Clinical trial NCT03014648
Conditions: Advanced Non-small Cell Lung Cancer
Sponsor: Liza Villaruz, MD
Start date: 2017-07-18; Completion date: 2022-03-31
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II clinical trial aimed at evaluating the efficacy of PD-L1 inhibition with atezolizumab in advanced squamous and non-squamous NSCLC patients previously treated with anti-PD-1 therapy with either nivolumab or pembrolizumab.

In order to account for the variability of response kinetics to PD-1 directed therapy, patients will be enrolled in 3 parallel cohorts based on the best overall response to PD-1 directed therapy.

* Cohort 1 (progressive disease)
* Cohort 2 (stable disease with minimum 12 weeks of therapy)
* Cohort 3 (partial to complete response followed by progressive disease)

Detailed description:
Atezolizumab will be given on day 1 of a 21-day cycle at 1200 mg IV. Radiographic assessments for disease response will occur every 6 weeks while on treatment. Confirmatory scans should be obtained ≥ 4 weeks following initial documentation of objective response or progressive disease on atezolizumab therapy.

Atezolizumab will be given as long as the patient continues to experience clinical benefit in the opinion of the investigator or until unacceptable toxicity, symptomatic deterioration attributed to disease progression.

Patients will be followed for 12 months or until death as per standard of care after discontinuation of Atezolizumab or until death, whichever occurs first.

Arms: arm 1: Atezolizumab will be given on day 1 of a 21-day cycle at 1200 mg IV over 60 (plus or minus 15) minutes for first infusion; can be decreased to 30 (plus or minus 10) minutes for subsequent cycles.

Atezolizumab will be given as long as the patient continues to experience clinical benefit in the opinion of the investigator or until unacceptable toxicity, symptomatic deterioration attributed to disease progression.

There will be no dose reduction for Atezolizumab. Patients may temporarily suspend study treatment for up to 84 days beyond the scheduled date of delayed infusion if study drug-related toxicity requiring dose suspension is experienced. If Atezolizumab is held because of adverse events for greater than 84 days beyond the scheduled date of infusion, the patient will be discontinued from Atezolizumab and will be followed for safety and efficacy.
Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Atezolizumab will be administered through an IV over 60 minutes at a dose of 1200mg on Day 1 of each 21-day cycle. If the first dose is tolerated without any infusion-related adverse events, the following doses can be administered over 30 minutes.

Protocol documents:
Prot_SAP_000.pdf: 
i 
SUMMARY OF CHANGES 
 
For Protocol  Version 9  
HCC #:  16-153 
 
Previous Protocol Date: 6/18/2020 
Current Protocol Date:  8/17/2020 
 
# 
Section 
Page(s) 
Change 
1 
7.3.2.4 
39 
Removed statement: “…or if the female partner of a male 
study subject becomes pregnant while the study subject is 
receiving the study drug or within 90…” 
 
Justification for the change: The Female pregnancy 
information is needed for 5 months per the most recent 
version of the US Package Insert for atezolizumab. 
2 
 7.3.4 
41 
Changed from: Events suggestive of hypersensitivity, 
infusion-related reactions, cytokine release syndrome, 
influenza-like illness, and systemic inflammatory response 
syndrome 
Changed to: Events suggestive of hypersensitivity, infusion-
related reactions, cytokine release syndrome, influenza-like 
illness, macrophage activating syndrome and 
hemophagocytic lymphohistiocytosis. 
Justification for the change: This has been updated for 
consistency with the most recent version of the US Package 
Insert for atezolizumab.  
3 
7.4 
42 
Replaced the safety reporting email with a Hotline Number 
for the reports.  
 
Justification for the change: The sponsor changed the 
manner in which safety reporting is conducted.  
 


 
1 
TITLE: A phase II clinical trial evaluating the efficacy of atezolizumab in advanced non-small 
cell lung cancer (NSCLC) patients previously treated with PD-1-directed therapy  
 
HCC #: 
16-153 
BB-IND#: 
N/A 
Phase: 
II 
Version: 
7 
Version Date: 
8/17/2020 
Investigational Agent: 
Atezolizumab  
Commercial Agent: 
N/A 
 
Sponsor-Investigator: 
Liza C. Villaruz, MD 
 
UPMC Cancer Pavilion, 5th floor 
 
5150 Centre Avenue  
 
Pittsburgh, PA 15232 
 
Email: villaruzl@upmc.edu 
 
Phone: 412-648-6578 
 
Fax: 412-648-6579 
 
Biostatistician: 
Daniel Normolle, PhD 
 
325 Sterling Plaza, Suite 325 
 
201 N. Craig Street 
 
Pittsburgh, PA 15213 
 
Email : dpn7@pitt.edu 
 
Phone : 412-383-1591 
 
Source of Support: 
Genentech  
 
 
 
 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
2 
SCHEMA 
This is a phase II clinical trial aimed at evaluating the efficacy of PD-L1 inhibition with 
atezolizumab in advanced squamous and non-squamous NSCLC patients previously treated with 
anti-PD-1 therapy with either nivolumab or pembrolizumab.  The kinetics of response to immune 
checkpoint inhibition can be variable and complicated by an initial increase in tumor burden or 
the appearance of new lesions, followed by disease response (pseudo-progression).  In order to 
account for the variability of response kinetics to PD-1 directed therapy, patients will be enrolled 
in 3 parallel cohorts based on the best overall response (BOR) to PD-1 directed therapy.  
 
 
Collection of archival tumor specimens pre-PD-1 directed therapy (if available), mandatory 
biopsies at the time of enrollment and optional re-biopsy at the time of disease progression on 
atezolizumab, as well as mandatory collection of peripheral blood on C1D1 and optional 
collection of peripheral blood on day 1 of C2 through C5, will be performed for completion of 
translational studies aimed at identifying candidate biomarkers of response and mediators of 
resistance to PD-1 and PD-L1 directed therapies.   
Primary Objective: 
• To estimate the BOR of atezolizumab in patients previously treated with PD-1 directed 
therapy, in each of three parallel cohorts defined by BOR to PD-1 directed therapy.   
Secondary Objectives: 
 
• To estimate the duration of response (DOR) of atezolizumab in patients previously 
treated with anti-PD-1 therapy, based on the BOR to PD-1 directed therapy.  
• To estimate the progression-free survival (PFS) of atezolizumab in patients previously 
treated with anti-PD-1 therapy, based on the BOR to PD-1 directed therapy. 
• To estimate the overall survival (OS) of atezolizumab in patients previously treated with 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
3 
anti-PD-1 therapy, based on the BOR to PD-1 directed therapy. 
• To estimate the safety of atezolizumab in patients previously treated with anti-PD-1 
therapy, as determined by grade ≥ 3treatment related adverse events. 
Exploratory objectives: 
 
• To understand mechanisms of immune escape and assess biomarkers of response, 
including but not limited to PD-L1 expression.   
 
Treatment Regimen   
Atezolizumab will be given on day 1 of a 21-day cycle at 1200 mg IV. Radiographic assessments 
for disease response will occur every 6 weeks while on treatment.  Confirmatory scans should be 
obtained ≥ 4 weeks following initial documentation of objective response or progressive disease 
on atezolizumab therapy.    
 
 
Statistical Methods 
 
Primary Objective: 
• For each cohort, a BOR rate of 15% would be promising compared to a null rate of 2%.  
The target enrollment is 37 evaluable patients within each cohort.  A stopping rule for 
futility is implemented using Simon’s optimal two-stage design, if none of the first 11 
evaluable patients within a cohort have a confirmed objective response.   Accrual may 
continue during follow-up for these patients. If 1 or more responses are observed in the 
first 11 evaluable patients in a cohort, an additional 26 patients will be enrolled.  
Importantly, if one cohort meets criteria for futility in stage 1, the other cohort(s) may 
proceed to stage 2, if indicated.  A promising study result would be if 3 or more 
responses are seen at the conclusion of stage 2.  This design has 80% power for each 
cohort to detect a true response rate of 15% (compared with a null rate of 2%). The one-
sided type 1 error rate is 0.05 for each cohort. 
 
Secondary Objectives: 
 
• For patients experiencing complete or partial tumor responses, the distribution of 
response duration, measured as the time from complete response (CR) or partial response 
(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) will be characterized by the median 
and quartiles, and graphical display of Kaplan-Meier estimates of response duration, 
separately for each cohort and for all responders. 
 
• Progression-free survival (PFS, months from start of treatment to time of progression, 
death or last radiographic assessment without PD, whichever occurs first) and overall 
survival (OS, months from first study treatment to death or last contact) will be 
summarized separately for each cohort.  The PFS function and median PFS will be 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
4 
estimated by the Kaplan-Meier method, with a 90% confidence interval using the 
Greenwood variance formula applied to log-transformed survival. 
 
 
• Adverse events will be graded using the Cancer Therapy Evaluation Program (CTEP) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4. Adverse events 
of grade 3 or greater determined to be possibly, probably or definitely related to 
treatment, or that result in dose holds or reductions, will be collected and reported. 
Adverse events and serious adverse events will be tabulated in order of prevalence, with 
the highest grade reported by each patient. The number and percent of subjects reporting 
adverse events will be summarized by category (i.e., “Blood and lymphatic system 
disorders”), for the most common adverse event subcategories (i.e., “anemia”), and for 
serious adverse events (defined in section 7.2). Narratives of all serious adverse events 
and deaths on-study will be provided.  All safety data will be tabulated separately by 
cohort, and for the full study sample. 
 
 
Exploratory Objectives: 
 
