Clinical trial NCT04923776
Conditions: Small-cell Lung Cancer
Keywords: Liver metastases Radiation chemotherapy Radiotherapy
Sponsor: Brian Henick, MD
Start date: 2021-09-20; Completion date: 2023-12-23
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate whether radiation treatment directed at liver metastases can be safely added to standard of care treatment for extensive stage small cell lung cancer (ES-SCLC). The current standard treatment for people who have ES-SCLC is chemotherapy including drugs called carboplatin and etoposide, that is combined with a type of immunotherapy called atezolizumab. However, patients with liver involvement of their ES-SCLC don't respond as well to this treatment. The study aims to answer whether adding radiation directed at liver metastases can improve responses to standard chemo-immunotherapy in this patient population. All study participants will get the same study intervention, which will be chemo-immunotherapy and radiation therapy.

Detailed description:
Although the clinical evidence for the combination of radiation therapy and immunotherapy is more limited, numerous case reports, retrospective studies, early stage trials, and ongoing prospective trials highlight the potential for combining radiation with immunotherapy in augmenting the anti-tumor response.

The combination of stereotactic body radiation therapy (SBRT) of liver lesions with immunotherapy has been less well studied. Given the findings that patients with ES-SCLC and liver involvement have a poor prognosis and a limited response to chemo-immunotherapy, the investigators aim to augment the systemic anti-tumor immune response with RT targeted to liver metastases administered in addition to standard of care treatment. Preclinical data and prior clinical studies support the reasoning for these treatment approaches, and the investigators hypothesize that combination RT with chemo-immunotherapy will lead to improved local control and progression free survival in ES-SCLC patients with liver involvement.

Arms: arm 1: Addition of SBRT, directed at liver metastases, to standard of care (SOC) treatment atezolizumab+chemotherapy in SCLC. All patients must undergo a mandatory biopsy of a liver lesion prior to chemotherapy initiation.

Cycle 1 of chemoimmunotherapy will be administered as per standard of care, with radiation planning to be done subsequently in anticipation of liver-directed SBRT.
Interventions: intervention 1: Carboplatin intervention 2: Etoposide intervention 3: Atezolizumab intervention 4: Stereotactic Body Radiation Therapy (SBRT)
Intervention descriptions: intervention 1: The dosage for this drug is area under the curve (AUC) 5 mg/ml/min intravenous, Day 1, every 21 days for 4 cycles. This is standard of care. intervention 2: The dosage for this drug is 100 mg/m2 Intravenous, Days 1-3, every 21 days for 4 cycles. This is standard of care. intervention 3: The dosage for this drug is 1200 mg Intravenous, Day 1, every 21 days until disease progression. This is standard of care. intervention 4: This radiotherapy is given within +/-3 days of cycle 2, 10 Gy 3 doses on alternating days. This is not standard of care and considered interventional.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Herbert Irving Comprehensive Cancer Center 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
1 
 
 
 
 
    NCT04923776 
CUMC IRB#: AAAT0174 
Version Date: 15Nov2021 
 
TITLE: A phase II trial of atezolizumab + carboplatin + etoposide with liver-directed 
radiotherapy in extensive stage small cell lung cancer (ES-SCLC) patients with liver metastases 
 
Coordinating Center: 
Columbia University Irving Medical Center 
 
Principal Investigator: 
Brian S. Henick, MD 
161 Fort Washington Avenue 
New York, NY 10032 
Telephone: 
Fax: 
bh2682@cumc.columbia.edu 
 
Co-Investigators: 
Catherine A. Shu, MD 
Mark B. Stoopler, MD 
Simon K. Cheng, MD, PhD 
Alexander Z Wei, MD 
 
Statistician (Co-Investigator):   Codruta Chiuzan, PhD 
722 West 168th St, 6th Floor, Room 651 
New York, NY 10032 
Telephone: 212-305-9107 
Fax: 212-305-9408 
cc3780@cumc.columbia.edu 
 
 
Regulatory Sponsor: 
Columbia University Irving Medical Center 
161 Fort Washington Avenue 
212-305-3997 
New York, NY 10032 
Funding Source: 
Genentech-BioOncology 
1 DNA Way Mailstop 258A 
South San Francisco, CA 94080 
(888) 662-6728 
Study Agent: 
Radiation therapy 
Other Agent: 
Atezolizumab, carboplatin, etoposide 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
2 
 
 
 
Affiliate Institutions: 
Site Principal Investigator and Contact Information: 
Other Investigators at Site 
Pending 
Pending 
 
 
Initial version: January 4 2021 
 
Versions: 15Nov2021 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
3 
 
 
 
Protocol Signature Page 
 
 
 
I confirm that I have read this protocol, I understand it, and I will work according to this 
protocol and to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practices, and the applicable 
federal, state, and local laws, rules, and regulations relating to the conduct of the protocol. I 
have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I will promptly submit the protocol to 
the applicable IRB for review and approval. Once the protocol has been approved by the 
IRB, I understand that any modification made during the course of the study must first be 
approved by the IRB, prior to implementation except when such modification is made to 
remove an immediate hazard to the subject. I certify that I, and the study staff, have 
received the requisite training to conduct this research protocol. I agree to maintain 
adequate and accurate records in accordance with Columbia University and Herbert Irving 
Comprehensive Cancer Center policies, Federal, state and local laws and regulations. I 
agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
Signature of Principal Investigator 
Date 
 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
 
Name of Institution 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
4 
 
 
 
Protocol Synopsis 
 
Title 
A phase II trial of atezolizumab + carboplatin + etoposide with liver- 
directed radiotherapy in extensive stage small cell lung cancer (ES- 
SCLC) patients with liver metastases 
Short Title 
Atezo+chemo+RT in ES-SCLC with liver metastases 
Protocol Number 
AAAT0174 
Phase 
Phase II 
Methodology 
Single arm, open label study 
Study Duration 
36 months 
Study Center(s) 
Multicenter, projected 3 centers in total 
Objectives 
To assess the efficacy of liver-directed SBRT added to standard of care 
first line chemoimmunotherapy as measured by the 6 month progression 
free survival rate in ES-SCLC patients with liver metastases 
Number of Subjects 18 patients 
Diagnosis and Main 
Inclusion Criteria 
Previously untreated ES-SCLC with measurable liver metastases 
Study Product, 
Dose, Route, 
Regimen 
Carboplatin AUC 5 mg/ml/min IV, Day 1, q21 days x4 cycles 
Etoposide 100 mg/m2 IV, Days 1-3, q21 days x 4 cycles 
Atezolizumab 1200 mg IV, Day 1, q21 days until disease progression 
SBRT within +/-3 days of cycle 2, 10 Gy 3 doses on alternating days 
Duration of 
administration 
Four 21-day cycles of atezolizumab+chemotherapy followed by 
atezoliuamb maintenance until progression 
Reference therapy 
Atezolizumab + carboplatin+ etoposide 
Statistical 
Methodology 
A total of 16 evaluable patients are needed to detect an increase in 6 
month PFS from 20% (historical control) to 45%. This estimate was 
based on one-sided exact binomial test, with a type I error of 0.10 and 
power of 0.80. To account for a 10% dropout rate, 18 patients will be 
accrued to the study. The remainder of the analysis is exploratory. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
5 
 
 
 
Protocol Schema: 
 
 
 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
6 
 
 
 
 
 
 
Contents 
Protocol Signature Page 
3 
1 
Introduction 
10 
2 
Study Objectives 
10 
2.1 
Primary Objective 
10 
2.2 
Secondary Objective 
10 
3 
Background 
11 
4 
Investigational Agents 
16 
4.1 
Atezolizumab 
16 
4.1.1 
Preclinical Data 
16 
4.1.2 
Clinical Pharmacokinetics and Immunogenicity 
17 
4.1.3 
Clinical Data to Date 
18 
4.1.4 
Safety Data to Date 
18 
4.2 
Other Agent(s) 
20 
4.3 
Radiation 
20 
5 
Study Design 
20 
5.1 
General Design 
20 
5.2 
Intervention 
21 
5.3 
Specimen Collection and Processing 
21 
6 
Subject Selection and Withdrawal 
22 
6.1 
Inclusion Criteria 
22 
6.2 
Exclusion Criteria 
24 
6.3 
Inclusion of Women and Minorities 
27 
6.4 
Subject Recruitment 
27 
6.5 
Early Withdrawal of Subjects 
27 
6.5.1 
When and How to Withdraw Subjects 
27 
6.5.2 
Treatment Beyond Radiographic Progression 
27 
6.5.3 
Data Collection and Follow-up for Withdrawn Subjects 
28 
7 
REGISTRATION PROCEDURES 
28 
CUIMC Research Participant Registration 
28 
8 
TREATMENT PLAN 
30 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
7 
 
 
8.1 
Agent Administration 
30 
8.2 
Radiation Therapy 
30 
8.3 
General Concomitant Medication and Supportive Care Guidelines 
30 
8.4 
Duration of Therapy 
32 
8.5 
Duration of Follow Up 
32 
8.6 
Criteria for Removal from Study 
32 
9 
DOSING DELAYS/DOSE MODIFICATIONS 
32 
9.1 
General Notes Regarding Dose Modification 
33 
9.2 
Atezolizumab Dose Modification 
33 
9.3 
Carboplatin Dose Modification 
34 
9.3.1 
Hematologic toxicity 
34 
9.3.2 
Non-hematologic toxicity 
35 
9.3.3 
Other toxicity 
36 
9.4 
Etoposide Dose Modification 
36 
9.5 
Potential Overlapping Toxicities 
36 
10 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
37 
10.1 
Safety Parameters and Definitions 
37 
10.2 
Definitions 
37 
10.3 
Recording of Adverse Events 
41 
10.3.1 Assessment of Adverse Event 
41 
10.3.2 Assessment of Severity of Adverse Events 
42 
10.4 
Reporting of Serious Adverse Events 
43 
10.4.1 Collection of Adverse Event Reports 
43 
10.4.2 Deaths 
43 
10.4.3 IRB Notification by Investigator 
43 
10.4.4 FDA Notification by Sponsor-Investigator 
44 
10.4.5 DSMC Reporting 
44 
10.4.6 Reporting to Drug Manufacturer by Sponsor-Investigator 
44 
10.5 
HICCC DSMC Reporting Process 
46 
11 PHARMACEUTICAL INFORMATION 
48 
11.1 
Description 
48 
11.2 
Treatment Regimen 
48 
11.3 
Method for Assigning Subjects to Treatment Groups 
49 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
8 
 
 
11.4 
Preparation and Administration of Study Drug 
49 
11.5 
Subject Compliance Monitoring 
51 
11.6 
Prior and Concomitant Therapy 
51 
11.7 
Packaging 
51 
11.8 
Receiving, Storage, Dispensing and Return 
51 
11.8.1 Receipt of Drug Supplies 
51 
11.8.2 Storage 
51 
11.8.3 Dispensing of Study Drug 
52 
12 STUDY CALENDAR 
53 
13 MEASUREMENT OF EFFECT 
56 
13.1 
Antitumor Effect – Solid Tumors 
56 
13.2 
Definitions 
56 
13.3 
Disease Parameters 
56 
13.4 
Methods for Evaluation of Measurable Disease 
57 
13.5 
Response Criteria 
59 
13.5.1 Evaluation of Target Lesions 
59 
13.5.2 Evaluation of Non-Target Lesions 
60 
13.5.3 Evaluation of Disease Control Relative to the Radiation Field 
60 
13.5.4 Evaluation of Best Overall Response 
60 
13.6 
Duration of Response 
61 
13.7 
Progression-Free Survival 
61 
13.8 
Exploratory Biomarkers 
61 
14 DATA REPORTING / REGULATORY REQUIREMENTS 
62 
14.1 
Data Collection 
62 
14.2 
Data Reporting 
62 
14.3 
Data and Safety Monitoring Committee 
62 
14.4 
Quality Control and Quality Assurance 
63 
14.5 
Confidentiality 
64 
14.6 
Source Documents 
64 
14.7 
Case Report Forms 
65 
14.8 
Records Retention 
65 
15 STATISTICAL CONSIDERATIONS 
65 
15.1 
Study Design 
65 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
9 
 
 
15.2 
Analytical Plan 
66 
15.3 
Size/Accrual Rate 
67 
15.4 
Stratification Factors 
67 
15.5 
Continuous Monitoring for Toxicity 
67 
15.6 
Reporting and Exclusions 
67 
16 Protection of Human Subjects [multi center studies] 
67 
17 Study Finances 
68 
17.1 
Conflict of Interest 
68 
18 GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES 
68 
18.1 
Multi-Site Communication 
68 
18.2 
New Protocol Distribution, IRB Submission, Modifications, and Annual Renewals 68 
18.3 
Regulatory Documents 
69 
18.4 
Site Activation 
69 
18.5 
Central Registration Procedures- Affiliate Institution Research Participant 
Registration Process: 
70 
18.6 
Protocol Deviation/Subject Waiver request for Affiliate Sites: 
71 
18.7 
Guidelines for Affiliate Site Monitoring 
71 
18.8 
Adverse event reporting 
73 
18.9 
Confidentiality 
75 
18.10 
Data Reporting Plan 
75 
18.11 
Data Acquisition and Submission 
75 
18.12 
Record Keeping and Record Retention 
76 
19 Publication Plan 
76 
20 References 
76 
21 APPENDICES 
80 
21.1 
Appendix  Preexisting Autoimmune Diseases and Immune Deficiencies 
80 
21.2 
Appendix Anaphylaxis Precautions 
81 
21.3 
Infusion-Related Reactions 
82 
22 Attachments 
83 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
10 
 
 
 
1 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Columbia University Irving Medical Center institutional research policies and procedures. 
 
The standard of care first-line treatment for extensive stage SCLC is atezolizumab with 
platinum-etoposide, based on the IMpower133 study. In this study, the overall survival benefit 
with atezolizumab was 16.8 vs. 11.2 months in patients without liver metastases (63% of 
patients) but only 9.3 vs.7.8 months in patients with liver metastases (37% of patients)1. These 
data and retrospective studies highlight that liver metastases are a negative prognostic factor in 
SCLC2. Additionally, the IMpower133 results suggest that liver involvement is associated with 
resistance to immune checkpoint inhibitors (ICI) in SCLC, an observation also seen in metastatic 
melanoma and non-small cell lung cancer3. It is hypothesized that liver-mediated tolerance 
mechanisms may induce systemic immune suppression that contributes to ICI resistance4,5. 
Using radiation therapy (RT) in this context may be a viable approach to overcoming resistance. 
Apart from direct cytotoxic effects, RT promotes tumor-specific immunity through several 
mechanisms. Radiation upregulates MHC-I expression on tumor cells and generates tumor 
neoantigens that promote immune surveillance. RT also stimulates the release of damage 
associated molecular patterns (DAMPs) after immunogenic cell death that promote effective T 
cell priming6,7. Preclinical studies suggest that RT can act synergistically with ICI to enhance the 
anti-tumor response8. Early clinical data also suggest that the combination of RT with ICI can 
promote a strong and durable anti-tumor response within and beyond the boundaries of the 
radiation target9-11. We therefore propose a phase II trial adding stereotactic body radiation 
therapy (SBRT), directed at liver metastases, to standard of care treatment 
atezolizumab+chemotherapy in SCLC. We hypothesize that this combination will lead to 
improved local control and progression free survival in ES-SCLC with liver involvement, and 
provide key insights into the mechanisms of immune response/evasion. 
2 
STUDY OBJECTIVES 
2.1 Primary Objective 
● To assess the efficacy of liver-directed SBRT when added to standard of care 
atezolizumab+chemotherapy as measured by the progression free survival rate at 6 
months 
2.2 Secondary Objective 
● To assess the efficacy of adding liver-directed SBRT as measured by overall survival, 
progression-free survival, and the overall response rate 
● To evaluate the feasibility and safety of adding liver-directed SBRT to standard of care 
atezolizumab+chemotherapy 
● To describe the rate of in-field local control and out of field disease progression. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
11 
 
 
 
3 
BACKGROUND 
 
SCLC Background 
 
SCLC accounts for approximately 15% of new cases of lung cancer, and is responsible for an 
estimated 250,000 annual deaths worldwide. Smoking is the strongest risk factor for SCLC 
development and the institution of smoking cessation programs has led to decreasing incidence.12 
Nevertheless, treatment options are limited and survival remains poor. SCLC is characterized by 
rapid tumor growth, earlier development of distant metastases and a high degree of genomic 
instability. Extensive stage (ES) disease is typically very sensitive to upfront chemotherapy with 
initial response rates of 60-65% but the disease rapidly recurs leading to median overall survival 
estimates historically under 10 months13,14. For decades the only therapeutic modalities with 
demonstrated clinical benefit were platinum-based chemotherapy and radiation, although in 
recent years there have been promising developments incorporating the use of immunotherapy 
and targeted agents. 
 
The phase III IMpower133 trial introduced a new standard of care for the first-line treatment of 
ES-SCLC. Newly diagnosed ES-SCLC patients were randomly assigned to receive 
carboplatin+etoposide with either atezolizumab or placebo for four 21-day cycles followed by 
atezolizumab or placebo. Median overall survival (OS) was 12.3 months with atezolizumab vs 
10.3 months in the placebo group (p=0.007). PFS was longer, at 5.2 months, with atezolizumab 
versus 4.3 months with chemotherapy alone.1 Based on these results the FDA approved 
atezolizumab in the first line setting in March 2019. Similarly, the addition of durvalumab to 
platinum based chemotherapy was associated with a 27% improvement in overall survival in the 
CASPIAN trial, which led to recent FDA approval in March 202015. 
 
Thoracic radiation and/or prophylactic cranial radiation can also be included in first-line 
treatment of ES-SCLC. Consolidative thoracic RT may be considered in patients with complete 
response to initial systemic therapy or those with low-bulk disease. Jeremic et al demonstrated 
that accelerated hyperfractionated RT as consolidative treatment was associated with an 
improved median survival of 17 vs 11 months.16 The Dutch CREST trial showed an 
improvement in 2-year but not 1-year survival with consolidative RT.17 Notably thoracic RT can 
potentially add significant toxicity depending on the radiation regimen. The role of thoracic RT 
is under investigation in the chemoimmunotherapy era. 
 
Prophylactic cranial radiation (PCI) is a controversial treatment modality in ES-SCLC, explored 
due to high rates of brain metastases. In the rare patients who achieve a complete response to 
chemotherapy, a meta-analysis showed that PCI was associated with a 5.4% survival benefit at 3 
years18. Additionally, in a randomized trial of PCI vs observation in ES-SCLC patients who had 
any response to chemotherapy, the PCI arm had reduced incidence of symptomatic brain 
metastases at one year with improved 1 year OS (27.1% vs 13.3%)19. However, this study did not 
standardize the radiation dose and did not require brain imaging prior to PCI, which may have 
skewed the results. A subsequent Japanese study found no difference in the OS of patients who 
received PCI and all patients had a brain MRI prior to radiation.20 Therefore, PCI or close brain 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
12 
 
 
 
surveillance imaging are considered acceptable options per the NCCN guidelines, but more 
definitively beneficial treatments are needed. 
 
Rationale for targeting patients with liver metastases 
 
Several studies have highlighted that liver metastases are a negative prognostic factor in SCLC. 
In an analysis of 6459 patients with SCLC with metastatic disease from the Surveillance, 
Epidemiology, and End Results (SEER) database collected between 2010 and 2012, the 
incidence of liver metastases was 61.9%, and in one third of patients the liver was the only site of 
metastatic disease. SCLC with liver metastases had a reduced median OS of 4 months compared 
to 6 months among patients with other metastases (p=0.017)21. Other retrospective studies also 
demonstrated poor outcomes for patients with liver metastases, including worse response to 
chemotherapy22,23. 
 
A proposed mechanism for worse survival outcomes among patients with liver involvement is 
that the liver is an immunosuppressive organ with impaired immune surveillance of intrahepatic 
metastases2. This hypothesis may also account for poor response to immunotherapy seen in 
patients with liver metastases. In the aforementioned IMpower133 study, patients without liver 
metastases (63% of patients) who received atezolizumab with chemotherapy had an OS of 16.8 
months versus 11.2 months in those who received chemotherapy alone. In the 37% of patients 
who had liver metastases, however, OS was 9.3 months with atezolizumab versus 7.8 months 
with chemotherapy alone (HR 0.81, 95% CI 0.55-1.20). A similar effect was seen on PFS where 
patients with liver metastases had no significant benefit from the addition of atezolizumab (4.3 
months with atezolizumab vs. 4.2 months with placebo)1. These results suggest that not only are 
liver metastases a poor prognostic factor in SCLC, but they also associate with immunotherapy 
resistance. 
 
