreasing, and then 
follow weekly. Restart atezolizumab if AST/ALT 
 3  ULN with bilirubin  2  ULN and steroid dose 
is  10 mg oral prednisone equivalent per day. 
IV  intravenous; LFT  liver function test; TNF  tumor necrosis factor alpha; ULN  upper limit of 
normal. 
  
4.4.2.4 
Dermatologic Toxicity 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases 
of rash were mild in severity and self-limited, with or without pruritus. 
A dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy 
should be performed unless contraindicated. Low-grade rash and pruritus irAEs have 
been treated with symptomatic therapy (e.g., antihistamines). Topical or parenteral 
corticosteroids may be required for more severe symptoms. 


 
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Dermatologic toxicity and rash should be managed according to the guidelines in Table . 
Table 7. Dose Modification Guidelines for Dermatologic Toxicity 
Toxicity 
Description 
Management 
Dermatologic toxicity/rash 
(e.g., maculopapular or 
purpura) 
Grade 1 Mild 
 10% BSA 
Continue atezolizumab symptomatic 
therapy with antihistamine PRN. 
Consider topical steroids and/or 
other symptomatic therapy (e.g., 
antihistamines). 
Grade 2: Moderate  
10%30% BSA 
Continue atezolizumab. Consider 
dermatologist referral. 
Administer topical steroids. 
Consider higher potency topical 
steroids if rash unresolved 
Grade 3: Severe  
 30% BSA 
Hold atezolizumab. Consult 
dermatologist. Administer oral 
prednisone 10 mg or equivalent. If 
the rash is unresolved after 4872 
hours administer oral prednisone 
60 mg or equivalent. 
Restart atezolizumab if rash is 
resolved and systemic dose is 
 10mg oral prednisone equivalent 
per day 
Permanently discontinue 
atezolizumab for life-threatening 
immune-related dermatologic 
toxicity. 
BSA  body surface area; PRN  as needed. 
  
4.4.2.5 
Endocrine Toxicity 
Hypothyroidism has been associated with the administration of atezolizumab. 
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental 
status changes, or constipation should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies, as well as for hyponatremia or hyperkalemia. An 
endocrinologist 
should 
be 
consulted 
if 
an 
endocrinopathy 
is 
suspected. 
Thyroid-stimulating hormone (TSH) and free T4 levels should be obtained to determine 
whether thyroid abnormalities are present. TSH, prolactin, and a morning cortisol level 
will help to differentiate primary adrenal insufficiency from primary pituitary insufficiency. 
Hypothyroidism should be managed according to the guidelines in Table . 


 
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Table 8. Dose Modification Guidelines for Endocrine Toxicity 
Toxicity 
Description 
Management 
Hypothyroidism 
TSH elevated, asymptomatic 
Continue atezolizumab. Start 
thyroid replacement hormone. 
Monitor TSH weekly 
TSH elevated, symptomatic 
Hold atezolizumab. Consider 
referral to an endocrinologist. 
Restart atezolizumab when 
symptoms are controlled by 
thyroid replacement and TSH 
levels are decreasing  
TSH  thyroid-stimulating hormone. 
  
4.4.2.6 
Pulmonary Toxicity 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumaband have primarily been observed in 
patients with underlying NSCLC. 
Mild to moderate events of pneumonitis have been reported with atezolizumab. All 
pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia/infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension and the following should be performed: 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
 
High-resolution CT scan of the chest 
 
Bronchoscopy with bronchoalveolar lavage and biopsy 
 
Pulmonary function tests (with diffusion capacity of the lung for carbon monoxide 
[DLCO]) 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study. 
Patients will also have CT scans of the chest at every tumor assessment 
(see Section 4.8.1). 
Pulmonary toxicity should be managed according to the guidelines in Table . 


 
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Table 9. Dose Modification Guidelines for Pulmonary Toxicity 
Toxicity 
Description 
Management 
Pulmonary toxicity 
GGO or non-infectious 
infiltrate in absence of 
hypoxia, or dyspnea 
Hold treatment with atezolizumab. Re-
evaluate after 1 week. 
If no worsening in GGO/infiltrates and 
patient still asymptomatic resume 
treatment with atezolizumab. 
If GGO/infiltrates worsen and patient is 
still asymptomatic continue to hold 
atezolizumab and refer for 
bronchoscopy. Consider starting low-
dose oral prednisone 10 mg or 
equivalent. Re-evaluate after 1 week. 
Resume atezolizumab if GGO/infiltrates 
improving.  
Hypoxia or dyspnea in 
presence GGO or infiltrate 
without alternative etiology 
Hold atezolizumab. Consult a 
pulmonologist. Investigate for other 
etiologies and consider bronchoscopy. If 
bronchoscopy is consistent with immune-
related etiology, start 60 mg prednisone 
equivalent per day followed by taper over 
2 weeks.  
Restart atezolizumab if symptomatically 
improved, infiltrates are resolved, and 
steroid use is ≤ 10 mg prednisone 
equivalent per day. 
Permanently discontinue atezolizumab 
for life-threatening immune-related 
pulmonary events. 
GGO  ground glass opacities. 
  
4.4.2.7 
Pericardial and Pleural Effusions 
Pericardial and pleural involvement with associated effusions is common in patients with 
cancer and has the theoretical potential to be exacerbated by inflammation associated 
with anti-tumor immunity following PD-L1 blockade. Patients presenting with dyspnea, 
chest pain, or unexplained tachycardia should be evaluated for the presence of a 
pericardial effusion. Patients with preexisting pericardial effusion should be followed 
closely for pericardial fluid volume measurements and impact on cardiac function. When 
intervention is required for pericardial or pleural effusions, appropriate workup includes 
cytology, LDH, glucose, cholesterol, protein concentrations (with pleural effusions), and 
cell count. For patients with a pericardial effusion causing end-diastolic right ventricular 
collapse, treatment may be restarted following the placement of a pericardial window, 
demonstration of hemodynamic stability, and resolution of right ventricular dysfunction. 
4.4.2.8 
Potential Pancreatic Toxicity 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with administration of other 


 
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immunomodulatory agents. The differential diagnosis of acute abdominal pain should 
include pancreatitis. Appropriate workup should include an evaluation for obstruction, as 
well as serum amylase and lipase tests. 
4.4.2.9 
Potential Eye Toxicity 
An ophthalmologist should evaluate visual complaints. Uveitis or episcleritis may be 
treated with topical corticosteroid eye drops. Atezolizumab should be permanently 
discontinued for immune-mediated ocular disease that is unresponsive to local 
immunosuppressive therapy. 
Ocular toxicity should be managed according to the guidelines in Table . 
Table 10. Dose Modification Guidelines for Ocular / Eye Toxicity 
Toxicity 
Description 
Management 
Eye toxicity (autoimmune 
uveitis, iritis, or episcleritis) 
Symptomatic 
Hold atezolizumab. Consult ophthalmologist 
and start topical corticosteroid eye drops. 
Atezolizumab may be restarted following 
resolution of the events. 
Permanently discontinue atezolizumab for 
immune-mediated ocular disease that is 
unresponsive to local immunosuppressive 
therapy 
  
4.5 
PATIENT DISCONTINUATION 
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator determines may jeopardize the patient’s 
safety if he or she continues in the study 
 
Investigator determines it is in the best interest of the patient 
 
Patient non-compliance, defined as repeated non-compliance with study protocol 
 
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate CRF. However, patients will not be followed for any reason after consent has 
been withdrawn. Patients who withdraw from the study will not be replaced. 
See Section 4.8.1 and Section 4.8.2 for assessments that are to be performed for 
patients who prematurely withdraw from the study during the treatment period. 


 
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4.6 
STUDY TREATMENT DISCONTINUATION 
Patients must discontinue study treatment if they experience any of the following: 
 
Pregnancy 
 
Unmanageable toxicity due to atezolizumab 
 
Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status.  
 
Intolerable toxicity related to atezolizumab, including development of an irAE 
determined by the investigator to be unacceptable given the individual patient’s 
potential response to therapy and severity of the event  
 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment  
 
Use of another non-protocol anti-cancer therapy (except for PCI) 
 
Delay of atezolizumabdosing by > 84 days 
The primary reason for study treatment discontinuation should be documented on the 
appropriate CRF. Patients who discontinue study treatment prematurely will not be 
replaced. 
4.7 
STUDY AND SITE DISCONTINUATION 
The Sponsor Investigator or Genentech have the right to terminate this study at any 
time. Reasons for terminating the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
 
The Sponsor Investigator will notify Genentech if the Sponsor Investigator decides to 
discontinue the study, and vice versa.  
The Sponsor Investigator has the right to close a site at any time. Reasons for closing a 
site may include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
  


 
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4.8 
CLINICAL AND LABORATORY EVALUATIONS 
4.8.1 
Study Assessments 
Flowcharts of scheduled study assessments are provided in Appendix 1. Patients will be 
closely monitored for safety and tolerability throughout the study. All assessments must 
be performed and documented for each patient. 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date, with subsequent visits rescheduled accordingly. 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment. The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
4.8.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases within the previous 5 years, 
smoking history, cancer history, prior cancer treatments and procedures, and all 
medications used by the patient within 7 days before the screening visit (including 
prescription, over-the-counter, and herbal/homeopathic remedies and therapies). 
Demographic data will include age, ECOG performance status, sex, and self-reported 
race/ethnicity. 
4.8.1.2 
Vital Signs 
Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic 
blood pressures while the patient is in a seated position, and temperature. 
For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressure, 
and temperature) should be determined within 60 minutes before, during (every 
15 [ 5] minutes), and 30 ( 10) minutes after the infusion. For subsequent infusions, vital 
signs will be collected within 60 minutes before and within 30 minutes after the infusion. 
Vital signs should be collected during the infusion only if clinically indicated. Patients will 
be informed about the possibility of delayed post-infusion symptoms and instructed to 
contact their study physician if they develop such symptoms. 


 
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4.8.1.3 
Physical Examination 
A complete physical examination will be performed at screening and at the treatment 
discontinuation visit and should include the evaluation of head, eye, ear, nose, and 
throat and cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
and neurologic systems. 
A limited physical examination will be performed at other visits to assess changes from 
baseline abnormalities and any new abnormalities and to evaluate patient-reported 
symptoms. New or worsened abnormalities should be recorded as AEs if appropriate. 
As part of tumor assessments, a physical examination should also include the evaluation 
of the presence and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly. 
All patients should be monitored for symptoms of brain metastases. Symptoms 
suggestive of new or worsening CNS metastases should prompt a full neurological 
examination. A CT or MRI scan of the head should be done as clinically indicated to 
confirm or refute new or worsening brain involvement. 
4.8.1.4 
Tumor and Response Evaluation 
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRI of the chest, abdomen, and pelvis (when appropriate). If a CT 
scan for tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast 
diagnostic CT scan.  
Bone scans and CT scans of the neck should also be performed if clinically indicated. At 
the investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.  
For subsequent tumor assessments, procedures for tumor assessment should be 
performed as clinically indicated. The same radiographic procedure used to assess 
disease sites at screening should be used throughout the study (e.g., the same contrast 
protocol for CT scans) when possible. All known sites of disease must be documented at 
screening and reassessed at each subsequent tumor evaluation. Response will be 
assessed by the investigator using RECIST v1.1 and modified RECIST criteria (see 
Appendices 6 and 7). The same evaluator should perform assessments if possible to 
ensure internal consistency across visits. At the investigator’s discretion, CT scans 
should be repeated at any time if progressive disease is suspected.  
Scans will be performed every two cycles during the administration of chemotherapy and 
for the first 4 cycles (12 weeks) of maintenance atezolizumab for patients in the 
experimental arm, and every 6 weeks for patients in the standard arm and for the first 4 
cycles (12 weeks) of observation. Thereafter scans will be performed ever 9 weeks until 
disease progression or study discontinuation.  