• PD-L1 expression will be measured in tissue from a mandatory biopsy conducted 
after discontinuation of the prior therapy and before initiation of study therapy. The 
primary analysis will examine associations between PD-L1 expression and best 
overall response by RECIST 1.1, for all cohorts combined.  These two ordinal 
variables (immunohistochemistry and response) will first be described graphically in 
a mosaic plot, which may suggest a clinically relevant dichotomization of PD-L1 
expression and/or best overall response.  Further analysis may use generalized linear 
model approaches for ordinal regression, or treat response as dichotomous or 
continuous, with limited models fit to avoid “p-hacking”. 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
5 
TABLE OF CONTENTS 
SCHEMA 
......................................................................................................................2 
1. 
OBJECTIVES ....................................................................................................................7 
1.1 
Primary Objectives...................................................................................................7 
1.2 
Secondary Objectives...............................................................................................7 
1.3 
Exploratory Objectives ............................................................................................7 
2. 
BACKGROUND ................................................................................................................7 
2.1 
Non-Small Cell Lung Cancer...................................................................................7 
2.2 
Atezolizumab .........................................................................................................10 
2.3 
Rationale ................................................................................................................12 
2.4 
Correlative Studies Background ............................................................................13 
3. 
PATIENT SELECTION .................................................................................................15 
3.1 
Inclusion Criteria ...................................................................................................15 
3.2 
Exclusion Criteria ..................................................................................................17 
3.3 
Inclusion of Women and Minorities ......................................................................21 
4. 
REGISTRATION PROCEDURES ................................................................................21 
4.1 
General Guidelines.................................................................................................21 
4.2 
Registration Process ...............................................................................................21 
5. 
TREATMENT PLAN ......................................................................................................21 
5.1 
Agent Administration.............................................................................................21 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................22 
5.3 
Duration of Therapy ...............................................................................................24 
5.4 
Duration of Follow Up ...........................................................................................25 
5.5 
Criteria for Removal from Study ...........................................................................25 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................26 
6.1 
Gastrointestinal Toxicity ........................................................................................27 
6.2 
Hepatotoxicity ........................................................................................................29 
6.3 
Dermatologic Toxicity ...........................................................................................30 
6.4 
Endocrine Toxicity.................................................................................................31 
6.5 
Pulmonary Toxicity ...............................................................................................31 
6.6 
Pericardial and Pleural Effusions ...........................................................................33 
6.7 
Potential Pancreatic Toxicity .................................................................................33 
6.8 
Potential Eye Toxicity............................................................................................33 
7. 
REPORTING OF SERIOUS ADVERSE EVENTS .....................................................34 
7.1 
Adverse Event Definitions .....................................................................................34 
7.2 
Documentation of Serious Adverse Events ...........................................................36 
7.3 
Methods and Timing for Assessing and Recording Safety Variables ...................38 
7.4 
Reporting of Suspected Adverse Reactions to Genentech .....................................41 
7.5 
Reporting adverse events to the responsible IRB ..................................................45 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
6 
8. 
PHARMACEUTICAL INFORMATION ......................................................................46 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ...................................47 
9.1 
Biomarker Studies ..................................................................................................48 
10. 
STUDY CALENDAR ......................................................................................................50 
11. 
MEASUREMENT OF EFFECT ....................................................................................52 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................52 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .....................................58 
12.1 
Data Safety Monitoring Plan .................................................................................58 
12.2 
Quality Control and Quality Assurance .................................................................59 
12.3 
Data Handling and Record-Keeping ......................................................................59 
12.4 
Institutional Review Board (IRB) Approval ..........................................................59 
12.5 
Ethical and Scientific Conduct of the Clinical Study ............................................60 
12.6 
Informed Consent...................................................................................................60 
13. 
STATISTICAL CONSIDERATIONS ...........................................................................61 
13.1 
Study Design/Endpoints.........................................................................................61 
13.2 
Sample Size ............................................................................................................61 
13.3 
Analysis cohorts .....................................................................................................62 
13.4 
Analysis plans ........................................................................................................62 
REFERENCES 
....................................................................................................................64 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..............................................67 
APPENDIX B 
ANAPHYLAXIS PRECAUTIONS ........................................................68 
APPENDIX C  
SAFETY REPORTING FAX COVER SHEET......................................1 
 
 
 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
7 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
• To estimate the BOR of atezolizumab in patients previously treated with PD-1 directed 
therapy, in each of three parallel cohorts defined by BOR to PD-1 directed therapy.   
 
1.2 
Secondary Objectives 
 
• To estimate the duration of response (DOR) of atezolizumab in patients previously 
treated with anti-PD-1 therapy, based on the BOR to PD-1 directed therapy.  
• To estimate the progression-free survival (PFS) of atezolizumab in patients previously 
treated with anti-PD-1 therapy, based on the BOR to PD-1 directed therapy. 
• To estimate the overall survival (OS) of atezolizumab in patients previously treated with 
anti-PD-1 therapy, based on the BOR to PD-1 directed therapy. 
• To estimate the safety of atezolizumab in patients previously treated with anti-PD-1 
therapy, as determined by grade ≥ 3treatment related adverse events. 
1.3 
Exploratory Objectives 
 
• To understand mechanisms of immune escape and assess biomarkers of response, 
including but not limited to PD-L1 expression.   
 
2. BACKGROUND 
 
2.1 
Non-Small Cell Lung Cancer 
 
Lung cancer is the leading cause of cancer-related deaths worldwide with an estimated incidence 
of 1.6 million cases resulting in 1.4 million deaths in annually (Jemal et al., 2011). Non-small-cell 
lung cancer (NSCLC) represents 80-85% of cases (Jemal et al., 2011). The majority of NSCLC 
patients present with advanced or metastatic disease, which is not amenable to surgical resection. 
Platinum-based combination chemotherapy has reached a therapeutic plateau with a median 
overall survival (OS) of 7.4 to 9.9 months. The recent advances in the treatment of NSCLC have 
come from the recognition that NSCLC is not a single disease entity but rather a collection of 
distinct molecularly driven neoplasms.  This principle is supported by the seminal finding that 
sensitizing epidermal growth factor receptor (EGFR) mutations are present in about 10-15% of 
lung cancers and are targetable with the FDA approved EGFR tyrosine kinase inhibitors (TKIs)  
(erlotinib, gefitinib and afatinib) (Jemal et al., 2011; Ettinger et al., 2010). Additionally, 
translocations involving the anaplastic lymphoma kinase (ALK) are found in 5-8% of 
adenocarcinomas of the lung and can be targeted by several ALK TKIs (crizotinib, ceritinib and 
alectinib) (Somasundaram et al., 2014; Kris et al., 2014).  
The therapeutic landscape of previously treated advanced NSCLC in the absence of an 
actionable oncogenic driver has shifted from a cytotoxic approach to modulation of the immune 
checkpoints.  The programmed death 1 receptor (PD-1) is expressed on activated T-cells and 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
8 
engaged by the programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) 
that are expressed on tumor cells and infiltrating immune cells (Pardoll et al., 2012). In NSCLC, 
tumor PD-L1 expression is prevalent and PD-1 interaction with the ligands, PD-L1 and PD-L2, 
inhibits cell activation and promotes tumor recognition and elimination (Chen et al., 2012; 
Velcheti et al., 2014). Nivolumab is a fully human IgG4 programmed death 1 immune 
checkpoint antibody inhibitor that disrupts PD-1-mediated signaling and restores antitumor 
immunity (Brahmer et al., 2010; Topalian et al., 2012). In phase I studies, nivolumab 
monotherapy showed a durable anti-tumor activity in NSCLC (Brahmer et al., 2010; Topalian et 
al., 2012; Gettinger et al., 2015) including NSCLC of squamous and non-squamous histology.  
In a landmark prospective randomized phase III study (CheckMate017) (Brahmer et al., 2015), 
two hundred and seventy-two patients with advanced squamous NSCLC previously treated with 
platinum based chemotherapy were treated with nivolumab (3 mg/kg every two weeks) versus 
docetaxel (75 mg/m2 every three weeks). The primary endpoint was overall survival, and PD-1 
inhibition with nivolumab was found to be associated with an improvement in median overall 
survival to 9.2 months versus 6.0 months with docetaxel (HR 0.59; P<0.001). The response rate 
with nivolumab was 20% versus 9% with docetaxel (p = 0.008), and the median progression-free 
survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (HR of 0.62; P < 
0.001). Additionally, PD-L1 protein expression utilizing the 28-8 antibody (Dako) was evaluated 
retrospectively in pre-treatment (archival or recent) tumor-biopsy specimens.  Interestingly, PD-
L1 expression was not predictive of benefit. Given the results of this study, nivolumab was 
approved in March of 2015 for treatment of advanced squamous NSCLC previously treated with 
a platinum based therapy regardless of PD-L1 expression.  
A phase III study (CheckMate057) examined the effect of nivolumab (3 mg/kg every two weeks) 
versus docetaxel (75 mg/m2 every three weeks) in a group of five hundred and eighty-two 
patients with non-squamous advanced NSCLC previously treated with platinum-doublet 
chemotherapy.  The primary endpoint was overall survival and was found to be longer in patients 
treated with nivolumab versus docetaxel with a median overall survival of 12.2 months in the 
nivolumab arm versus 9.4 months in the docetaxel arm (HR 0.73; P=0.002).  The objective 
response rate was also higher with nivolumab (19%) versus docetaxel (12%; P=0.02) (Borghaei 
et al., 2015). Similar to Brahmer et al., PD-L1 protein expression was assessed retrospectively in 
archival or recent tumor biopsy specimens utilizing the 28-8 antibody (Dako).  In the group with 
≥10% PD-L1 expression treated with nivolumab, the objective response was 37% (95% CI 27 to 
48). In contrast, in the group ≥10% PD-L1 expression treated with docetaxel, the objective 
response rate was 13% (95% CI 6 to 22). Amongst patients whose tumors expressed PD-L1, 
nivolumab nearly doubled median overall survival as compared with docetaxel (Borghaei et al., 
2015).  
Pembrolizumab is a highly selective humanized, IgG4 monoclonal antibody against PD-1.  
Recently, Pembrolizumab given at 2 mg/kg every 3 weeks was granted accelerated approval for 
the treatment of metastatic NSCLC patients whose tumors express PD-L1 with disease 
progression after platinum-based chemotherapy. The KEYNOTE-010 compared the 
administration of pembrolizumab at 2 mg/kg every three weeks versus pembrolizumab at 10 
mg/kg every three weeks versus standard of care treatment docetaxel at 75 mg/m2. Patients in 
this large multi-center phase II/III study had advanced NSCLC with PD-L1 expressing tumors by 
the 22C3 antibody (Dako). Both squamous and non-squamous histologies were included. In this 
trial, one thousand and thirty-four patients were randomized 1:1:1 to receive pembrolizumab at 2 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
9 
mg/kg, pembrolizumab at 10 mg/kg or docetaxel at 75 mg/ m2 (Herbst et al., 2015).  In this 
clinical trial, pembrolizumab at either dose significantly improved OS compared with docetaxel, 
an9ffectt which was particularly pronounced in patients with tumors with ≥ 50% PD-L1 
expression.  In this clinical trial, the median overall survival was 10.4 months (95% CI 9.4 -11.9) 
with pembrolizumab at 2 mg/kg, 12.7 months (95% CI 10.0 – 17.3) with pembrolizumab at 10 
mg/kg and 8.5 months (95% CI 7.5 – 9.8) with docetaxel. Among patients with tumors with at 
least 50% PD-L1 expression, the median overall survival was 14.9 months (95% CI 10.4 – NR) 
in the pembrolizumab 2 mg/kg group, 17.3 months (95% CI 11.8 – NR) in the pembrolizumab10 
mg/kg group and 8.2 months (95% CI  6.4 – 10.7) for the docetaxel group (Herbst et al., 2015).   
Durvalumab is a human IgG1 monoclonal antibody that blocks both PD-L1 binding to PD-1 and 
CD80. In a phase I/II study of durvalumab in patients with multiple solid tumor types, 200 
NSCLC patients were evaluable for response (112 non-squamous and 88 squamous histology), in 
whom the ORR was 16% with a disease control rate of 42% at 12 weeks. In patients with PD-L1 
positive disease (determined using the SP263 antibody IHC assay, Ventana), the ORR was 27% 
(95% CI 18.2-38.2) compared with 5% (95% CI 1.8-12.2) in PD-L1 negative patients (Rizvi et 
al. 2015).   
Atezolizumab is a fully humanized monoclonal antibody of IgG1 isotype against programmed 
death ligand-1. A phase II study (POPLAR) randomized previously treated NSCLC patients to 
atezolizumab given 1200 mg every three weeks versus docetaxel at 75 mg/m2 (Spira et al, 2015; 
Vansteenkiste et al, 2015), stratified by PD-L1 immune cell (IC) status.  PD-L1 expression was 
scored on a scale of 0 to 3 on both the tumor cells (TC) and the immune cells (IC) by IHC using 
the SP142 antibody assay (Ventana).  PD-L1 inhibition with atezolizumab was associated with a 
trend toward improved efficacy in patients with high PD-L1 expressing tumors (TC3 or IC3) 
with a median OS of 15.5 months in the atezolizumab group and 11.1 months in the docetaxel 
group (HR 0.49; P=0.068). In patients with moderate to high PD-L1 expression (TC2/3 or 
IC2/3), there was a statistically significant improvement in median OS from 7.4 months with 
docetaxel to 15.1 months with atezolizumab (HR 0.54; P=0.014).  An OS benefit was also seen 
in patients with any PD-L1 expression (TC1/2/3 or IC1/2/3; median OS 15.5 months versus 9.2 
months, atezolizumab versus docetaxel, respectively, HR 0.59, P=0.005).  Patients with the 
lowest PD-L1 expression levels (TC0 and IC0) did not appear to have any benefit from 
atezolizumab with a median OS of 9.7 months in both the atezolizumab and docetaxel arms (HR 
1.04; P=0.871) (Spira et al., 2015; Vansteenkiste et al, 2015). The safety of atezolizumab in 142 
patients treated on this study was consistent with prior clinical studies; patients receiving 
atezolizumab experienced fewer grade 3 and 4 treatment related adverse side effects (ASEs) 
compared with docetaxel (11% versus 39%, respectively), and fewer grade 5 treatment related 
ASEs (1% versus 2%, respectively).  Adverse events occurring in ≥ 5% patients treated with 
atezolizumab included anorexia, dyspnea, fever, arthralgias, insomnia, pneumonia and 
hypothyroidism.   
BIRCH is a single-arm phase II clinical trial of atezolizumab in treatment naïve and previously 
treated NSCLC patients with at least moderate PD-L1 tumor staining (TC2/3 or IC2/3) (Besse et 
al., 2015). In previously untreated patients, the ORR was 26% (95%CI 16-39) in patients with 
high PD-L1 (TC3 or IC3) expressing tumors and 19% (95% CI 13-27) in patients with moderate 
to high PD-L1 (TC2/3 or IC2/3) expressing tumors.  In the second line setting, atezolizumab was 
associated with an ORR of 24% (95% CI 17-32) in previously treated patients with high PD-L1 
expressing tumors and 17% in (95% CI 13-22) in patients with moderate to high PD-L1 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
10 
expressing tumors.  In patients receiving atezolizumab in the 3rd line and beyond, the ORR was 
27% (95% CI 19-36) in patients with high PD-L1 expressing tumors and 17% (95% CI 13-23) in 
patients with moderate to high PD-L1 expressing tumors (Besse et al. 2015).  In 659 safety 
evaluable patients, 11% patients experienced grade 3 and 4 treatment related ASEs, similar to 
prior studies. The most common treatment related ASEs were fatigue, diarrhea, nausea, pruritus, 
fever, anorexia, weakness, rash, and arthralgia.   
FIR is a single arm phase II clinical trial in which patients with moderate to high PD-L1 
expressing tumors (TC2/3 or IC 2/3) were treated with atezolizumab in the 1st line and in the 2nd 
line and beyond (Chaft  et al., 2015).  Atezolizumab was associated with an ORR of 29% (95% 
CI 14-48) in patients treated in the 1st line; the ORR was 29% in patients with high PD-L1 
expressing tumors (TC3 and/or IC3).   In previously treated patient without brain metastases, 
atezolizumab was associated with an ORR of 17% (95% CI 10-27%); the ORR in patients with 
high PD-L1 expressing tumors was 26% (95% CI 13-43).  In previously treated patients with 
treated brain metastases, the ORR was 23% (95% CI 5-54); in the ORR in patients with high PD-
L1 expressing tumors was 25% (95% CI 3-65). In 137 safety evaluable patients, 15% patients 
experienced grade 3 and 4 treatment related ASEs, similar to prior studies. The most common 
treatment related ASEs were fatigue, nausea, anorexia, diarrhea, fever, pruritus, arthralgia, 
myalgias, vomiting and anima.   
In February of 2015, atezolizumab received “Breakthrough Therapy” designation from the 
Federal Drug Administration for the treatment of NSCLC that expresses PD-L1 with disease 
progression during or after standard platinum-based chemotherapy or targeted therapy.   
 