The resistance to immune checkpoint inhibitors seen in SCLC with liver metastases has also 
been observed in other cancer types including non-small cell lung cancer (NSCLC) and 
melanoma. Tumeh et al. assessed the response to pembrolizumab in several cohorts of patients 
treated under the Keynote 001, 002, and 006 trials. Presence of liver metastases was an 
independent predictive marker of reduced PFS among melanoma patients in a multivariable 
analysis (odds ratio of PFS 1.85, 95% CI 1.37-2.50, p<0.0001). Among 223 patients with 
melanoma, those with liver metastases had a PFS of 5.1 months compared to 20.1 months for 
patients without liver metastases (p=0.001). Similarly, among 165 patients with NSCLC who 
were treated with pembrolizumab, including 46 with liver metastases, PFS was significantly 
reduced in the liver metastases group (1.28 months vs 4.03 months, p=0.0094).3 In this and other 
retrospective studies in NSCLC, worse clinical outcomes in patients with liver metastases were 
observed irrespective of PD-L1 status24. 
 
The degree of tumor CD8+ T cell infiltration at the invasive margin has previously been shown 
to correlate with response to immunotherapy in melanoma. Tumeh et al. also used pre-treatment 
tumor samples from melanoma patients who participated in the Keynote trials to show that the 
subset of patients with liver metastases had depleted marginating CD8+ T cells in their distant 
and cutaneous metastases3. A separate group showed that melanoma patients with liver 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
13 
 
 
 
metastases had a lower CD8/Foxp3+ T reg ratio and a decreased percentage of activated PD- 
1+/CTLA-4+ CD8 cells in the immune infiltrates of the distant primary tumor.4 These findings 
suggest that the presence of liver metastases has an immunosuppressive effect beyond the liver. 
However, the systemic impact of liver metastases on antitumor immunity is not well understood. 
 
Preclinical rationale for combining radiation with immunotherapy 
 
Using radiation in combination with immunotherapy may be a promising approach to overcome 
immunotherapy resistance in patients with liver metastases. Tumor cells evolve to avoid 
recognition and destruction by the immune system through several escape mechanisms including 
downregulation of MHC class I expression, upregulation of inhibitory cytokines, and increased 
infiltration of the tumor by immunosuppressive cells. Beyond its cytotoxic effects through lethal 
DNA damage, radiation may convert the tumor immune microenvironment into an immune 
activated state. 
 
Evidence of immunomodulation via radiation therapy (RT) includes upregulation of MHC class I 
expression on tumor cells in a dose-dependent manner after RT exposure25. RT also results in 
increased peptide production, including formation of novel proteins, and enhanced antigen 
presentation to primed CD8+ T cells, augmenting the anti-tumor response. Additionally, RT 
promotes the release of inflammatory cytokines and chemokines by stressed tumor and stromal 
cells that attract immune effector cells into the tumor microenvironment. This includes the 
upregulation of interferon by infiltrating myeloid cells, which augments the cross-priming 
capacity of dendritic cells to expand antigen specific T cells and produce T cell dependent tumor 
regression26. Furthermore, local irradiation promotes increased infiltration and retention of tumor 
antigen-reactive CD8+ T cells27. Notably, in mouse models, CD8+ T cell depletion largely 
diminishes the therapeutic effect of RT28. Together the aforementioned mechanisms may 
augment the immune system’s anti-tumor response and contribute to the abscopal effect, a rare 
phenomenon, where radiation induces metastatic tumor regression at unradiated sites. 
 
Despite the adaptive immune response that may be triggered by radiation, tumors can also 
develop resistance mechanisms to escape immune mediated destruction. One mechanism is 
through the inhibition of T cell function by upregulation of PD-L1 on tumor cells after 
irradiation through interferon γ mediated signaling29. Based on this finding Deng et al. 
administered anti-PD-L1 blockade with high dose ionizing irradiation (IR) and demonstrated 
enhanced tumor regression in an animal model. Additionally they found evidence of the abscopal 
effect in their model. In evaluating the immunomodulating effects of combination treatment, they 
showed that it enhanced tumor antigen-specific T cell function locally and systemically and 
decreased inhibitory myeloid-derived suppressor cells (MDSCs) within the tumor 
microenvironment8. Other groups have also provided evidence to support the use of combination 
PD-L1 or CTLA-4 blockade with radiation in enhancing the anti-tumor response in animal 
models29-31. 
 
Clinical rationale for combining radiation with immunotherapy 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
14 
 
 
 
Although the clinical evidence for the combination of radiation therapy and immunotherapy is 
more limited, numerous case reports, retrospective studies, early stage trials, and ongoing 
prospective trials highlight the potential for this approach in augmenting the anti-tumor response. 
 
Several phase I trials suggested the safety of combining ipilimumab with radiation in the 
treatment of solid malignancies. However the efficacy of anti-CTLA-4 blockade with 
hypofractionated radiation was not robust with clinical benefit defined as partial response or 
stable disease outside of the radiation field seen in 23-36% of patients31-33 In a prospective trial 
of 22 stage IV melanoma patients 50% of patients had a clinical benefit, including 27% who 
achieved an ongoing complete response32. In these trials the combination therapy was generally 
well tolerated. Clinical benefit was associated with increased markers of T cell reinvigoration 
and expansion of CD8+ T cells33. The increased expression of PD-L1 with this treatment 
suggests a role for adding anti- PD-1/PD-L1 targeted treatment31. 
 
Notably, in one study, liver irradiation produced increased proportions of T cells expressing 
ICOS, GITR, and 4-1BB, that are associated with proimmune activity. However, it also 
increased the proportion of cells expressing LAG3, TIM3, and PD1, which promote immune 
inhibition. This finding suggests that hepatic irradiation supports early systemic immune 
activation with compensatory mechanisms of increasing inhibitory antigen expression33. 
 
The clinical data regarding anti PD-1/PD-L1 blockade in combination with RT is more limited. 
In completed and ongoing trials a variety of schedules for immunotherapy and radiation 
administration have been adopted but the optimal timing and dosage for RT has not been 
established. In NSCLC, the PACIFIC trial randomized 713 patients with unresectable NSCLC to 
chemoradiation followed by adjuvant treatment with durvalumab, an anti-PD-L1 agent, or 
placebo. It demonstrated a significantly prolonged PFS of 16.8 months for the durvalumab 
patients compared to 5.6 months for those who received placebo34. 
 
However other studies suggest the superior efficacy of concurrent RT with immunotherapy. 
Despite inherent limitations of the study design, in a retrospective study of 758 patients who 
received immunotherapy and radiation, concurrent ICB with RT and hypofractionated RT was 
associated with improved OS35. In a recent phase I trial, 21 patients with stage III NSCLC 
received pembrolizumab, an anti-PD-1 agent, concurrently with chemoradiation in a 3+3 design. 
The 12 month PFS was 69.7% in this trial compared to 55.7% seen in the PACIFIC study. Of 
note, both trials had elevated rates of pneumonitis, including 33% of patients with at least grade 
2 pneumonitis in the phase I trial34,36. A phase II study of concurrent chemoradiation with 
pembrolizumab is underway. A signal for synergy between radiation and anti-PD-1 was also 
seen in the metastatic NSCLC setting in a phase II trial of pembrolizumab with stereotactic body 
RT (SBRT) on a single tumor site. In this study, the overall response rate was 36% at 12 weeks 
with combination treatment compared to 18% with pembrolizumab alone. However the trial did 
not meet its prespecified end point critiera of 50% ORR at 12 weeks for the combination 
treatment group10. In the oligometastatic disease setting, a single-arm phase II study investigating 
pembrolizumab following local ablative therapy revealed improved PFS compared to historical 
controls9. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
15 
 
 
 
The trials of combination immunotherapy with RT in ES-SCLC are still in early phases and 
mostly ongoing. In a phase I trial, patients with ES-SCLC who completed induction 
chemotherapy received 45 Gy of thoracic RT in 15 daily fractions along with pembrolizumab 
every 3 weeks for up to 16 cycles in a 3+3 dose escalation design. Thirty-three patients 
completed treatment per protocol with no dose limiting toxicities and few high-grade adverse 
events. Notably the trial enrolled patients regardless of their response to induction chemotherapy 
and PD-L1 status. The reported median PFS was 6.1 months and OS was 8.4 months compared 
to historical results of 4 months PFS and 8 months OS with thoracic RT alone in chemotherapy 
responders in a phase III trial17,37. Although the clinical benefits are not clear from this trial, a 
larger study with a homogeneous population is necessary to assess relative efficacy. Several 
ongoing trials are also evaluating the combination of thoracic RT with anti-CTLA4 and/or anti- 
PD-1 after induction chemotherapy (NCT03923270, NCT03043599). Additionally there are a 
few studies under way of immunotherapy with RT in the second line setting (NCT02701400, 
NCT03262454). Of note, in all of these trials RT has been targeted at thoracic lesions. To our 
knowledge, no trials with RT targeting metastatic lesions in combination with ICI have been 
previously done. 
 
Stereotactic radiation therapy for liver metastases 
 
Stereotactic radiation therapy for liver lesions has been well described for both primary 
hepatocellular carcinoma and metastatic disease38-40. In a large multi-institutional retrospective 
series of 427 patients with 568 liver metastatic lesions (from various histologies) treated with 
SBRT, local control (LC) of the treated lesions was durable. Median duration of local control 
was 51 months. Small tumors (< 40 cm3) were noted to have improved median local control rates 
of 52 months, compared to 39 months for tumor volumes  ≥ 40 cm3. No grade 3 or higher 
toxicity was reported. The selected dose/fractionation of 30 Gy in 3 fractions in the study has 
also been shown to be well tolerated40. In a phase I dose-escalation study of SBRT for liver 
metastases, the 30 Gy in 3 fraction regimen shows no grade 3 or higher toxicity41. This regimen 
is also an accepted treatment dose for the current SABR-COMET-10 phase III trial analyzing the 
effect of ablative SBRT in patients with oligometastatic disease42. 
 
The combination of SBRT of liver lesions with immunotherapy has been less well studied. A 
small series of five patients with unresectable hepatocellular carcinoma who were treated with 
SBRT followed by anti-PD1 antibodies had 1-year LC and OS rates of 100%. One patient had 
grade ≥ 3 toxicities (pneumonitis and skin reaction), but no radiation-induced liver toxicity was 
noted43. 
 
Given the findings that patients with ES-SCLC and liver involvement have a poor prognosis and 
a limited response to chemo-immunotherapy, we aim to augment the systemic anti-tumor 
immune response with RT targeted to liver metastases administered in addition to standard of 
care treatment. Preclinical data shows that radiation upregulates MHC class I expression, 
increases tumor antigen release, enhances CD8+ T cell infiltration, modulates the tumor immune 
microenvironment and upregulates PD-L1 expression, and that immunotherapy can synergize 
with RT to enhance tumor regression. Prior clinical studies also support a synergistic role for 
these treatment approaches. We hypothesize that combination RT with chemo-immunotherapy 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
16 
 
 
 
will lead to improved local control and progression free survival in ES-SCLC patients with liver 
involvement, and provide key insights into the mechanisms of immune response/evasion. 
Administration of radiation at the beginning of cycle 2 of chemoimmunotherapy will allow 
patients to receive the putative immunogenic benefit of radiation without compromising prompt 
initiaton of standard of care chemotherapy with cycle 1 while awaiting radiation planning. 
 
4 
INVESTIGATIONAL AGENTS 
4.1 
Atezolizumab 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 and 
inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells. Therapeutic blockade of PD- 
L1 binding by atezolizumab has been shown to enhance the magnitude and quality of tumor- 
specific T-cell responses, resulting in improved anti tumor activity (Fehrenbacher et al. 2016; 
Rosenberg et al. 2016)44,45. Atezolizumab has minimal binding to Fc receptors, thus eliminating 
detectable Fc-effector function and clinically relevant associated antibody-mediated clearance of 
activated effector T cells. 
 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is being 
investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is being 
studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy. Atezolizumab is 
approved for the treatment of urothelial carcinoma, NSCLC, SCLC, and triple-negative breast 
cancer. 
 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical studies. 
 
4.1.1 Preclinical Data 
Comprehensive pharmacology, PK, and toxicology evaluations have been undertaken with 
atezolizumab. 
Atezolizumab binds to its target with high affinity and blocks binding to receptors B7-1 and PD- 
1. It was engineered to reduce its binding to Fcγ receptors and exhibits minimal binding to 
human Fcγ receptors. Several studies demonstrated enhanced anti-tumor immunity when 
administered to mice with established tumors of colorectal and melanoma origin, suggesting PD- 
L1 blockade as a compelling strategy for enhancing the anti-tumor T cell response in solid 
tumors. 
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 toxicity and pharmacokinetics. 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the proposed 
Phase I starting doses. The results of the toxicology program were consistent with the 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
17 
 
 
 
anticipated pharmacologic activity of down-modulating the PD-L1/PD-1 pathway and supported 
entry into clinical trials in patients. 
For further details please refer to the IB for atezolizumab. 
 
4.1.2 Clinical Pharmacokinetics and Immunogenicity 
The clinical pharmacokinetics for atezolizumab have been derived from the following 
atezolizumab monotherapy studies: PCD4989g, JO28944, IMvigor210, IMvigor211, BIRCH, 
POPLAR, FIR, and OAK. 
 
Per the IB, the pharmacokinetics of atezolizumab monotherapy have been characterized in 
patients in Study PCD4989g at doses 0.01 mg/kg to 20 mg/kg q3w, including the fixed dose 
1200 mg (equivalent to 15 mg/kg). Exposure to atezolizumab increased dose proportionally over 
the dose range of 1 mg/kg to 20 mg/kg. While a subset of antidrug antibody (ADA)-positive 
patients in Study PCD4989g receiving 0.3 to 3 mg/kg atezolizumab q3w experienced a reduction 
of atezolizumab Cmin to below the PK assay lower limit of quantification (LOQ), patients 
receiving 10 to 20 mg/kg atezolizumab, including the fixed 1200 mg dose, maintained geometric 
mean Cmin that was in excess of both the LOQ and the target serum concentration of 6 μg/mL46. 
 
Based on an analysis of exposure, safety, and efficacy data, the following factors had no 
clinically relevant effect: age (21- 89 years), body weight, sex, albumin levels, tumor burden, 
region or race, renal impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG 
status. Positive ADA status against atezolizumab led to approximately 13% reduction in overall 
exposure. 
 
Combined atezolizumab PK data obtained in metastatic urothelial carcinoma patients from 
IMvigor210 and IMvigor211 and in NSCLC patients from BIRCH, POPLAR, FIR, and OAK 
were consistent with the Phase Ia Study PCD4989g popPK model estimates. These results 
suggest that atezolizumab PK characteristics are similar across a range of tumor types and 
studies. 
 
Antidrug antibodies to atezolizumab have been observated at all dosing levels (≤1 mg/kg to 20 
mg/kg and 1200 m). Treatment-emergent ADAs were detected at 1 or more post dose timepoints 
in ADA positive patients across 20 studies of atezolizumab used as monotherapy or in 
combination. ADA status appeared to have no clinically relevant impact on pharmacokinetics or 
safety. Although some variability was observed across the studies, overall, ADA status appeared 
to have no clinically relevant impact on efficacy. 
 
The fixed dose of 1200 mg (equivalent to an average body weight-based dose of 15 mg/kg) 
administered every 3 weeks was selected on the basis of both nonclinical studies and available 
clinical data from PCD4989g; this was the dose used in the Impower133 study establishing the 
survival benefit of atezolizumab in combination with standard of care chemotherapy in ES- 
SCLC. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
18 
 
 
 
Please refer to the IB for additional data regarding clinical pharmacokinetics and 
immunogenicity. 
 
4.1.3 Clinical Data to Date 
As of May 2019, 101 Sponsor studies are ongoing with atezolizumab as a single 
agent or in combination with other therapies. Of these, efficacy or and/or safety data that are 
considered sufficiently robust and clinically relevant are available for more than 30 studies. The 
most efficacy data is available in NSCLC patients (n=1636) with trials including BIRCH, 
POPLAR, OAK, IMpower150, IMpower131, FIR and the NSCLC cohort of PCD4989g. 
Additionally 983 patients with metastatic urothelial carcinoma have been administered 
atezolizumab through PCD4989g, IMvigor210 and IMvigor211. 
 
In NSCLC, use of single agent atezolizumab in the second and third line setting in the 
PCD4989g, FIR, OAK, POPLAR and BIRCH trials resulted in a meaningful improvement in 
overall survival compared to standard of care across all PD-L1 expression groups. Additionally, 
IMpower132 demonstrated benefit of atezolizumab with chemotherapy in NSCLC. 
 
The clinical data for atezolizumab in SCLC comes from the IMpower133. As found in the 
atezolizumab IB, IMpower133 was a Phase I/III randomized, double-blind placebo-controlled 
study of carboplatin and etoposide (CE) with or without atezolizumab (1200 mg) in patients with 
chemotherapy-naïve extensive-stage SCLC. 
 
The study met the co-primary endpoints of OS and investigator-assessed PFS in the ITT 
population (n=403). As of the CCOD of 24 April 2018, 238 death events had been observed in 
the ITT population. A statistically significant and clinically meaningful improvement was 
demonstrated in OS with Atezo + CE (n=201) compared with placebo(PBO) + CE 
(n=202):stratified HR 0.701 (95% CI 0.541, 0.909; log rank p-value <0.0069; median OS 12.3 
months vs. 10.3 months). A statistically significant improvement was also demonstrated in 
investigator-assessed PFS (stratified HR 0.772; 95% CI: 0.624, 0.955; log-rank p-value 0.017). 
Consistent with the benefit observed in the overall ITT population, an OS and PFS benefit with 
atezolizumab + CE arm compared with PBO + CE arm was observed in the majority of the 
subgroups analyzed. The ORR and median DOR were similar between the treatment arms. More 
patients in the atezolizumab + CE arm compared with the placebo + CE arm had an ongoing 
response at the time of the CCOD. 
 
4.1.4 Safety Data to Date 
From the IB, pooled safety data for atezolizumab monotherapy are available for 3178 treated 
patients in 8 studies: IMvigor210, IMvigor211, OAK, BIRCH, POPLAR, FIR, IMmotion150, 
and PCD4989g. 
 
The majority of patients (over 97%) received atezolizumab at a dose of 1200 mg q3w, and the 
remaining patients, from Study PCD4989g, received atezolizumab at doses in the range of 1-20 
mg/kg q3w. The safety data indicate that atezolizumab was well tolerated and the observed AEs 
were consistent with the known mechanism of action of atezolizumab or the underlying 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
19 
 
 
 
disease. The safety profile was generally consistent between the UC population (983 patients) 
and NSCLC population (1636 patients). 
 
The majority (96.0%) of patients in the overall pooled population experienced at least 
one AE during the course of study treatment. Treatment-related AEs were reported in 68.2% of 
patients, with the most common events (≥20%) being fatigue, decreased appetite, nausea, cough, 
constipation, dyspnea, and pyrexia. 
 
In the pooled population of patients receiving atezolizumab monotherapy, Grade 3-4 AEs were 
reported by 46.5% of patients. The most common (>3% of patients) events were anemia (5.0%), 
dyspnea (3.7%), fatigue (3.4%), hyponatremia (3.1%), and pneumonia (3.0%). 
 
The overall incidence of Grade 5 AEs occurring within 30 days of last study drug intake 
or prior to initiation of non-protocol therapy was 3.8% (122/3178). Grade 5 AEs were reported in 
a variety of System Organ Classes (SOCs), and the following events were reported for more than 
1 patient: death (19), pneumonia (12), sepsis (8), septic shock (5), respiratory failure (5), cardiac 
failure (3), sudden death (3), disease progression (3), myocardial infarction (2), lung infection 
(2), pulmonary sepsis (2), respiratory distress (2), pneumonia aspiration (2), pulmonary 
embolism (2), cerebral hemorrhage (2), cerebrovascular accident (2), ischemic stroke (2), 
embolism (2), and hepatic failure (2). Eleven Grade 5 events were considered by the investigator 
as treatment related; one case each of pulmonary hypertension, respiratory failure, death, 
intestinal perforation, pneumonia, sepsis, general physical condition abnormal, hepatic failure, 
cardiac failure, pericarditis constrictive, and toxic epidermal necrolysis. 
 
The incidence of serious adverse events (SAEs) in the pooled population of patients receiving 
atezolizumab montherapy was 41.2%. The most common SAEs were pneumonia (3.1%), 
dyspnea (2.8%), pyrexia (2.5%), UTI (1.9%) and pleural effusion, pulmonary embolism, and 
sepsis (1.3%). 
 