 
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4.8.1.5 
Laboratory Assessments 
Samples for hematology, serum chemistries, coagulation, urinalysis, and the pregnancy 
test will be analyzed at the study site’s local laboratory. Local laboratory assessments 
will include the following: 
 
Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count) 
 
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, magnesium, 
chloride, 
bicarbonate, 
calcium, 
phosphorus, 
total 
bilirubin, 
ALT, 
AST, 
alkaline phosphatase, LDH, total protein, and albumin) 
 
Coagulation (aPTT and INR) 
 
Serum pregnancy test (for women of childbearing potential, including women who 
have had a tubal ligation) 
 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
 
Thyroid function testing (TSH, free T3, and free T4) 
 
EBV serology (EBNA IgG) 
 
HBV serology (HBsAg, antibodies against HBsAg, hepatitis B core antigen) 
– 
HBV DNA test is required for patients who have positive serology for anti-HBc  
 
HCV serology (anti-HCV) 
– 
HCV RNA test is required for patients who have positive serology for anti-HCV 
 
Auto-antibody testing 
– 
Anti-nuclear antibody 
– 
Antidouble-stranded DNA 
– 
Circulating anti-neutrophil cytoplasmic antibody 
– 
Perinuclear anti-neutrophil cytoplasmic antibody 
 
 
Archival tumor tissue sample 
Representative tumor specimens in paraffin blocks (preferred) or at least 10 
unstained slides, with an associated pathology report, are requested but not 
mandatory for enrollment of patients on study. In addition, exploratory 
biomarkers (including but not limited to markers related to immune or SCLC 
biology) may be evaluated. Tumor tissue should be of good quality based on 
total and viable tumor content. Instructions on tissue shipping will be provided 
at conclusion of the study. 
 
4.8.1.6 
Cardiac Function Tests 
Electrocardiograms 


 
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Twelve-lead ECG is required at screening and as clinically indicated. ECGs should be 
obtained on the same machine whenever possible. Lead placement should be as 
consistent as possible. ECG recordings should be performed after the patient has been 
resting in a supine position for at least 10 minutes.  
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site. Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF.  
Echocardiograms 
Echocardiograms will be obtained in patients with a known history of pericardial 
effusions during screening, Day 1 of Cycle 2, as clinically indicated or per standard of 
care thereafter during treatment, and at the treatment discontinuation visit.  
4.8.2 
Treatment Discontinuation Visit 
Patients who discontinue from treatment will be asked to return to the clinic not more 
than 30 days after the last treatment for a treatment discontinuation visit. The visit at 
which a response assessment shows progressive disease may be used as the treatment 
discontinuation visit. 
4.8.3 
Follow-Up Assessments 
All visits must occur within -2 or +7 days from the scheduled date unless otherwise noted 
(see Appendix 1). All assessments will be performed on the day of the specified visit 
unless a time window is specified. Assessments scheduled on the day of study 
treatment administration (Day 1) of each cycle should be performed prior to study 
treatment infusion unless otherwise noted.  
Please see the study flowchart provided in Appendix 1 for the schedule of treatment 
period assessments.  
The following assessments may be performed ≤ 96 hours before Day 1 of each cycle: 
ECOG performance status, limited physical examination, and local laboratory tests.  
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date 
with subsequent dosing continuing on a 21-day schedule. If treatment was postponed for 
fewer than 2 days, the patient can resume the original schedule.  
After concurrent chemotherapy with atezolizumab for patients in the experimental arm, 
one of three cycles may be delayed by 1 week (28 days instead of 21 days for one 
cycle) to allow for vacations.  


 
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4.8.4 
Post-Treatment Evaluations 
Patients who discontinue early from treatment or who complete the initial study 
treatment in full will be asked to return to the clinic not more than 30 days after the last 
treatment for a treatment discontinuation visit. The visit at which a response assessment 
shows progressive disease prompting patient discontinuation may be used as the 
treatment discontinuation visit.  
Please see the study flowcharts provided (see Appendix 1) for assessments to be 
performed at the treatment discontinuation visit.  
Female patients of reproductive potential must practice adequate birth control for a 
minimum of 12 months post-treatment. Male patients who are not surgically sterile must 
practice adequate birth control for a minimum of three months post-treatment. 
 
5. 
STATISTICAL CONSIDERATIONS 
The primary objective of the Phase I portion of this study is to establish the safety and 
tolerability of atezolizumab administered with carboplatin and etoposide. The primary 
objective of the Phase II portion of the trial is to evaluate the PFS according to RECIST 
v1.1 in patients receiving first-line carboplatin, etoposide and atezolizumab for ED-SCLC 
compared with patients receiving carboplatin and etoposide alone. The final study 
analysis will be based on patient data collected through study discontinuation. Analyses 
will be based on the safety-evaluable population, defined as all patients who receive any 
amount of study treatment. In general, data will be summarized as warranted, and 
listings will be provided in place of tables when sample sizes are small. All summaries 
will be presented by the assigned dose regimen and, where applicable, treatment arm. 
Kaplan-Meier estimates will be used to describe the PFS and OS distribution and 
logrank statistic will be used to compare the PFS and OS of patients receiving 
atezolizumab with carboplatin and etoposide and those receiving carboplatin and 
etoposide alone. The response rate and its confidence interval will be calculated using 
exact binomial calculation given the small sample size. The analysis of biomarkers will 
also be descriptive given the limited sample sizes.  
Analysis of the Conduct of the Study 
Enrollment and major protocol violations, study treatment administration, and reasons for 
patient discontinuations from the study will be described and listed or summarized. 
Demographic and baseline characteristics, such as age, sex, race/ethnicity, weight, and 
baseline ECOG performance status, will be summarized. 


 
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5.1 
SAFETY ANALYSES: ADVERSE EVENTS, LABORATORY TESTS, 
ECGS, AND VITAL SIGNS 
Safety will be assessed through summaries of DLTs, AEs, changes in laboratory test 
results, changes in vital signs and ECGs, and exposure to components of study 
treatment. All patients who receive any amount of study treatment will be included in the 
analyses. Verbatim descriptions of AEs will be mapped to thesaurus terms. AE data will 
be listed by study site, dose cohort, treatment arm, patient number, and study day. 
Events occurring on or after treatment on Cycle 1 Day 1 will be summarized by 
thesaurus term, appropriate thesaurus level, and NCI CTCAE v4.0 grade. Serious AEs, 
including deaths, will be listed separately and summarized.  
AEs leading to treatment discontinuation will be listed. AEs meeting the criteria for DLT 
will be listed. Patients who withdraw from the study prior to completing the DLT 
assessment window for reasons other than a DLT will be considered unevaluable for 
DLT assessments. 
Relevant laboratory and vital signs (heart rate, blood pressure, and temperature) and 
ECG data will be displayed by time, with NCI CTCAE v4.0 Grade 3 and 4 values 
identified where appropriate. Additionally, all laboratory data will be summarized by 
grade using NCI CTCAE v4.0. 
5.2 
ANTI-TUMOR ACTIVITY ANALYSES 
The analyses described below will be based on definitions of responses according to 
RECIST v1.1. Response assessment data, duration of objective response (for 
responders), and PFS will be listed for all patients with measurable disease by dose 
level (in the Phase I portion) and study arm (in the Phase II portion). 
Objective response is defined as a complete or partial response, as determined by 
investigator assessment using RECIST v1.1 and confirmed by repeat assessments > 4 
weeks after initial documentation. Patients with missing or no response assessments will 
be classified as non-responders. PFS will be defined as the time from study treatment 
initiation (Cycle 1 Day 1) to the first occurrence of documented disease progression or 
death from any cause during the study, whichever occurs first. For patients who do not 
have documented progressive disease or death during the study, PFS will be censored 
at the day of the last tumor assessment. OS is defined as the time from the first dose of 
study treatment to the time of death from any cause on study. 
5.3 
DETERMINATION OF SAMPLE SIZE FOR PHASE I 
The sample size for the Phase I portion will be determined by the dose-escalation rules 
described above. Any patient who does not complete the DLT assessment window for 
any reason other than a DLT will be considered non-evaluable for dose-escalation 


 
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decisions and MTD assessment and will be replaced by an additional patient at that 
same dose level. It will require a minimum of 6 and a maximum of 24 evaluable patients. 
Table 9 describes the probability of not observing any DLTs in 3 patients, and the 
probability of observing fewer than two DLTs in 6 patients for different underlying DLT 
rates. 
Table 11. Probability of Observing DLTs for Different Underlying DLT Rates 
Underlying 
DLT Rate 
Probability of Observing 
No DLTs in 3 Patients 
Probability of Observing 
Fewer Than Two DLTs in 6 
Patients 
0.10 
0.73 
0.89 
0.20 
0.51 
0.66 
0.30 
0.30 
0.36 
0.40 
0.22 
0.23 
0.50 
0.13 
0.11 
0.60 
0.06 
0.04 
 
For a given DLT with a true rate of 10%, 5%, or 1%, the probability of observing at least 
one such AE in a given cohort of 6 patients is 47%, 26.5%, and 5.8%, respectively.  
 
5.4 
DETERMINATION OF SAMPLE SIZE AND DATA ANALYSIS FOR 
PHASE II 
The primary endpoint of the Phase II portion is progression free survival (PFS). The 
sample size estimation is completed using the log-rank test with the stochastic 
curtailment/conditional power adjusted type II error for one futility analysis. With the 
proposed sample size of 160 (80 patients per arm), it provides  80% power to detect a 
2.7 months improvement of the PFS for the test arm, i.e. 8 months for carboplatin, 
etoposide and atezolizumab vs. 5.3 months for carboplatin and etoposide alone, with 
one-sided type I error = 5%. The total number of required events is 154. The 
assumptions of this power analysis are the accrual time is approximately 36 months and 
an additional follow-up time is about 18 months. 
Interim analysis: The interim analysis will be based on the stochastic curtailment 
method. One interim analysis for futility will be performed at 77 events by calculation of 
conditional power, an estimate of the probability that the study shows a statistically 
significant effect on the primary endpoint given the results to date and assumptions 
regarding outcome through the end of the study. A recommendation to stop the trial for 
futility will require a conditional power below 10%, under the observed efficacy trend at 
the time of interim analysis, at the one-sided type I error less than 5%. 
Data analysis plan for the primary endpoint: Demographic information such as age 
and race will be tabulated.  Descriptive statistics, including means, standard deviations, 
and ranges for continuous parameters, as well as percents and frequencies for 


 
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categorical parameters, will be presented.  Adverse medical events will be tabulated.  
NCI toxicity Grade 3 and Grade 4 laboratory abnormalities will be listed.   
For the univariate analysis, i.e., the primary analysis of comparing the progression free 
survival between two arms, the two study groups will be compared for survival with 
Kaplan-Meier estimates and log-rank tests (two-sided) upon observing the full 154 
events. When the test is used for claiming efficacy, the more stringent two-sided 
significance level of 5% will be used, namely, one-sided at 2.5%.  For the multivariable 
data analysis, the proportional hazard model will be used for adjusted tests of 
significance and estimates of hazard ratios. The strategy to be used for developing 
multivariable models involves the following steps: apply multiple imputation for missing 
covariate values to make good use of partial information; choose an appropriate 
statistical model based on the nature of the response variable; decide on the allowable 
complexity of the model (i.e., the number of covariates) based on the effective sample 
size available; allow for nonlinear predictor effects using regression splines; incorporate 
pre-specified interactions; check distributional assumptions; adjust the variance-
covariance matrix for multiple imputation; graphically interpret the model using partial 
effect plots; quantify the clinical utility (discrimination ability) of the model; internally 
validate the calibration and discrimination of the model using the bootstrap approach, 
i.e., .632+ bootstrap, to estimate the model's likely performance on a new set of 
subjects. 
There are four secondary objectives of this trial. 
1. To evaluate the response rate (RR) with carboplatin, etoposide and atezolizumab 
compared to chemotherapy alone according to RECIST v1.1,  
2. To evaluate the hazard ratio (HR) for overall survival (OS) in patients receiving 
first-line carboplatin, etoposide and atezolizumab for ED-SCLC compared with 
patients receiving carboplatin and etoposide alone, 
3. To evaluate the 6-month and 12-month survival in patients receiving carboplatin, 
etoposide and atezolizumab compared to chemotherapy alone, 
4. To evaluate the safety and tolerability of atezolizumab when given with 
carboplatin plus etoposide. 
 