2.2 
Atezolizumab 
 
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids) and is produced in Chinese 
hamster ovary cells.  Atezolizumab was engineered to eliminate Fc-effector function via a single 
amino acid substitution (asparagine to alanine) at position 298 on the heavy chain, which results 
in a non-glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-effector 
function at expected concentrations in humans. Atezolizumab targets human programmed death-
ligand 1 (PD-L1) and inhibits its interaction with its receptor, programmed death-1 (PD-1). 
Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction that is reported to provide 
additional inhibitory signals to T cells. 
Atezolizumab (TecentriqTM) is approved in the United States for the treatment of locally 
advanced or metastatic urothelial cancer (UC) and non-small cell lung cancer which has grown 
on or after chemotherapy.  Atezolizumab is being investigated as a potential therapy against solid 
tumors and hematologic malignancies in humans.   
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 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
11 
nonclinical model for understanding the safety, pharmacokinetics, and toxicokinetics of 
atezolizumab. 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the proposed 
Phase I starting doses.  The results of the toxicology program were consistent with the 
anticipated pharmacologic activity of down-modulating the PD-L1/PD-1 pathway and supported 
entry into clinical trials in patients. 
Clinical Safety 
The presented safety data for atezolizumab have been derived mainly from the treatment of 
patients in Phase Ia Study PCD4989g.  As of 10 May 2014, atezolizumab has been administered 
to approximately 775 patients with solid and hematologic malignancies.  No dose-limiting 
toxicities (DLTs) have been observed at any dose level, and no maximum tolerated dose (MTD) 
was established.  Fatigue was the most frequently reported adverse event (AE).  
Adverse Events 
The following safety data are from PCD4989g, in which atezolizumab is being used as single-
agent therapy in patients with locally advanced or metastatic solid tumors or hematologic 
malignancies.  In 412 treated patients, 97.1% reported an AE while on study.  Of these Aes, 
48.8% were Grade 1 or 2 in maximum severity on the basis of National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).  The most 
frequently observed Aes (occurring in ≥ 10% of treated patients) included fatigue, nausea, 
decreased appetite, pyrexia, dyspnea, diarrhea, constipation, cough, headache, back pain, 
vomiting, anemia, arthralgia, rash, insomnia, asthenia, abdominal pain, chills, pruritus, and upper 
respiratory tract infection.   
Grade ≥ 3 Aes were reported by 199 of 412 patients (48.3%).  There were 51 patients (12.4%) 
who reported Grade ≥ 3 Aes that were assessed as related to study drug by the investigators.  
The most frequently reported related Grade ≥ 3 Aes included fatigue (5 patients [1.2%]), 
increased ALT and increased AST (each reported in 4 patients [1.0%]); and asthenia, 
autoimmune hepatitis, and hypoxia (each reported in 3 patients [0.7%]).  
Immune-Related Adverse Events 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated Aes have been closely monitored during the atezolizumab clinical program.  
These include potential dermatologic, hepatic, endocrine, and respiratory events as well as events 
of hepatitis/elevated liver function tests (LFTs) and influenza-like illness.  Expected adverse 
drug reactions associated with atezolizumab include the following:  hepatitis/transaminitis, 
hypothyroidism, infusion-related reactions (IRRs), pneumonitis, influenza-like illness, and 
dermatologic reactions.  Potential adverse drug reactions include the following:  anti-therapeutic 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
12 
antibodies (ATAs), colitis, endocrine disorders, hypersensitivity, neurologic disorders, and 
pericardial effusion.   
Clinical Pharmacokinetics and Immunogenicity 
On the basis of available preliminary PK data (0.03-20 mg/kg), atezolizumab appeared to show 
linear pharmacokinetics at doses ≥ 1 mg/kg.  For the 1-mg/kg and 20-mg/kg dose groups, the 
mean clearance (CL) and the mean volume at steady state (Vss) had a range of 3.20-4.43 mL/kg 
and 48.1-64.1 mL/kg, respectively, which is consistent with the expected profile of an IgG1 
antibody in humans. 
The development of ATAs has been observed in patients in all dose cohorts and was associated 
with changes in pharmacokinetics for some patients in the lower dose cohorts (0.3, 1, and 3 
mg/kg).  The development of detectable ATAs has not had a significant impact on 
pharmacokinetics for doses from 10-20 mg/kg.  Patients dosed at the 10-, 15-, and 20-mg/kg 
dose levels have maintained the expected target trough levels of drug despite the detection of 
ATAs.  To date, no clear relationship between detection of ATAs and Aes or IRRs has been 
observed. 
2.3 
Rationale 
The therapeutic landscape of previously treated advanced NSCLC in the absence of an 
actionable oncogenic driver has shifted from a cytotoxic approach to modulation of the immune 
checkpoints.   It is notable that while inhibition of the PD-1 axis is associated with improved 
response rates versus cytotoxic therapy in patients with previously treated NSCLC, the majority 
of patients will not benefit from an objective response.  It is also notable that anti-PD-1 and anti-
PD-L1 antibodies block distinct inhibitory pathways, possibly resulting in different clinical 
outcomes. While anti-PD-1 antibodies block PD-1 binding to PD-L1 and PD-L2, they do not 
affect the inhibitory signal occurring upon the PD-L1/B7.1 interaction. Conversely, while anti-
PD-L1 antibodies block PD-L1 binding to B7.1 and PD-1, they do not impede the inhibitory 
signaling provided by the interaction of PD-1 and PD-L2. This clinical trial is critical to 
evaluating the efficacy of sequencing PD-L1 inhibition in patients with stable or progressing 
disease on PD-1 directed therapy and to the identification of candidate biomarkers of response 
and resistance to PD-1/PD-L1 directed therapies.   
The kinetics of response to immune checkpoint inhibition can be variable and complicated by an 
initial increase in tumor burden or the appearance of new lesions, followed by disease response 
(pseudo-progression).  In 129 pretreated advanced NSCLC patients receiving nivolumab 1, 3, or 
10 mg/kg every 2 weeks, tumor burden was assessed by RECIST (version 1.0) every 8 weeks 
(Gettinger et al., 2015).  Among 22 patients (17%) with objective responses, estimated median 
response duration was 17.0 months. An additional six patients (5%) had unconventional 
immune-pattern responses (Figure 1). In order to account for the variability of response kinetics 
to PD-1 directed therapy, patients will be enrolled in 3 parallel cohorts based on the best overall 
response (BOR) to PD-1 directed therapy with either nivolumab or pembrolizumab.   


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
13 
 
Figure 1.  Tumor burden kinetics in patients with NSCLC treated with nivolumab 3 mg/kg, in whom baseline tumor 
measurements are standardized to zero. Red triangles indicate first occurrence of new lesion. Horizontal dashed line 
at 30% indicates threshold for defining objective response (partial tumor regression) in absence of new lesions or 
nontarget disease progression, according to RECIST (version 1.0); vertical dashed line at 96 weeks indicates 
protocol-defined maximum duration of continuous nivolumab therapy.  Gettinger at el. J Clin Oncol 2015; 33:2004-
2012. 
 