Safety data is also available for atezolizumab in combination with chemotherapy, as proposed in 
this trial. In IMpower133 patients with ES-SCLC received atezolizumab 1200 mg IV on day 1, 
carboplatin at AUC 5 mg/ml/min on day 1 and etoposide 100 mg/m2 IV on days 1-3 in 21 days 
cycles. In the combination atezolizumab+chemotherapy group, 94.9% of patients experienced a 
treatment related AE. 67.7% of patients experienced a grade 3-4 AE, compared to 63.3% with 
chemotherapy alone. The most common grade 3-4 AEs included neutropenia (22.7%), anemia 
(14.1%), and thrombocytopenia (10.1%) with combination therapy. Most immune related AEs 
(irAEs) were graded as 1-2, including rash (18.2%), hypothyroidism (12.6%), and hepatitis 
(6.1%) although grade 3-4 irAE also occurred including rash (2%), infusion-related reaction 
(2%), and hepatitis (1.5%). 3 patients in the atezolizumab+chemotherapy group experienced a 
death related to trial regimen including 1 from neutropenia, 1 from pneumonia, and one from an 
unspecified cause. 3 patiens also died in the chemotherapy alone group (1 from pneumonia, 1 
from septic shock, and 1 from cardiopulmonary failure). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
20 
 
 
 
4.2 
Other Agent(s) 
A platinum chemotherapy plus etoposide was the previous standard of care treatment for patients 
with ES-SCLC, and is still an approved regimen per the National Cancer Comprehensive 
Network guidelines. Carboplatin is preferred over cisplatin given equivalent efficacy with less 
risk of nephrotoxicity, neuropathy and otoxicity. The carboplatin-etoposide combination has 
been evaluated in several clinical trials47-50. The preferred dosing is etoposide 100 mg/m2 on 
days 1, 2, and 3 and carboplatin AUC 5 on day 1 every 21 days. Toxicities associated with this 
regimen include grade 3/4 myelosuppression and infection.  A meta-analysis of carboplatin 
based regimens in ES-SCLC reported a median OS of 9.4 months, PS of 5.3 months and an 
objective response rate of 66%13. 
 
4.3 
Radiation 
Details regarding radiation administration can be found in Section 8.2. 
 
 
5 
STUDY DESIGN 
 
5.1 
General Design 
This is a single-arm, open-label phase II study to assess the efficacy of liver-directed SBRT 
added to first-line atezolizumab, carboplatin, and etoposide in ES-SCLC, as measured by 6- 
month PFS. We hypothesize that the addition of SBRT, directed at liver metastases, to standard 
of care treatment atezolizumab+chemotherapy in SCLC patients will increase the 6-month PFS 
by 25% as compared to 20% historical control rate1. A single stage design based on one-side 
exact binomial test will be used, with a type I error of 0.10 and a power of 80%. This design 
requires a total of 16 evaluable patients. If at least 6 out of 16 patients have not experienced 
progression at 6 months, this combination therapy will be considered worthy of further study. 
Figure 1 depicts the study design. Schedules of assessments are provided in Study Calendar in 
Section 12. 
 
Figure 1. 
 
 
 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
21 
 
 
 
5.2 
Intervention 
All patients must undergo a mandatory biopsy of a liver lesion prior to chemotherapy 
initiation. Cycle 1 of chemoimmunotherapy will be administered as per standard of care, with 
radiation planning to be done subsequently in anticipation of liver-directed SBRT (3 doses of 
10 Gy administered on alternating days to up to three liver lesions, measuring no greater than 5 
cm each) to be given within +/-3 days of cycle 2. 
 
Subjects will continue to receive study treatment (four 21-day cycles of induction 
chemoimmunotherapy followed by maintenance atezolizumab every 3 weeks) until disease 
progression or intolerance of treatment. During the maintenance phase, prophylactic cranial 
irradiation is permitted; consolidative thoracic radiation may be considered if deemed clinically 
appropriate by the treating investigator in discussion with the principal investigator. 
 
If clinically feasible, it is recommended that the patient undergo a tumor biopsy sample 
collection at the time of radiographic disease progression. These data will be used to explore 
whether radiographic findings are consistent with the presence of a tumor. Additionally, these 
data will be analyzed to evaluate the association between changes in tumor tissue and clinical 
outcome and to further understand the potential mechanisms of progression and resistance to 
study treatment. This exploratory biomarker evaluation will not be used for any treatment-related 
decisions. 
 
Patients will undergo tumor assessments prior to radiation administration and every 6 weeks (± 7 
days) for the first 12 months following Cycle 1, Day 1, regardless of treatment dose delays. After 
12 months, tumor assessments will be required every 9 weeks (± 7 days). Patients will undergo 
tumor assessments until radiographic disease progression per RECIST v1.1, withdrawal of 
consent, study termination by the principal investigator, or death, whichever occurs first. 
 
Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 will 
continue to undergo tumor assessments every 6 weeks (± 7 days), or sooner if symptomatic 
deterioration occurs. For these patients, tumor assessments should continue every 6 weeks (± 7 
days), regardless of time in the study, until study treatment is discontinued. 
 
Patients who discontinue treatment for reasons other than radiographic disease progression (e.g., 
toxicity) will continue scheduled tumor assessments at the same frequency as would have been 
followed if the patient had remained on study treatment (i.e., every 6 weeks [± 7 days] for the 
first 12 months following Cycle 1, Day 1 and then every 9 weeks [± 7 days] thereafter, 
regardless of treatment dose delays) until radiographic disease progression per RECIST v1.1, 
withdrawal of consent, study termination by the principal investigator, or death, whichever 
occurs first, regardless of whether patients start a new anti-cancer therapy. 
 
5.3 
Specimen Collection and Processing 
Tumor Tissue 
Tissue obtained from the pre-treatment liver biopsy will be processed for standard pathology 
evaluation and remaining tumor tissue will be partitioned and processed in the following ways: 
- 
Snap-frozen in liquid nitrogen at -80 degrees Celcius for future DNA and RNA extraction 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
22 
 
 
 
- 
Processed as single-cell suspensions of tumor and infiltrating immune cells and then 
frozen at -80 degrees Celcius for future T-cell assays 
- 
Processed as formalin-fixed tissue and embedded in paraffin for future IHC assays 
 
Sufficient material must be collected to permit all planned correlative studies including (1) 
frozen material for DNA/RNA extraction, (2) FFPE material for IHC, and (3) digested cellular 
material for single-cell suspensions. Adjudication of sufficient material for (1) and (2) will be 
further certified by review of Diff-Quik or H&E stained slide/touch prep from frozen and FFPE 
material to ensure tumor is present in collected material Adequacy of material for single-cell 
suspensions will be determined by collection of at least 20 million live cells total. 
 
Peripheral Blood 
- 
Mononuclear cells will be isolated from patients by centrifugation and cryopreserved for 
later analysis by ELISpot assay, FLOW cytometry, and/or CyTOF/CyTEK. 
- 
Plasma will be stored for germline sequencing as a companion to somatic tumor DNA 
sequencing 
Please see Laboratory Manual for further details. 
 
6 
SUBJECT SELECTION AND WITHDRAWAL 
Patients may be eligible if they are chemotherapy- and immunotherapy-naïve and have ES-SCLC 
with liver metastases if the following criteria are met. 
 
6.1 
Inclusion Criteria 
1. Age≥ 18 years 
2. Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration 
Lung Study Group [VALG] staging system) 
3. No prior treatment for ES-SCLC 
4. ECOG performance status 0 or 1 
5. Patients with a history of treated, asymptomatic CNS metastases are eligible providing 
they meet the following criteria 
● Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla or spinal cord) 
● No ongoing requirement for corticosteroids as therapy for CNS disease 
● No stereotactic brain radiation within 7 days 
● No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study 
● Patients with new asymptomatic CNS metastases detected at the screening scan 
must receive radiation therapy and/or surgery for CNS metastases. Following 
treatment, these patients may then be eligible without the need for an additional 
brain scan prior to randomization, if all other criteria are met. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
23 
 
 
 
6. At least one liver metastasis measuring 1 cm. 
7. Measurable disease, as defined by RECIST v1.1, in addition to the liver lesion(s) to 
which SBRT is planned. 
8. Patients must submit a pre-treatment tumor tissue sample from a liver metastasis. Tumor 
tissue must be obtained prior to the start of treatment. 
9. Adequate hematologic and end organ function, defined by the following laboratory 
results: 
● ANC ≥1500 cells/μL without granulocyte colony-stimulating factor support 
● Lymphocyte count ≥500/μL 
● Platelet count ≥100,000/μL without transfusion 
● Hemoglobin ≥9.0 g/dL Patients may be transfused to meet this criterion. 
● INR or aPTT ≤1.5×upper limit of normal (ULN) 
This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation should be on a 
stable dose. 
● AST, ALT, and alkaline phosphatase ≤5×ULN 
● Serum albumin ≥ 25 g/L (2.5 g/dL) 
● Serum bilirubin ≤1.25×ULN 
o Patients with known Gilbert disease who have serum bilirubin level 
≤3×ULN may be enrolled. 
● Serum creatinine ≤1.5×ULN 
10. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods as defined below: 
 
● Women must remain abstinent or use contraceptive methods with a failure rate of 
< 1% per year during the treatment period and for 6 months after the final dose of 
atezolizumab, carboplatin and etoposide 
● A woman is considered to be of childbearing potential if she is postmenarchal, has 
not reached a postmenopausal state (≥12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements. 
● Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
● The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not adequate methods of contraception 
11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
With female partners of childbearing potential or pregnant female partners, men must remain 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
24 
 
 
abstinent or use a condom during treatment with atezolizumab and chemotherapy 
(i.e.,carboplatin and etoposide) and for at least 6 months after the last dose of atezolizumab and 
chemotherapy to avoid exposing the embryo. 
● The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence and withdrawal are not acceptable methods of contraception. 
12. Negative HIV test at screening, with the following exception: patients with a positive 
HIV test at screening are eligible, provided they are stable on anti-retroviral therapy, have 
a CD4 count3 200/µL, and have an undetectable viral load 
13. Ability to understand and the willingness to sign a written informed consent document. 
14. Ability to comply with the study protocol, in the investigator’s judgment 
 
6.2 
Exclusion Criteria 
Patients who meet any of the criteria below will be excluded from study entry: 
1. Active or untreated CNS metastases as determined by computed tomography (CT) or 
magnetic resonance imaging (MRI) evaluation during screening and prior radiographic 
assessments 
2. Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for ≥1 week prior to randomization 
3. Leptomeningeal disease 
4. Prior radiation treatment of SCLC outside of the CNS 
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., 
PleurX®) are allowed. 
6. Uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 
mg/dL or corrected serum calcium >ULN) 
7. Patients who are receiving denosumab prior to randomization must be willing and eligible to 
discontinue its use and replace it with a bisphosphonate while in the study. 
8. Malignancies other than SCLC within 5 years prior to randomization, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year OS >90%) treated 
with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous-cell skin cancer, localized prostate cancer treated surgically with curative 
intent, ductal carcinoma in situ treated surgically with curative intent) 
a. Prior radiation for non-SCLC malignancies >5 years prior to randomization will 
be permitted, with the exception of those who have undergone liver-directed 
treatments 
9. Child-Pugh class B cirrhosis or worse 
10. History of liver-directed ablative therapy for any indication, including radiation, 
chemoembolization, radiofrequency ablation, or other similar modalities 
11. Women who are pregnant, lactating, or intending to become pregnant during the study. Pregnant women 
are excluded from this study because carboplatin and etoposide are category D agents with the potential 
for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
25 
 
 
nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding should be discontinued if 
the mother is treated with atezolizumab. 
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
14. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s 
granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, 
or glomerulonephritis (see Appendix 21.1 for a more comprehensive list of autoimmune 
diseases) 
a. Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible for this study. 
b. Patients with controlled Type I diabetes mellitus on a stable dose of insulin 
regimen are eligible for this study. 
15. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted, provided that they meet the following conditions: 
o Rash must cover less than 10% of body surface area 
o Disease is well controlled at baseline and only requires low potency topical 
steroids 
o No acute exacerbations of underlying condition within the last 12 months (not 
requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency, or oral steroids) 
16. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan 
● History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
17. Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or hepatitis C 
● Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of 
HBsAg) are eligible. HBV DNA must be obtained in these patients prior to 
randomization. 
● Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA. 
18. Active tuberculosis 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
26 
 
 
 
19. Severe infections within 4 weeks prior to study initiation and at the time of enrollment, 
including but not limited to hospitalization for complications of infection, bacteremia, or 
severe pneumonia 
20. Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within 3 months prior to randomization, unstable 
arrhythmias, or unstable angina 
● Patients with known coronary artery disease, congestive heart failure not meeting 
the above criteria, or left ventricular ejection fraction <50% must be on a stable 
medical regimen that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate. 
21. Major surgical procedure other than for diagnosis within 28 days prior to randomization or 
anticipation of need for a major surgical procedure during the course of the study 
22. Prior allogeneic bone marrow transplantation or solid organ transplant 
23. Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or render 
the patient at high risk for treatment complications 
24. Previous anti-cancer therapy for ES-SCLC 
25. Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent within 28 days prior to enrollment 
26. Administration of a live, attenuated vaccine (e.g., FluMist) within 4 weeks before 
randomization 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 through May in the Northern Hemisphere and 
approximately April through September in the Southern Hemisphere). 
● Patients must agree not to receive live, attenuated influenza vaccine (e.g., 
FluMist®) within 28 days prior to randomization, during treatment or within 90 
days following the last dose of atezolizumab/placebo. 
27. Prior treatment with immune checkpoint blockade therapies, anti−PD-1, and anti−PD-L1 
therapeutic antibodies 
28. Treatment with systemic immunosuppressive medications (including, but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor 
necrosis factor [anti-TNF] agents) within 2 weeks prior to randomization 
● Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled 
in the study after discussion with and approval by the Principal Investiator 
● The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension, and low-dose supplemental corticosteroids for adrenocortical 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
27 
 
 
insufficiency are allowed. 
 
29. History of allergic reactions to carboplatin or etoposide 
30. Uncontrolled tumor-related pain: 
a. Patients requiring pain medication must be on a stable regimen at study entry. 
b. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be 
recovered from the effects of radiation. There is no required minimum recovery period. 
c. Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain 
with further growth (e.g., epidural metastasis that is not currently associated with spinal cord 
compression) should be considered for loco-regional therapy if appropriate prior to 
enrollment. 
31. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment: 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive 
pulmonary disease exacerbation) are eligible for the study. 
32. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti−CTLA-4, 
anti−PD-1, and anti−PD-L1 therapeutic antibodies 
33. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and 
interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of 
study treatment. 
6.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
6.4 
Subject Recruitment 
Patients will be recruited from the referral population within the investigator and co-investigators’ 
clinical practices. 
 
6.5 
Early Withdrawal of Subjects 
6.5.1 When and How to Withdraw Subjects 
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: 
● 
Intolerable toxicity related to study treatment, including development of an immune- 
mediated adverse event 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 
study treatment 
● 
Investigator determines it is in the best interest of the patient 
● 
Use of another non-protocol anticancer therapy 
● 
Pregnancy 
● 
Loss of clinical benefit as determined by the investigator after an integrated assessment 
of radiographic and biochemical data, local biopsy results (if available), and clinical 
status (e.g., symptomatic deterioration such as pain secondary to disease) (see Section 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
28 
 
 
6.5.2 for details) 
● If one component of study treatment is discontinued permanently because of tolerability 
concerns, the patient may continue with other components of study treatment until 
disease progression if agreed upon by the investigator and patient 
● If the patient fails to comply with the defined treatment plan and follow-up evaluations 
● If the patient withdraws consent for continued participation 
 
6.5.2 
Treatment Beyond Radiographic Progression 
To better accommodate standard clinical practice which is guided by the fact that these patients 
have, in general, limited treatment options and such options also have limited efficacy and 
significant toxicity, patients may be considered for treatment beyond radiographic progression 
per RECIST v1.1 at the discretion of the investigator and after appropriate discussion with the 
patient and obtaining informed consent, only if all of the following criteria are met: 
● Evidence of clinical benefit as assessed by the investigator 
● Absence of symptoms and signs (including worsening of laboratory values [e.g., new or 
worsening hypercalcemia]) indicating unequivocal progression of disease 
● No decline in ECOG performance status that can be attributed to disease progression 
● Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) 
that cannot be managed by protocol-permitted medical interventions 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
29 
 
 
 
● Patients must provide written consent to acknowledge deferring alternative treatment 
options in favor of continuing study treatment at the time of initial progression. 
Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 
should be closely monitored clinically and a follow-up scan should be performed in 6 weeks, or 
sooner if symptomatic deterioration occurs. Treatment should be discontinued if clinical 
deterioration due to disease progression occurs at any time or if persistent disease growth is 
confirmed in a follow-up scan. In addition, patients should be discontinued for unacceptable 
toxicity or for any other signs or symptoms of deterioration attributed to disease progression as 
determined by the investigator after an integrated assessment of radiographic data and clinical 
status. 
 
6.5.3 
Data Collection and Follow-up for Withdrawn Subjects 
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 in the patient’s medical 
records. If a patient requests to be withdrawn from the study, this request must be documented in 
the source documents and signed by the investigator. Patients who withdraw from the study 
before on-treatment study effects can be assessed will be replaced. If >3 patients (~20% of 
projected enrollment) require replacement, enrollment will be paused for the study team to 
review safety data until that point to assure safe continuation of the study. If it is determined that 
DLTs of special interest from liver-directed SBRT are occurring at a higher rate than would be 
expected in previous studies of chemoimmunotherapy and liver-directed SBRT, respectively, we 
will implement a dose reduction of SBRT as described in Section 9.6 for an additional 3 patients 
and reassess the rate of toxicity before completing enrollment. 
 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
 
7 
REGISTRATION PROCEDURES 
 
CUIMC Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process. Furthermore, properly delegated/trained 
Physician Investigators (e.g., MD, MD PhD) are required to sign/verify a protocol specific 
Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
30 
 
 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST 
(excluding holidays and weekends). Same day patient registrations (and after hour 
registrations) will be accommodated on a case by case basis provided that the study team 
has expressed all time sensitive registration concerns/cases in a timely manner to the 
Central Registration Office. 
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@columbia.edu or fax to 
212.305.5292, with the subject line “AAAT0174 Pending Subject Registration Request (PHI)”. 
Upon receipt, applicable subject information as well as a “pending eligibility” status will be 
entered into HICCC’s institutional database. This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 
pending registration submissions are as follows: 
 
● 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (e.g., tissue, DNA, etc.), as applicable. 
● 
The completed/signed IRB approved HIPAA Authorization form 
 
● 
Completed/signed CPDM ICF checklist 
 
● 
Completed/signed HICCC personal census form 
 
● 
Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
 
● 
The completed/signed study specific Eligibility Checklist (signed by an Physician level 
Investigator) 
● 
Copies of source documentation necessary for each item to be verified on the CPDM 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
 
o Copy of pathology and surgical reports 
Copy of clinic note(s) or other appropriate medical records capturing the consent process information, along 
with providing source documentation of any other items needed for screening/eligibility that are not captured 
in other source document forms (e.g., positive investigator statements of unique eligibility items not captured 
via other direct source documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
31 
 
 
● 
Please note: subject line of email or fax should include the following: “AAAT0174 
Complete Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional CTMS database by the Central Registration 
Registrar. Upon completion, an official subject registration notification email will be sent to the 
PI/research team which will include eligibility/enrollment status, as well as subject ID 
information. Protocol therapy may not be initiated prior to receipt of this notification from the 
Central Registration Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
 
8 
TREATMENT PLAN 
 
8.1 
Agent Administration 
See Section 11 for further information 
 
8.2 
Radiation Therapy 
Radiation will be administered in 3 fractions of 10 Gy, given every other day. As many as 3 
lesions, each no greater than 5 cm in diameter on study tumor assessment scan, will be targeted. 
If more than 3 lesions meeting study criteria are present, those to be targeted will be selected 
based on the Radiation Oncologist and treating investigator’s shared judgment of those least 
likely to cause toxicity. The SBRT treatment planning, normal tissue constraints, and delivery 
methods used in this study have been previously described51. 
8.3 
General Concomitant Medication and Supportive Care Guidelines 
Permitted Therapy 
Premedication with antihistamines may be administered for any atezolizumab infusions after 
Cycle 1. 
 
The following therapies should continue while patients are in the study: 
• 
Oral contraceptives 
• 
Hormone-replacement therapy 
• 
Prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin or warfarin at a stable dose level) 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
32 
 
 
 
• 
Palliative radiotherapy (e.g., treatment of known bony metastases) only if deemed 
appropriate by principal investigator 
o At minimum, palliative radiotherapy should not interfere with the assessment of 
tumor target lesions (e.g., the lesion being irradiated is not the only site of disease, 
as that would render the patient not evaluable for response by tumor assessments 
according to RECIST v1.1) 
• 
Inactive influenza vaccinations 
• 
Megestrol administered as an appetite stimulant 
• 
Inhaled corticosteroids for chronic obstructive pulmonary disease 
• 
Mineralocorticoids (e.g., fludrocortisone) 
• 
Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency 
In general, investigators should manage a patient’s care with supportive therapies as clinically 
indicated per local standards. Patients who experience infusion-associated symptoms may be 
treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or 
another H2 receptor antagonist per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice). Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation, or respiratory distress should be managed with supportive therapies as clinically 
indicated (e.g., supplemental oxygen and β2-adrenergic agonists; see Appendix 21.2, 21.3). All 
medications must be recorded on the appropriate Concomitant Medications eCRF. 
 