Data analysis plan for the secondary endpoints: The Fisher’s exact test will be 
applied to study the association between two treatment arms and the response rate.  
The exact two-sided 95% confidence intervals (CIs) of the RR rate will be reported for 
each treatment arm. For lifetime data analyses, e.g., overall survival, the possible risk 
factors will be compared for survival with Kaplan-Meier estimates and log-rank tests.  
The proportional hazard model will be used for adjusted tests of significance and 
estimates of hazard ratio.  The 95% CIs for the 6-month and 12-month survival rate will 
be reported. The Fisher’s exact test as well as the Wilcoxon rank sum test will be applied 
to examine the correlation between the treatment arms and the toxicities outcomes. 


 
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The standard  reported OS is  10.9 months in the control arm (Spigel, JCO 2011).  There 
is 80% statistical power to show a median survival difference of 6 months or hazard ratio 
of 0.645. See Table below. 
Table1. Statistical determination of overall survival (OS) 
Sample 
size 
Alpha 
(one‐
sided) 
Power 
HR 
median 
OS in 
control 
group 
(months) 
median OS in 
treatment  
group 
(months) 
Improvement 
of OS 
(months) 
Expected 
Events in 
control 
group 
Expected 
Events in 
treatment 
group 
160  
0.05 
70% 
0.684
10.9
15.93
5.03
70 
62
160  
0.05 
80% 
0.645
10.9
16.89
5.99
70 
60
160 
0.05 
90% 
0.594
10.9
18.35
7.45
70 
58
 
The statistical analyses will be completed by either R 3.1.1 or SAS 9.4 statistical 
program in this project. 
5.5 
DATA QUALITY ASSURANCE 
The data will be collected via EDC through use of eCRFs. The site will be responsible for 
data entry into the EDC system. In the event of discrepant data, the CRO will request 
data clarification from the sites, which the sites will resolve electronically in the EDC 
system. The CRO will be responsible for the data management of this trial, including 
quality checking of the data. 
6. 
ASSESSMENT OF SAFETY 
This is an open-label study with two parts, a Phase I study and a randomized Phase II 
study. This study is the first trial in which atezolizumab will be administered to humans in 
combination with carboplatin plus etoposide. Nonclinical and Phase IA data for 
atezolizumab suggest that there is minimal overlap of the atezolizumab safety profile 
with the well-defined safety profiles of carboplatin plus etoposide. Specific potential 
safety issues anticipated in this trial, as well as measures intended to avoid, minimize, 
and manage such toxicities, are detailed in the protocol. Safety assessments will consist 
of monitoring and reporting AEs and SAEs that are considered related to atezolizumab, 
all events of death, and any study specific issue of concern. 
The definitions of DLT have been designed to keep the degree and frequency of severe 
toxicity observed in this study within acceptable limits for Phase I trials in oncology. As 
with any Phase I clinical trial, unpredicted safety issues may arise during the course of 
study. Eligibility criteria for this trial have been established to ensure the safety of 
participating patients. A number of exclusion criteria are specifically based on the well-


 
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established safety profiles of carboplatin plus etoposide as well as nonclinical and 
clinical data for atezolizumab. 
Safety will be evaluated in this study through the monitoring of all serious and non-
serious AEs and laboratory abnormalities, defined and graded according to NCI CTCAE 
v4.0. General safety assessments will include interval histories, physical examinations, 
and specific laboratory studies, including serum chemistry and blood counts. Grade 3 or 
4 AEs during the DLT assessment window and all SAEs will be reported in an expedited 
fashion to the Principal Investigator and to Drug Safety for entry into the safety 
database. In addition, the Sponsor and the investigators will review and evaluate 
observed AEs on a regular basis. 
The PD-1/PD-L1 pathway is involved in peripheral tolerance; therefore, such therapy 
may increase the risk of irAEs, specifically the induction or enhancement of autoimmune 
conditions. Although most irAEs observed with immunomodulatory agents have been 
mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications. Suggested workup procedures for suspected irAEs 
are included in the protocol.  
All patients will return to the clinic for an end of treatment visit within 30 days after the 
last dose of study treatment. All AEs will be recorded until 60 days after the last dose of 
study treatment or until initiation of another anti-cancer therapy, whichever occurs first. 
After this period, only ongoing SAEs determined by the investigator to be treatment 
related will be recorded. Additionally, patients with unresolved AEs or abnormal 
laboratory values deemed to be related to study treatment may be contacted by 
telephone for follow up of these events. 
6.1 
RISKS ASSOCIATED WITH ATEZOLIZUMAB 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy 
may increase the risk of irAEs, specifically the induction or enhancement of autoimmune 
conditions. Whereas the MTD was not reached in a Phase I clinical study of an antiPD-
1 monoclonal antibody (nivolumab) in patients with cancer, evidence of autoimmune 
conditions including pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis 
were reported [34]. Another Phase I clinical study of an antiPD-L1 monoclonal antibody 
(BMS-936559) reported drug-related AEs with potential immune-related causes 
including 
rash, 
hypothyroidism, 
hepatitis, 
adrenal 
insufficiency, 
sarcoidosis, 
endophthalmitis, diabetes mellitus, and myasthenia gravis [33]. As of 10 May 2014, AEs 
with 
potentially 
immune-related 
causes, 
including 
rash, 
hypothyroidism, 
hepatitis/transaminitis, and pneumonitis, have been observed. A more comprehensive 
list of observed AEs is provided in Section 1.2.2. 
Although most irAEs observed with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid 


 
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potential major complications [42]. Suggested workup procedures for suspected irAEs 
are provided in Section 4.4.  
Cynomolgus monkeys receiving weekly IV or subcutaneous doses of atezolizumab at 15 
or 50 mg/kg in a repeat-dose toxicity study had histologic evidence of 
arteritis/periarteritis in medium-sized arteries. This finding is consistent with a known 
spontaneous condition in this species and may reflect an underlying predisposition to 
this autoimmune condition. AntiPD-L1 therapy appears to have increased the incidence 
of this finding, which is compatible with the blocking of PD-L1 and the deregulation of 
peripheral tolerance. Of note, there were no apparent clinical sequelae of the arteritis in 
any of the animals. In addition, no toxicities were observed in cynomolgus monkeys that 
were given weekly IV doses of atezolizumab at 5 mg/kg (total nine doses). In an 
exploratory toxicology study in mice, findings attributed to atezolizumab were limited to 
minimal neuropathy of the sciatic nerve in C57Bl/6 mice at both doses tested (10 and 
50 mg/kg). This observation is consistent with the observation that female 
PD-1deficient mice develop autoimmune inflammation in multiple tissues, including 
peripheral nerves, whereas no such lesions were observed in age-matched 
PD-1sufficient mice [43]. No microscopic findings related to atezolizumab were 
observed in CD-1 mice, suggesting that this strain may not be predisposed to 
autoimmune inflammation under PD-L1 blockade. 
In an exploratory research study, mortality was observed in mice acutely infected with 
clone 13 variant of lymphocytic choriomeningitis virus (LCMV CL-13) when a chimeric 
derivative of atezolizumab was administered. However, additional data in the 
LCMV CL-13 acute infection model suggest that this mortality is not unique to this 
chimeric antibody or the inhibition of the PD-L1/PD-1 pathway, because similar 
mortalities were observed with other PD-L1 and PD-1 inhibitors, as well as with IL-2 
administration. Mortality was not observed in LCMV CL-13 chronically infected mice 
when a chimeric derivative of atezolizumab was administered. Additionally, PD-L1 
blockade did not result in mortality in other models of acute viral infections (LCMV 
Armstrong, adenovirus, or vaccinia). These data suggest that the coincident broad tissue 
tropism, the high, sustained viral burden, and the large LCMV-specific T-cell response, 
features that distinguish LCMV CL13 from known human infections, may account for the 
mortalities observed in LCMV CL13. Because of the potential risks associated with 
infections, the Phase I study will exclude patients with a history of HIV, hepatitis B, or 
hepatitis C (except for patients with HCC co-infected with HBV or HCV) or with or with 
evidence of significant active infection. Atezolizumab dosing will also be held for new 
clinically significant infections and may resume if the infection resolves within 42 days. 
Despite these potential risks, it should be noted that there is no reported evidence to 
date of an increased morbidity risk resulting from acute viral or bacterial infections in 
patients who have been treated with CT-011 or MDX-1106. There was no 
atezolizumab-dependent 
cytokine 
release 
detected 
following 
incubation 
with 
human PBMCs representing concentrations approximately 750-fold above the expected 


 
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maximum observed concentration at the proposed starting dose, suggesting that the risk 
for exaggerated cytokine release associated with atezolizumab administration is low. 
Refer to the atezolizumab (MPDL3280A) Investigator’s Brochure for additional details 
regarding the nonclinical studies. 
6.2 
RISKS ASSOCIATED WITH CARBOPLATIN 
Carboplatin is known to cause bone marrow suppression including myelosuppression, 
anemia, and thrombocytopenia. Carboplatin-based chemotherapy is considered to be 
moderately emetogenic. Patients will be monitored for carboplatin-related AEs. For more 
details regarding the safety profile of carboplatin, please refer to the carboplatin Package 
Insert. 
6.3 
RISKS ASSOCIATED WITH ETOPOSIDE 
Etoposide is known to cause bone marrow suppression including myelosuppression, 
anemia, thrombocytopenia, diarrhea, hepatotoxicity and alopecia. Etoposide-based 
chemotherapy is considered to be moderately emetogenic. Etoposide carries a small risk 
of secondary hematologic malignancy. Patients will be monitored for etoposide-related 
AEs. For more details regarding the safety profile of etoposide, please refer to the 
etoposide Package Insert. 
6.4 
POTENTIAL OVERLAPPING TOXICITIES 
The risk of overlapping toxicities between atezolizumab, carboplatin and etoposide is 
thought to be minimal. Nevertheless, the attribution and management of certain AEs that 
have been associated with each agent separately (e.g., hepatotoxicity, skin, and GI 
toxicity) may not be unambiguous when the agents are administered together. It is 
theoretically possible that allergic or inflammatory AEs associated with carboplatin and 
etoposide (e.g., dermatitis, infusion-associated symptoms) could be exacerbated by the 
immunostimulatory activity of atezolizumab. Toxicities should initially be managed 
according to the protocol, with dose holds and modifications (if applicable) applied to the 
component of the study treatment judged to be the primary cause. For severe (Grade 3) 
or persistent Grade 1/2 diarrhea, an endoscopic evaluation should be considered. 
Additional tests, such as autoimmune serology or biopsies, may be used to determine a 
possible immunogenic etiology for AEs listed above. If, in the opinion of the investigator, 
atezolizumab is a potential inciting factor, the dose of atezolizumab may be held for a 
maximum of 42 days beyond when next dose should have been given. Prompt 
symptomatic management is appropriate for mild IRAEs. In severe cases, immune-
related toxicities may be acutely managed with topical corticosteroids, systemic 
corticosteroids, or tumor necrosis factor-alpha inhibitors. 