2.4 
Correlative Studies Background 
 
In a study aimed at the identification of predictive correlates of response to atezolizumab in 
patients with solid tumors, 277 patients with advanced cancers received atezolizumab every 3 
weeks (Herbst et al. 2014).  Tumor responses were assessed using the Response Evaluation 
Criteria in Solid Tumors, version 1.1, and available pre-treatment and on treatment formalin-
fixed, paraffin embedded (FFPE) tissue tumor specimens were utilized for correlative studies.  
Tumor cells (TC) and immune cells (IC) were stained for PD-L1 with an anti-human PD-L1 
rabbit monoclonal antibody (clone SP142; Ventana, Tucson, AZ) on an automated staining 
platform (Benchmark; Ventana). In NSCLC patients, there was an association between response 
to atezolizumab and IC PD-L1 expression (p = 0.015), while no association was noted between 
TC PD-L1 expression and response to atezolizumab (p = 0.920).  Serial on-treatment biopsies 
were performed in 28 patients.  Regressing lesions were characterized by a dense immune 
infiltrate and extensive tumor cell necrosis accompanied by the apparent sterilization of cancer 
cells in some cases, in addition to an increase in PD-L1 expression on tumor-infiltrating immune 
cells and tumor cells, which was accompanied by changes in tumor IFNγ expression. In contrast, 
on-treatment biopsies from a subset of patients with progressive disease were characterized by 
lack of PD-L1 upregulation by either tumor cells or tumor infiltrating immune cells.  These 
growing tumors were characterized by little or no tumor immune cell infiltration, presence of an 
intra-tumoral immune infiltrate with minimal to no expression of PD-L1 or presence of an 
immune infiltrate solely around the outer edge of the tumor cell mass.   
 
PD-L1 expression levels on tumor cells and tumor-infiltrating immune cells was further 
evaluated as a predictive biomarker of PD-L1 benefit in the context of a phase 2 randomized 
controlled trial, in which patients with NSCLC who progressed on post-platinum chemotherapy 
were treated with either atezolizumab 1200 mg or docetaxel 75 mg/m² once every 3 weeks 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
14 
(Fehrenbacher et al., 2016).  Patients were stratified by PD-L1 tumor-infiltrating immune cell 
status, histology, and previous lines of therapy.  Baseline PD-L1 expression was scored by 
immunohistochemistry (IHC) in tumor cells as the percentage of PD-L1-expressing tumor cells: 
≥50% (TC3), ≥5% and <50% (TC2), ≥1% and <5% (TC1), and <1% (TC0), and in tumor-
infiltrating immune cells as the percentage of tumor area: ≥10% (IC3), ≥5% and <10% (IC2), 
≥1% and <5% (IC1), and <1% (IC0). In the intention-to-treat population, the OS was 12.6 
months (95% CI 9.7–16.4) for atezolizumab versus 9.7 months (8.6–12.0) for docetaxel (HR 
0.73 [95% CI 0.53–0.99]; p=0.04). Increasing improvement in overall survival was associated 
with increasing PD-L1 expression (TC3 or IC3 HR 0.49 [0.22–1.07; p=0.068], TC2/3 or IC2/3. 
HR 0.54 [0.33–0.89; p=0.014], TC1/2/3 or IC1/2/3 HR 0.59 [0.40–0.85; p=0.005], TC0 and IC0 
HR 1.04 [0.62–1.75; p=0.871]), indicating the predictive benefit of PD-L1 expression.  
 
NSCLC specimens from pre-treatment tumor samples across atezolizumab trials (n = 498) and a 
non-trial cohort (n = 706) were evaluated for PD-L1 expression in TC and IC using the SP142 
IHC assay (Gettinger et al., 2015). TC3 or IC3, TC2/3 or IC2/3, and TC1/2/3 or IC1/2/3 tumors 
represented about 20%, 40% and 65% of NSCLCs, respectively.  IC3 and TC3 tumors 
represented two distinct tumor types; IC3 tumors had a high frequency of immune infiltrates 
within the tumor, stroma and tumor/stroma interface, with higher expression of B- and NK-cell 
signatures.   TC3 tumors, in contrast, were characterized by distinct histopathologic 
characteristics, with a dense desmoplastic and sclerotic tumor microenvironment, a lower 
frequency of immune infiltrates, which when present were primarily located in the surrounding 
stroma. Higher levels of PD-L1 promoter methylation were inversely correlated with PD-L1 
expression in TC, suggesting that PD-L1 may be influenced in part by epigenetic modification. 
Tumors that were TC0 and IC0, representing about 35% of NSCLCs, showed little to no 
evidence of immune infiltration or activation, consistent with immunologic ignorance.  Similar 
results have also been noted in a separate analysis of tumor specimens from 1,360 patients 
prescreened and/or enrolled in NSCLC atezolizumab trials and from 39 patients treated at 
Memorial Sloan Kettering Cancer Center (Kowanetz et al., 2016).   Among a subset of patients 
with paired tumor samples, PD-L1 expression was similar across synchronous and metachronous 
tissues.   
 
In addition to the PD-L1 and PD-1 expression pattern, other biomarkers for response to PD1/PD-
L1 directed therapy are under investigation, including genetic mutations within cancer cells and 
neoantigens, cancer epigenetics and effector T cell landscape, and the microbiota (Zou et al., 
2016).  Utilizing whole-exome sequencing of NSCLC tumors in patients treated with 
pembrolizumab, higher nonsynonymous mutation burden was associated with improved 
objective response, durable clinical benefit, and progression-free survival (Rizvi et al., 2015). 
Efficacy has also been correlated with a molecular smoking signature, higher neoantigen burden, 
and DNA repair pathway mutations, suggesting that the genomic landscape of lung cancers is a 
determinant of response to anti–PD-1 therapy (Rizvi et al., 2015; McGranahan et al., 2016).   
 
There remains much to learn of immune escape mechanisms and mechanisms of innate or 
acquired resistance.  In mouse models of lung adenocarcinoma, mRNA sequencing of tumors 
progressing on anti-PD-1 therapy was associated with upregulation of alternative immune 
checkpoints, in particular T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody-bound T 
cells (Koyama et al., 2015).   In addition, treatment with a TIM-3 blocking antibody confers a 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
15 
survival advantage following failure of PD-1 blockade. In two patients who developed adaptive 
resistance to anti-PD-1 treatment, TIM-3 upregulation in blocking antibody-bound T cells was 
noted at the time of treatment failure (Koyama et al., 2015).  
 
Collection of archival tumor specimens pre-PD-1 directed therapy (if available), mandatory 
biopsies at the time of enrollment and optional re-biopsy at the time of disease progression on 
atezolizumab, as well as mandatory collection of peripheral blood on C1D1 and optional 
collection of peripheral blood on day 1 of C2 through C5 will be performed for completion of 
translational studies aimed at identifying candidate biomarkers of response and mediators of 
resistance to PD-1 and PD-L1 directed therapies.  The primary biomarker to be explored will be 
PD-L1 IHC of FFPE patient tumor specimens.  Other biomarkers to be explored, based on the 
availability of funding, include, but are not limited to, whole exome sequencing of FFPE patient 
tumor specimens, sequencing of cell-free DNA (cfDNA) from plasma and immunophenotyping 
of PBMCs.   
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
3.1.1 Patients with Stage IIIB/IV squamous or non-squamous NSCLC (American Joint 
Committee on Cancer 7th Edition Staging) who have had prior treatment with nivolumab 
or pembrolizumab will be enrolled in one of 3 parallel cohorts based on the following: 
 
• Cohort 1: Patient with progressive disease on nivolumab or pembrolizumab as the 
BOR (defined in Section 11.1).  Progressive disease must be confirmed with a 
confirmatory scan ≥ 4 weeks after the 1st documented date of progression. 
• Cohort 2: Patients with stable disease as the BOR (defined in Section 11.1) on a 
minimum of 12 weeks of therapy with nivolumab or pembrolizumab.   
• Cohort 3:  Patients with partial or complete response as the BOR (defined in Section 
11.1), followed by progressive disease, on nivolumab or pembrolizumab.  A 
confirmatory scan at the time of disease progression must be performed ≥ 4 weeks 
after the 1st documented date of progression. 
3.1.2 Patients must have resolution of toxic effects to Grade 1 or less from prior therapy 
(except alopecia).  
 
3.1.3 Patients must sign Informed Consent Form (ICF) and show ability and willingness to 
comply with the requirements of the study protocol 
 
3.1.4 Age ≥ 18 years 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
16 
3.1.5 Willingness to undergo a biopsy ≤ 6 weeks of the start of study treatment to obtain 
formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks are 
preferred) or at least 15 unstained slides, with an associated pathology report, for central 
testing of tumor PD-L1 expression  
 
• Archival tissue is acceptable if obtained within the protocol specified period and if 
there is no intervening therapy between the tumor biopsy and the initiation of 
atezolizumab.  Tumor tissue should be of good quality based on total and viable 
tumor content.  Fine-needle aspiration, brushing, cell pellet from pleural effusion, 
bone metastases, and lavage samples are not acceptable.  For core-needle biopsy 
specimens, at least three cores should be submitted for evaluation. 
• Patients who do not have tissue specimens meeting eligibility requirements will be 
required to undergo a biopsy during the screening period.  Acceptable samples 
include core-needle biopsies for deep tumor tissue (minimum of three cores) or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. 
• Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable. 
3.1.6 Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):  
 
• ANC ≥ 1500 cells/µL 
• WBC counts > 2500/µL 
• Lymphocyte count ≥ 300/µL 
• Platelet count ≥ 100,000/µL  
• Hemoglobin ≥ 9.0 g/dL 
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN) with the following exception:  
 Patients with known Gilbert disease who have serum bilirubin 
level ≤ 3 × ULN may be enrolled. 
• AST and ALT ≤ 3.0 × ULN with the following exception: 
 Patients with liver involvement:  AST and/or ALT ≤ 5 × ULN 
• Alkaline phosphatase ≤ 2.5 × ULN with the following exception: 
 Patients with documented liver involvement or bone metastases: 
alkaline phosphatase ≤ 5 × ULN 
• Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min on the basis of 
the Cockcroft-Gault glomerular filtration rate estimation: 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
17 
o (140 − age) × (weight in kg) × (0.85 if female) 
72 × (serum creatinine in mg/dL)  
 
3.1.7 Measurable disease per RECIST v1.1 for patients with solid malignancies 
 
3.1.8 For female patients of childbearing potential and male patients with partners 
of childbearing potential, agreement (by patient and/or partner) to use highly effective 
form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when 
used consistently and correctly) and to continue its use for 5 months after the last dose of 
atezolizumab. 
 
3.1.9 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 
A). Patients with an ECOG Performance Status of 2 will be allowed at the discretion of 
the Treating Investigator in agreement with the Sponsor-Investigator.  
 