Cautionary Therapy 
Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab. Therefore, in situations where systemic corticosteroids or 
TNF-α inhibitors would be routinely administered, alternatives, including antihistamines, should 
be considered first by the treating physician. If the alternatives are not clinically appropriate, 
systemic corticosteroids and TNF-α inhibitors may be administered at the discretion of the 
treating physician except in the case of patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance) 
 
Systemic corticosteroids are recommended, with caution, at the discretion of the treating 
physician, for the treatment of specific adverse events when associated with atezolizumab 
therapy. 
 
Refer to the atezolizumab Investigator’s Brochure for additional information on the 
management of immune-mediated adverse events. 
 
Prohibited Therapy 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority−approved or experimental, is prohibited for various time periods prior to starting study 
treatment, depending on the anti-cancer agent, and during study treatment until disease 
progression is documented and patient has discontinued study treatment. This includes, but is not 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
33 
 
 
 
limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy (unless otherwise noted). 
 
The following medications are prohibited while on study, unless otherwise noted: 
• 
Traditional herbal medicines, because their use may result in unanticipated drug-drug 
interactions that may cause or confound assessment of toxicity 
• 
Denosumab; patients who are receiving denosumab prior to enrollment must be willing 
and eligible to receive a bisphosphonate instead while in the study 
• 
Any live, attenuated vaccine (e.g., FluMist®) within 28 days prior to randomization, 
during treatment, or within 90 days following the last dose of atezolizumab/placebo 
• 
Use of steroids to premedicate patients for whom CT scans with contrast are 
contraindicated (i.e., patients with contrast allergy or impaired renal clearance); in such 
patients, non-contrast CT scans of the chest and non-contrast CT scans or MRIs of the 
abdomen and pelvis should be performed 
8.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for 2 years (34 
cycles) or until one of the following criteria applies: 
 
● Disease progression 
● Intercurrent illness that prevents further administration of treatment 
● Unacceptable adverse events(s) 
● Patient decides to withdraw from the study 
● General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
8.5 
Duration of Follow Up 
 
Patients will be followed for 2 years after completion or removal from study or until death, 
whichever occurs first. Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
8.6 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 6.5 applies. The 
reason for study removal and the date the patient was removed will be documented in the Case 
Report Form. 
 
 
9 
DOSING DELAYS/DOSE MODIFICATIONS 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
34 
 
 
 
9.1 
General Notes Regarding Dose Modification 
Reasons for dose modifications or delays, the supportive measures taken, and the outcomes will 
be documented in the patient's chart and recorded on the eCRF. The severity of adverse events 
will be graded according to the NCI CTCAE v5.0 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, dose 
modifications should be made 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, etoposide, or radiation) 
and the dose of that component is delayed or modified in accordance with the guidelines 
below, other components may be administered if there is no contraindication. 
● When treatment is temporarily interrupted because of toxicity caused by atezolizumab, 
carboplatin, etoposide, or radiation, the treatment cycles should be restarted such that the 
atezolizumab infusions remain synchronized and aligned with the chemotherapy 
schedule. 
● If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
chemotherapy drug, the dose of the other chemotherapy drug does not require 
modification. The investigator may use discretion in modifying or accelerating the dose 
modification guidelines described below depending on the severity of toxicity and an 
assessment of the risk versus benefit for the patient, with the goal of maximizing patient 
compliance and access to supportive care. 
9.2 
Atezolizumab Dose Modification 
There will be no dose reduction for atezolizumab in this study. Patients may temporarily suspend 
study treatment for up to 105 days beyond the last dose if they experience an adverse event that 
requires a dose to be held. If atezolizumab is withheld because of adverse events for more than 
105 days beyond the last dose, then the patient will be discontinued from atezolizumab 
treatment. If a patient must be tapered off steroids used to treat adverse events, atezolizumab 
may be withheld for additional time beyond 105 days from the last dose until steroids are 
discontinued or reduced to prednisone dose (or dose equivalent) ≤10 mg/day. The acceptable 
length of interruption will depend on agreement between the investigator and the Medical 
Monitor. Dose interruptions for reason(s) other than adverse events, such as surgical procedures, 
may be allowed with Medical Monitor approval. The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor. 
 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Although most immune-mediated adverse events 
observed with immunomodulatory agents have been mild and self-limiting, such events should 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
35 
 
 
 
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-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids or other immunosuppressive agents. The investigator should consider 
the benefit-risk balance a given patient may be experiencing prior to further administration of 
atezolizumab. Atezolizumab should be permanently discontinued in patients with life- 
threatening immune-mediated adverse events. 
 
The primary approach to Grade 1−2 immune-related adverse events (irAEs) is supportive and 
symptomatic care with continued treatment with atezolizumab; for higher grade irAEs, 
atezolizumab should be held and oral/parenteral steroids administered. Recurrent Grade 2 irAEs 
may also mandate holding atezolizumab or the use of steroids. Consideration for 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 immune-related adverse events. 
 
Refer to the atezolizumab Investigator’s Brochure for more detailed information regarding 
dose modification. 
 
9.3 
Carboplatin Dose Modification 
Dose modifications for carboplatin are permitted according to the carboplatin prescribing 
information and local standard-of-care. The following are suggested recommendations for dose 
modification of carboplatin for hematologic and non-hematologic toxicities. 
 
9.3.1 Hematologic toxicity 
At the start of each cycle, the ANC should be ≥1500/mm3 and the platelet count should be 
≥100,000/mm3. Treatment should be delayed for up to 42 days to allow sufficient time for 
recovery. If the counts have not recovered in 3 weeks, the patient’s carboplatin may be dose- 
reduced, held until adequate neutrophil recovery, or discontinued, according to physician 
judgment and local standard practice. Growth factors may be used in accordance with American 
Society of Clinical Oncology (ASCO) and the 2015 NCCN guidelines52. Upon recovery, dose 
adjustments at the start of a subsequent cycle may be made on the basis of the lowest platelet and 
neutrophil values from the previous cycle (see Table 1). 
 
Table. 1 Carboplatin Dose Modification for Hematologic Toxicities 
Toxicitya 
Carboplatin 
ANC <500/mm3 and platelets ≥50,000/mm3 
75% of previous dose 
Platelets <25,000/mm3, regardless of ANC 
75% of previous dose 
Platelets <50,000/mm3, with grade ≥2 bleeding regardless of ANC 
75% of previous dose 
ANC <1000/mm3 plus fever of ≥38.5°C 
75% of previous dose 
aNadir prior to cycle 
 
Dose reductions for the first episode of neutropenic fever or thrombocytopenia (platelet count 
<25,000 or <50,000 with bleeding or that requires transfusion) should be considered permanent. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
36 
 
 
 
If a second episode of neutropenic fever or thrombocytopenia requiring dose reduction occurs, 
the dose of carboplatin should be reduced according to physician judgment and local standard 
practice. Colony-stimulating factors, such as granulocyte colony-stimulating factor, may be used 
instead of dose reduction for neutropenic fever or Grade 4 neutropenia according to the local 
standard practice and ASCO guideline. Patients who require a third dose reduction should be 
considered for permanent discontinuation of carboplatin. 
 
In the event that dose adjustments are needed for both ANC and platelets, patients should receive 
the lower dose. 
 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, infection, 
or febrile neutropenia so that these complications can be promptly and appropriately managed. 
Patients should be made aware of these signs and encouraged to seek medical attention at the 
earliest opportunity. 
 
If carboplatin is withheld because of hematologic toxicity, full blood counts (including 
differential WBC) should be obtained weekly until the counts reach the lower limits for 
treatment as outlined. The treatment schedule should then proceed in the usual sequence. 
 
No dose reductions are needed for anemia. Patients may be supported per the treating 
physician’s institution’s guidelines. 
 
9.3.2 Non-hematologic toxicity 
For Grade 3 or 4 non-hematologic toxicities, treatment should be delayed until 
resolution to less than or equal to the patient’s baseline value. Dose reductions at 
the start of the subsequent cycle should be made on the basis of non-hematologic 
toxicities from the dose administered in the preceding cycle. Table 2 provides 
recommended dose adjustments for non-hematologic toxicities. 
 
Table 2 Carboplatin Dose Modification on the Basis of Non-Hematologic Toxicities in the Preceding 
Cycle 
Toxicity 
Adjusted Carboplatin Dose as 
% of Previous Dosea 
Diarrhea 
Grade 3 or 4b 
100% 
Oral mucositis 
Grade 3 or 4 
75% 
Nausea/vomiting 
Grade 3 or 4 
75% 
Neurotoxicity 
(motor or sensory) 
Grade 2 
Grade 3 or 4 
100% 
75% 
Transaminase 
elevation 
Grade 3 
Grade 4 
75% 
Discontinue 
Other 
Grade 3 or 4 
75% 
AUC= area under the concentration-time curve 
aIf deemed appropriate by the treating physician, adjust carboplatin dose to the specified 
percentage of the previous AUC 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
37 
 
 
 
 
 
Nausea and/or vomiting may be controlled with adequate anti-emetics. If Grade 3 or 4 
nausea/vomiting occurs despite the use of anti-emetics, the dose may be reduced by 25% for the 
next course. If tolerated, the dose may be increased back to 100% as soon as possible. If, on Day 
1 of any treatment cycle, the patient has oral mucositis, carboplatin may be withheld until the 
oral mucositis is cleared. If the oral mucositis has not cleared in 3 weeks, carboplatin may be 
discontinued. If acute Grade 3 oral mucositis occurs at any time, the dose may be given at a 75% 
dose when the oral mucositis is completely cleared. This may be considered a permanent dose 
reduction. 
 
9.3.3 Other toxicity 
For any Grade 3 or 4 toxicity not mentioned above, carboplatin may be withheld until the patient 
recovers completely or to Grade 1 toxicity. The treatment may then be resumed at 50% dose. 
This may be considered a permanent dose reduction. If recovery to Grade 1 toxicity does not 
occur within 3 weeks, the patient’s carboplatin may be discontinued. For Grade 1 and 2 
toxicities, no dose reduction should be made. 
 
9.4 
Etoposide Dose Modification 
Dose modifications for etoposide are permitted according to the etoposide prescribing 
information and local standard-of-care. Once reduced, the current dose cannot be increased back 
to 100%. Suggested recommendations for dose modification of etoposide are provided in Table 
3. 
 
Table 3. Etoposide Dose Modification for Renal Impairment 
Creatinine clearance (mL/min) 
Etoposide Dose 
>50 
100% 
15-50 
75% of dose 
 
9.5 
Radiation Dose Modification 
We will assess the rate of liver SBRT-specific toxicities in excess of those expected from atezolizumab + 
chemotherapy. If >3 patients (~20% of projected enrollment) require replacement, enrollment will be paused 
for the study team to review safety data until that point to assure safe continuation of the study. 
 
Specifically, toxicities of special interest will include those anatomically relevant to the radiation field, 
including but not limited to: dysfunction, pain, inflammation, obstruction, stenosis, ulceration, perforation, 
hemorrhage, necrosis, or vasculopathy of the alimentary or hepatopancreaticobiliary tracts. Excess irAEs will 
also be investigated as possibly related to study combination therapy. 
 
If it is determined that excess toxicity is resulting from the study combination, enrollment may resume at an 
SBRT dose reduction from 10 to 6 Gy to per dose. After dose-reduction, if an additional patient requires 
replacement due to toxicity, we will again pause enrollment for safety review. An additional dose-reduction 
to 4 Gy per dose may then be considered. If further toxicity of special interest is observed we will close the 
study. 
 
9.6 
Potential Overlapping Toxicities 
bOr any grade of diarrhea requiring hospitalization 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
38 
 
 
The risk of overlapping toxicities between atezolizumab, carboplatin, and etoposide is thought to 
be minimal. Nevertheless, the attribution and management of certain adverse events that have 
been associated with each agent separately (e.g., hepatotoxicity, skin and gastrointestinal 
toxicity) may be ambiguous 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 recommendations in Sections 9.1-9.3 
with dose holds and modifications (if applicable) applied to the component of the study drug 
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 adverse events 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 105 days beyond when the next dose should 
have been given (see Section 9.1). Prompt symptomatic management is appropriate for mild 
immune-mediated adverse events. In severe cases, immune-mediated toxicities may be acutely 
managed with systemic corticosteroids or TNF-α inhibitors. These cases should be discussed 
with the Medical Monitor. 
 
10 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
10.1 Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording adverse events, including serious 
adverse events and non-serious adverse events of special interest; measurement of protocol- 
specified safety laboratory assessments; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. Assessment 
will occur per protocol. Certain types of events require immediate reporting to the Principal 
Investigator, as outlined in Section 10.4. 
 
A comprehensive list of all reported adverse events and any potential risks associated with 
atezolizumab, carboplatin, and etoposide can be found in the manufacturer’s package insert for 
each agent. 
 
10.2 Definitions 
Adverse Event: 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including abnormal sign, symptom or disease, temporally associated with the subject’s 
participation in research, whether or not considered related to the subject’s participation in the 
research. Abnormal results of diagnostic procedures are considered to be adverse events if the 
abnormality: 
● 
results in study withdrawal 
● 
is associated with a serious adverse event 
● 
is associated with clinical signs or symptoms 
● 
leads to additional treatment or to further diagnostic tests 
● 
is considered by the investigator to be of clinical significance 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
39 
 
 
 
AE could also be a Pre Existing medical condition (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. 
Serious Adverse Event: 
Adverse events are classified as serious or non-serious. A serious adverse event (SAE) is any AE 
that is: 
● 
Death(i.e., the AE actually causes or leads to death). 
● 
life-threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death). 
● 
requires inpatient hospitalization/prolongation of existing hospitalization, unless: 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
40 
 
 
 
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (procedures such as central line placements, paracentesis, 
pain control) 
o elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above/below and not resulting in hospital administrations 
o social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
● 
results in persistent or significant disability or incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions) 
● 
a congenital anomaly or birth defect 
● 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious events should be regarded as 
non-serious adverse events. 
 
Serious adverse events are required to be reported by the investigator to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 10.4 for reporting instructions). 
 
Unanticipated Problem: 
An unanticipated problem is any incident, experience or outcome involving risks to subjects or 
others in any human subjects research that meets all of the following criteria: 
● Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB-approved protocol and informed consent document, and (b) the 
characteristics of the subject population being studied; 
● Related or possibly related to participation in such research (e.g., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the procedures 
involved in such research); and 
● Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or recognized. 
Adverse Event of Special Interest (AESI) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication to the Principal Investigator is 
required. Such an event might require further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the Principal 
Investigator to other parties (e.g., Regulatory Authorities) may also be warranted. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
41 
 
 
 
The following AEs are considered of special interest and must be reported to the Principal 
Investigator expeditiously, irrespective of regulatory seriousness criteria: 
 
 
The following confirmed treatment-emergent autoimmune conditions: 
o Systemic lupus erythematosus 
o 
o Nephritis 
o Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
o Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
o Vasculitis 
o Autoimmune hemolytic anemia. 
o Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
o Events suggestive of hypersensitivity, cytokine release syndrome, infusion-related 
reactions, macrophage activating syndrome, hemophagocytic lymphohistiocytosis 
● Cases of potential drug--induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law 
• 
Treatment-emergent ALT or AST ≥3x ULN in combination with total bilirubin 
≥2x ULN 
• 
Treatment-emergent ALT or AST ≥3x ULN in combination with clinical 
jaundice 
 
● Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
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. 
Adverse Event Reporting Period 
The study period during which AEs and SAEs where the patient has been exposed to Genentech 
product must be reported during the reporting period which begins after informed consent is 
obtained. Subjects will be followed for serious adverse events and adverse events of special 
interest for 90 days after their last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first. For all other adverse events, Subjects will be followed for 30 days after 
their last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first. 
Investigators are instructed to report all SAEs and AESIs considered related to study treatment 
regardless of time after study. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
42 
 
 
 
Post-study Adverse Event 
Subjects 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 anti-cancer treatment is initiated, the 
patient is lost to follow-up, the patient withdraws consent, or it has been determined that study 
treatment or participation is not the cause of the adverse event. At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject or the 
treating physician believes might reasonably be related to participation in this study. 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include: 
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?” 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
Baseline/Preexisting Condition 
A baseline/preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or if the character of 
the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition. At the end of the study, any new clinically significant findings/abnormalities that meet 
the definition of an adverse event must also be recorded and documented as an adverse event. 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met: 
● 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
● 
The abnormality suggests a disease and/or organ toxicity 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
43 
 
 
 
● 
The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc.). 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol. Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
● 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition. Surgery should not be reported as an outcome of an adverse event if 
the purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
● 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
● 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless 
it is a worsening or increase in frequency of hospital admissions as judged by the treating investigator. 
 
10.3 Recording of Adverse Events 
At each contact with the subject, the treating investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination. Information on all adverse 
events should be recorded immediately in the source document, and also in the appropriate 
adverse event module of the case report form (CRF). All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should recorded in the source document, though should 
be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause. Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
 
10.3.1 Assessment of Adverse Event 
Each reported AE or SAE will be described by its duration (i.e., start and end dates), regulatory 
seriousness criteria if applicable, severity, casuality (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
 
Yes (definitive, probable, possible, unlikely) 
There is a plausible temporal relationship between the onset of the AE and administration of 
study drugs or radiation and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
44 
 
 
Life-threatening consequences or urgent intervention indicatedd 
Death related to adverse eventd 
4 
5 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
Moderate; minimal, local, or non-invasive intervention indicated; 
or limiting age−appropriate instrumental activities of daily living a 
● 
Severe or medically significant, but not immediately 
life−threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; or limiting self-care activities of daily living 
b,c 
3 
● 
2 
● 
1 
Severity 
Grade 
 
to atezolizumab, carboplatin, etoposide, or liver-directed radiation; and/or the AE abates or 
resolves upon discontinuation of study treatment or dose reduction and, if applicable, reappears 
upon re-challenge. 
 
No (unrelated) 
Evidence exists that the AE has an etiology other than the study treatment (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
the AE has no plausible temporal relationship to study treatment (e.g., cancer diagnosed 2 days 
after first dose of atezolizumab). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (PI) or current Investigator Brochure (IB). 
 
Unexpected adverse events are those not listed in the PI or current IB or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the description 
in the PI or IB. For example, under this definition, hepatic necrosis would be unexpected if the 
PI or IB referred only to elevated hepatic enzymes or hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
 
10.3.2 Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for assessing 
adverse event severity. Table 4 should be used for assessing severity for adverse events that are 
not specifically listed in the NCI CTCAE. 
 
Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI 
CTCAE 
 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
45 
 
 
 
 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events. 
Note: Based on the most recent version of NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as performed 
by patients who are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a 
serious adverse event 
d Grade 4 and 5 events must be reported as serious adverse events 
Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 5 months after the 
last dose of study drug, a report should be completed and expeditiously submitted to Genentech, 
Inc. Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether 
accidental, therapeutic, or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the study drug should be reported as an SAE. 
 
10.4 Reporting of Serious Adverse Events 
10.4.1 Collection of Adverse Event Reports 
The Sponsor will be responsible for collecting all protocol-defined Adverse Events 
(AEs)/Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation 
Reports (including pregnancy reports) and Product Complaints (with or without an AE) 
originating from the Study for the Product. 
 
10.4.2 Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 10.2), 
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” 
 
10.4.3 IRB Notification by Investigator 
Reports of all events (including follow-up information) that meet the definition of an unanticipated 
problem posing risk to subjects or others must be submitted to the IRB within one week (5 business 
days) following the occurrence of the unanticipated problem or the principal investigator’s 
learning of the unanticipated problem in accordance with IRB policy. Additionally, the 
investigator will submit a summary of all Unanticipated problems that occurred since the 
beginning of the study at the time of continuing review. Copies of each report and documentation 
of IRB notification and receipt will be kept in the Regulatory binder. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
46 
 
 
 
 
Sponsor of the study will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
 
10.4.4 FDA Notification by Sponsor-Investigator 
The Columbia University Irving Medical Center Sponsor Investigator must report to the FDA 
and any affiliate site investigators as follows: 
 
 
● Any unexpected fatal or life-threatening event must be reported as soon as possible, but no 
later than 7 calendar days after the sponsor investigator initial receipt of the information 
● Any findings from epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not conducted by the 
sponsor-investigator, that suggest a significant risk in humans exposed to the drug must be 
reported as soon as possible but no later than 15 calendar days after the investigator 
determines that the information qualifies for reporting 
● Any findings from animal or in vitro testing whether or not conducted under an IND, and 
whether or not conducted by the sponsor-investigator, that suggest a significant risk in 
humans exposed to the drug must be reported as soon as possible but no later than 15 
calendar days after the sponsor-investigator determines that the information qualifies for 
reporting 
● Any clinically important increase in the rate of a serious suspected adverse reactions over 
that listed in the protocol or Investigator Brochure 
● Expected SAEs and AEs will be included in Annual Reports. 
 