 
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6.5 
SAFETY PARAMETERS AND DEFINITIONS 
6.5.1 
Overview 
Safety assessments will consist of monitoring and recording protocol-defined AEs and 
SAEs; measurement of protocol-specified hematology, clinical chemistry, and urinalysis 
variables; measurement of protocol-specified vital signs; and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug. 
The Principal Investigator is responsible for reporting relevant SAEs to the Competent 
Authority, other applicable regulatory authorities, and participating investigators, in 
accordance with ICH guidelines, FDA regulations, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements. Unexpected fatal or life-
threatening events associated with the use of the study drug will also be reported to the 
regulatory agencies and competent authorities by telephone or fax within 7 calendar 
days after being notified of the event. Investigators are responsible for reporting other 
relevant SAEs associated with the use of the study medication to their IRBs per local 
requirements by a written safety report within 15 calendar days of notification. 
6.5.2 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other protocol-
imposed intervention, regardless of attribution. 
This includes the following: 
 
AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated small cell lung cancer 
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. 
 
6.5.3 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
 
It results in death (i.e., the AE actually causes or leads to death). 
 
It is life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death.). 
 
It requires or prolongs inpatient hospitalization. 


 
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 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions). 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
All AEs that do not meet any of the criteria for serious should be regarded as 
nonserious AEs. The terms “severe” and “serious” are not synonymous. Severity refers 
to the intensity of an AE (as in mild, moderate, or severe pain); the event itself may be of 
relatively minor medical significance (such as severe headache). “Serious” is a 
regulatory definition and is based on patient or event outcome or action criteria usually 
associated with events that pose a threat to a patient’s life or vital functions. Seriousness 
(not severity) serves as the guide for defining regulatory reporting obligations. Severity 
and seriousness should be independently assessed when recording AEs and SAEs on 
the eCRF. 
6.5.4 
Dose-Limiting Toxicities 
AEs that meet the definition of a DLT (see Section 3.3.4) will be recorded on the AE 
eCRF. DLTs also meet the definition of an SAE or a protocol-defined event of special 
interest, and qualify for expedited reporting to the Sponsor (see Sections 6.7.2.11 and 
Section 6.7 for reporting instructions). Investigators will also participate in frequent 
teleconferences with the Sponsor during which they will report any DLTs observed 
during the DLT assessment window for each patient in the dose-escalation stage of the 
study. 
 
6.6 
METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES  
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 U.S. Food and Drug 
Administration (FDA), appropriate IRB(s), and Genentech, Inc./Roche in accordance 
with CFR 312.32 (IND Safety Reports).  
6.6.1 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is 
earlier. After this period, investigators should only report SAEs that are attributed to prior 
study treatment. 


 
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6.6.2 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to the study drug (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the atezolizumab, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the atezolizumab; and/or the AE abates or 
resolves upon discontinuation of the atezolizumab or dose reduction and, if 
applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the atezolizumab (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
atezolizumab administration (e.g., cancer diagnosed 2 days after first dose of study 
drug). 
 
Expected AEs are those AEs that are listed or characterized in the Package Insert or 
current Investigator Brochure.  
Unexpected AEs are those not listed in the Package Insert or current Investigator’s 
Brochure or not identified. This includes AEs for which the specificity or severity is not 
consistent with the description in the Package Insert or Investigator’s Brochure. For 
example, under this definition, hepatic necrosis would be unexpected if the Package 
Insert or Investigator’s Brochure only referred to elevated hepatic enzymes or hepatitis. 
6.7 
PROCEDURES FOR ELICITING, RECORDING, AND 
REPORTING ADVERSE EVENTS  
6.7.1 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all patient evaluation timepoints should be 
adopted. Examples of non-directive questions include:  
 
“How have you felt since your last clinical visit?” 
 
“Have you had any new or changed health problems since you were last here?”  
 
6.7.2 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 


 
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6.7.2.1 
Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a 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. 
6.7.2.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 6.6.1), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the single medical concept. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, report “Unexplained Death”. 
6.7.2.3 
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”). 
6.7.2.4 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE. If a patient is hospitalized to undergo a medical or surgical 
procedure as a result of an AE, the event responsible for the procedure, not the 
procedure itself, should be reported as the SAE. For example, if a patient is hospitalized 
to undergo coronary bypass surgery, record the heart condition that necessitated the 
bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for 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. 
 
6.7.2.5 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 90 days after the last 
dose of study drug. A Pregnancy Report Form should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) submitted to 


 
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Genentech/Roche Drug Safety. Pregnancy should not be recorded on the Adverse 
Event CRF. The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring of 
the patient should continue until conclusion of the pregnancy. Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event CRF. 
6.7.2.6 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
90 days after completing treatment with atezolizumab. Male patients who received study 
treatment should not attempt to father a child until end of study. A Pregnancy Report 
Form should be completed by the investigator immediately (i.e., no more than 24 hours 
after learning of the pregnancy) and submitted to Genentech/Roche Drug Safety. 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug. The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy. Once the authorization has been 
signed, the investigator will update the Pregnancy Report CRF with additional 
information on the course and outcome of the pregnancy. An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician. 
6.7.2.7 
Abortions 
Any spontaneous/therapeutic abortion should be classified as a serious adverse event 
(as Genentech considers spontaneous abortions to be medically significant events), 
recorded on the Adverse Event CRF, and reported to Genentech/Roche Drug Safety 
immediately (i.e., no more than 24 hours after learning of the event). 
6.7.2.8 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as an SAE, recorded on the 
Adverse Event CRF, and reported to Genentech/Roche Drug Safety immediately (i.e., 
no more than 24 hours after learning of the event). 
6.7.2.9 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has 
completed or discontinued study participation if attributed to prior atezolizumab 
exposure. If the investigator should become aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a female patient who 
participated in the study, this should be reported as an SAE.  


 
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6.7.2.10 
Safety Reconciliation 
The Sponsor Investigator agrees to conduct reconciliation for the product. Genentech 
and the Sponsor Investigator will agree to the reconciliation periodicity and format, but 
agree at minimum to exchange monthly line listings of cases received by the other party. 
If discrepancies are identified, the Sponsor Investigator and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall handle the 
matter on a case-by-case basis until satisfactory resolution. The sponsor shall receive 
reconciliation guidance documents within the ‘Activation Package’. 
6.7.2.11 
Adverse Events of Special Interest  
Protocol-defined events of special interest include SAEs and DLTs occurring during the 
DLT assessment window. For this protocol, “real-time” safety monitoring will be 
employed for DLT assessments and dose-escalation decisions. Investigators will be 
required to report all SAEs, DLTs, and Grade 3 or Grade 4 AEs to the Medical Monitor 
by e-mail or phone and via the EDC system within 24 hours of the event (see Section 
6.7.2.12 for instructions on expedited reporting). 
AEs of special interest (AESIs) are defined as a potential safety problem, identified as a 
result of safety monitoring of the IMP. The following events are events of special interest 
and will need to be reported to the Sponsor expeditiously (see Section 6.7.2.12 for 
reporting instructions) irrespective of regulatory seriousness criteria: 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies: e.g. diabetes mellitus, pancreatitis, thyroid dysfunction, adrenal 
insufficiency or hypothyroidism 
 
Hepatitis 
 
Transaminitis: AST or ALT  3  ULN and bilirubin  2  ULN or AST/ALT  10  ULN  
 
Systemic lupus erythematosus 
 
Guillain-Barré syndrome  
 
Myasthenia gravis 
 
Meningoencephalitis 
 
Nephritis 
 
Events suggestive of hypersensitivity, cytokine release, influenza like illness, SIRS, 
SIA (systemic inflammatory activation), or infusion-reaction syndromes 
 
Suspected Transmission of an Infectious Agent (STIAMP) by the study drug 
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 the study drug is suspected. 


 
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6.7.2.12 
Adverse Event Reporting 
Investigators must report all SAEs to Genentech/Roche and the Georgetown University 
IRB within the timelines described below. The completed MedWatch/case report should 
be submitted immediately via fax / E-mail to Genentech/Roche Drug Safety at: 
Email: welwyn.pds-pc@roche.com 
Fax: +44 1707 377 967/ 373 779/ 373 793/ 390 959  
 
The MedWatch/case report should also be faxed immediately to the Georgetown 
University IRB at: 
(202) 687-4847 
Relevant follow-up information should be submitted to Genentech/Roche Drug Safety 
and the Georgetown University IRB as soon as it becomes available. 
SAE, AESIs and Pregnancy reports whether related or unrelated to atezolizumab will be 
transmitted to Genentech/Roche within 24 hours of the Awareness Date. 
Additional reporting requirements to Genentech/Roche and the Georgetown University 
IRB include the following: 
 
All non-serious atezolizumab AEs originating from the study will be forwarded 
Genentech/Roche quarterly 
 
Note: Investigators should also report events to the Coordinating Site at the Georgetown 
Lombardi Comprehensive Cancer Center (Giuseppe Giaccone: email: 
gg496@georgetown.edu; Fax 202-687-0313) and to their local IRB as required. 
OR 
Any life-threatening (i.e., imminent risk of death) or fatal AE that is attributed by the 
investigator to the investigational product will be telephoned to the Principal Investigator 
immediately, followed by submission of written case details on an AE eCRF within 24 
hours. 
Principal Investigator Contact Information: 
Medical Monitor: Giuseppe Giaccone, M.D., Ph.D. 
Telephone No.: 202-687-7072 
 
Investigators will submit reports of all SAEs, regardless of attribution, and all protocol-
defined events of special interest to Genentech/Roche and the Georgetown University 
IRB within 24 hours of learning of the events. For initial SAE and protocol-defined events 
of special interest reports, investigators should record all case details that can be 
gathered within 24 hours on an AE eCRF and submit the report via the EDC system. A 
report will be generated and sent to Genentech/Roche Drug Safety by the EDC system. 