3.1.10 INR and aPTT ≤ 1.5 × ULN.  This applies only to patients who do not receive therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular-
weight heparin or warfarin) should be on a stable dose. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Any approved anticancer therapy, including chemotherapy, hormonal therapy, 
or radiotherapy, within 3 weeks prior to initiation of study treatment; however, 
the following are allowed:  
 
• Hormone-replacement therapy or oral contraceptives  
 
• Herbal therapy > 1 week prior to Cycle 1, Day 1 (herbal therapy intended as 
anticancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1) 
 
• Hormonal therapy for prostate cancer or breast cancer provided criteria in 3.2.21 are met. 
 
 
3.2.2 Aes from prior anticancer therapy that have not resolved to Grade ≤ 1 except for alopecia 
 
3.2.3 History of grade 4 immune-related adverse events requiring treatment with prednisone or 
history of grade 3 immune-related adverse events requiring prednisone >10 mg/kg 
for >12 weeks. 
 
3.2.4 Bisphosphonate therapy for symptomatic hypercalcemia 
 
• Use of bisphosphonate therapy for other reasons (e.g., bone metastasis 
or osteoporosis) is allowed. 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
18 
3.2.5 Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis; cirrhosis; fatty liver; and inherited liver disease 
 
3.2.6 Patients with acute leukemias, accelerated/blast-phase chronic myelogenous leukemia, 
chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-
secretory myeloma 
 
3.2.7 Known primary central nervous system (CNS) malignancy or symptomatic CNS 
metastases 
 
• Patients with asymptomatic untreated CNS disease may be enrolled, provided all of 
the following criteria are met: 
o Evaluable or measurable disease outside the CNS 
o No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 
mm of the optic apparatus (optic nerves and chiasm) 
o No history of intracranial hemorrhage or spinal cord hemorrhage 
o No ongoing requirement for dexamethasone for CNS disease; patients on a stable 
dose of anticonvulsants are permitted. 
o No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, Day 1 
• Patients with asymptomatic treated CNS metastases may be enrolled, provided 
treating MD believes the patient to be clinically stable to begin trial treatment. 
3.2.8 Patients who are pregnant, are lactation, or breastfeeding 
 
3.2.9 Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies 
 
3.2.10 Inability to comply with study and follow-up procedures 
 
3.2.11 History or risk of autoimmune disease, including but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, 
vasculitis, or glomerulonephritis 
 
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible. 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
19 
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
• Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular 
manifestations 
• Rash must cover less than 10% of body surface area (BSA) 
• Disease is well controlled at baseline and only requiring low potency topical steroids 
(e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, 
desonide 0.05%, aclometasone dipropionate 0.05%) 
• 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) 
3.2.12 History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) 
scan 
 
• History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
3.2.13 Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation of 
the results or render the patient at high risk from treatment complications 
 
3.2.14 History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection 
 
• Patients with past or resolved hepatitis B infection (defined as having a negative 
hepatitis B surface antigen [HbsAg] test and a positive anti-HBc [antibody to hepatitis 
B core antigen] antibody test) are eligible. 
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA. 
3.2.15 Active tuberculosis 
 
3.2.16 Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited 
to hospitalization for complications of infection, bacteremia, or severe pneumonia 
 
3.2.17 Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
20 
3.2.18 Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 
 
• Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible. 
3.2.19 Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need 
for a major surgical procedure during the course of the study 
 
3.2.20 Administration of a live, attenuated vaccine within 4 weeks before enrollment or 
anticipation that such a live attenuated vaccine will be required during the study or for 5 
months after the last dose of atezolizumab 
 
Influenza vaccination should be given during influenza season only (approximately 
October to March).   
 
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 
weeks prior to enrollment, at any time during the study, or for 5 months after the last dose 
of atezolizumab. 
 
3.2.21 Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, 
with the exception of those with a negligible risk of metastasis or death or 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, or ductal carcinoma in situ treated surgically with curative intent) or undergoing 
active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia 
Rai Stage 0, prostate cancer with Gleason score ≤ 6, and prostate-specific antigen [PSA] 
≤ 10 mg/mL, etc.) 
 
3.2.22 Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within 
five half-lives of the investigational product, whichever is longer) 
 
3.2.23 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 Cycle 1, Day 1 
 
• Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. 
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
3.2.24 History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
21 
3.2.25 Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally by the Study Coordinator.  
Following registration, patients should begin protocol treatment within 5 days.   
Issues that would cause treatment delays should be discussed with the Investigator. The Study 
Coordinator should be notified of cancellations as soon as possible. 
 
4.2 
Registration Process 
 
Once the signed informed consent has been obtained, all pretreatment evaluations have been 
performed, and patient’s eligibility has been confirmed by the coordination team and the treating 
physician investigator, a patient will be entered on study. To register a patient, the research nurse 
or data manager must complete the eligibility/registration form and review the signed Informed 
Consent, and HIPAA authorization form. 
 
To complete the registration process, the research nurse or data manager will: 
 
• 
Verify the eligibility 
• 
Register the patient on study 
• 
Assign a patient accession number 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 7. Appropriate dose modifications are described in Section 6. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy. 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Atezolizumab 
None* 
 
1200 mg  
in 250 mL 
NSS 
IV over 60 
(± 15) minutes 
for first 
Day 1 
21 days  
(3 weeks) 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
22 
infusion; can be 
increased to 30 
(± 10)  minutes 
for subsequent 
cycles** 
 
* No premedication will be allowed for the first dose of atezolizumab.  Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician.   
The management of IRRs will be according to severity as follows: 
• 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion rate 
should be reduced to half the rate being given at the time of event onset.  Once the event has 
resolved, the investigator should wait for 30 minutes while delivering the infusion at the 
reduced rate.  If tolerated, the infusion rate may then be increased to the original rate. 
• 
In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or flushing, 
fever, or throat pain, the infusion should be immediately interrupted and the patient should 
receive aggressive symptomatic treatment.  The infusion should be restarted only after the 
symptoms have adequately resolved to baseline grade.  The infusion rate at restart should be 
half of the infusion rate that was in progress at the time of the onset of the IRR. 
• 
For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be 
stopped immediately, and aggressive resuscitation and supportive measures should be 
initiated.  Patients experiencing severe or life-threatening IRRs will not receive further 
infusion and will be further managed as clinically indicated until the event resolves. 
For anaphylaxis precautions, please see Appendix B. 
** The initial dose of atezolizumab will be delivered over 60 (± 15) minutes.  If the first infusion 
is tolerated without infusion-associated Aes, the second infusion may be delivered over 30 (± 10) 
minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered 
over 30 (± 10) minutes.  For the first infusion, the patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) should be determined within 60 minutes before, during 
(every 15 [± 5] minutes), and 30 (± 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before and within 30 minutes after the infusion.  
Vital signs should be collected during the infusion only if clinically indicated.  Patients will be 
informed about the possibility of delayed post-infusion symptoms and instructed to contact their 
study physician if they develop such symptoms. 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding the screening evaluation and the treatment 
discontinuation visit. 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
23 
antagonist, as per standard practice (for sites outside the United States, equivalent medications 
may be substituted per local practice).  Serious infusion-associated events manifested by 
dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated 
(e.g., supplemental oxygen and β2-adrenergic agonists. 
Systemic corticosteroids and TNFα inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab but may be administered at the discretion of the treating 
physician.  If feasible, alternatives to corticosteroids should be considered.  Premedication may 
be administered for Cycles ≥ 2 at the discretion of the treating physician.  The use of inhaled 
corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic 
hypotension or adrenocortical insufficiency is allowed.  Megastrol administered as appetite 
stimulant is acceptable while the patient is enrolled in the study.   
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or therapeutic 
anticoagulation therapy (such as low-molecular-weight heparin or warfarin at a stable dose 
level), or other allowed maintenance therapy should continue their use.  Males and females of 
reproductive potential should use highly effective means of contraception.  
Excluded Therapy 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited.  This includes but is not limited to the 
following: 
• Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy. 
• Palliative radiotherapy (e.g., treatment of known bony metastases) allowed, provided 
it does not interfere with the assessment of tumor target lesions (e.g. the lesion being 
irradiated is not the only site of disease, because that would render the patient not 
evaluable for response by tumor assessments according to RECIST v1.1). 
• It is not a requirement to withhold atezolizumab during palliative radiotherapy. 
• It is strongly recommended that:  
• Traditional herbal medicines not be administered because the ingredients of many 
herbal medicines are not fully studied and their use may result in unanticipated 
drug-drug interactions that may cause, or confound assessment of, toxicity 
• The use of a RANKL inhibitor (denosumab) be discontinued during the study; 
this agent could potentially alter the activity and the safety of atezolizumab 
• Initiation or increased dose of granulocyte colony-stimulating factors 
(e.g., granulocyte colony-stimulating factor, granulocyte/macrophage 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
24 
colony-stimulating factor, and/or pegfilgrastim) is prohibited for patients with solid 
malignancies.   
• Patients are not allowed to receive immunostimulatory agents, including but not 
limited to IFN-α, IFN-γ, or IL-2, during the entire study.  These agents, in 
combination with atezolizumab, could potentially increase the risk for autoimmune 
conditions. 
• Patients should also not be receiving immunosuppressive medications, including but 
not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide.  These 
agents could potentially alter the activity and the safety of atezolizumab.  Systemic 
corticosteroids and anti-TNFα agents may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab but may be administered at the discretion of 
the treating physician.  If feasible, alternatives to these agents should be considered. 
• In addition, all patients (including those who discontinue the study early) should not 
receive other immunostimulatory agents for 10 weeks after the last dose of 
atezolizumab. 
5.3 
Duration of Therapy 
 
Atezolizumab treatment will be given as long as the patient continues to experience clinical 
benefit in the opinion of the investigator or until unacceptable toxicity, symptomatic 
deterioration attributed to disease progression, or any of the other reasons for treatment 
discontinuation listed in this Section. 
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment for up to 84 days beyond the scheduled date of delayed infusion if study 
drug-related toxicity requiring dose suspension is experienced.  If atezolizumab is held because 
of Aes for > 84 days beyond the scheduled date of infusion, the patient will be discontinued from 
atezolizumab and will be followed for safety and efficacy as specified in Section 5.4. 
If a patient must be tapered off steroids used to treat Aes, atezolizumab may be held for 
additional time beyond 84 days from the scheduled dose until steroids are discontinued or 
reduced to a prednisone dose (or dose equivalent) of ≤ 10 mg/day.  The acceptable length of 
interruption will be at the discretion of the investigator. 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression.  Patients with radiographically confirmed disease 
progression may continue on study treatment if, in the opinion of the treating 
investigator and Sponsor-Investigator, the patient continues to benefit clinically 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
25 
from atezolizumab. 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
 
• 
Unacceptable adverse event(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 
 
 
5.4 
Duration of Follow Up 
 
Patients will be followed for 12 months or until death as per standard of care after 
discontinuation of study therapy or until death, whichever occurs first.   
 
The following information will be collected through chart review and/or when the subject is seen 
in clinic for their standard of care appointment/procedures: 
• ECOG Performance Status 
• CBC with Diff 
• Serum Chemistry 
• Concomitant Medication and Anticancer Therapy Review including radiation 
• Adverse Event Review 
Patients who have an ongoing study treatment-related AE upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline grade, the 
event is assessed by the investigator as stable, new anticancer treatment is initiated, the patient is 
lost to follow-up, the patient withdraws consent, or until it has been determined that study 
treatment or participation is not the cause of the AE.  
 