 
10.4.5 DSMC Reporting 
Serious adverse events not constituting unanticipated problems are to be reported to the HICCC 
DSMC. Reporting should occur within 24 hours of knowledge of the SAE occurring at our 
institution or affiliate sites. 
 
10.4.6 Reporting to Drug Manufacturer by Sponsor-Investigator 
Investigators must report single case reports as mentioned in Section 10.4.1 adequately within 
the timelines described below. The completed Genentech approved reporting forms should be 
faxed/emailed immediately upon completion to Genentech at the following contacts: 
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy 
reports) and Product Complaints with an AE should be sent to: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
All Product Complaints without an AE should be reported to: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
47 
 
 
 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs, 
SAEs, AESIs, Special Situation reports (including pregnancy reports) and Product Complaints 
(with or without an AE) originating from the study. 
 
These single case reports will be exchanged between the parties as outlined below so that 
regulatory obligation are met. Transmission of these reports (initial and follow-up) will be 
either electronically or by fax and within the timelines specified below: 
 
SADRs (Serious Adverse Drug Reaction) 
Serious AE reports that are related to the Product shall be transmitted to Genentech within 
thirty (30) calendar days of the awareness date. 
 
Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within 
thirty (30) calendar days of the awareness date. 
 
AESIs 
AESIs requiring expedited reporting shall be forwarded to Genentech within thirty (30) 
calendar days of the awareness date. 
 
Special Situation Reports 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined 
herein, any reports of pregnancy (including pregnancy occurring in the partner of a male study 
subject), where the fetus may have been exposed to the Product, shall be transmitted to 
Genentech within thirty (30) calendar days of the awareness date. Pregnancies will be followed 
up until the outcome of the pregnancy is known, whenever possible, based upon due diligence 
taken to obtain the follow-up information. 
 
 
Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations 
Reports should be collected and transmitted to Genentech even in the absence of an Adverse 
Event within thirty (30) calendar days: 
● Data related to product usage during breastfeeding 
● Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
48 
 
 
 
● In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population 
Product Complaints 
All Product Complaints (with or without an AE) shall be forwarded to Genentech within thirty 
(30) calendar days of the awareness date. 
A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, 
durability, effectiveness, or performance of a product after it has been released and distributed 
to the commercial market or clinical trial. 
 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
Genentech as the Marketing Authorization Holder will be responsible for the reporting of 
individual case safety reports from the study to the regulatory authority in compliance with 
applicable regulations 
 
The Sponsor of the Study, will be responsible for the expedited reporting of safety reports originating from the Study 
to the EMA through Eudravigilance Clinical Trial Module (EVCTM), where applicable. 
 
The will be responsible for the expedited reporting of safety reports originating from the Study to the Ethics 
Committees and Institutional Review Boards (IRB), where applicable. 
 
Sponsor will be responsible for the distribution of safety information to its own investigators, where relevant, in 
accordance with local regulations. 
 
Case Transmission Verification of Single Case Reports 
 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech via Sponsor Investigator (Columbia 
University Irving Medical Center) emailing Genentech a Quarterly line-listing documenting 
single case reports sent by Sponsor Investigator to Genentech in the preceding time period. 
The periodic line-listing will be exchanged within five (5) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period mutually 
agreed upon. 
 
If discrepancies are identified, the Sponsor 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’. 
 
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Sponsor Investigator to Genentech within five (5) calendar 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
49 
 
 
days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to 
Genentech 
 
10.5 
HICCC DSMC Reporting Process 
All SAEs must be reported using the HICCC DSMC Serious Adverse Event Reporting Form and 
submitted to the central HICCC DSMC email at: HICCC_DSMC@lists.cumc.columbia.edu. 
Affiliate sites will report all SAEs directly to the HICCC CPDM Multicenter Trials Core. 
Any events that qualify for FDA reporting to the applicable IND/IDE, must be vetted through the 
CPDM IND officer, in collaboration with the applicable regulatory staff. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
50 
 
 
 
 
 
 
10.6 AGGREGATE REPORTS 
 
Development Safety Update Report 
 
The Sponsor of the Study, will be responsible for the preparation of their own Development Safety Update Report 
(DSUR) for the Study and for the submission of the report to the regulatory authorities and Ethics Committees of the 
concerned Member States, where applicable. The Sponsor agrees to share a copy of their own DSUR with Genentech 
as soon as reasonably possible after completion. 
 
Genentech agrees to forward to the Sponsor an executive summary of the Genentech DSUR upon request. 
Furthermore, Genentech agrees that Sponsor may cross-reference the executive summary of the Genentech DSUR, as 
applicable. 
 
Sponsor will forward a copy of the Final Study Report to Genentech upon completion of the Study. 
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). 
In addition to the Final Study Report, any literature articles that are a result of the study should be 
sent to Genentech by the Sponsor-Investigator. Copies of such reports should be mailed to the 
assigned Clinical Operations contact for the study: 
 
Atezolizumab IIS Clinical Operations: anti-pdl-1-mpd3280a-gsur@gene.com 
 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
QUERIES 
Queries related to the Study will be answered by Columbia University Irving Medical Center 
(Sponsor Investigator). However, responses to all safety queries from regulatory authorities or for 
publications will be discussed and coordinated between the Parties. The Parties agree that 
Genentech shall have the final say and control over safety queries relating to the Product. Sponsor 
Investigator agrees that it shall not answer such queries from regulatory authorities and other 
sources relating to the Product independently but shall redirect such queries to Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests 
for information or review of data are met. The Parties will clearly indicate on the request the reason 
for urgency and the date by which a response is required. 
 
SAFETY CRISIS MANAGEMENT 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
51 
 
 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on 
the conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict 
the way in which the Product is used, or where there is media involvement, the Party where the 
crisis originates will contact the other Party as soon as possible. 
 
The Parties agree that Genentech shall have the final say and control over safety crisis management 
issues relating to the Product. Columbia University Irving Medical Center (Sponsor Investigator) 
agrees that it shall not answer such queries from media and other sources relating to the Product 
but shall redirect such queries to Genentech. 
 
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
52 
 
 
 
The Parties shall follow their own procedures for adherence to AE reporting timelines. 
Each Party shall monitor and, as applicable, request feedback from the other Party regarding AE 
report timeliness in accordance with its own procedures. The Parties agree to provide written 
responses in a timely manner to inquiries from the other Party regarding AE reports received 
outside the agreed upon Agreement timelines. If there is any detection of trends of increasing or 
persistent non-compliance to transmission timelines stipulated in this Agreement, both Parties 
agree to conduct ad hoc or institute a regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange timelines, with 
this Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving the 
issues causing non-compliance. Every effort will be made by the non-compliant Party to solve the 
non-compliance issues and inform the other Party of the corrective and preventative actions taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit 
 
 
11 
PHARMACEUTICAL INFORMATION 
Study Drugs 
11.1 
Description 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 
and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as 
CD80), both of which function as inhibitory receptors expressed on T cells. Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude and 
quality of tumor−specific T−cell responses, resulting in improved anti-tumor activity. 
Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc−effector 
function and associated antibody-mediated clearance of activated effector T cells. 
 
Atezolizumab, carboplatin and etoposide are commercially available and are considered to be 
non-Investigational Medicinal Products (NIMPs). 
 
11.2 
Treatment Regimen 
Induction phase- four cycles of 21 days duration each will be administered as follows: 
● Atezolizumab fixed dose of 1200 mg administered IV on day 1 
● Carboplatin AUC=5 administered IV on day 1 
● Etoposide 100 mg/m2 on days 1, 2, and 3 of each cycle 
● Stereotactic body radiation therapy administered to up to 3 liver lesions within +/-3 days 
of cycle 2 day 1. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
53 
 
 
Subsequent Infusions 
First Infusion 
 
Maintenance phase: atezolizumab 1200 mg administered on day 1 in 21 day cycles until 
withdrawal criteria are met as outlined in Section 5.5. 
 
11.3 
Method for Assigning Subjects to Treatment Groups 
All patients enrolled in this study will receive the same study treatment protocol. 
 
11.4 
Preparation and Administration of Study Drug 
Atezolizumab, carboplatin and etoposide are prepared according to the recommendations from 
the manufacturers’ label. All drugs are obtained through standard commercial pharmacies. 
 
Any overdose or incorrect administration of any of the study treatments should be noted in the 
patient’s medical records and reported according to Section 10.4 (Special Situations 
Reports). Adverse events associated with an overdose or incorrect administration of any of the 
study treatments should be recorded in the patient’s medical records 
 
Guidelines for dosage modification treatment interruption or discontinuation for patients who 
experience adverse events are provided in Section 9. 
 
Atezolizumab Administration 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. For anaphylaxis precautions, see Appendix 21.2. Atezolizumab 
infusions will be administered per the instructions outlined in Table 5. 
 
Table 5 
Administration of First and Subsequent Atezolizumab Infusions 
 
● No premedication is permitted prior to the 
atezolizumab infusion. 
● Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to 
the infusion. 
● Atezolizumab should be infused over 
60 (± 15) minutes. 
● If clinically indicated, vital signs should 
be measured every 15 (± 5) minutes 
during the infusion and at 
30 (± 10) minutes after the infusion. 
● Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
● If the patient experienced an infusion- 
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
● Vital signs should be measured within 
60 minutes prior to the infusion. 
● Atezolizumab should be infused over 
30 (± 10) minutes if the previous 
infusion was tolerated without an 
infusion-related reaction, or 60 (± 15) 
minutes if the patient experienced an 
infusion-related reaction with the 
previous infusion. 
● If the patient experienced an infusion- 
related reaction with the previous 
infusion or if clinically indicated, vital 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
54 
 
 
 
 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix 21.3. 
 
No dose modification for atezolizumab is allowed. 
 
Carboplatin Administration 
Carboplatin should be administered after completion of atezolizumab/placebo by IV infusion 
over 30−60 minutes to achieve an initial target AUC of 5 mg/mL/min (Calvert formula dosing) 
with standard anti-emetics per local practice guidelines. Because the effects of corticosteroids on 
T-cell proliferation have the potential to attenuate atezolizumab-mediated anti-tumor immune 
activity, premedication with corticosteroids should be minimized to the extent that is clinically 
feasible. 
The carboplatin dose of AUC 5 will be calculated using the Calvert formula (Calvert et al. 1989): 
Calvert FormulaTotal dose (mg)=(target AUC)×(glomerular filtration rate [GFR]+25) 
NOTE: The GFR used in the Calvert formula to calculate AUC-based dosing should not exceed 
125 mL/min. 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the creatinine 
clearance (CRCL). The CRCL is calculated by institutional guidelines or by the method of 
Cockcroft and Gault (1976) using the following formula: 
CRCL=
("#$%&'()(*+) (× 0.85 𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓) 
,-./01 
 
Where:  
CRCL=creatinine clearance in mL/min 
age=patient's age in years 
wt=patient’s weight in kg 
Scr=serum creatinine in mg/dL 
 
NOTE: For patients with an abnormally low serum creatinine level, estimate the GFR through 
use of a minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 125 mL/min. 
 
If a patient’s GFR is estimated based on serum creatinine measurements by the isotope dilution 
mass spectroscopy method, the FDA recommends that physicians consider capping the dose of 
carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. On the 
signs should be measured during the 
infusion and at 30 (± 10) minutes after 
the infusion. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
55 
 
 
 
basis of the Calvert formula described in the carboplatin label, the maximum doses can be 
calculated as follows: 
Maximum carboplatin dose (mg)=target AUC (mg×min/mL)×(GFR+25 mL/min) 
The maximum dose is based on a GFR estimate that is capped at 150 mL/min for patients with 
normal renal function. No higher estimated GFR values should be used. 
 
For a target AUC=5, the maximum dose is 5×150=750 mg. 
For a target AUC=4, the maximum dose is 4×150=600 mg. 
 
Refer to the FDA’s communication regarding carboplatin dosing with use of the following Web 
site for more details: 
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm22897 
4.htm 
 
Etoposide Administration 
During the induction phase (Cycles 1−4), on Day 1 of each cycle, etoposide (100 mg/m2) should 
be administered intravenously over 60 minutes following carboplatin administration. On Days 2 
and 3 of each cycle, etoposide (100 mg/m2) should be administered intravenously over 60 
minutes. Premedication should be administered according to local standard-of-care. Because the 
effects of corticosteroids on T cell proliferation have the potential to attenuate atezolizumab- 
mediated anti-tumor immune activity, premedication with corticosteroids should be minimized to 
the extent that is clinically feasible. 
 
11.5 
Subject Compliance Monitoring 
Compliance will be monitored by office visit documentation. 
 
11.6 
Prior and Concomitant Therapy 
All history pertaining to prior and/or concomitant medical therapy will be collected at the time of 
study enrollment.  See Section 8.3 for details regarding which concomitant 
medications/therapies are permitted during the study. 
 
11.7 
Packaging 
Atezolizumab, carboplatin and etoposide are considered non-Investigational Medicinal Products 
(NIMPs). Atezolizumab, carboplatin and etoposide will be used in the commercially available 
formulation. For information on the formulation, packaging, and handling of carboplatin and 
etoposide see the prescribing information for each drug. 
 
11.8 
Receiving, Storage, Dispensing and Return 
11.8.1 Receipt of Drug Supplies 
Atezolizumab, carboplatin and etoposide will be used in the commercially available formulation 
since they are NIMPs. 
 
11.8.2 Storage 
Storage conditions are described in the Manufacturer’s Package Insert for atezolizumab, 
carboplatin and etoposide. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
56 
 
 
 
 
11.8.3 Dispensing of Study Drug 
Regular study drug reconciliation will be performed to document drug administration. This 
reconciliation will be logged on the drug reconciliation form, and signed and dated by the study 
team. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
57 
 
 
 
12 
STUDY CALENDAR 
 
Every 3 week cycles (±2 days) 
Procedure/Interventiona 
Screenin 
g 
Induction Phase 
Maintenanc 
e Phase 
Treatment 
Discontinuatio 
n Visit 
Survival 
Follow 
up 
Days -28 
to -1 
C1D 
1 
C2D 
1 
C3D 
1 
C4D 
1 
CXD1 
<30 days after 
last dose 
Every 3 
months 
Informed Consent 
X 
Tumor Biopsyb 
X 
Liver metastasis biopsyc 
X 
Clinical Assessments 
Medical and Cancer 
History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
ECOG performance 
status 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsd 
X 
X 
X 
X 
X 
Survival Statuse 
X 
Treatment 
Atezolizumabf 
X 
X 
X 
X 
X 
Carboplating 
X 
X 
X 
X 
Etoposideg 
X 
X 
X 
X 
Liver-directed radiationh 
X 
Tumor Assessments 
Optional tumor biopsy 
At time of progression 
Brain MRI or CT head 
w/ contrast 
X 
CT chest and abdomen 
w/ contrasti 
Xj 
X 
Xk 
X 
Xl 
PET/CT (if applicable) 
X 
Laboratory Assessmentsm 
CBC 
X 
X 
X 
X 
X 
X 
X 
Chemistryn 
X 
X 
X 
X 
X 
X 
X 
PT/PTT 
X 
TSH, free T3, free T4o 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
Serum beta-HCGp 
X 
X 
EBV, HIV, HCV, HBV 
serologyq 
X 
Research bloodsr 
Xs,t 
Xt 
Xt 
Xt 
Xt 
Xt 
Xt 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
58 
 
 
 
1. Assessments should be performed prior to study drug infusion 
2. Histologic confirmation of SCLC diagnosis 
3. Liver biopsy must be obtained prior to pre-treatment for evaluation of exploratory biomarkers 
4. All serious adverse events and adverse events of special interest, regardless of relationship to 
study drug, will be reported until 90 days after the last dose of study drug or initiation of new 
anti-cancer therapy, whichever occurs first. All other adverse events, regardless of relationship to 
study drug, will be reported until 30 days after the last dose of study drug or initiation of new 
anti-cancer therapy, whichever occurs first. After this period, the investigator should report any 
serious adverse events or adverse events of special interest believed to be related prior to study 
drug treatment. 
5. Survival visits are to occur every 4 to 6 months from the date of the 6 month Follow-up visit. 
Survival follow-up information will be collected via telephone calls, patient medical records, 
and/or clinic visits. Study staff may use a public information source (e.g., county records), when 
permissible, to obtain information about survival status only. 
6. For atezolizumab, the initial dose will be delivered over 60 ( ± 15) minutes. If the first infusion is 
well tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes until loss of 
clinical benefit. 
7. For carboplatin and etoposide, drug should be administered as described in Section 11 
8. Liver directed radiation with three doses of 10Gy delivered on alternate days up to three liver 
lesions measuring no greater than 5 cm each should be started within 7 (+/-3) days ofC2D1 
9. CT scans (with oral/IV contrast unless contraindicated) or MRI scans of the chest and abdomen. 
10. A CT scan of the pelvis is required at screening and as clinically indicated or as per local 
standard-of-care at subsequent response evaluations. 
11. Perform every 6 weeks (±7 days) (approximately every two cycles) for 12 months following 
Cycle 1, Day 1 and then every 9 weeks (±7 days) thereafter, regardless of treatment delays, until 
radiographic disease progression, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first. Patients who continue treatment beyond radiographic disease 
progression per RECIST v1.1 will continue to undergo tumor assessments every 6 weeks (±7 
days) or sooner if symptomatic deterioration occurs. For these patients, tumor assessments should 
continue every 6 weeks (±7 days), regardless of time on study, until study treatment is 
discontinued. 
12. If the patient discontinued study treatment for any reason other than disease progression (e.g., 
toxicity), tumor assessments will continue at the same frequency as would have been followed if 
the patient had remained on study treatment until radiographic disease progression, withdrawal of 
consent, death, or study termination by the principal investigator, whichever occurs first, even if 
the patient starts another anti-cancer therapy after study treatment discontinuation, unless consent 
is withdrawn. 
13. Laboratory assessments to be done within 2 days prior to study drug infusion. 
14. Serum chemistries include Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], 
SGPT [ALT], sodium, and magnesium. 
15. Thyroid function testing (TSH, free T3, free T4) collected at Cycle 1, Day 1 and every fourth 
cycle thereafter. 
16. Serum pregnancy test must be performed within 14 days prior to C1D1. 
17. HBV DNA must be collected on or before Cycle 1, Day 1 in patients who have negative serology 
for hepatitis B surface antigen and positive serology for HBcAb. HCV RNA must be collected on 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
59 
 
 
 
or before Cycle 1, Day 1 in patients who test positive for anti-HCV. Screening EBV serology 
samples will be collected, but tests will be performed only if patients subsequently experience an 
acute inflammatory event such as systemic inflammatory response syndrome while receiving 
study treatment. 
18. Research Blood Samples are not to be collected on days when treatment is being delayed or held. 
19. At screening, research bloods will be drawn for a) germline sequencing as a companion to 
somatic tumor DNA sequencing , b) T-cell subsets, and c) HLA-typing (see Laboratory 
Manual) 
20. PBMC isolation, serum and plasma (see Laboratory Manual) 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
60 
 
 
 
13 
MEASUREMENT OF EFFECT 
 
13.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients will undergo a baseline scan during screening and should 
be re-evaluated for response every 6 weeks for 12 months beginning within -7d of Cycle 4, Day 
1 and thereafter every 9 weeks. 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)53. 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 
13.2 
Definitions 
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with atezolizumab, carboplatin and etoposide. 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. SBRT-treated liver lesions should not be counted as target lesions for disease 
response. 
 
13.3 
Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for 
nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
61 
 
 
 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable). Cystic lesions 
thought to represent cystic metastases can be considered as measurable lesions if they meet the 
definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. The liver lesions that undergo SBRT will be excluded from the target 
lesions. Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
13.4 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
62 
 
 
 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g., for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with 
IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements 
and can be used interchangeably with conventional CT in accurately measuring cancer lesions 
over time. Note, however, that the PET portion of the CT introduces additional data which may 
bias an investigator if it is not routinely or serially performed. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
 
Endoscopy/Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Cytology/Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
63 
 
 
 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG- 
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
• 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
13.5 
Response Criteria 
 
13.5.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
64 
 
 
 
13.5.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions. 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). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
13.5.3 Evaluation of Disease Control Relative to the Radiation Field 
In-field local control will be assessed in patients with at least 6 months of follow-up imaging 
post-SBRT. Follow-up images will be compared (by using image fusion software) with the 
SBRT treatment plan to evaluate local control (LC). 
 