 
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In the event the EDC system is unavailable, a completed AE paper reporting form and 
fax 
coversheet 
should 
be 
submitted 
immediately 
upon 
completion 
to 
Genentech’s/Roche’s Drug Safety Department or its designee at the fax numbers or E-
mail address indicated below. Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system.  
E-mail: welwyn.pds-pc@roche.com 
Fax: +44 1707 377 967/ 373 779/ 373 793/ 390 959  
Relevant follow-up information should be submitted to Genentech’s Drug Safety 
Department or its designee as soon as it becomes available and/or upon request. 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (item 5) of the MedWatch 3500A form: 
 
Protocol description (and number, if assigned) 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the AE to each investigational 
product and suspect medication 
 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e., D.O.B. initial, patient number), protocol description and number, if 
assigned, brief AE description, and notation that additional or follow-up information 
is being submitted. (The patient identifiers are important so that the new information 
is added to the correct initial report.) 
Occasionally Genentech/Roche may contact the reporter for additional information, 
clarification, or current status of the patient for whom and AE was reported. For 
questions regarding SAE reporting, you may contact the Genentech Drug Safety 
representative noted above or the Medical Science Liaison assigned to the study. 
Relevant follow-up information should be submitted to Genentech/Roche Drug Safety as 
soon as it becomes available and/or upon request. 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 


 
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6.7.3 
Additional Reporting Requirements for IND 
For investigator-sponsored IND studies, some additional reporting requirements for the 
FDA apply in accordance with the guidance set forth in 21 CFR § 600.80. 
Events meeting the following criteria need to be submitted to the FDA as expedited IND 
Safety Reports according to the following guidance and timelines: 
Seven Calendar Day Telephone or Fax Report 
The investigator is required to notify the FDA of any fatal or life-threatening AE that is 
unexpected and assessed by the investigator to be possibly related to the use of 
atezolizumab. An unexpected AE is one that is not already described in the 
atezolizumab Investigator’s Brochure. Such reports are to be telephoned or faxed to the 
FDA and Genentech/Roche within 7 calendar days of first learning of the event. 
Fifteen Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably 
or possibly related to the use of atezolizumab. An unexpected AE is one that is not 
already described in the atezolizumab (MPDL3280A) Investigator’s Brochure.  
Written IND Safety reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32. All safety reports previously filed by the investigator 
with the IND concerning similar events should be analyzed and the significance of the 
new report in light of the previous, similar reports commented on. 
Written IND safety reports with analysis of similar events are to be submitted to the FDA, 
Genentech/Roche, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a MedWatch 3500 form, but 
alternative formats are acceptable (e.g., summary letter).  
Contact Information for IND Safety Reports 
FDA fax number for IND safety reports: 
Fax: (800) FDA-0178 
 
All written IND safety reports submitted to the FDA by the investigator must also 
be submitted via fax/e-mail to the following: 
E-mail: welwyn.pds-pc@roche.com 
Fax: +44 1707 377 967/ 373 779/ 373 793/ 390 959  
Site’s IRB: 202-687-1506 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 


 
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6.7.4 
IND Annual Reports 
Copies of all IND annual reports submitted to the FDA by the Sponsor-Investigator 
should be sent to Genentech/Roche Drug Safety via fax/E-mail at: 
E-mail: welwyn.pds-pc@roche.com 
Fax: +44 1707 377 967/ 373 779/ 373 793/ 390 959  
 
6.8 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be 
sent to Genentech. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
 
Atezolizumab (MPDL3280A) Protocols 
Email: anti-pdl-1-mpd3280a-gsur@gene.com 
Fax: (866) 706-3927 
 
7. 
ETHICAL CONSIDERATIONS 
7.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
Patients who comply with the requirements of the protocol, are tolerating study 
treatment, and may be receiving benefit will be offered dosing beyond Cycle 1 at the 
investigator’s discretion after a careful assessment and thorough discussion of the 
potential risks and benefits of continued treatment with the patient. Such patients may 
have the option to receive atezolizumab treatment as long as they continue to 
experience clinical benefit in the opinion of the investigator until the earlier of 
unacceptable toxicity, symptomatic deterioration attributed to disease progression, or 
any of the other reasons for treatment discontinuation listed in Section 4.5. 
This study will be conducted in accordance with the U.S. FDA regulations, the ICH E6 
Guideline for GCP, and applicable local, state, and federal laws, as well as other 
applicable country laws. 
7.2 
INFORMED CONSENT 
The informed consent document must be signed by the subject or the subject’s legally 
authorized representative before his or her participation in the study. The case history for 
each subject shall document that informed consent was obtained prior to participation in 
the study. A copy of the informed consent document must be provided to the subject or 
the subject's legally authorized representative. If applicable, it will be provided in a 
certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification by study monitors at any time. 


 
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7.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
APPROVAL 
This protocol, the informed consent document, and relevant supporting information must 
be submitted to the IRB for review and must be approved before the study is initiated. 
The study will be conducted in accordance with U.S. FDA, applicable national and local 
health authorities, and IRB requirements. 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate, but in any 
case the IRB must be updated at least once a year. The Principal Investigator must also 
keep the IRB informed of any significant adverse events. 
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected. This generally refers to serious adverse 
events that are not already identified in the Investigator Brochure and that are 
considered possibly or probably related to the molecule or study drug by the investigator. 
Some IRBs may have other specific adverse event requirements that investigators are 
expected to adhere. Investigators must immediately forward to their IRB any written 
safety report or update provided by Genentech (e.g., IND safety report, Investigator 
Brochure, safety amendments and updates, etc.). 
7.4 
CONFIDENTIALITY 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization to use and disclose personal health information) signed by the patient or 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local health 
authorities, Genentech monitors/representatives and collaborators, and the IRB/EC for 
each study site, if appropriate. 
8. 
STUDY MEDICAL MONITORING REQUIREMENTS 
This clinical research study will be monitored both internally by the PI and externally by 
the Georgetown University IRB. In terms of internal review, the PI will continuously 
monitor and tabulate adverse events. Appropriate reporting to the Georgetown 
University IRB will be made. The PI of this study will also continuously monitor the 
conduct, data, and safety of this study to ensure that: 
 
Interim analyses occur as scheduled; 
 
Stopping rules for toxicity and/or response are met; 


 
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 
Risk/benefit ratio is not altered to the detriment of the subjects; 
 
Appropriate internal monitoring of adverse events and outcomes is done; 
 
Over-accrual does not occur; 
 
Under-accrual is addressed with appropriate amendments or actions; 
 
 Data are being appropriately collected in a reasonably timely manner. 
 
Routine monitoring will be carried out via a periodic team conference among 
investigators during which toxicity data, including all SAEs, will be reviewed and other 
issues relevant to the study such as interim assessment of accrual, outcome and 
compliance with study guidelines will be discussed. Monitoring will be carried out on an 
ongoing basis. The severity, relatedness and whether or not the event is expected will 
be reviewed. 
8.1 
INVESTIGATOR REQUIREMENTS 
8.1.1 
Study Initiation 
Before the start of this study and any study-related procedures at a specific site, the 
following documents must be on file with Genentech or a Genentech representative: 
 
U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator. The 
names of any sub-investigators must appear on this form. Investigators must also 
complete all regulatory documentation as required by local and national regulations. 
 
Current curricula vitae and evidence of licensure of the Principal Investigator and all 
sub-investigators 
 
Complete financial disclosure forms for the Principal Investigator and all sub-
investigators listed on the U.S. FDA Form 1572 
 
Federal-wide Assurance number or IRB statement of compliance 
 
Written documentation of IRB approval of the protocol (identified by protocol number 
or title and date of approval) and Informed Consent Form (identified by protocol 
number or title and date of approval) 
 
A copy of the IRB -approved Informed Consent Form. A Clinical Research 
Agreement signed and dated by the study site 
 
Investigator’s Brochure Receipt signed and dated by the Principal Investigator 
 
Certified translations of an approved Informed Consent Form, and any other written 
information to be given to the patient (when applicable), IRB approval letters, and 
pertinent correspondence 
 
A Protocol Acceptance Form signed and dated by the Principal Investigator 
8.1.2 
Study Completion 
The following data and materials are required by Genentech before a study can be 
considered complete or terminated: 


 
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 
Laboratory findings, clinical data, and all special test results from screening through 
the end of the study follow-up period 
 
All laboratory certifications for laboratories performing the analysis (if other than 
Genentech-approved central laboratory), as well as current normal laboratory 
ranges for all laboratory tests 
 
eCRFs (including queries) properly completed by appropriate study personnel and 
electronically signed and dated by the investigator 
 
Completed Drug Accountability Records (Retrieval Record, Drug Inventory Log, and 
Inventory of Returned Clinical Material forms) 
 
Copies of protocol amendments and IRB approval/notification, if appropriate 
 
A summary of the study prepared by the Principal Investigator (IRB summary close 
letter is acceptable) 
 
All essential documents (e.g., curriculum vitae for each Principal Investigator and 
sub-investigator, U.S. FDA Form 1572 for each site) 
 
Signed and dated Protocol Amendment Acceptance Form(s), if applicable 
 
Updated financial disclosure forms for the Principal Investigator and all sub-
investigators listed on the U.S. FDA Form 1572 (applicable for 1 year after the last 
patient has completed the study) 
8.1.3 
Informed Consent Form 
A Sample Informed Consent Form will be provided to each site. Confirmation of IRB 
approval will be provided to Genentech. 
The Consent Forms must be signed by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history for each 
patient shall document the informed consent process and that written informed consent 
was obtained prior to participation in the study. A copy of each signed Consent Form 
must be provided to the patient or the patient’s legally authorized representative. If 
applicable, it will be provided in a certified translation of the local language. All signed 
and dated Consent Forms must remain in each patient’s study file and must be available 
for verification by study monitors at any time. 
The Informed Consent Form should be revised whenever there are changes to 
procedures outlined in the informed consent or when new information becomes available 
that may affect the willingness of the patient to participate. For any updated or revised 
Consent Forms, the case history for each patient shall document the informed consent 
process and that written informed consent was obtained for the updated/revised Consent 
Form for continued participation in the study. The final revised IRB-approved Informed 
Consent Form must be provided to Genentech for regulatory purposes.  
If the site utilizes a separate Authorization Form for patient authorization to use and 
disclose personal health information under the U.S. Health Insurance Portability and 
Accountability Act (HIPPA) regulations, the review, approval, and other processes 
outlined above apply except that IRB review and approval may not be required per study 
site policies. 


 
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8.1.4 
Communication with Institutional Review Board 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB by the Principal 
Investigator for review and approval before the study is initiated. In addition, any patient 
recruitment materials must be approved by the IRB. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB annually or more frequently in accordance with the regulatory 
requirements and policies and procedures established by the IRB. Investigators are also 
responsible for promptly informing the IRB of any protocol changes or amendments and 
of any unanticipated problems involving risk to human patients or others. In addition to 
the requirements to report protocol-defined AEs to the Sponsor, investigators are 
required to promptly report to their respective IRB all unanticipated problems involving 
risk to human patients. Some IRBs may want prompt notification of all SAEs, whereas 
others require notification only about events that are serious, assessed to be related to 
study treatment, and are unexpected. Investigators may receive written IND safety 
reports or other safety-related communications from Genentech. Investigators are 
responsible for ensuring that such reports are reviewed and processed in accordance 
with regulatory requirements and with the policies and procedures established by their 
IRB and archived in the site’s study file. 
8.1.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to 
the patient, a revised consent form might be required. The written amendment, and if 
required the amended consent form, must be sent to the IRB for approval prior to 
implementation.  
8.1.6 
Study Monitoring Requirements 
The Principal Investigator will permit Genentech monitors/representatives and 
collaborators, the U.S. FDA, other regulatory agencies, IRBs, and the respective national 
or local health authorities to inspect facilities and records relevant to this study 
8.1.7 
Electronic Case Report Forms 
All eCRFs should be completed by designated, trained examining personnel or the study 
coordinator as appropriate. The eCRF should be reviewed and electronically signed and 
dated by the investigator. In addition, at the end of the study, the investigator will receive 
patient data for his or her site in a readable format on a compact disc that must be kept 
with the study records. 