At the discretion of the sponsor-investigator the study may be closed prematurely. 
 
5.5 
Criteria for Removal from Study 
 
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: 
1. Patient withdrawal of consent at any time 
2. Any medical condition that the investigator or Sponsor determines may jeopardize the 
patient’s safety if he or she continues in the study 
3. Investigator or Sponsor determines it is in the best interest of the patient 
4. Patient non-compliance, defined as not complying with treatment visits and imaging.  


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
26 
Every effort should be made to obtain information on patients who withdraw from the study.  
The primary reason for withdrawal from the study should be documented on the appropriate 
Case Report Form (CRF).  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will be replaced. 
Sponsor-Investigator and Genentech have the right to terminate this study at any time.  Reasons 
for terminating the study may include, but are not limited to, the following: 
1. The incidence or severity of Aes in this or other studies indicates a potential health 
hazard to patients. 
2. Patient enrollment is unsatisfactory. 
Sponsor-Investigator and Genentech has the right to close a site at any time.  Reasons for closing 
a site may include, but are not limited to, the following: 
1. Excessively slow recruitment 
2. Poor protocol adherence 
3. Inaccurate or incomplete data recording 
4. Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice (GCP) 
5. No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology. 
 
Although most immune-related adverse events (irAEs) observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of atezolizumab may not have an 
immediate therapeutic effect and, in severe cases, immune related toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, mycophenolate, or TNFα 
inhibitors. 
 
The primary approach to Grade 1 to 2 irAEs is supportive and symptomatic care with continued 
treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be withheld and oral 
and/or parenteral steroids administered.  Recurrent Grade 2 irAEs may also mandate withholding 
atezolizumab or the use of steroids.  Assessment of the benefit risk balance should be made by 
the investigator, with consideration of the totality of information as it pertains to the nature of the 
toxicity and the degree of clinical benefit a given patient may be experiencing prior to further 
administration of atezolizumab.  Atezolizumab should be permanently discontinued in patients 
with life threatening irAEs. 
 
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
27 
suspend study treatment for up to 84 days beyond the scheduled date of delayed infusion if study 
drug-related toxicity requiring dose suspension is experienced.  If atezolizumab is held because 
of Aes for > 84 days beyond the scheduled date of infusion, the patient will be discontinued from 
atezolizumab and will be followed for safety and efficacy as specified in Section 5.4. 
 
If a patient must be tapered off steroids used to treat Aes, atezolizumab may be held for 
additional time beyond 84 days from the scheduled dose until steroids are discontinued or 
reduced to a prednisone dose (or dose equivalent) of ≤ 10 mg/day.  The acceptable length of 
interruption will be at the discretion of the investigator. 
 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be allowed.  
The acceptable length of interruption will be at the discretion of the Sponsor-Investigator. 
 
Any toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology.  Although most irAEs 
observed with immunomodulatory agents have been mild and self-limiting, such events should 
be recognized early and treated promptly to avoid potential major complications.   
 
Discontinuation of atezolizumab may not have an immediate therapeutic effect, and there is no 
available antidote for atezolizumab.  In severe cases, immune related toxicities may be acutely 
managed with topical corticosteroids, systemic corticosteroids, mycophenolate, or TNFα 
inhibitors. 
 
Patients should be assessed clinically (including review of laboratory values) for toxicity prior to, 
during, and after each infusion.  If unmanageable toxicity due to atezolizumab occurs at any time 
during the study, treatment with atezolizumab should be discontinued. 
 
Management of hepatitis/transaminitis, colitis, rash, and hypothyroidism are presented in this 
section as they have been observed in this study and are potentially immune related.  See Section 
5.1 for guidelines for the management of IRRs (see Appendix B for precautions for anaphylaxis). 
 
6.1 
Gastrointestinal Toxicity 
 
Immune-mediated colitis has been associated with the administration of atezolizumab. 
Patients should be advised to inform the investigator if any diarrhea occurs, even if it is mild. 
If the event is of significant duration or magnitude, or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased CRP or platelet count or bandemia), it is 
recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with 
three to five specimens for standard paraffin block be performed.   
 
Treatment may be restarted following the resolution of colitis.  In addition, if the patient is being 
managed with corticosteroids, treatment should not be restarted until the steroids have been 
tapered down to a prednisone dose ≤ 10 mg/day.  Patients who resume treatment should be 
monitored closely for signs of renewed diarrhea.  Table 1 provides a summary of dose 
modification guidelines for gastrointestinal toxicities. 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
28 
 
 
 
 
 
 
Table 1 
Dose Modification Guidelines for Gastrointestinal Toxicity 
Toxicity 
Description 
Management 
Diarrhea 
Grade 2 (4−6 stools per day 
over baseline) < 5 days 
Hold atezolizumab and discontinue 
NSAIDS (or other medications 
known to exacerbate colitis). 
Investigate for etiology.  Restart 
atezolizumab once at baseline stool 
frequency. 
Grade 2 (4−6 stools per day 
over baseline) > 5 days 
Hold atezolizumab and discontinue 
NSAIDS (or other medications 
known to exacerbate colitis) while 
etiology is being investigated.  
Consider referral to a 
gastroenterologist. 
Administer anti-diarrheal agent 
(e.g., Imodium). 
Consider oral budesonide, 
mesalamine, or 10 mg oral 
prednisone equivalent per day.   
Restart atezolizumab once at 
baseline stool frequency. 
Abdominal pain 
 
Blood or mucus in stool 
 
OR 
 
Grade ≥ 3 (≥ 7 stools/day 
over baseline) with 
peritoneal signs, ileus, or 
fever 
Hold atezolizumab and discontinue 
NSAIDS (or other medications 
known to exacerbate colitis). 
Rule out bowel perforation.  
Consider administering prednisone 
60 mg/day or equivalent.  
Taper steroids over 1 month.  
Restart atezolizumab if diarrhea is 
resolved and systemic steroid dose 
is ≤ 10 mg oral prednisone 
equivalent per day. 
Permanently discontinue 
atezolizumab for life-threatening, 
immune-related diarrhea or colitis. 
NSAID = nonsteroidal anti-inflammatory drug. 
 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
29 
6.2 
Hepatotoxicity 
 
Immune-mediated hepatitis has been associated with the administration of atezolizumab. 
While in this study, patients presenting with right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should have LFTs performed immediately, and LFTs should be 
reviewed before administration of the next dose of study drug. 
 
If LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies should 
be considered and addressed, as appropriate.  Imaging of the liver, gall bladder, and biliary tree 
should be performed to rule out neoplastic or other causes of increased LFTs.  Anti-nuclear 
antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-liver kidney microsomal, and 
anti-smooth muscle antibody tests should be performed if an autoimmune etiology is considered. 
Patients with LFT abnormalities should be managed according to the guidelines in Table 2. 
 
Table 2 
Dose Modification Guidelines for Hepatotoxicity 
Toxicity 
Description 
Management 
LFT 
abnormalities 
AST/ALT (> ULN to 
3 × ULN) with total 
bilirubin < 2 × ULN 
Continue with the standard monitoring plan (i.e., 
LFTs every 3 weeks before dosing). 
 
AST/ALT (> 3 × ULN to  
< 10 × ULN) with total 
bilirubin < 2 × ULN 
 
Continue atezolizumab.   
Monitor LFTs at least weekly.   
Consider referral to a hepatologist. 
 
AST/ALT > 10 × ULN 
 
Hold atezolizumab.   
Consider administering IV steroids for 24−48 
hours (prednisone 60 mg/day equivalent) followed 
by an oral prednisone (or equivalent) taper over 
2−4 weeks.  If LFT results do not decrease within 
48 hours after initiation of systemic steroids, 
addition of an alternative immunosuppressive 
agent (e.g., mycophenolate or TNFα antagonist) to 
the corticosteroid regimen may be considered.  
Monitor LFTs every 48−72 hours until decreasing 
and then follow weekly.   
Restart atezolizumab if AST/ALT ≤ 3 × ULN with 
bilirubin < 2 × ULN and steroid dose is ≤ 10 mg 
oral prednisone equivalent per day. 
Permanently discontinue atezolizumab for life-
threatening, immune-related hepatic events. 
 
 
 
 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
30 
 
Table 2 
Dose Modification Guidelines for Hepatotoxicity (cont.) 
Toxicity 
Description 
Management 
LFT 
abnormalities  
(cont.) 
AST/ALT ≥ 3 × ULN with 
bilirubin > 2 × ULN 
Hold atezolizumab.   
Consult a hepatologist.   
Consider administering IV steroids for 24−48 
hours (prednisone 60 mg/day equivalent) 
followed by oral taper over 1 month.  If LFTs 
results do not decrease within 48 hours after 
initiation of systemic steroids, addition of an 
alternative immunosuppressive agent (e.g., 
mycophenolate or TNFα antagonist) to the 
corticosteroid regimen may be considered.  
Monitor LFTs every 48−72 hours until decreasing 
and then follow weekly.  Restart atezolizumab if 
AST/ALT ≤ 3 × ULN with bilirubin < 2 × ULN 
and steroid dose is ≤ 10 mg oral prednisone 
equivalent per day. 
IV = intravenous; LFT = liver function test; TNFα = tumor necrosis factor alpha; ULN = upper 
limit of normal. 
 
6.3 
Dermatologic Toxicity 
 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus. 
 
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should be 
performed unless contraindicated.  Low-grade rash and pruritus irAEs have been treated with 
symptomatic therapy (e.g., antihistamines).  Topical or parenteral corticosteroids may be 
required for more severe symptoms. 
 
Dermatologic toxicity and rash should be managed according to the guidelines in Table 3. 
 
Table 3 
Dose Modification Guidelines for Dermatologic Toxicity 
Toxicity 
Description 
Management 
Dermatologic 
toxicity/rash (e.g., 
maculopapular or 
purpura) 
Grade 1:  Mild 
< 10% BSA 
Continue atezolizumab symptomatic therapy 
with antihistamine PRN. 
Consider topical steroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Grade 2:  Moderate  
10%−30% BSA 
Continue atezolizumab.  Consider 
dermatologist referral. 
Administer topical steroids. 
Consider a higher potency topical steroid if 
rash is unresolved. 
Grade 3:  Severe  
Hold atezolizumab.   


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
31 
> 30% BSA 
Consult dermatologist.  Administer oral 
prednisone 10 mg or equivalent.  If the rash is 
unresolved after 48−72 hours, administer oral 
prednisone 60 mg or equivalent. 
Restart atezolizumab if rash is resolved and 
systemic dose is ≤ 10 mg oral prednisone 
equivalent per day. 
Permanently discontinue atezolizumab for 
life-threatening, immune-related dermatologic 
toxicity. 
BSA = body surface area; PRN = as needed. 
 
6.4 
Endocrine Toxicity 
 
Hypothyroidism has been associated with the administration of atezolizumab. 
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental status 
changes, or constipation should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies, as well as for hyponatremia or hyperkalemia.  An endocrinologist should be 
consulted if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) and free T4 
levels should be obtained to determine whether thyroid abnormalities are present.  TSH, 
prolactin, and a morning cortisol level will help to differentiate primary adrenal insufficiency 
from primary pituitary insufficiency. 
 