In-field local progression: Defined as new or progression lesions that develop within or at the 
margin of the radiation planning target volume (PTV) 
 
Out-of-field progression: Defined as the development of lesions outside the PTV as assessed by 
RECIST v1.1. criteria. 
 
13.5.4 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (e.g., Target Disease) 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
65 
 
 
 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST v1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint (not applicable to 
this study given PFS6 as primary endpoint). 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 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 the objective 
progression even after discontinuation of treatment. 
 
 
13.6 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
13.7 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression as defined 
by RECIST v1.1 or death, whichever occurs first. The 6-month PFS (PFS6) is defined as the 
proportion of patients that are progression free and alive at 6 months from the start of treatment. 
 
13.8 
Exploratory Biomarkers 
An exploratory objective of this study is to identify potential biomarkers of response to the study 
treatment. Such blood and tissue biomarkers may provide evidence for the synergistic benefit of 
radiation with chemoimmunotherapy and may inform selection of patients most likely to benefit 
from this treatment. Biomarker analysis may include PBMC and tumor analyses including but not 
limited to TCR sequencing, flow cytometry, CITE-SEQ and CyTOF. Tumor specific analyses may 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
66 
 
 
 
include, but not be limited to, whole exome and RNA sequencing, TCR sequencing, multiplex 
immunoflourescence analyses. 
 
14 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 
(Adverse Events: List and Reporting Requirements). The Data Safety Monitoring Plan is 
described in Section 14.3. 
 
14.1 
Data Collection 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be 
built into the CTMS for data entry. The system has full auditing capabilities which is web-based 
and housed on a server in a fully HIPAA compliant server room with restricted access and video 
camera monitoring. All users must login with their own application username and password. 
Users off campus must first access the Virtual Private Network with their assigned campus 
username and password and then use their application credentials. Users are only able to see 
study information if they are indicated as study personnel in our electronic IRB system. Users are 
limited to access based on the role assigned in their corresponding protocol. Subject data is 
entered directly into the system, which (in the case of Columbia subjects) confirms the correct 
identity of patients via an interface with the electronic medical patient index. Staff with the 
appropriate IRB defined roles can run reports within the system for reporting purposes. 
 
14.2 
Data Reporting 
 
Case Report Forms will be completed for each subject enrolled into the clinical study through the 
CTMS. It is the investigator’s responsibility for ensuring that all clinical and laboratory data 
entered on the corresponding CRFs are complete, accurate and authentic. 
 
14.3 
Data and Safety Monitoring Committee 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on 
this protocol for toxicity. This protocol will adhere to the policies of the currently approved 
HICCC Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and 
CUIMC-IRB policy and guidelines. The committee is chair is appointed by the HICCC Director. 
The committee consists of HICCC faculty and staff with expertise in oncology, research 
pharmacy, research nursing, and data management. The DSMC convenes twice a month to 
review patient safety and the conduct of the trial. The PI will submit data and safety monitoring 
reports to the DSMC at a frequency to be determined by the DSMC based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for 
safety review to the CUIMC IRB. Any modifications that are required by the DSMC to ensure 
patient safety will be submitted to the IRB. All protocol deviations, violations, and eligibility 
waivers will be submitted to and approved by the DSMC prior to being reported to the IRB. All 
study data reviewed and discussed during these meetings will be kept confidential. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
67 
 
 
 
 
For multicenter research, the principal investigator will assure that there is a mechanism in place 
to distribute the report to all participating investigators for submission to their local IRB. The 
report will document that a review of data and outcomes across all centers took place on a given 
date. It will summarize the DSMC’s review of the cumulative toxicities reported from all 
participating sites without specific disclosure by treatment arm. It will also inform site 
investigators of the study the DSMC’s conclusion with respect to progress or need for 
modification of the protocol. 
 
14.4 
Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC. Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. The investigator-sponsor and 
Columbia University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review the 
study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical endpoints 
(e.g., stopping rules), etc. for the full DSMC membership at the regularly scheduled meetings. 
 
Internal On-site Monitoring: 
 
● 
Initial, recurrent, and close-out on-site monitoring visits will also be conducted at remote 
clinical sites, as appropriate/feasible. Other sites will have monitoring performed remotely (see 
below for further details). 
 
● 
The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
● 
The Compliance Coordinator will communicate with the site coordinator/Site Principal 
Investigator to schedule the monitoring visit and arrange for access to study materials and 
documentation. 
 
● 
The assigned Compliance Coordinator will monitor IIT trials within 1 month after the 
first subject is enrolled and throughout the life of the study to ensure that the study is being 
conducted in accordance with the protocol, GCP, applicable federal and local regulations, and 
per all applicable SOPs. The Compliance Coordinator is responsible to notify the PI and 
CRNP/CRN/CRC of upcoming monitor visits and convey what information and documentation 
will be required for the visit(s). The Compliance Coordinator is responsible for verifying that 
informed consent is properly obtained, eligibility is met (via the central registration process), 
and all study procedures are conducted according to the study protocol. The Compliance 
Coordinator will also verify that the data reported in the CRF’s accurately reflect source 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
68 
 
 
 
documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a timely 
and efficient manner. The Compliance Coordinator will also monitor for applicable regulatory 
compliance and research pharmacy compliance (if applicable) and communicate any 
deficiencies as appropriate. 
 
14.5 
Confidentiality 
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the ICF (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 
representatives and collaborators, and the IRB/Ethics Committee (EC) for each study site, if 
appropriate. 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
● 
What protected health information (PHI) will be collected from subjects in this study 
● 
Who will have access to that information and why 
● 
Who will use or disclose that information 
● 
The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (e.g., that the subject is alive) 
at the end of their scheduled study period. 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator and study staff will have access to the file. 
14.6 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents. Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
69 
 
 
 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
14.7 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All missing data must be explained. If a space on the CRF 
is left blank because the procedure was not done or the question was not asked, write “N/D”. If the 
item is not applicable to the individual case, write “N/A”. 
 
14.8 
Records Retention 
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. 
 
This minimum retention period applies whether or not any subjects were enrolled in the study. 
 
Clinical records, including consent forms that document clinical intervention or clinical 
diagnostic procedure research-related procedures, must be retained in medical records by the 
institution for at least seven years, per CUIMC and NYP policy which is based on state law. 
 
15 
STATISTICAL CONSIDERATIONS 
 
15.1 Study Design 
This is a single-arm, open-label phase II study to assess the efficacy of liver-directed SBRT 
added to first-line atezolizumab, carboplatin, and etoposide in ES-SCLC patients as measured by 
6-month PFS (primary endpoint). We hypothesize that the addition of SBRT will increase the 6- 
month PFS from 20% (historical control rate) to 45%. A single-stage design based on one-sided 
exact binomial test will be used, with a type I error of 0.10 and a power of 80%. This design 
requires a total of 16 evaluable patients. If at least 6 out of 16 patients have not experienced 
progression at 6 months, this combination therapy will be considered worthy of further study. In 
order to account for an estimated 10% dropout rate, 18 patients will be accrued to this study. 
 
Primary endpoint: 
● 6-month PFS rate will be defined as the proportion of patients that are progression free 
and alive at 6 months from the start of treatment. 
Secondary endpoints: 
● Overall survival (OS) will be defined as the time from treatment start to date of death or 
last follow up. Patients lost to follow-up at the cut-off date will be censored in the 
analysis. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
70 
 
 
 
● Overall response rate (ORR) will be defined as the proportion of patients who have a 
partial (PR) or complete response (CR) after beginning study treatment. Only patients 
who have received at least one cycle of therapy and have had their disease re-evaluated 
will be considered evaluable for response (see Section 13.5.2). 
● Disease control rate (DCR) will be defined as the proportion of patients who have a 
partial (PR) or complete response (CR) or stable disease (SD) after beginning study 
treatment. Only patients who have received at least one cycle of therapy and have had 
their disease re-evaluated will be considered evaluable for response (see Section 13.5.3). 
● Best overall response (BOR) will be defined as the best response recorded from the start 
of the treatment until disease progression (see Section 13.5.4). 
● Duration of response will be defined as measured from the time measurement criteria are 
met for CR or PR until the first date that recurrent or progressive disease is objectively 
documented (see Section 13.6) 
● The safety and tolerability of liver-directed SBRT will be determined by reported AEs, 
physical examinations and laboratory tests. Frequencies of toxicities by grade according 
to NCI CTCAE (version 5.0) will be tabulated. 
● In-field local control will be defined as the absence of disease progression within the 
planning target volume (PTV) as per RECIST v1.1 on CT at 6 months following 
radiation treatment 
● Out of field disease progression will be defined as the development of lesions outside the 
PTV as assessed by RECIST v1.1 criteria at 6 months following radiation treatment 
15.2 
Analytical Plan 
Descriptive statistics will be used to describe all the study endpoints. Mean (standard deviation) 
and/or median (interquartile range) will be used to summarize the continuous variables. 
Frequencies and percentages will be used to describe categorical variables. 
 
The primary efficacy analysis will be based on the treated, response-evaluable . All patients who 
meet eligibility criteria, receive at least one dose of the study drug, and have evaluable 6-month 
outcomes will be included in the analysis of the primary and secondary endpoints, even if there 
are subsequent protocol deviations. Patients who withdraw from the study before on-treatment 
study effects can be assessed will be replaced 
 
Analysis of Primary Endpoints 
The 6-month PFS rate and its exact two-sided 95% confidence interval (CI) will be calculated. 
The primary analysis will be conducted after patients have been on treatment for 6 months. As 
secondary analysis, we will also evaluate the 6-month PFS as a time-to-event outcome using a 
non-parametric (Kaplan-Meier) or parametric Weibull model, based on the distribution of the 
survival function. 
 
Analysis of Secondary Endpoints 
The overall survival and progression free survival probabilities will be estimated using Kaplan- 
Meier method. The median survival and the corresponding 95% CI will also be provided. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
71 
 
 
The estimates of the overall response rate (ORR), disease control rate (DCR), best overall 
response (BOR), duration of response, rate of in-field local control and out of field disease 
progression will be provided with the corresponding 95% CIs. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
72 
 
 
 
 
15.3 
Size/Accrual Rate 
The total sample of 18 patients is expected to be accrued over the course of two years 
(approximately 1 patient/month). 
 
15.4 
Stratification Factors 
No stratification factors are applicable to this study. 
 
15.5 Continuous Monitoring for Toxicity 
Sequential boundaries will be used to monitor the toxicity rate throughout the trial. If an 
excessive number of dose-limiting toxicities are seen the DSMC will have the option of halting 
study accrual. The boundaries at which the study is halted are listed in Table 6. This is a Pocock- 
type boundary that yields at most a 5% probability of crossing the boundary when the rate of 
dose-limiting toxicity is equal to the acceptable rate 30%. The trial will be stopped if the number 
of dose limiting toxicities is equal to or exceeds bn out of n patients with completed follow-up. 
This boundary is equivalent to testing the null hypothesis, after each patient, that the toxicity rate 
is equal to 0.3, using a one-sided level 0.023 test54. 
 
Table 6. Continuous monitoring of toxicity using Pocock-type boundary 
 
Number of 
Patients, n 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Boundary, 
bn 
- 
- 
- 
4 
5 
5 
6 
6 
7 
7 
7 
8 
8 
9 
9 
10 
10 
10 
 
 
15.6 Reporting and Exclusions 
Evaluation of toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the study 
drug. 
 
16 
PROTECTION OF HUMAN SUBJECTS [MULTI CENTER STUDIES] 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study conduct. The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be obtained before commencement of 
this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
73 
 
 
 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study. The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure. This consent form must be 
signed by the subject or legally acceptable surrogate, as outlined in the IRB approved protocol, 
and the investigator-designated research professional obtaining the consent. 
 
17 
STUDY FINANCES 
 
17.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the Columbia University Conflict of Interest Committee with a Committee- 
sanctioned conflict management plan that has been reviewed and approved prior to participation 
in this study. All CUIMC investigators will follow the University conflict of interest policy. 
 
18 GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES 
 
18.1 
Multi-Site Communication 
The CPDM Office at CUIMC provides administration, data management, and organizational 
support for the affiliate sites in the conduct of a multicenter clinical trial. The CPDM Office will 
coordinate, at minimum, regularly scheduled conference calls with affiliate sites. 
The following issues will be discussed, as appropriate: 
● Enrollment information 
● Cohort updates (e.g., DLTs) 
● Adverse events (e.g., new adverse events and updates on unresolved adverse events and 
new safety information) 
● Protocol violations 
● Other issues affecting the conduct of the study 
 
18.2 
New Protocol Distribution, IRB Submission, Modifications, and Annual Renewals 
● Protocol specific documents are distributed to affiliate sites once CUIMC IRB approval 
has been obtained. 
● The affiliate site must submit a draft of site specific revisions to protocol and/or consent 
form documents for review and approval by the sponsor-investigator prior to submission 
to the local IRB. Draft documents should be sent to the study specific email address. The 
site will be provided confirmation that they are approved to submit to their local IRB. 
● Protocol amendments must be approved by the affiliate site’s local IRB within 90 days of 
distribution to the site by the sponsor-investigator. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
74 
 
 
 
18.3 
Regulatory Documents 
Prior to Site Initiation: 
Sponsor-Investigator will ensure that proper requests are made of sites and that the following 
documentation is collected, prior to the initiation of an affiliate site. 
 
● CV of PI, Co-I’s and other research staff listed on FDA 1572 (signed and dated copy 
within 2 years) 
● Medical Licenses of PI and Co-I’s (current copy) 
● Human subjects training certificates for PI and Co-I’s 
● CLIA/Laboratory Certifications for Local Laboratories listed on FDA 1572 
● Local Laboratory Director’s CV and License 
● Local Laboratory Reference Ranges 
● IRB roster or statement of compliance 
● FDA Form 1572, if applicable (wet ink originals required) 
● Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals 
required) 
 
Ongoing Regulatory Documentation: Sponsor-Investigator will ensure that proper requests are 
made of sites and that the following documentation is collected throughout the course of the study. 
● IRB approval letters for all protocol modifications and all renewals 
● IRB-approved consent forms 
● Current IRB roster, if statement of compliance is not provided as part of site initiation 
● FDA Form 1572, if applicable as updates are required 
● Updated investigator and site information where relevant (e.g., CV, medical licensure 
and Financial Disclosure for new sub-investigator, local laboratory information) 
Regulatory documents may be sent to AAAT0174@lists.cumc.columbia.edu or to the following 
address if wet ink originals are required: 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 
Mezzanine Level, M-203 
New York, NY 10032 
 
18.4 
Site Activation 
Columbia University will schedule a site initiation visit once IRB approval has been submitted 
from the affiliate site, if applicable. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
75 
 
 
 
18.5 
Central Registration Procedures- Affiliate Institution Research Participant 
Registration Process: 
All Affiliate Institutions must register subjects with the coordinating center (CUIMC) prior to 
any administration of study drug/intervention/local institution registration. Please see instructions 
below: 
1. Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate 
Institution CRN and/or CRC is required to submit the following documents to the CPDM 
Multicenter Trials Core at AAAT0174@lists.cumc.columbia.edu. The coordinating 
center’s designee will review the documents for accurateness, and subsequently submit the 
documents to the CPDM Central Registration Office via email with a request to register 
the patient “pending eligibility.” The title of the email should read, “AAAT0174 Pending 
Subject Registration Request (PHI)”. The following documents should be submitted with 
the pending registration request, as applicable: 
a. Redacted Completed/signed IRB approved/stamped Informed Consent Forms, 
including additional study ICFs (e.g., tissue, DNA, etc.), as applicable 
b. Redacted Signed HIPAA (or institutional equivalent) 
c. MCT CPDM Velos Note to File form 
2. The Affiliate Institution’s investigator/research nurse/data manager/coordinator must contact 
the coordinating center’s designee (CUIMC’s study specific Clinical Research Coordinatoror 
Clinical Research Nurse) via telephone or email to communicate the following: 
● Notify of pending registration request 
● Confirm method of registration request submission (email or fax) 
● Communicate expected timeline of registration request submission (e.g., same day, next 
day, within the hour, etc.) 
3. To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUIMC CPDM 
Multicenter Trials Core at the study listserv AAAT0174@lists.cumc.columbia.edu: 
● A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
● Copies of redacted source documentation necessary for each item to be verified on the 
CUIMC specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for screening/eligibility 
that are not captured in other source document forms. (e.g., positive investigator 
statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc.) 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
76 
 
 
 
o Protocol deviation/waiver approvals (if applicable) 
● Please note: subject line of email or fax should include the following: “AAAT0174 
Complete Subject Registration Request (PHI)”. 
4. Upon receipt of the abovementioned documents, the designated study specific Clinical 
Research Coordinator will review all documents and verify patient eligibility. If any questions 
arise during the review process, queries in the form of emails will be addressed to the 
applicable affiliate site study team personnel for clarification prior to enrollment. Upon 
verification, the CUIMC study specific designee will then forward all documents to the 
CPDM Central Registration Office for central registration (as described above). The CPDM 
Central Registration Registrar will review all applicable documents and communicate to the 
CUIMC study specific designee in order to clarify any items. The CUIMC study specific 
designee will communicate with the applicable site study team personnel for additional 
clarifications necessary prior to enrollment. 
5. Upon receipt of the subject registration notification email, the CUIMC study specific designee 
will forward the notification email (which will include the study specific patient ID) to the 
affiliate site’s Principal Investigator, Consenting Professional, and applicable research 
personnel. This notification should be filed in the patient research binder accordingly. 
Protocol therapy may not be initiated prior to receipt of this notification from the coordinating 
center. 
6. All screenfail/ineligible subjects, as well as subjects who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration Office 
in a manner analogous to the procedures noted above. Applicable source documentation will 
be required within the corresponding submissions. 
 
18.6 
Protocol Deviation/Subject Waiver request for Affiliate Sites: 
The Affiliate site MUST submit a prospective deviation request to the CUIMC lead PI for review 
and submission to the HICCC DSMC and CUIMC IRB. Approvals must be obtained from all 
entities prior to implementation at the Affiliate site. If a prospective protocol deviation request is 
submitted for review (from an Affiliate site), the PI/site memo(s), HICCC DSMC approval(s) and 
correspondence and CUIMC IRB eligibility deviation approval letter(s) should be forwarded to 
the Affiliate site for documentation. The Affiliate site is also required to obtain prospective local 
IRB approval as per institutional policies/procedures prior to implementing the proposed deviation 
and registering/enrolling the subject via CUIMC Central Registration. All documents and 
determinations must be clearly documented in the study subject’s medical record, research chart 
and regulatory binder, as described. Please note that the HICCC DSMC will no longer be approving 
deviations to eligibility criteria. 
 
18.7 
Guidelines for Affiliate Site Monitoring 
On-Site MCT Monitoring: 
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at Affiliate 
sites, as appropriate/feasible. Other sites will have monitoring performed remotely (see 
below for further details). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
77 
 
 
 
a. The study Monitoring Visit Log will be completed and signed by the monitor and 
the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
Principal Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
3. The Compliance Coordinator will monitor IIT trials within 1 month after the first subject 
is enrolled at the Affiliate site and throughout the life of the study to ensure that the study 
is being conducted in accordance with the protocol, GCP, applicable federal and local 
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible to 
notify the participating site PI and CRNP/CRN/CRC of upcoming monitor visits and 
convey what information and documentation will be required for the visit(s). The 
Compliance Coordinator is responsible for verifying that informed consent is properly 
obtained, eligibility is met (via the central registration process), and all study procedures 
are conducted according to the study protocol. The Compliance Coordinator will also 
verify that the data reported in the CRF’s accurately reflect source documents, that all 
toxicities have been reported to date, and that all SAE’s/UPs/deviations/violations have 
been reported according to Coordinating Center, local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a 
timely and efficient manner. The Compliance Coordinator will also monitor for applicable 
regulatory compliance and research pharmacy compliance (if applicable) and communicate 
any deficiencies as appropriate. 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being made 
available (if applicable) and before any subjects are enrolled on a study at the Affiliate site. 
 