 
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8.1.8 
Source Data Documentation 
Study monitors will perform ongoing SDV to confirm that critical protocol data (i.e., 
source data) entered into the eCRFs by authorized site personnel are accurate, 
complete, and verifiable from source documents. Source documents are where patient 
data are recorded and documented for the first time. They include but are not limited to 
hospital records, clinical and office charts, laboratory notes, memoranda, patient diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in a clinical trial. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must never be obliterated or destroyed. To facilitate SDV, the 
investigator(s) and institution(s) must provide the Sponsor direct access to applicable 
source documents and reports for trial-related monitoring, Sponsor audits, and IRB 
review. The investigational site must also allow inspection by applicable regulatory 
authorities. 
8.1.9 
Use of Computerized Systems 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with FDA requirements pertaining to computerized systems used in clinical 
research. An acceptable computerized data collection system (for clinical research 
purposes) would be one that 1) allows data entry only by authorized individuals; 2) 
prevents the deletion or alteration of previously entered data and provides an audit trail 
for such data changes (e.g., modification of file); 3) protects the database from 
tampering; and 4) ensures data preservation. In collaboration with the study monitor, 
Genentech’s Quality Assurance group may assist in assessing whether electronic 
records generated from computerized medical record systems used at investigational 
sites can serve as source documents for the purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for the 
purposes of clinical research (as opposed to general clinical practice), applicable 
hardcopy source documents must be maintained to ensure that critical protocol data 
entered into the eCRFs can be verified. 
8.1.10 
Study Medication Accountability 
All study drug required for completion of this study will be provided by Genentech. The 
recipient will acknowledge receipt of the drug by returning the appropriate 


 
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documentation form indicating shipment content and condition. Damaged supplies will 
be replaced. 
Accurate records of all study drug received at, dispensed from, returned to, and 
disposed of by the study site should be recorded by using the Drug Inventory Log. Study 
drug will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to Genentech or designee with the 
appropriate documentation, as determined by the study site. If the study site chooses to 
destroy study drug, the method of destruction must be documented. Genentech must 
evaluate and approve the study site’s drug destruction standard operating procedure 
prior to the initiation of drug destruction by the study site. 
8.1.11 
Data Management and Monitoring 
The Principle Investigator and will conduct weekly safety monitoring with several co-
investigators. The investigators shall meet on a weekly basis to review toxicities and 
follow up on results of patients enrolled on the study. 
The Georgetown Lombardi Comprehensive Cancer Center (LCCC) will be responsible 
for the data and safety monitoring of this multi-site trial. As this study is an investigator 
initiated study utilizing an FDA approved agent, it is considered a moderate risk study 
which requires real-time monitoring by the PI and study team and semi-annual reviews 
by the LCCC Data and Safety Monitoring Committee (DSMC). 
The Principal Investigator and the Co-Investigators will review the data including safety 
monitoring at their weekly institution based disease group meetings and on monthly 
teleconferences.  
All SAEs are required to be reported to the IRB. Based on SAEs, the IRB retains the 
authority to suspend further accrual pending more detailed reporting and/or 
modifications to further reduce risk and maximize the safety of participating patients. 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data 
and Safety Monitoring Committee every 6 months from the time the first patient is 
enrolled on the study. Results of the DSMC meetings will be forwarded to the IRB with 
recommendations regarding need for study closure. 
DSMC recommendations should be based not only on results for the trial being 
monitored as well as on data available to the DSMC from other studies. It is the 
responsibility of the PI to ensure that the DSMC is kept apprised of non-confidential 
results from related studies that become available. It is the responsibility of the DSMC to 
determine the extent to which this information is relevant to its decisions related to the 
specific trial being monitored. 


 
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A written copy of the DSMC recommendations will be given to the trial PI and the IRB. If 
the DSMC recommends a study change for patient safety or efficacy reasons the trial PI 
must act to implement the change as expeditiously as possible. In the unlikely event that 
the trial PI does not concur with the DSMC recommendations, then the LCCC Associate 
Director of Clinical Research must be informed of the reason for the disagreement. The 
trial PI, DSMC Chair, and the LCCC AD for Clinical Research will be responsible for 
reaching a mutually acceptable decision about the study and providing details of that 
decision to the IRB. Confidentiality must be preserved during these discussions. 
However, in some cases, relevant data may be shared with other selected trial 
investigators and staff to seek advice to assist in reaching a mutually acceptable 
decision. 
If a recommendation is made to change a trial for reasons other than patient safety or 
efficacy the DSMC will provide an adequate rationale for its decision. If the DSMC 
recommends that the trial be closed for any reason, the recommendation will be 
reviewed by the Associate Director for Clinical Research at G-LCCC. Authority to close a 
trial for safety reasons lies with the IRB, with the above described input from DSMC and 
the AD for Clinical Research. 
8.1.12 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
8.1.13 
Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval.  
For any such emergency modification implemented, an IRB modification form must be 
completed within five (5) business days of making the change.  
8.1.14 
Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility criteria of this 
study requires the approval of the Principal Investigator and the IRB.  
8.1.15 
Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. According to the IRB, a protocol deviation is any unplanned 
variance from an IRB approved protocol that:  
Is generally noted or recognized after it occurs 
Has no substantive effect on the risks to research participants 
Has no substantive effect on the scientific integrity of the research plan or the value 
of the data collected  
Did not result from willful or knowing misconduct on the part of the investigator(s).  
An unplanned protocol variance is considered a violation if the variance: 


 
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Has harmed or increased the risk of harm to one or more research participants. 
Has damaged the scientific integrity of the data collected for the study. 
Results from willful or knowing misconduct on the part of the investigator(s). 
Demonstrates serious or continuing noncompliance with federal regulations, State 
laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, 
please follow the guidelines below: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by study personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems. 
8.1.15 
Disclosure of Data 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization to use and disclose personal health information) signed by the patient or 
unless permitted or required by law. Medical information may be given to a patient’s 
personal physician or other appropriate medical personnel responsible for the patient’s 
welfare for treatment purposes. Data generated by this study must be available for 
inspection upon request by representatives of the U.S. FDA and other regulatory 
agencies, national and local health authorities, Genentech monitors/representatives and 
collaborators, and the IRB for each study site, if appropriate. 
8.1.16 
Retention of Records 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 
4.9 of the guideline) require that records and documents pertaining to the conduct of this 
study and the distribution of investigational drug, including eCRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 2 years after the last marketing application approval in an ICH 
region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of the investigational product. All state and local laws for retention of 
records also apply. No records should be disposed of without the written approval of 
Genentech. Written notification should be provided to Genentech for transfer of any 
records to another party or moving them to another location.  
 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). Source documents include all recordings of 
observations or notations of clinical activities and all reports and records necessary for 
the evaluation and reconstruction of the clinical research study. Government agency 


 
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regulations and directives require that all study documentation pertaining to the conduct 
of a clinical trial must be retained by the study investigator. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for 
at least two years after the last approval of marketing application in an ICH region. In all 
other cases, study documents should be kept on file until three years after the 
completion and final study report of this investigational study. 
8.1.17 
Obligations of Investigators 
The PI is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The 
Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators 
and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study 
completion. 
 
The PI at each institution or site will be responsible for assuring that all the required data 
will be collected and entered onto the Case Report Forms. Periodically, monitoring visits 
will be conducted and the PI will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms 
will be reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
8.2 
STUDY MEDICATION ACCOUNTABILITY  
If study drug will be provided by Genentech, the recipient will acknowledge receipt of the 
drug by returning the INDRR-1 form indicating shipment content and condition. 
Damaged supplies will be replaced. 
Accurate records of all study drug dispensed from and returned to the study site should 
be recorded by using the institution’s drug inventory log or the NCI drug accountability 
log. 
All partially used or empty containers should be disposed of at the study site according 
to institutional standard operating procedure. Return unopened, expired, or unused 
study drug with the Inventory of Returned Clinical Material form as directed by 
Genentech. 
8.3 
DATA COLLECTION 
The study coordinator and investigators are responsible for ensuring that the eligibility 
checklist is completed in a legible and timely manner for every patient enrolled on study 
and that data is recorded on the appropriate forms and in a timely manner. Any errors on 
source data should be lined through, but not obliterated, with the correction inserted, 


 
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initialed and dated by the study coordinator or PI. All source documents will be available 
for inspection by the FDA and the Georgetown University IRB. 
8.4 
MULTI-INSTITUTION STUDY COORDINATION 
8.4.1   
Personnel 
At each site, personnel dedicated to this protocol will be: 
 
A study PI 
 
A research coordinator 
 
A data manager 
In addition, at Lombardi-Georgetown, there will be a dedicated “multi-institutional” 
research coordinator who will play the primary role in coordinating the trial between 
Lombardi-Georgetown and additional sites. This coordinator will be the main point of 
contact for the overall PI and the other site PIs for any study related concerns, and to 
screen each patient being considered for enrollment (Including “remote” screening for 
the patients being screened at other sites). This coordinator will also be the point of 
contact for the data managers for data entry questions. Finally, this coordinator will play 
a major role in regulatory coordination of the study, specifically by: 1) Reviewing and 
confirming all study-related adverse events; 2) Submitting all SAE reports to the 
Georgetown IRB (The research coordinators at the other sites will prepare SAE reports 
for patients treated at their respective sites, but the “multi-institutional” coordinator will 
submit the final report); 3) Gathering and preparing all primary source data for 
review/audit by Genentech. 
8.4.2.  Patient Enrollment 
Enrollment at the sites will be competitive. If a patient is being screened for enrollment, 
the local research coordinator must send an email within 24 hours containing the 
patient’s name, to the local PI, to the overall study PI, and to the multi-institutional 
coordinator. If a patient is successfully screened, the local research coordinator must 
send all supporting documentation to the multi-institutional research coordinator (by 
email or fax). Patients should not start therapy until both the overall study PI and the 
multi-institutional coordinator have reviewed the patient’s records and confirmed that the 
patient is eligible for enrollment. 
8.4.3.  Data Collection and Management  
Patient data will be entered into the on-line accessible database. This database is 
housed at Lombardi-Georgetown, but is accessible anywhere there is internet access. 
The data manager and research coordinator at each site will attend an on-line training 
session so that they may learn how to enroll data into the data base. All screening data 


 
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should be entered prior to starting therapy, and all ongoing patient data should be 
entered within one week of each patient visit.  
8.4.4 Conference Calls 
A monthly conference call will be held between Lombardi-Georgetown and the other 
sites to review patient enrollment, toxicity, and response assessment.  
8.4.5.  Trial Auditing 
Lombardi-Georgetown will provide trial auditing. The multi-institutional coordinator will 
arrange all primary source documents for the patients to be audited. This will include 
collecting copies of the primary source data for any patients treated at other sites. 
8.5 
 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 
4.9 of the guideline) require that records and documents pertaining to the conduct of 
clinical trials and the distribution of investigational drug, patient records, consent forms, 
laboratory test results, and medication inventory records, must be retained for 2 years 
after the last marketing application approval in an ICH region or after at least 2 years 
have elapsed since formal discontinuation of clinical development of the investigational 
product. All state and local laws for retention of records also apply.  
For studies conducted outside the U.S. under a U.S. IND, the Principal Investigator must 
comply with the record retention requirements set forth in the U.S. FDA IND regulations 
and the relevant national and local health authorities, whichever is longer. 
9. 
CORRELATIVE STUDIES 
Exploratory Biomarker Assessments 
There are several factors which may potentially predict clinical response to 
atezolizumab. We will systematically investigate these factors as described below. 
Tumor tissue will be collected and analyzed for exploratory biomarkers to assess 
correlation with clinical outcomes from study participants. Informed consent will be 
obtained from all patients. 
Tumor analysis 
Formalin-fixed paraffin-embedded (FFPE) archival tumor specimens will be acquired. If a 
patient has multiple archival tumor tissue samples, the most recently obtained tissue 
sample is preferred.  
A 
reference 
laboratory 
will 
receive 
the 
tumor 
samples 
and 
perform 
immunohistochemistry (IHC) using antibodies for PD-L1 and PD-L2. PD-L1 and PD-L2 