Hypothyroidism should be managed according to the guidelines in Table 4. 
 
Table 4 
Dose Modification Guidelines for Endocrine Toxicity 
Toxicity 
Description 
Management 
Hypothyroidism 
TSH elevated, asymptomatic 
Continue atezolizumab.   
Start thyroid-replacement hormone, at the 
discretion of the treating physician.   
 
TSH elevated, symptomatic 
Hold atezolizumab.   
Start thyroid-replacement hormone, at the 
discretion of the treating physician.   
Consider referral to an endocrinologist.    
Restart atezolizumab when symptoms are 
controlled by thyroid replacement and TSH 
levels are decreasing.  
TSH = thyroid-stimulating hormone. 
 
 
6.5 
Pulmonary Toxicity 
 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab and have primarily been observed in patients with 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
32 
underlying NSCLC. 
 
Mild-to-moderate events of pneumonitis have been reported with atezolizumab.  All pulmonary 
events should be thoroughly evaluated for other commonly reported etiologies such as 
pneumonia/infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, chronic 
obstructive pulmonary disease (COPD), or pulmonary hypertension and the following should be 
performed, as outlined in Table 5: 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
High-resolution CT scan of the chest 
Bronchoscopy with bronchoalveolar lavage and biopsy 
Pulmonary function tests (with diffusion capacity of the lung for carbon monoxide [DLCO]) 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study.  Patients will 
also have CT scans of the chest at every tumor assessment. 
 
Pulmonary toxicity should be managed according to the guidelines in Table 5. 
 
 
Table 5 
Dose Modification Guidelines for Pulmonary Toxicity 
Toxicity 
Description 
Management 
Pulmonary toxicity GGO or non-infectious 
infiltrate in absence of 
hypoxia, or dyspnea 
Hold treatment with atezolizumab.   
Re-evaluate after 1 week. 
If no worsening in GGO/infiltrates and 
patient still asymptomatic, resume 
treatment with atezolizumab. 
If GGO/infiltrates worsen and patient is 
still asymptomatic, continue to hold 
atezolizumab and refer for bronchoscopy.  
Consider starting low-dose oral prednisone 
10 mg or equivalent.   
Re-evaluate after 1 week.  Resume 
atezolizumab if GGO/infiltrates improving.  


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
33 
Hypoxia or dyspnea in 
presence of GGO or infiltrate 
without alternative etiology 
Hold atezolizumab.   
Consult a pulmonologist.  Investigate for 
other etiologies and consider 
bronchoscopy.  If bronchoscopy is 
consistent with immune-related etiology, 
start 60 mg prednisone equivalent per day 
followed by taper over 2 weeks.  
Restart atezolizumab if symptomatically 
improved, infiltrates are resolved, and 
steroid use is ≤ 10 mg prednisone 
equivalent per day. 
Permanently discontinue atezolizumab for 
life-threatening, immune-related 
pulmonary events. 
GGO = ground glass opacities. 
 
6.6 
Pericardial and Pleural Effusions 
 
Pericardial and pleural involvement with associated effusions is common in patients with cancer 
and has the theoretical potential to be exacerbated by inflammation associated with anti-tumor 
immunity following PD-L1 blockade.  Patients presenting with dyspnea, chest pain, or 
unexplained tachycardia should be evaluated for the presence of a pericardial effusion.  Patients 
with pre-existing pericardial effusion should be followed closely for pericardial fluid volume 
measurements and impact on cardiac function.  When intervention is required for pericardial or 
pleural effusions, appropriate workup includes cytology, LDH, glucose, cholesterol, protein 
concentrations (with pleural effusions), and cell count.  For patients with a pericardial effusion 
causing end-diastolic right ventricular collapse, treatment may be restarted following the 
placement of a pericardial window, demonstration of hemodynamic stability, and resolution of 
right ventricular dysfunction. 
 
6.7 
Potential Pancreatic Toxicity 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with administration of other immunomodulatory agents.  The 
differential diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup 
should include an evaluation for obstruction, as well as serum amylase and lipase tests. 
 
6.8 
Potential Eye Toxicity 
 
An ophthalmologist should evaluate visual complaints.  Uveitis or episcleritis may be treated 
with topical corticosteroid eye drops.  Atezolizumab should be permanently discontinued for 
immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. 
Ocular toxicity should be managed according to the guidelines in Table 6. 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
34 
Table 6 
Dose Modification Guidelines for Eye Toxicity 
Toxicity 
Description 
Management 
Eye toxicity (autoimmune 
uveitis, iritis, or episcleritis) 
Symptomatic 
Hold atezolizumab.   
Consult ophthalmologist and start 
topical corticosteroid eye drops.   
Atezolizumab may be restarted 
following resolution of the events. 
Permanently discontinue 
atezolizumab for immune-mediated 
ocular disease that is unresponsive 
to local immunosuppressive therapy. 
 
7. REPORTING OF SERIOUS ADVERSE EVENTS  
 
7.1 
Adverse Event Definitions 
 
Adverse event means any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related.   
 
Suspected adverse reaction. Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event (considered “possibly related”). For the purposes of safety 
reporting, "reasonable possibility" means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
 
Adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset of 
suspected adverse reactions where there is reason to conclude that the drug caused the event. 
 
Serious Adverse Event: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Specifically, results in death, is life-threatening, 
requires inpatient hospitalization or causes prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an 
important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.)  Any 
subject death within 30 days of the last dose of study drug, regardless of the causality or a 
secondary malignancy should also be recorded as a serious adverse event. 
 
Life-threatening, suspected adverse reaction.  A suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site principal investigator), its 
occurrence places the patient or research subject at immediate risk of death.  It does not include a 
suspected adverse reaction that had it occurred in a more severe form, might have caused death. 
 
Unexpected, suspected adverse reaction.  A suspected adverse reaction is considered 
“unexpected” if it is not listed in the general investigational plan or clinical protocol; or is not 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
35 
listed at the specificity or severity that has been previously observed and/or specified.  If an 
investigator brochure is not required or available, suspected adverse reaction is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application, as amended.  "Unexpected," as used in this definition, also refers to adverse events 
or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.  Any clinically 
important increase in the rate of a serious suspected adverse reaction over that listed in the 
protocol or investigator brochure can also be considered unexpected.  An aggregate analysis of 
specific events observed in a clinical trial (such as known consequences of the underlying 
disease or condition under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more frequently in the 
drug treatment group than in a concurrent or historical control group. 
 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, 
regardless of study group or suspected causal relationship to the study drug(s) will be recorded in 
the subjects’ case histories.  For all adverse events, sufficient information will be pursued and/or 
obtained so as to permit 1) an adequate determination of the outcome of the event (i.e., whether 
the event should be classified as a serious adverse event) and; 2)  an assessment of the casual 
relationship between the adverse event and the study drug(s).  All toxicities encountered during 
the study will be evaluated on an ongoing basis according to the NCI Common Toxicity Criteria 
version 4.0.  
 
Adverse events or abnormal test findings felt to be associated with the study drug(s) will be 
followed until the event (or its sequelae) or the abnormal test finding resolves or stabilizes at a 
level acceptable to the Principal Investigator. 
 
In the event of an adverse event the first concern will be for the safety of the subject.   
 
Review of safety information. The principal investigator / sponsor must promptly review all 
information relevant to the safety of the drug obtained or otherwise received from foreign or 
domestic sources, including information derived from any clinical or epidemiological 
investigations, animal or in vitro studies, reports in the scientific literature, and unpublished 
scientific papers, as well as reports from foreign regulatory authorities and reports of foreign 
commercial marketing experience for drugs that are not marketed in the United States.  The 
study sponsor must notify all participating investigators of potential serious risks, from clinical 
trials or any other source, as soon as possible. 
 
7.2 
Assessment of Adverse Events  
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the atezolizumab (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guideline: 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
36 
 
Yes 
 
There is a plausible temporal relationship between the onset of the AE and administration of 
atezolizumab, and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to atezolizumab; and/or the AE abates or resolves upon discontinuation of 
atezolizumab or dose reduction and, if applicable, reappears upon re- challenge. 
 
No 
 
Evidence exists that the AE has an etiology other than atezolizumab (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to atezolizumab administration (e.g., 
cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I) 
or current Investigator Brochure (I.B). 
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. 
This includes adverse events for which the specificity or severity is not consistent with the 
description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be 
unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
7.3 
Documentation of Serious Adverse Events  
 
In the event of a serious adverse event, the PI, the institutional review board (per institutional 
reporting requirements), and Genentech will be notified using the internal CRS departmental 
SAE form.   
 
All events meeting the definition of a serious adverse event should be recorded on the CRS 
internal departmental SAE form and submitted to 
 
1. PI: Liza Villaruz, MD 
a. Phone: 412-648-6577 
b. Fax: 412-648-6579 
c. Email: villaruzl@upmc.edu 
2. CRM: Jennifer Ruth 
a. Phone: 412-623-8963 
b. Fax:  412- 623-7862 
c. Email: ruthj2@upmc.edu 
3. CRSSafetySubmissions@upmc.edu 
4. Local Institutional Review Board per institutional reporting requirements 
5. Genentech:  (Using Appendix C Fax Coversheet) 
Fax: 650-238-6067 or Email: usds aereporting-d@gene.com 
 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the Narrative (Section C) on the CRS internal departmental SAE form: 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
37 
 
• CTCAE term(s) and grade(s)  
• current status of study drug 
• all interventions to address the AE (testing and result, treatment and response) 
• hospitalization and/or discharge dates 
• event relationship to study drug 
• 
Protocol description (and number, if assigned)  
• 
Description of event, severity, treatment, and outcome if known 
 
The adverse event severity grading scale for the NCI CTCAE (v4) will be used for assessing adverse 
event severity. Below Table should be used for assessing severity for adverse events that are not 
specifically listed in the NCI CTCAE. 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), 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  
 
 
 
Follow-up reports:   
 
Additional information may be added to a previously submitted report by adding to the original 
departmental SAE form and submitting it as follow-up, creating supplemental summary 
information or Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B. initial, patient number), protocol description and number, if assigned, brief adverse event 
description, and notation that additional or follow-up information is being submitted (The patient 
identifiers are important so that the new information is added to the correct initial report) 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
38 
7.3 
Methods and Timing for Assessing and Recording Safety Variables 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol.  This includes all events of death, and any study specific 
issue of concern.  
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. 
in accordance with CFR 312.32 (IND Safety Reports). 
7.3.1 Adverse Event Reporting Period 
 
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and initiation of study treatment and ends 30 days following the last administration of study 
treatment or study discontinuation/termination, whichever is earlier. After this period, 
investigators should only report SAEs that are attributed to prior study treatment. 
7.3.2 Genentech Specific Instructions for Recording 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?” 
 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations.  
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. 
7.3.2.1 
Deaths 
 
All deaths that occur during the protocol-specified AE reporting period (see Section 7.3.1), 
regardless of attribution, will be reported to the appropriate parties. When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as the single 
medical concept. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death”. 
7.3.2.2 
Pre-existing Medical Conditions 
 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be re-


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
39 
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
7.3.2.3 
Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study. 
 