MCT Remote Monitoring: 
● When necessary (due to logistical constraints), Affiliate sites will be monitored remotely 
by a designated Compliance Coordinator. Sites will be informed of this remote monitoring 
process on a site-by-site basis. 
● Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory level, 
as well as a clinical data/source documentation review level. 
● Redacted source documents (applicable to supporting the protocol specific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure 
email for all subjects enrolled at Affiliate sites. Timelines for submission procedures will 
be defined on a case-by-case basis. 
● The Compliance Coordinator will review all submitted redacted source documents against 
the data entered on the protocol specific CRFs. The Compliance Coordinator will issue 
queries when/if necessary. 
● The Affiliate site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
78 
 
 
 
● The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance regarding: 
a. Informed consent procedures 
b. Eligibility criteria 
c. Protocol specific treatment compliance 
d. Protocol specific toxicity/outcome documentation/compliance 
e. Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on study, 
follow-up) 
f. Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, INDSR 
submissions, etc.). 
g. Required specimen submissions (e.g., tissue specimens, research bloodspecimens, 
etc.) 
h. Pharmacy accountability records 
i. Adherence to the CRF submission timeframes to CUIMC (within the protocol 
specified timeframes) 
● Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and 
Affiliate sites after each remote monitoring review. Reports will include information 
regarding data submission timeliness/accuracy, protocol adherence items, query resolution 
status, regulatory status, and overall Affiliate site performance. These reports will be 
generated by the Compliance Coordinator and reviewed with the Compliance Core 
Manager prior to dissemination. 
 
18.8 
Adverse event reporting 
Sponsor reporting: Notifying participating investigators at affiliate sites of adverse events 
It is the responsibility of the study sponsor to notify all affiliate sites, in a written IND safety report, 
of any adverse event associated with the use of the drug that is both serious and unexpected, as 
well as any finding from tests in laboratory animals that suggest a significant risk for human 
subjects. Additionally, sponsors are also required to identify in IND safety reports all previous 
reports concerning similar adverse events and to analyze the significance of the current event in 
light of the previous reports. 
 
Serious Adverse Event Reporting 
Each participating investigator is required to abide by the reporting requirements set by Columbia 
University Medical Center. The study must be conducted in compliance with FDA regulations, 
local safety reporting requirements, and reporting requirements of the principal investigator. 
Participating investigators must report each serious adverse event to the Columbia University 
Medical Center Overall Principal Investigator and the CPDM Multicenter Trials Core within 24 
hours of learning of the occurrence using the HICCC DSMC SAE Report Form.The CPDM 
Multicenter Trials Core will report the event to the HICCC DSMC and Genentech on the subsite’s 
behalf. In the event that the participating investigator does not become aware of the serious adverse 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
79 
 
 
 
event immediately (e.g., participant sought treatment elsewhere), the participating investigator is 
to report the event within 24 hours after learning of it and document the time of his or her first 
awareness of the adverse event. Report serious adverse events by telephone, email or facsimile to: 
 
Brian Henick, MD 
Fax: 646-317-6321 
bh2682@cumc.columbia.edu 
AAAT0174@lists.cumc.columbia.edu 
 
The participating investigator must provide follow-up information on the serious adverse event 
until resolution of the event. Follow-up information should describe whether the event has 
resolved or continues, if and how the event was treated, and whether the participant will continue 
or discontinue study participation. 
 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow- up to the previously reported SAE 
and giving the date of the original report. Each re-occurrence, complication, or progression ofthe 
original event should be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, and whether the subject continued or withdrew from study participation or if study 
drug was interrupted or discontinued. 
 
If the SAE is not previously documented in the Investigator’s Brochure for the study drug (new 
occurrence) and is thought to be related to the investigational agent, the sponsor-investigator may 
urgently require further information from the investigator for reporting to Health Authorities. 
 
Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the Columbia University Medical Center Overall 
Principal Investigator on the toxicity Case Report Forms. 
 
Reporting to the Institutional Review Board (IRB) and the Data and Safety Monitoring 
Committee: 
All Unanticipated Problems (UPs) will be reported to the CUIMC IRB. SAEs not constituting UPs 
will reported to the HICCC DSMC. 
 
Each affiliate site will be responsible for safety reporting to their local IRB. Investigators are 
responsible for complying with their local IRB’s reporting requirements, though must submit the 
required reports to their IRB no later than 7 calendar days following the occurrence of the UP or 
the Principal’s Investigator’s acquiring knowledge of the UP. Copies of each report and 
documentation of IRB notification and receipt must be included in the regulatory binder. 
Expected AEs must be reported at the time of continuing review of a protocol. 
 
Reporting to Hospital Risk Management 
Affiliate Site investigators will report to their local Risk Management Office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
80 
 
 
 
18.9 
Confidentiality 
Each affiliate site will be assigned a site number. Each subject that signs consent should be 
assigned a unique code number consisting of site number followed by a number with each new 
subject being assigned the next sequential number (e.g., 04-10). All sites will be required to enter 
their data in the Velos eResearch, the Clinical Trial Management System used for all Cancer- 
related clinical research at CUIMC. All users must login with their own application username and 
password. Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials. 
 
Subject confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations. 
 
Except when required by law, study information shared with persons and organizations outside of 
Columbia University Medical Center must not identify the patient by name, social security 
number, address, telephone number, or any other direct personal identifier. 
 
If the results of this research project are published or presented at a scientific or medical meeting, 
the patient not be identified. Otherwise, all results will be kept confidential and will not be divulged 
(except as required by law) without permission. 
 
18.10 Data Reporting Plan 
Columbia University Irving Medical Center (CUIMC) is deeply committed to research integrity 
and strong credibility when it comes to the discovery of new treatment concepts, implementation 
of new clinical research techniques, and acceptance of its researcher's findings by the medical 
establishment. In accord with these ethics, CUIMC encourages and supports its investigators in 
the sharing of final research data and/or details of newly developed clinical treatments. 
 
CUIMC's policies that pertain to patient data sharing conform to CUIMC IRB rules, local and state 
laws, and HIPAA privacy regulations. The primary reason for this is to protect the privacy of 
patients who participate in clinical trials. The data can be made available for continuing review by 
federal agencies upon request and for ongoing study safety reviews by the Principal Investigator, 
Statistician, Data Safety and Monitoring Board (DSMC), and, in other instances, the CUIMC IRB. 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or transferred 
to other collaborators. Prior to transfer, the data collected must comply with, and must be limited 
by, the CUIMC's guidelines for Protecting the Rights and Privacy of Human Subjects. 
 
18.11 Data Acquisition and Submission 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior to their 
participation. Always keep the original signed and dated consent form, with the redacted source 
documents and eligibility checklist. Velos eResearch will be used as the electronic clinical trials 
and data management system. Affiliate sites will enter data directly into Velos eResearch via 
customized case report forms for the study. The research staff will generate reports from Velos 
eResearch to ensure timely submission of data by affiliate sites. This resource allows for the timely 
analysis of particular data sets for safety analysis. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
81 
 
 
 
18.12 Record Keeping and Record Retention 
The Sponsor is required to maintain adequate records of the disposition of the drug, including 
dates, quantity, and use by subjects, as well as written records of the disposition of the drug when 
the study ends. 
 
The Sponsor is required to prepare and maintain adequate and accurate case histories that record 
all observations and other data pertinent to the investigation on each individual administered the 
investigational drug or employed as a control in the investigation. Case histories include the case 
report forms and supporting data including, for example, signed and dated consent forms and 
medical records including, for example, progress notes of the physician, the individual's hospital 
chart(s), and the nurses' notes. The case history for each individual shall document that informed 
consent was obtained prior to participation in the study. Study documentation includes all CRFs, 
data correction forms or queries, source documents, Sponsor-Investigator correspondence, 
monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, CHR 
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. In accordance with FDA 
regulations, the investigator shall retain records for a period of 2 years after the investigation is 
discontinued and FDA is notified. 
 
19 
PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor. Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
20 
REFERENCES 
1. 
Horn L, Mansfield AS, Szczęsna A, et al: First-Line Atezolizumab plus 
Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 379:2220-2229, 2018 
2. 
Riihimäki M, Hemminki A, Fallah M, et al: Metastatic sites and survival in lung 
cancer. Lung Cancer 86:78-84, 2014 
3. 
Tumeh PC, Hellmann MD, Hamid O, et al: Liver Metastasis and Treatment 
Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC. Cancer 
Immunol Res 5:417-424, 2017 
4. 
Lee J, Mehdizadeh S, Tsai K, et al: Immunological Insights Into Liver 
Metastasis Associated Resistance To Checkpoint Blockade Cancer Immunotherapy. Journal of 
Immunology 200:122.26, 2018 
5. 
Shiroyama T, Suzuki H, Tamiya M, et al: Clinical Characteristics of Liver 
Metastasis in Nivolumab-treated Patients with Non-small Cell Lung Cancer. Anticancer Res 
38:4723-4729, 2018 
6. 
Shabason JE, Minn AJ: Radiation and Immune Checkpoint Blockade: From 
Bench to Clinic. Semin Radiat Oncol 27:289-298, 2017 
7. 
Wang Y, Deng W, Li N, et al: Combining Immunotherapy and Radiotherapy for 
Cancer Treatment: Current Challenges and Future Directions. Front Pharmacol 9:185, 2018 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
82 
 
 
 
8. 
Deng L, Liang H, Burnette B, et al: Irradiation and anti-PD-L1 treatment 
synergistically promote antitumor immunity in mice. J Clin Invest 124:687-95, 2014 
9. 
Bauml JM, Mick R, Ciunci C, et al: Pembrolizumab After Completion of Locally 
Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer: A Phase 2 Trial. JAMA 
Oncol, 2019 
10. 
Theelen W, Peulen HMU, Lalezari F, et al: Effect of Pembrolizumab After 
Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With 
Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized 
Clinical Trial. JAMA Oncol, 2019 
11. 
Welsh JW, Tang C, de Groot P, et al: Phase II Trial of Ipilimumab with 
Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose 
Radiation-Related Abscopal Responses. Cancer Immunol Res 7:1903-1909, 2019 
12. 
Gazdar AF, Bunn PA, Minna JD: Small-cell lung cancer: what we know, what we 
need to know and the path forward. Nat Rev Cancer 17:765, 2017 
13. 
Rossi A, Di Maio M, Chiodini P, 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 30:1692-8, 2012 
14. 
Lara PN, Jr., Natale R, Crowley J, et al: Phase III trial of irinotecan/cisplatin 
compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and 
pharmacogenomic results from SWOG S0124. J Clin Oncol 27:2530-5, 2009 
15. 
Paz-Ares L, Dvorkin M, Chen Y, et al: Durvalumab plus platinum-etoposide 
versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer 
(CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 394:1929-1939, 2019 
16. 
Jeremic B, Shibamoto Y, Nikolic N, et al: Role of radiation therapy in the 
combined-modality treatment of patients with extensive disease small-cell lung cancer: A 
randomized study. J Clin Oncol 17:2092-9, 1999 
17. 
Slotman BJ, van Tinteren H, Praag JO, et al: Use of thoracic radiotherapy for 
extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385:36-42, 
2015 
18. 
Aupérin A, Arriagada R, Pignon JP, et al: Prophylactic cranial irradiation for 
patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation 
Overview Collaborative Group. N Engl J Med 341:476-84, 1999 
19. 
Slotman B, Faivre-Finn C, Kramer G, et al: Prophylactic cranial irradiation in 
extensive small-cell lung cancer. N Engl J Med 357:664-72, 2007 
20. 
Takahashi T, Yamanaka T, Seto T, et al: Prophylactic cranial irradiation versus 
observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, 
open-label, phase 3 trial. Lancet Oncol 18:663-671, 2017 
21. 
Ren Y, Dai C, Zheng H, et al: Prognostic effect of liver metastasis in lung cancer 
patients with distant metastasis. Oncotarget 7:53245-53253, 2016 
22. 
Bremnes RM, Sundstrom S, Aasebø U, et al: The value of prognostic factors in 
small cell lung cancer: results from a randomised multicenter study with minimum 5 year follow- 
up. Lung Cancer 39:303-13, 2003 
23. 
Nakazawa K, Kurishima K, Tamura T, et al: Specific organ metastases and 
survival in small cell lung cancer. Oncol Lett 4:617-620, 2012 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
83 
 
 
 
24. 
Sridhar S, Paz-Ares L, Liu H, et al: Prognostic Significance of Liver Metastasis in 
Durvalumab-Treated Lung Cancer Patients. Clin Lung Cancer 20:e601-e608, 2019 
25. 
Reits EA, Hodge JW, Herberts CA, et al: Radiation modulates the peptide 
repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. 
J Exp Med 203:1259-71, 2006 
26. 
Burnette BC, Liang H, Lee Y, et al: The efficacy of radiotherapy relies upon 
induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71:2488-96, 
2011 
27. 
Lugade AA, Moran JP, Gerber SA, et al: Local radiation therapy of B16 
melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to 
the tumor. J Immunol 174:7516-23, 2005 
28. 
Lee Y, Auh SL, Wang Y, et al: Therapeutic effects of ablative radiation on local 
tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114:589-95, 2009 
29. 
Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al: Acquired resistance to 
fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 74:5458- 
68, 2014 
30. 
Demaria S, Kawashima N, Yang AM, et al: Immune-mediated inhibition of 
metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast 
cancer. Clin Cancer Res 11:728-34, 2005 
31. 
Twyman-Saint Victor C, Rech AJ, Maity A, et al: Radiation and dual checkpoint 
blockade activate non-redundant immune mechanisms in cancer. Nature 520:373-7, 2015 
32. 
Hiniker SM, Reddy SA, Maecker HT, et al: A Prospective Clinical Trial 
Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. Int J 
Radiat Oncol Biol Phys 96:578-88, 2016 
33. 
Tang C, Welsh JW, de Groot P, et al: Ipilimumab with Stereotactic Ablative 
Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells. Clin 
Cancer Res 23:1388-1396, 2017 
34. 
Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after Chemoradiotherapy in 
Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377:1919-1929, 2017 
35. 
Samstein R, Rimner A, Barker CA, et al: Combined Immune Checkpoint 
Blockade and Radiation Therapy: Timing and Dose Fractionation Associated with Greatest 
Survival Duration Among Over 750 Treated Patients, International Journal of Radiation 
Oncology, 2017, pp S129 - S130 
36. 
Jabbour SK, Berman AT, Decker RH, et al: Phase 1 Trial of Pembrolizumab 
Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell 
Lung Cancer: A Nonrandomized Controlled Trial. JAMA Oncol, 2020 
37. 
Welsh JW, Heymach JV, Chen D, et al: Phase I Trial of Pembrolizumab and 
Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer. J 
Thorac Oncol 15:266-273, 2020 
38. 
Scorsetti M, Comito T, Clerici E, et al: Phase II trial on SBRT for unresectable 
liver metastases: long-term outcome and prognostic factors of survival after 5 years of follow-up. 
Radiat Oncol 13:234, 2018 
39. 
Schaub SK, Hartvigson PE, Lock MI, et al: Stereotactic Body Radiation Therapy 
for Hepatocellular Carcinoma: Current Trends and Controversies. Technol Cancer Res Treat 
17:1533033818790217, 2018 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
84 
 
 
 
40. 
Mahadevan A, Blanck O, Lanciano R, et al: Stereotactic Body Radiotherapy 
(SBRT) for liver metastasis - clinical outcomes from the international multi-institutional 
RSSearch® Patient Registry. Radiat Oncol 13:26, 2018 
41. 
Rule W, Timmerman R, Tong L, et al: Phase I dose-escalation study of 
stereotactic body radiotherapy in patients with hepatic metastases. Ann Surg Oncol 18:1081-7, 
2011 
42. 
Palma DA, Olson R, Harrow S, et al: Stereotactic ablative radiotherapy for the 
comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): study protocol 
for a randomized phase III trial. BMC Cancer 19:816, 2019 
43. 
Chiang CL, Chan ACY, Chiu KWH, et al: Combined Stereotactic Body 
Radiotherapy and Checkpoint Inhibition in Unresectable Hepatocellular Carcinoma: A Potential 
Synergistic Treatment Strategy. Front Oncol 9:1157, 2019 
44. 
Fehrenbacher L, Spira A, Ballinger M, et al: Atezolizumab versus docetaxel for 
patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, 
phase 2 randomised controlled trial. Lancet 387:1837-46, 2016 
45. 
Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with 
locally advanced and metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909-20, 
2016 
46. 
Deng R, Bumbaca D, Pastuskovas CV, et al: Preclinical pharmacokinetics, 
pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal 
antibody, an immune checkpoint inhibitor. MAbs 8:593-603, 2016 
47. 
Skarlos DV, Samantas E, Kosmidis P, et al: Randomized comparison of 
etoposide-cisplatin vs. etoposide-carboplatin and irradiation in small-cell lung cancer. A Hellenic 
Co-operative Oncology Group study. Ann Oncol 5:601-7, 1994 
48. 
Okamoto H, Watanabe K, Kunikane 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 97:162-9, 2007 
49. 
Socinski MA, Smit EF, Lorigan P, 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 27:4787-92, 2009 
50. 
Schmittel A, Sebastian M, Fischer von Weikersthal L, et al: A German 
multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide- 
carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol 
22:1798-804, 2011 
51. 
Rusthoven KE, Kavanagh BD, Cardenes H, et al: Multi-institutional phase I/II 
trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol 27:1572-8, 2009 
52. 
Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations 
for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J 
Clin Oncol 24:3187-205, 2006 
53. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
54. 
Ivanova A, Qaqish BF, Schell MJ: Continuous toxicity monitoring in phase II 
trials in oncology. Biometrics 61:540-5, 2005 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
85 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
APPENDICES 
21.1 Appendix Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital immune 
deficiencies or autoimmune disease. Patients with any history of immune deficiencies or autoimmune 
disease listed in the table below are excluded from participating in the study. Possible exceptions to this 
exclusion could be patients with a medical history of such entities as atopic disease or childhood 
arthralgias where the clinical suspicion of autoimmune disease is low. Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for 
this study. In addition, transient autoimmune manifestations of an acute infectious disease that resolved 
upon treatment of the infectious agent are not excluded (e.g., acute Lyme arthritis). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
86 
 
 
 
Autoimmune Diseases and Immune Deficiencies 
 
● Acute disseminated 
encephalomyelitis 
● Addison disease 
● Ankylosing spondylitis 
● Antiphospholipid antibody 
syndrome 
● Aplastic anemia 
● Autoimmune hemolytic anemia 
● Autoimmune hepatitis 
● Autoimmune 
hypoparathyroidism 
● Autoimmune hypophysitis 
● Autoimmune myocarditis 
● Autoimmune oophoritis 
● Autoimmune orchitis 
● Autoimmune 
thrombocytopenic purpura 
● Behçet disease 
● Bullous pemphigoid 
● Chronic fatigue syndrome 
● Chronic inflammatory 
demyelinating polyneuropathy 
● Churg-Strauss syndrome 
● Crohn disease 
● Dermatomyositis 
● Diabetes mellitus type 1 
● Dysautonomia 
● Epidermolysis bullosa 
acquisita 
● Gestational pemphigoid 
● Giant cell arteritis 
● Goodpasture syndrome 
● Graves disease 
● Guillain-Barré syndrome 
● Hashimoto disease 
● IgA nephropathy 
● Inflammatory bowel disease 
● Interstitial cystitis 
● Kawasaki disease 
● Lambert-Eaton myasthenia 
syndrome 
● Lupus erythematosus 
● Lyme disease, chronic 
● Meniere syndrome 
● Mooren ulcer 
● Morphea 
● Multiple sclerosis 
● Myasthenia gravis 
● Neuromyotonia 
● Opsoclonus myoclonus 
syndrome 
● Optic neuritis 
● Ord thyroiditis 
● Pemphigus 
● Pernicious anemia 
● Polyarteritis nodosa 
● Polyarthritis 
● Polyglandular autoimmune 
syndrome 
● Primary biliary cirrhosis 
● Psoriasis 
● Reiter syndrome 
● Rheumatoid arthritis 
● Sarcoidosis 
● Scleroderma 
● Sjögren syndrome 
● Stiff-Person syndrome 
● Takayasu arteritis 
● Ulcerative colitis 
● Vitiligo 
● Vogt-Koyanagi-Harada disease 
● Wegener granulomatosis 
 
21.2 
Appendix Anaphylaxis Precautions 
EQUIPMENT NEEDED 
● 
Monitoring devices: ECG monitor, blood pressure monitor, oxygen saturation monitor, and 
thermometer 
● 
Oxygen 
● 
Epinephrine for intravenous, intramuscular, and endotracheal administration in accordance 
with institutional guidelines 
● 
Antihistamines 
● 
Corticosteroids 
● 
Intravenous infusion solutions, tubing, catheters, and tape 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
87 
 
 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, the following 
procedures should be performed: 
1. 
Stop the study treatment infusion. 
2. 
Call for additional medical assistance. 
3. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse oximetry 
monitoring, if possible. 
4. 
Administer antihistamines, epinephrine, or other medications as required by participant 
status and as directed by the physician in charge. 
5. 
Continue to observe the participant and document observations. 
6. 
Draw serum/plasma samples for immunogenicity testing. 
7. 
Ask participant to return for washout immunogenicity sample if appropriate. 
 