 
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status of both the tumor cells and the tumor infiltrating lymphocytes (TILs) will be 
quantified. In addition, the reference lab will perform IHC to characterize tumor infiltrating 
lymphocytes (TILs), including CD3, CD4, CD8, FoxP3, Granzyme B, PD-1, CD20, and 
CD68. The abundance of each protein(s) monitored will be correlated with clinical 
endpoints. Finally, a standard hematoxylin and eosin (H&E) stain will be obtained for 
each tumor sample to assess tumor histology, to quantify mitotic figures, and to evaluate 
for tumor necrosis.  
In addition, the Genentech Immunochip assay will be obtained for each tumor sample. 
This assay, which has been previously described [44] measures expression levels of 
~90 immune-related markers from paraffin. From this dataset, we hope to establish 
which gene(s) correlate with tumor response. An “inflammatory signature” (also called a 
“Th1 signature”) has previously been described to be important for response to 
atezolizumab in other tumor types [44]. 
FFPE tumor tissue may also be evaluated also by fluorescent in-situ hybridization 
(FISH), genetic mutation detection methods (such as targeted next generation 
sequencing, exome sequencing, and/or RNA sequencing), qPCR, epigenetic alterations 
detection methods (to determine gene methylation status), and/or proteomic studies 
(such as reverse phase protein array) as part of additional exploratory analyses of 
putative biomarkers thought to be associated with response or resistance. Such 
analyses will be completed retrospectively and within the scope of informed consent. 


 
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Appendix 1 
Study Flowchart 
 
Screeninga
Cycle 1 
Cycles > 2 
End of 
Treatment b 
Follow 
Up 
Assessment Window (days) 
-28 to -1 
1 
2 
3 
8 
15 
1 c
( + 2-7) 
15-21 
< 30 days after 
last dose 
 
Signed Informed Consent Form 
Xa
 
 
 
 
 
 
 
 
 
Review of eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Medical, surgical, and cancer histories including 
demographic information d 
X 
 
 
 
 
 
 
 
 
 
EBV, CMV, HBV, HCV serology e 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications f 
X 
X 
 
 
X 
X 
X 
 
X 
 
Tumor assessment 
X 
 
 
 
 
 
 
X 
X 
X 
Complete physical examination h 
X 
 
 
 
 
 
 
 
 
 
Limited physical examination i 
 
X 
 
 
X 
X 
X 
 
 
 
ECOG performance status 
X 
X 
 
 
X 
 
 
 
X 
 
Vital signs, height, weight j 
X 
X 
 
 
X 
X 
X 
 
X 
 
Echocardiogramk 
X 
 
 
 
 
 
X 
 
X 
 
12-lead electrocardiogram l 
X 
 
 
 
 
 
 
 
X 
 
Hematology m 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Serum chemistry n 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Coagulation panel (aPTT, INR) 
X 
 
 
 
 
 
 
 
X 
 
Serum pregnancy test o 
X 
 
 
 
 
 
 
 
 
 
TSH, free T3, free T4 
X 
 
 
 
 
 
 
 
X 
 
Auto-antibody testing p 
X 
 
 
 
 
 
X q
 
X 
 
Adverse events 
 
X 
 
 
X 
X 
X 
 
X 
X 
Atezolizumab administration 
 
X 
 
 
 
 
X 
 
 
 
Carboplatin administration r 
 
X 
 
 
 
 
X r
 
 
 
Etoposide administration s 
 
X 
X 
X 
 
 
X s
 
 
 
Archival tumor tissue specimen t 
X 
 
 
 
 
 
 
 
 
 
Survival follow up u 
 
 
 
 
 
 
 
 
 
X u
a. Written informed consent is required before performing any study-specific tests or procedures. Results of standard-of-care tests or examinations performed prior to 
obtaining consent and within 28 days prior to study entry may be used for screening assessments rather than repeating such tests. Screening local laboratory 
assessments obtained < 96 hours prior to Cycle 1, Day 1 do not have to be repeated for Cycle 1. Test results should be reviewed prior to administration of study treatment. 
b. Patients will be asked to return to the clinic 30 days after the last dose of study treatment for an end of treatment visit. After this visit, all adverse events (including serious 
adverse events and protocol-defined events of special interest), regardless of attribution, will be recorded until 90 days after the last dose of study treatment or until 
initiation of another anti-cancer therapy, whichever occurs first. Patients will be contacted at 60 and 90 days after the last dose of study treatment to determine if any new 
adverse events have occurred. Ongoing adverse events thought to be related to study treatment will be followed until the event has resolved to baseline grade, the event 
is assessed by the investigator as stable, new anti-cancer treatment is initiated, the patient is lost to follow up, the patient withdraws consent, or it is determined that the 
study treatment or participation is not the cause of the adverse event. Scans performed within 6 weeks prior to the end of treatment visit do not need to be repeated. 
c. The window for study treatment infusion on Cycle 2, Day 1 is + 2 days (not – 2 days). All subsequent Day 1 infusions and all examinations and labs may be administered 
with a window of -2 to +7 days. 


 
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d. Cancer history includes date of diagnosis, presence of brain metastases, and any prior radiation treatment. Demographic information includes age, sex, and self-reported 
race/ethnicity. 
e. HBV DNA must be collected prior to Cycle 1, Day 1 in patients who have a positive serology for the anti-HBc antibody 
f. Concomitant medications include any prescription or over-the-counter medications. At screening, any medications the patient has used within the 7 days prior to the 
screening visit should be documented. At subsequent visits, changes to current medications or medications used within the last documentation of medications will be 
recorded. 
g. Tumor assessments will be performed at the end of cycles 2, 4, 6, 8, 12 and 16 and as clinically indicated. Patients who discontinue study treatment for reasons other than 
disease progression (e.g. toxicity) should continue to undergo scheduled tumor assessments every 12 weeks until the patient dies, experiences disease progression or 
initiates further systemic anti-cancer therapy, whichever occurs first. All measurable and evaluable lesions should be assessed and documented using physical 
examination and image-based evaluation. Screening assessments should include CT scans with oral and intravenous contrast of the chest, abdomen, and pelvis, and a 
brain scan (CT or MRI with contrast). Bone scans and CT of the neck should also be performed if clinically indicated. If a PET/CT is performed, the CT portion of the study 
must be consistent with standards for a full-contrast CT scan and the CT scan must be used to measure lesions selected for response assessment. Disease status will be 
assessed using RECIST v1.1. Other methods of assessment of measurable disease according to RECIST may be used. The same radiographic procedure used to define 
measurable lesions at baseline must be used throughout the study for each patient. Results must be reviewed by the investigator before dosing at the next cycle.  
h. A complete physical examination at screening and the end of treatment visit should include the evaluation of head, eye, ear, nose, and throat and cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems. Changes in abnormalities noted at baseline should be recorded at the end of 
treatment visit. New or worsened abnormalities should be recorded as adverse events if appropriate. A limited physical examination will be performed at other visits to 
assess changes from baseline abnormalities and any new abnormalities to evaluate patient-reported symptoms. New or worsened abnormalities should be recorded as 
adverse events if appropriate. 
i. ECOG performance status, limited physical examination, and local laboratory assessments may be obtained < 96 hours prior to Day 1 of each cycle 
j. Vital signs include heart rate, blood pressure and temperature. For the first three infusions of atezolizumab, the patient’s vital signs should be determined up to 60 minutes 
before, during (every 30 [+ 5] minutes during 90 and 60 minute infusions only). And at the end of atezolizumab infusion. For subsequent infusions, vital signs are required 
to be obtained only before and after atezolizumab infusion if the prior infusion was tolerated without symptoms. Vital signs will also be recorded after the last infusion on 
each clinic day. Height is only required for the screening visit. 
k. Echocardiograms will be obtained in patients with a known history of pericardial effusions during screening, Day 1 of Cycle 2, then as clinically indicated or per standard of 
care thereafter during treatment, and at the treatment discontinuation visit 
l. Twelve-lead ECGs are required as part of the screening assessment and at the end of treatment visit. ECGs will be reviewed by the investigator to determine patient 
eligibility at screening. 
m. Hematology consists of CBC including hemoglobin, hematocrit, WBC count with automated or manual differential) and platelet count. 
n. Serum chemistry includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline 
phosphatase, lactate dehydrogenase, total protein and albumin. 
o. Serum pregnancy test (for women of childbearing potential, including women who have had tubal ligation) must be performed and documented as negative within 14 days 
prior to Cycle 1, Day 1.  
p. Includes anti-nuclear antibody, anti-double stranded DNA, circulating anti-neutrophil cytoplasmic antibody and perinuclear anti-neutrophil cytoplasmic antibody. 
q. On Day 1 of Cycle 3 and every 2 cycles thereafter 
r. Carboplatin will be given for only 4 cycles 
s. Etoposide will be given on days 1-3 of the first 4 cycles 
t. Archival tumor tissue specimen may be obtained from any prior tumor excision or biopsy performed during the course of the patient’s illness and does not need to be 
obtained during the 28 day screening window. 
u. Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death, loss to follow-up, 
or study termination by the Sponsor. All patients will be followed for survival unless the patient requests to be withdrawn from follow-up. This request must be documented 
in the source documents and signed by the investigator. If the patient withdraws from study treatment but not from follow-up, the study staff may use a public information 
source (e.g., county records) to obtain information about survival status only. 


 
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Appendix 2 
Calculation of Creatinine Clearance Using the 
Cockcroft-Gault Formula 
 
Creatinine Clearance (men)  (140-Age)  Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL)  72 
 
Creatinine Clearance (women)  0.85  (140-Age)  Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL)  72 
Reference: 
Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from 
adjusted serum creatinine (editorial). Nephron 1992;62:249. 
 


 
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Appendix 3 
Safety Reporting Fax Cover Sheet 
 
GENENTECH SUPPORTED RESEARCH 
AE/SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-4630 
 
Page 1 of ___ 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
Initial Report Date 
 
 
/ 
/ 
 
 
dd / mmm / yyyy 
Follow-up Report Date 
 
 
/ 
/ 
 
 
dd / mmm / yyyy 
Patient Initials 
(Please enter a dash if the 
patient has no middle name) 
____ - ____ -____ 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 
 


 
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Appendix 4 
FDA MedWatch 3500 Form 
This form is included in the study start-up zip file to be sent to sites via email. 
 


 
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Appendix 5 
Current NCI Common Terminology Criteria for 
Adverse Events (CTCAE) 
 
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


 
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Appendix 6 
Response Evaluation Criteria in Solid Tumors 
(RECIST) 
Modified Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
a. 
Measurable Tumor Lesions 
Tumor Lesions. Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum 
size of:  
 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater 
than 5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be  15 mm in the 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. See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement. 
b. 
Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm 
or pathological lymph nodes with  10 to  15 mm short axis), as well as truly 
non-measurable 
lesions. 
Lesions 
considered 
truly 
non-measurable 
include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable 
by 
reproducible 
imaging 
techniques.
                                            
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
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Protocol ML29640, Version 11 
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c. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions: 
 
Bone scan, positron emission tomography (PET) scan, or plain films are 
not considered adequate imaging techniques to measure bone lesions. However, 
these techniques can be used to confirm the presence or disappearance of 
bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such 
as CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
 
Target Lesions: Specifications by Methods of Measurements  
a. 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
b. 
Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study. 
Imaging-based evaluation should always be the preferred option. 
Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and  10 mm in diameter as assessed using calipers (e.g., skin nodules). 


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A9 
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested. 
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans 
with intravenous (IV) contrast due to allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease. For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible. Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward. Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The utilization of 
these techniques for objective tumor evaluation cannot generally be advised. 
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate 
the overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements. Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above. 


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A10 
Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up 
to a maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline. This means in instances where patients 
have only one or two organ sites involved, a maximum of two lesions (one site) 
and four lesions 
(two 
sites), 
respectively, 
will 
be 
recorded. 
Other 
lesions 
(albeit measurable) in those organs will be recorded as non-measurable lesions (even 
if the size is  10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, should 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 that can be measured reproducibly should 
be selected. 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor. As noted above, 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of  15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid tumor. 
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan, this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short 
axis. For example, an abdominal node that is reported as being 20 mm  30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 
mm should be recorded as the node measurement. All other pathological nodes (those 
with short axis  10 mm but  15 mm) should be considered non-target lesions. Nodes 
that have a short axis  10 mm are considered non-pathological and should not be 
recorded or followed. 
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 of diameters. If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum. The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, 
should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as “present,” 
“absent,” or in rare cases “unequivocal progression.” 


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A11 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
Response Criteria 
a. 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for 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 diameters of target 
lesions, taking as reference the baseline sum of diameters 
 
Progressive disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline 
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
 
Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study 
 
b. 
Special Notes on the Assessment of Target Lesions 
Lymph Nodes. Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to  10 mm on study. This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
 10 mm. 
Target Lesions That Become Too Small to Measure. While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure. When this occurs, it 
is important that a value be recorded on the CRF as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked. (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A12 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked.) 
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked. 
Lesions That Split or Coalesce on Treatment. When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may 
be maintained that would aid in obtaining maximal diameter measurements of 
each individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion. 
c. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol. 
 
CR: disappearance of all non-target lesions and (if applicable) normalization 
of tumor marker level) 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD: persistence of one or more non-target lesion(s) and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD: unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
 
d. 
Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare. 
When the Patient Has Only Non-Measurable Disease. This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease. 
The same general concepts apply here as noted above; however, in this instance, 
there is no measurable disease assessment to factor into the interpretation of an 
increase in non-measurable disease burden. Because worsening in non-target disease 


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A13 
cannot be easily quantified (by definition: if all lesions are truly non-measurable), 
a useful test that can be applied when assessing patients for unequivocal progression 
is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease, that is, an increase in tumor burden 
representing an additional 73% increase in volume (which is equivalent to a 
20% increase in diameter in a measurable lesion). Examples include an increase in 
a pleural effusion from “trace” to “large” or an increase in lymphangitic disease from 
localized to widespread or may be described in protocols as “sufficient to require a 
change in therapy.” If unequivocal progression is seen, the patient should be considered 
to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible 
to do so; therefore, the increase must be substantial. 
e. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions). This is particularly important when the patient’s baseline lesions show partial or 
complete response. For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
Evaluation of Response 
a. 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. 
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is 
to be used. 


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A14 
Table 1. Timepoint Response: Patients with Target Lesions (with or without Non-Target 
Lesions) 
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 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
 
Table 2. Timepoint Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised. 
 
b. 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response. This would be most likely 
to happen in the case of PD. For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and, during the study, only two lesions were assessed, but those 
gave a sum of 80 mm; the patient will have achieved PD status, regardless of the 
contribution of the missing lesion.  


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A15 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable. Similarly, if one or more non-target lesions are not assessed, the response for 
non-target lesions should be “unable to assess” except where there is clear progression. 
Overall response would be “unable to assess” if either the target response or the non-
target response is “unable to assess,” except where this is clear evidence of progression 
as this equates with the case being not evaluable at that timepoint. 
Table 3. Best Overall Response When Confirmation Is Required 
Overall Response at 
First Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
NE 
NE 
NE 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR). Best response would depend on whether the 
minimum duration for SD was met. However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
  
c. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size ( 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 


Appendix 6 Response Evaluation Criteria in Solid Tumors 
(RECIST) (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A16 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy. The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1  3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment progression is confirmed, 
the date of progression should be the earlier date when progression was suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate. This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.


 
Atezolizumab 
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Appendix 7 
Immune-Related Response Criteria 
INTRODUCTION 
Increasing clinical experience indicates that traditional response criteria (e.g., Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health 
Organization [WHO]) may not be sufficient to characterize fully activity in the new era of 
target therapies and/or biologics. In studies with cytokines, cancer vaccines, 
and monoclonal antibodies, complete response, partial response, or stable disease has 
been shown to occur after an increase in tumor burden as characterized by progressive 
disease by traditional response criteria. Therefore, conventional response criteria may 
not adequately assess the activity of immunotherapeutic agents because progressive 
disease (by initial radiographic evaluation) does not necessarily reflect therapeutic 
failure. Long-term effect on the target disease must also be captured. The 
immune-related response criteria1 (irRC) are criteria that attempt to do that by enhancing 
characterization 
of 
new 
response 
patterns 
that 
have 
been 
observed 
with 
immunotherapeutic agents (i.e., ipilimumab). (Note: The irRC only index and measurable 
new lesions are taken into account.) 
GLOSSARY 
Term 
Definition 
SPD 
sum of the products of the two largest perpendicular diameters
Tumor burden 
SPDindex lesions  SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irBOR 
immune-related best overall response 
 
BASELINE ASSESSMENT USING irRC 
Step 1. Identify the index lesions (five lesions per organ, up to ten visceral lesions and 
five cutaneous lesions).  
Step 2. Calculate the SPD of all of these index lesions: 
SPD  
i
(Largest diameter of lesion i)  (Second largest diameter of lesion i). 
                                            
1  Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Can Res 2009;15:741220. 


Appendix 7 
Immune-Related Response Criteria (cont.) 
Atezolizumab 
Protocol ML29640, Version 11 
A18 
POST-BASELINE ASSESSMENTS USING irRC 
Step 1. Calculate the SPD of the index lesions.  
Step 2. Identify new, measurable lesions ( 5  5 mm; up to five new lesions per organ: 
five new cutaneous lesions and ten visceral lesions).  
Step 3. Calculate the SPD of the new, measurable lesions. 
Step 4. Calculate the tumor burden: 
Tumor burden  SPDindex lesions  SPDnew, measurable lesions 
Step 5. Calculate the change in tumor burden relative to baseline and the change 
in tumor burden relative to nadir. 
Step 6. Derive the overall response using the table below. 
Overall Response Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or not, 
and no new lesions) confirmed by a repeat, consecutive assessment 
 4 weeks from the date first documented 
irPR 
Decrease in tumor burden  50% relative to baseline confirmed by a 
consecutive assessment  4 weeks from the date first documented 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require 
confirmation 
irPD 
Increase in tumor burden  25% relative to nadir confirmed by a 
consecutive assessment  4 weeks from the date first documented 
irCR  immune-related complete response; irPD  immune-related progressive disease; 
irPR  immune-related partial response; irSD  immune-related stable disease. 
 
DETERMINATION OF irBOR 
Once a patient has completed all tumor assessments, his/her irBOR may be determined: 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR  immune-related best overall response; irCR  immune-related complete response; 
irPD  immune-related progressive disease; irPR  immune-related partial response; 
irSD  immune-related stable disease. 
 


 
Atezolizumab 
Protocol ML29640, Version 11 
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Appendix 8 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about  50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair  50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 


 
Atezolizumab 
Protocol ML29640, Version 11 
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Appendix 9 
Anaphylaxis Precautions 
EQUIPMENT NEEDED 
 
Tourniquet 
 
Oxygen 
 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice  
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study drug infusion, 
the following procedures should be performed: 
1. 
Stop the study drug infusion. 
2. 
Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug. Do not obstruct arterial flow in the limb. 
3. 
Maintain an adequate airway. 
4. 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
5. 
Continue to observe the patient and document observation. 
 
 


 
Atezolizumab 
Protocol ML29640, Version 11 
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Appendix 10 
References 
 
1. 
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer 
J Clin, 2015. 65(1): p. 5-29. 
2. 
Govindan, R., et al., Changing epidemiology of small-cell lung cancer in 
the United States over the last 30 years: analysis of the surveillance, 
epidemiologic, and end results database. J Clin Oncol, 2006. 24(28): p. 
4539-44. 
3. 
Turrisi, A.T., 3rd, et al., Twice-daily compared with once-daily thoracic 
radiotherapy in limited small-cell lung cancer treated concurrently with 
cisplatin and etoposide. N Engl J Med, 1999. 340(4): p. 265-71. 
4. 
Roth, B.J., et al., Randomized study of cyclophosphamide, doxorubicin, 
and vincristine versus etoposide and cisplatin versus alternation of these 
two regimens in extensive small-cell lung cancer: a phase III trial of the 
Southeastern Cancer Study Group. J Clin Oncol, 1992. 10(2): p. 282-91. 
5. 
Rossi, A., et al., Carboplatin- or cisplatin-based chemotherapy in first-line 
treatment of small-cell lung cancer: the COCIS meta-analysis of individual 
patient data. J Clin Oncol, 2012. 30(14): p. 1692-8. 
6. 
Pujol, J.L., et al., Etoposide plus cisplatin with or without the combination 
of 4'-epidoxorubicin plus cyclophosphamide in treatment of extensive 
small-cell lung cancer: a French Federation of Cancer Institutes 
multicenter phase III randomized study. J Natl Cancer Inst, 2001. 93(4): p. 
300-8. 
7. 
Noda, K., et al., Irinotecan plus cisplatin compared with etoposide plus 
cisplatin for extensive small-cell lung cancer. N Engl J Med, 2002. 346(2): 
p. 85-91. 
8. 
Eckardt, J.R., et al., Open-label, multicenter, randomized, phase III study 
comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment 
for chemotherapy-naive patients with extensive-disease small-cell lung 
cancer. J Clin Oncol, 2006. 24(13): p. 2044-51. 
9. 
Hanna, N., et al., Randomized phase III trial comparing irinotecan/cisplatin 
with etoposide/cisplatin in patients with previously untreated extensive-
stage disease small-cell lung cancer. J Clin Oncol, 2006. 24(13): p. 2038-
43. 
10. 
Okamoto, H., et al., Randomised phase III trial of carboplatin plus 
etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk 
patients with extensive disease small-cell lung cancer: JCOG 9702. Br J 
Cancer, 2007. 97(2): p. 162-9. 
11. 
Socinski, M.A., et al., Phase III study of pemetrexed plus carboplatin 
compared with etoposide plus carboplatin in chemotherapy-naive patients 
with extensive-stage small-cell lung cancer. J Clin Oncol, 2009. 27(28): p. 
4787-92. 
12. 
Rudin, C.M., et al., Randomized phase II Study of carboplatin and 
etoposide with or without the bcl-2 antisense oligonucleotide oblimersen 
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