21.3 VA lung Study Group’s (VALG) 2 stage SCLC classification scheme 
Limited stage disease: confined to the ipsilateral hemithorax, which can be safely encompassed 
within a radiation field. Contralateral mediastinal and ipsilateral supraclavicular 
lymphadenopathy falls within the category of limited stage disease. 
Extensive stage disease: disease beyond the ipsilateral hemithorax, including malignant pleural 
or pericardial effusion or hematogenous metastases 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
88 
 
 
 
 
 
 
22 
ATTACHMENTS 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
89 
 
 
Appendix 
Safety Reporting Fax Cover Sheet 
 
SAFETY REPORTING FAX COVER SHEET 
GENENTECH SUPPORTED RESEARCH 
AE / SAE FAX No: (650) 238-6067 
 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient has no middle 
name) 
[ ] - [ ] - [ ] 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
90 
 
 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated with the 
administration of atezolizumab. Patients will be assessed for pulmonary signs and symptoms throughout the study 
and will have computed tomography (CT) scans of the chest performed at every tumor assessment. 
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies such as pneumonia or 
other infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic obstructive pulmonary 
disease, or pulmonary hypertension. Management guidelines for pulmonary events are provided in Table 1. 
Table 1 Management Guidelines for Pulmonary Events, Including Pneumonitis 
 
Event 
Management 
Pulmonary event, 
Grade 1 
• Continue atezolizumab and monitor closely. 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
Pulmonary event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to pulmonary and infectious disease specialists and consider bronchoscopy or 
BAL. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab. c 
• For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. c 
• Bronchoscopy or BAL is recommended. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
BAL = bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
91 
 
 
HEPATIC EVENTS 
Immune-related hepatitis has been associated with the administration of atezolizumab. Eligible patients must have 
adequate liver function, as manifested by measurements of total bilirubin and hepatic transaminases, and liver 
function will be monitored throughout study treatment. Management guidelines for hepatic events are provided in 
Table 2. 
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should have liver function 
tests (LFTs) performed immediately and reviewed before administration of the next dose of study drug. 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic etiologies should be 
considered and addressed, as appropriate. 
Table 2 
Management Guidelines for Hepatic Events 
 
Event 
Management 
Hepatic event, Grade 1 
• Continue atezolizumab. 
• Monitor LFTs until values resolve to within normal limits or to baseline values. 
Hepatic event, Grade 2 
All events: 
• Monitor LFTs more frequently until return to baseline values. 
Events of > 5 days’ duration: 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab. c 
LFT = liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
92 
 
 
Table 2 
Management Guidelines for Hepatic Events (cont.) 
 
Event 
Management 
Hepatic event, Grade 3 or 
4 
• Permanently discontinue atezolizumab. c 
• Consider patient referral to gastrointestinal specialist for evaluation and liver biopsy to 
establish etiology of hepatic injury. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
LFT = liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 
 
 
GASTROINTESTINAL EVENTS 
Immune-related colitis has been associated with the administration of atezolizumab. Management guidelines for 
diarrhea or colitis are provided in Table 3. 
 
All events of diarrhea or colitis should be thoroughly evaluated for other more common etiologies. For events of 
significant duration or magnitude or associated with signs of systemic inflammation or acute-phase reactants 
(e.g., increased C-reactive protein, platelet count, or bandemia): Perform sigmoidoscopy (or colonoscopy, if 
appropriate) with colonic biopsy, with three to five specimens for standard paraffin block to check for inflammation 
and lymphocytic infiltrates to confirm colitis diagnosis. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
93 
 
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
 
Event 
Management 
Diarrhea or colitis, 
Grade 1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for > 7 days. 
• Monitor closely. 
Diarrhea or colitis, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist >5 days, initiate treatment with corticosteroids 
equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab. c 
Diarrhea or colitis, 
Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV methylprednisolone and 
convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab. c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
94 
 
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) (cont.) 
 
Event 
Management 
Diarrhea or colitis, 
Grade 4 
• Permanently discontinue atezolizumab. c 
• Refer patient to GI specialist for evaluation and confirmation biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV methylprednisolone and 
convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 
 
 
ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been associated with the 
administration of atezolizumab. Management guidelines for endocrine events are provided in Table 4. 
 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, constipation, or mental status 
changes should be investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies. The patient 
should be referred to an endocrinologist if an endocrinopathy is suspected. Thyroid-stimulating hormone (TSH) and 
free triiodothyronine and thyroxine levels should be measured to determine whether thyroid abnormalities are 
present. Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, follicle- 
stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) 
and magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to differentiate primary 
pituitary insufficiency from primary adrenal insufficiency. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
95 
 
 
Table 4 
Management Guidelines for Endocrine Events 
 
Event 
Management 
Asymptomatic hypothyroidism 
• Continue atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
Symptomatic hypothyroidism 
• Withhold atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
Asymptomatic hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• Continue atezolizumab. 
• Monitor TSH every 4 weeks. 
TSH < 0.1 mU/L: 
• Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with anti-thyroid drug such as methimazole or carbimazole as 
needed. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and thyroid function is 
improving. 
• Permanently discontinue atezolizumab. c 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Table 4 
Management Guidelines for Endocrine Events (cont.) 
Version Date: November 15 2021 
96 
 
 
 
Event 
Management 
Symptomatic adrenal 
insufficiency, Grade 2−4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better and patient is stable on replacement therapy, 
resume atezolizumab. b 
• If event does not resolve to Grade 1 or better or patient is not stable on replacement 
therapy while withholding atezolizumab, permanently discontinue atezolizumab. c 
Hyperglycemia, Grade 1 or 2 
• Continue atezolizumab. 
• Investigate for diabetes. If patient has Type 1 diabetes, treat as a Grade 3 event. If 
patient does not have Type 1 diabetes, treat as per institutional guidelines. 
• Monitor for glucose control. 
Hyperglycemia, Grade 3 or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Resume atezolizumab when symptoms resolve and glucose levels are stable. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Table 4 
Management Guidelines for Endocrine Events (cont.) 
Version Date: November 15 2021 
97 
 
 
 
Event 
Management 
Hypophysitis (pan- 
hypopituitarism), Grade 2 or 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan- 
hypopituitarism), Grade 4 
• Permanently discontinue atezolizumab. c 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
98 
 
 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). Management guidelines for 
ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
 
Event 
Management 
Ocular event, Grade 1 
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab. c 
Ocular event, Grade 3 or 
4 
• Permanently discontinue atezolizumab. c 
• Refer patient to ophthalmologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
99 
 
 
IMMUNE-RELATED MYOCARDITIS 
Immune-related myocarditis has been associated with the administration of atezolizumab. Immune-related 
myocarditis should be suspected in any patient presenting with signs or symptoms suggestive of myocarditis, 
including, but not limited to, laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope. Immune-related myocarditis needs to be 
distinguished from myocarditis resulting from infection (commonly viral, e.g., in a patient who reports a recent history 
of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy. 
 
All patients with possible myocarditis should be urgently evaluated by performing cardiac enzyme assessment, an 
ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per institutional guidelines.  A 
cardiologist should be consulted. An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 6. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
100 
 
 
Table 6 
Management Guidelines for Immune-Related Myocarditis 
 
Event 
Management 
Immune-related myocarditis, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, 
temporary pacemaker, ECMO, or VAD as appropriate. 
• Consider treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
Immune-related myocarditis, 
Grade 3-4 
• Permanently discontinue atezolizumab. c 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, 
temporary pacemaker, ECMO, or VAD as appropriate. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV methylprednisolone 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 
 
 
1. 
Infusion-Related Reactions and Cytokine-Release Syndrome 
No premedication is indicated for the administration of Cycle 1 of atezolizumab. However, patients who experience an 
infusion-related reaction (IRR) or cytokine-release cyndrome (CRS) with atezolizumab may receive medication with 
antihistamines, antipyretics and/or analgesics (e.g., acetaminophen). Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
IRRs are known to occur with the administration of monoclonal antibodies and have been reported with atezolizumab. These 
reactions, which are thought to be due to release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
 
CRS is defined as a supraphysiologic response following administration of any immune therapy that results in activation or 
engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive, always include 
fever at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction [58]. CRS has been well 
documented with chimeric antigen receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also been 
reported with immunotherapies that target PD-1 or PD-L1 [59, 60], including atezolizumab. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
101 
 
 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of the challenges in clinically 
distinguishing between the two, consolidated guidelines for medical management of IRRs and CRS are provided in Table 7. For 
subsequent cycles, IRRs should be managed according to institutional guidelines. 
 
Table 7 
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome 
Event 
Management 
Grade 1a 
Feverb with or 
without 
constitutional 
symptoms 
● Immediately interrupt infusion. 
● Upon symptom resolution, wait 30 minutes and then restart infusion at half the 
rate being given at the time of event onset. 
● If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate 
may be increased to the original rate. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment,c including maintenance of IV fluids for 
hydration. 
● In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per Grade 2. 
● For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs 
and/or CRS. 
Grade 2a 
Feverb with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygend 
by nasal cannula 
or blow-by 
● Immediately interrupt atezolizumab infusion. 
● Upon symptom resolution, wait for 30 minutes and then restart infusion at half 
the rate being given at the time of event onset. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment.c 
● For hypotension, administer IV fluid bolus as needed. 
● Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate). Administer IV fluids as clinically indicated and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
● Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy.e 
● Consider hospitalization until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize patient 
(monitoring in the ICU is recommended), permanently discontinue 
atezolizumab. 
● If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose of 
atezolizumab may be administered. For subsequent infusions, consider 
administration of oral premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
● If symptoms do not resolve to Grade 1 or better for 3 consecutive days, contact 
the sponsor-investigator. 
Grade 3a 
Feverb with 
hypotension 
requiring a 
vasopressor (with 
● Permanently discontinue atezolizumab.f 
● Administer symptomatic treatment.c 
● For hypotension, administer IV fluid bolus and vasopressor as needed. 
● Monitor cardiopulmonary and other organ function closely; monitoring in the 
ICU is recommended. Administer IV fluids as clinically indicated and manage 
constitutional symptoms and organ toxicities as per institutional practice. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
102 
 
 
or without 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy.e 
● Hospitalize patient until complete resolution of symptoms. If no improvement 
within 24 hours, manage as per Grade 4, that is, admit patient to ICU and initiate 
hemodynamic monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed; for patients who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of the investigator. 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow 
oxygend 
by nasal cannula, 
face mask, non- 
rebreather mask, 
or venturi mask 
Grade 4a 
Feverb with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
● Permanently discontinue atezolizumab.f 
● Administer symptomatic treatment.c 
● Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed. Monitor other organ 
function closely. Manage constitutional symptoms and organ toxicities as per 
institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy.e For patients who are refractory to anti-cytokine 
therapy, experimental treatmentsg may be considered at the discretion of the 
investigator. 
● Hospitalize patient until complete resolution of symptoms. 
Hypoxia requiring 
oxygen by 
positive pressure 
(e.g., CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
ASTCT= American Society for Transplantation and Cellular Therapy; BiPAP= bi-level positive airway 
pressure; CAR= chimeric antigen receptor; CPAP= continuous positive airway pressure; 
CRS= cytokine-release syndrome; HLH= hemophagocytic lymphohistiocytosis; IRR = infusion-related 
reaction; MAS= macrophage activation syndrome. 
 
Note: The management guidelines have been adapted from NCCN guidelines for management of 
CAR T-cell-related toxicities (Version 2.2019). 
a. Grading system for management guidelines is based on ASTCT consensus grading for CRS. NCI 
CTCAE (version as specified in the protocol) should be used when reporting severity of IRRs, CRS, 
or organ toxicities associated with CRS on the Adverse Event eCRF. Organ toxicities associated 
with CRS should not influence overall CRS grading. 
b. Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop 
CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer 
required when subsequently determining event severity (grade). In this case, the grade is driven by 
the presence of hypotension and/or hypoxia. 
c. Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may 
be administered as per institutional practice. 
d. Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered 
at > 6 L/min. 
e. There are case reports where anti-cytokine therapy has been used for treatment of CRS with immune 
checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are limited, and the 
role of such treatment in the setting of antibody-associated CRS has not been established. 
f. Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab 
according to institutional guidelines and the above table. For subsequent infusions, administer oral 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
  
CUMC IRB – AAAT0174 
 
Version Date: November 15 2021 
103 
 
 
premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs 
and/or CRS. Premedication with corticosteroids and extending the infusion time may also be 
considered after considering the benefit-risk ratio. 
g. Refer to Riegler et al. [61] for information on experimental treatments for CRS. 
PANCREATIC EVENTS 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of pancreatitis, have 
been associated with the administration of atezolizumab. The differential diagnosis of acute abdominal pain should 
include pancreatitis. Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests. Management guidelines for pancreatic events, including pancreatitis, are provided in 
Table 7. 
Table 7 
Management Guidelines for Pancreatic Events, Including Pancreatitis 
 
Event 
Management 
Amylase and/or lipase elevation, 
Grade 2 
Amylase and/or lipase > 1.5−2.0 × ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., > 3 weeks), consider treatment with corticosteroids 
equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0−5.0 × ULN: 
• Treat as a Grade 3 event. 
Amylase and/or lipase elevation, 
Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with corticosteroids equivalent to 
1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
• For recurrent events, permanently discontinue atezolizumab. c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
104 
 
 
Table 8 
Management Guidelines for Pancreatic Events, Including Pancreatitis (cont.) 
 
Event 
Management 
Immune-related pancreatitis, Grade 2 
or 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
• For recurrent events, permanently discontinue atezolizumab. c 
Immune-related pancreatitis, Grade 4 
• Permanently discontinue atezolizumab. c 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
105 
 
 
DERMATOLOGIC EVENTS 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases of rash were mild in 
severity and self limited, with or without pruritus. Although uncommon, cases of severe cutaneous adverse reactions 
such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with atezolizumab. A 
dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy should be considered unless 
contraindicated. Management guidelines for dermatologic events are provided in Table 8. 
Table 8 
Management Guidelines for Dermatologic Events 
 
Event 
Management 
Dermatologic event, 
Grade 1 
• Continue atezolizumab. 
• Consider treatment with topical corticosteroids and/or other symptomatic therapy (e.g., 
antihistamines). 
Dermatologic event, 
Grade 2 
• Continue atezolizumab. 
• Consider patient referral to dermatologist for evaluation and, if indicated, biopsy. 
• Initiate treatment with topical corticosteroids. 
• Consider treatment with higher-potency topical corticosteroids if event does not improve. 
Dermatologic event, 
Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
• Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, increasing dose 
to 1−2 mg/kg/day if event does not improve within 48−72 hours. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab. c 
Dermatologic event, 
Grade 4 
• Permanently discontinue atezolizumab. c 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal necrolysis: 
• Withhold atezolizumab for suspected Stevens-Johnson syndrome or toxic epidermal 
necrolysis. 
• Confirm diagnosis by referring patient to a specialist (dermatologist, ophthalmologist, or 
urologist as relevant) for evaluation and, if indicated, biopsy. 
• Follow the applicable treatment and management guidelines above. 
• If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, permanently 
discontinue atezolizumab. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
106 
 
 
NEUROLOGIC DISORDERS 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent atezolizumab. Patients may 
present with signs and symptoms of sensory and/or motor neuropathy. Diagnostic workup is essential for an 
accurate characterization to differentiate between alternative etiologies. Management guidelines for neurologic 
disorders are provided in Table 9. 
Table 9 
Management Guidelines for Neurologic Disorders 
 
Event 
Management 
Immune-related 
neuropathy, Grade 1 
• Continue atezolizumab. 
• Investigate etiology. 
Immune-related 
neuropathy, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Investigate etiology. 
• Initiate treatment as per institutional guidelines. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab. c 
Immune-related 
neuropathy, Grade 3 or 4 
• Permanently discontinue atezolizumab. c 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
Guillain-Barré syndrome 
(any grade) 
• Permanently discontinue atezolizumab. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day oral or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 
 
 
IMMUNE-RELATED MENINGOENCEPHALITIS 
Immune-related meningoencephalitis is an identified risk associated with the administration of atezolizumab. 
Immune-related meningoencephalitis should be suspected in any patient presenting with signs or symptoms 
suggestive of meningitis or encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness. Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis resulting from infection 
(bacterial, viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process. 
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT scan and/or MRI scan 
of the brain to evaluate for metastasis, inflammation, or edema. If deemed safe by the treating physician, a lumbar 
puncture should be performed and a neurologist should be consulted. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
107 
 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified alternate etiology, should 
be treated according to the guidelines in Table 10. 
Table 10 Management Guidelines for Immune-Related Meningoencephalitis 
 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
• Permanently discontinue atezolizumab. a 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator (or an appropriate 
delegate). 
 
 
RENAL EVENTS 
Immune-related nephritis has been associated with the administration of atezolizumab. Eligible patients must have 
adequate renal function. Renal function, including serum creatinine, should be monitored throughout study 
treatment. Patients with abnormal renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as non-steroidal anti-inflammatory 
drugs). Refer the patient to a renal specialist if clinically indicated. A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. 
 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 11. 
Table 11 Management Guidelines for Renal Events 
 
Event 
Management 
Renal event, Grade 1 
• Continue atezolizumab. 
• Monitor kidney function, including creatinine, closely until values resolve to within normal 
limits or to baseline values. 
Renal event, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab. c 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
108 
 
 
Renal event, Grade 3 or 4 
• Permanently discontinue atezolizumab. 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. Patients can be re-challenged with atezolizumab only after approval has been documented by the 
investigator (or an appropriate delegate). 
 
 
 
 
IMMUNE-MEDIATED MYOSITIS 
Immune-mediated myositis has been associated with the administration of atezolizumab. Myositis or inflammatory 
myopathies are a group of disorders sharing the common feature of inflammatory muscle injury; dermatomyositis 
and polymyositis are among the most common disorders. Initial diagnosis is based on clinical (muscle weakness, 
muscle pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle biopsy. 
 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 12. 
Table 12 Management Guidelines for Immune-Mediated Myositis 
 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
• Continue atezolizumab. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a and contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider treatment with corticosteroids equivalent to 1−2 mg/kg/day IV methylprednisolone 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• If corticosteroids are initiated and event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. c 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
  
CUMC IRB – AAAT0174 
 
Version Date: November 15 2021 
109 
 
 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event. Patients can be re-challenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Medical Monitor. 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
110 
 
 
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.) 
 
Immune-mediated 
myositis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset a and contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV methylprednisolone, or 
higher-dose bolus if patient is severely compromised (e.g., cardiac or respiratory symptoms, 
dysphagia, or weakness that severely limits mobility); convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. c 
• For recurrent events, treat as a Grade 4 event. 
Immune-mediated 
myositis, Grade 4 
• Permanently discontinue atezolizumab and contact Medical Monitor. c 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV methylprednisolone, or 
higher-dose bolus if patient is severely compromised (e.g., cardiac or respiratory symptoms, 
dysphagia, or weakness that severely limits mobility); convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event. Patients can be re-challenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Medical Monitor. 
 
 
 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic lymphohistiocytosis 
(HLH) and macrophage activation syndrome (MAS). 
 
Patients with suspected HLH should be diagnosed according to published criteria by McClain and Eckstein (2014). 
A patient should be classified as having HLH if five of the following eight criteria are met: 
• 
Fever ≥ 38.5°C 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
111 
 
 
• 
Splenomegaly 
• 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
– 
Platelet count < 100 × 109/L (100,000/µL) 
– 
ANC < 1.0 × 109/L (1000/µL) 
• 
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L (150 mg/dL) 
• 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• 
Low or absent natural killer cell activity 
• 
Ferritin > 500 mg/L (500 ng/mL) 
• 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard deviations above age-adjusted 
laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic juvenile idiopathic 
arthritis by Ravelli et al. (2016). A febrile patient should be classified as having MAS if the following criteria are met: 
• 
Ferritin > 684 mg/L (684 ng/mL) 
• 
At least two of the following: 
– 
Platelet count ≤ 181 × 109/L (181,000/µL) 
– 
AST ≥ 48 U/L 
– 
Triglycerides > 1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 13. 
 
Table 13 Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome 
 
Event 
Management 
Suspected HLH or 
MAS 
• Permanently discontinue atezolizumab and contact Medical Monitor. 
• Consider patient referral to hematologist. 
• Initiate supportive care, including intensive care monitoring if indicated per institutional 
guidelines. 
• Consider initiation of IV corticosteroids and/or an immunosuppressive agent. 
• If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
 
 
References 


Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
CUMC IRB – AAAT0174 
Version Date: November 15 2021 
112 
 
 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. Up to Date [resouce 
on the Internet]. 2014 [updated 29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-hemophagocytic-lymphohistiocytosis. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation syndrome complicating 
systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum 
Dis 2016;75:481−9.