7.3.2.4 
Pregnancies in Female Patients 
 
If a female subject or female partner of a male study subject  becomes pregnant while receiving 
atezolizumab or within  5 months after the last dose of atezolizumab, 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 atezolizumab 
should be reported as an SAE. 
 
 
7.3.2.5 
Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior atezolizumab exposure. If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study, this should be reported as 
an SAE adequately to Genentech Drug Safety during follow-up period 
7.3.3 Safety Reconciliation 
 
The Sponsor agrees to conduct reconciliation to ensure that all single case reports have been 
adequately received by Genentech via the Sponsor emailing Genentech a quarterly line-listing 
documenting single case reports sent by Sponsor to Genentech in the preceding time period  


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
40 
The periodic line-listing will be exchanged within seven (7) 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-Investigator and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall handle the matter on 
a case-by-case basis until satisfactory resolution.  The sponsor shall receive reconciliation 
guidance documents within the ‘Activation Package’. 
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Sponsor to Genentech within five (5) calendar days from request 
by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to 
Genentech 
 
7.3.4 Adverse Events of Special Interest  
 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the product, 
for which ongoing monitoring and rapid communication by the Investigator to the Sponsor is required. 
Such an event might require further investigation in order to characterize and understand it. Depending 
on the nature of the event, rapid communication by the trial Sponsor to other parties (e.g., Regulatory 
Authorities) may also be warranted. 
  
Non Drug Specific Adverse Events of Special Interest: 
 
Adverse Events of Special Interest (Immediately Reportable to the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the Sponsor 
immediately  
Adverse events of special interest for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law  
and based on the following observations: 
– 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
– 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
• 
Suspected transmission of an infectious agent by the study treatment, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of study treatment is suspected. 
Adverse Events of Special Interest for Atezolizumab:  


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
41 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis 
• 
Hepatitis, including AST or ALT > 10 × ULN 
• 
Systemic lupus erythematosus 
• 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, 
influenza-like illness, macrophage activating syndrome and hemophagocytic 
lymphohistiocytosis. 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia  
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic epidermal 
necrolysis) 
 
7.4 
Reporting of Suspected Adverse Reactions to Genentech 
 
Exchange OF SINGLE CASE REPORTS  
 
 
Sponsor will be responsible for collecting all protocol-defined Adverse Events (AEs), Serious 
Adverse Events (SAEs), AEs of Special Interest (AESIs), Product Complaints (with or 
without an AE) and Special Situation Reports (including pregnancy reports) originating from 
the Study for the Product.  
 
Investigators must report all the above mentioned single case reports adequately to Genentech 
within the timelines described below. The completed Genentech approved reporting forms 
(internal CRS departmental SAE form) should be faxed immediately upon completion to 
Genentech Drug Safety using fax cover sheet (appendix C) at: 
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy reports) 
and Product Complaints with an AE should be sent to: 
 
 




HCC #:16-153 
Version 9 Dated 8/17/2020 
 
43 
• 
Data related to overdose, abuse, misuse or medication error (including potentially exposed 
or intercepted medication errors) 
•     In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population 
• 
 
Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech 
within fifteen (15) calendar days of the awareness date. 
 
A Product Complaint is defined as any written or oral information received from a 
complainant that alleges deficiencies related to identity, quality, safety, strength, 
purity, reliability, durability, effectiveness, or performance of a product after it has 
been released and distributed to the commercial market or clinical trial. 
 
 Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an adverse event was reported. 
 
It is understood and agreed that the Sponsor will perform adequate due diligence with regard 
to obtaining follow-up information on incomplete AE, Special Situations and pregnancy 
reports. 
 
 
 
 
7.5 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
Sponsor of the Study, will be responsible for the expedited reporting of safety reports originating from 
the Study to the Regulatory Authorities (FDA) where it has filed a clinical trial approval, in 
compliance with local regulations 
 
Sponsor will be responsible for the distribution of safety information to its own investigators, where 
relevant 
 
 
Additional Reporting Requirements for IND Holders:  
 
For Investigator-Initiated IND Studies, some additional reporting requirements for the FDA apply in 
accordance with the guidance set forth in 21 CFR § 
600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration (FDA) as 
expedited IND Safety Reports according to the following guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the Investigator to be possibly related to the use of atezolizumab. An 
unexpected adverse event is one that is not already described in the atezolizumab Investigator 
Brochure. Such reports are to be telephoned or faxed to the FDA and Genentech/Roche within 7 
calendar days of first learning of the event. 
 




HCC #:16-153 
Version 9 Dated 8/17/2020 
 
45 
 
 
 
 
7.8 
Queries 
 
Queries related to the Study will be answered by Sponsor. 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 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. 
 
7.9 
Safety Crisis Management 
 
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. Sponsor agrees that it shall not answer such 
queries from media and other sources relating to the Product but shall redirect such 
queries to Genentech. 
 
7.10 
Reporting adverse events to the responsible IRB 
 
In accordance with applicable policies of the University of Pittsburgh Institutional Review Board 
(IRB), the Sponsor-Investigator will report, to the IRB, any observed or volunteered adverse 
event that is determined to be 1) associated with the investigational drug or study treatment(s); 
2) serious; and 3) unexpected. Adverse event reports will be submitted to the IRB in accordance 
with the respective IRB procedures. 
 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later 
than 10 calendar days following the sponsor-investigator’s receipt of the respective information. 
Adverse events which are 1) associated with the investigational drug or study treatment(s); 2) 
fatal or life-threatening; and 3) unexpected will be reported to the IRB within 24 hours of the 
Sponsor-Investigator’s receipt of the respective information. 
 
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the 
relevant information is available. If the results of the Sponsor-Investigator’s follow-up 
investigation show that an adverse event that was initially determined to not require reporting to 
the IRB does, in fact, meet the requirements for reporting; the Sponsor-Investigator will report 
the adverse event to the IRB as soon as possible, but in no event later than 10 calendar days, after 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
46 
the determination was made. 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1 
Atezolizumab 
 
Mode of Action: Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two 
heavy chains (448 amino acids) and two light chains (214 amino acids). Atezolizumab was 
engineered to eliminate Fc-effector function via a single amino acid substitution that results in a 
non-glycosylated heavy chain that has minimal binding to Fc receptors and prevents Fc-effector 
function at expected concentrations in humans. Atezolizumab targets human PD-L1 and inhibits 
its interaction with its receptor PD-1. Atezolizumab also blocks the binding of PD-L1 to B7.1, an 
interaction that is reported to provide additional inhibitory signals to T cells (Butte et al. 2007). 
Therapeutic blockade of PD-L1 by atezolizumab is expected to enhance the magnitude and 
quality of the tumor-specific T-cell responses, resulting in improved anti-tumor activity. 
 
How Supplied: The atezolizumab drug product is provided in a single-use, 20-cc USP/Ph. Eur. 
Type 1 glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution 
intended for IV administration.  The vial is designed to deliver 20 mL (1200 mg) of 
atezolizumab solution but may contain more than the stated volume to enable delivery of the 
entire 20 mL volume.  The atezolizumab drug product is formulated as 60 mg/mL atezolizumab 
in 20 mM histidine acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8. 
Preparation and storage: Atezolizumab must be refrigerated at 2°C − 8°C (36°F − 46°F) upon 
receipt until use.  Atezolizumab vials should not be used beyond the expiration date provided by 
the manufacturer.  No preservative is used in the atezolizumab drug product; therefore, each vial 
is intended for single use only.  Discard any unused portion of drug left in a vial.  Vial contents 
should not be frozen or shaken and should be protected from direct sunlight. 
For further details, see the Atezolizumab Investigator’s Brochure. 
 
Route of Administration: Intravenous (IV) infusion. 
 
Method of Administration: The dose level of atezolizumab to be tested in this study is 1200 mg 
(equivalent to an average body weight−based dose of 15 mg/kg) administered by IV infusion 
every 3 weeks (21 [± 2] days).  Atezolizumab will be delivered in infusion bags with IV infusion 
lines that have product contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 µm 
in-line filters (filter membrane of polyethersulfone [PES]).  No incompatibilities have been 
observed between atezolizumab and PVC or polyolefin infusion materials (bags or infusion 
lines).  
Administration of atezolizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
47 
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes.  If the first infusion is 
tolerated without infusion-associated AEs, the second infusion may be delivered over 30 (± 10) 
minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered 
over 30 (± 10) minutes.  For the first infusion, the patient’s vital signs (heart rate, respiratory 
rate, blood pressure, and temperature) should be determined within 60 minutes before, during 
(every 15 [± 5] minutes), and 30 (± 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before and within 30 minutes after the infusion.  
Vital signs should be collected during the infusion only if clinically indicated.  Patients will be 
informed about the possibility of delayed post-infusion symptoms and instructed to contact their 
study physician if they develop such symptoms. 
Patient Care Implications: No premedication will be allowed for the first dose of atezolizumab.  
Premedication may be administered for Cycles ≥ 2 at the discretion of the treating physician.  
The management of IRRs will be according to severity as follows: 
• In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion 
rate should be reduced to half the rate being given at the time of event onset.  Once the 
event has resolved, the investigator should wait for 30 minutes while delivering the 
infusion at the reduced rate.  If tolerated, the infusion rate may then be increased to the 
original rate. 
• In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or 
flushing, fever, or throat pain, the infusion should be immediately interrupted and the 
patient should receive aggressive symptomatic treatment.  The infusion should be 
restarted only after the symptoms have adequately resolved to baseline grade.  The 
infusion rate at restart should be half of the infusion rate that was in progress at the time 
of the onset of the IRR. 
• For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be 
stopped immediately, and aggressive resuscitation and supportive measures should be 
initiated.  Patients experiencing severe or life-threatening IRRs will not receive further 
infusion and will be further managed as clinically indicated until the event resolves. 
 
For anaphylaxis precautions, see Appendix B. 
Potential Drug Interactions: Cytochrome P450 enzymes as well as 
conjugation/glucuronidation reactions are not involved in the metabolism of atezolizumab. No 
drug interaction studies for atezolizumab have been conducted or are planned. There are no 
known interactions with other medicinal products or other form of interactions. 
 
Agent Ordering and Agent Accountability: The Sponsor investigator of the study will ensure 
maintenance of complete and accurate records of the receipt, dispensation, and disposal or return 
of all study drug in accordance with 21 Code of Federal Regulations (CFR), Part 312.57 and 
312.62, and Genentech requirements. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
48 
9.1 
Biomarker Studies 
 
9.1.1 Archival and Fresh Tumor Tissue Samples for Screening 
 
If available, archival specimens prior to PD-1 directed therapy with nivolumab or 
pembrolizumab must be collected. Mandatory biopsies at the time of enrollment will be 
performed ≤ 6 weeks prior to study treatment initiation.  Representative tumor specimens in 
paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, 
must be submitted at screening for determination of PD-L1 status by IHC utilizing the SP142 
antibody (Ventana, Tucson, AZ). Additional exploratory biomarkers may be evaluated, based on 
the availability of rationale and funding. 
 
• Archival tissue is acceptable if obtained within the protocol specified period (≤6 
weeks prior to the initiation of atezolizumab) and if there is no intervening therapy 
between the tumor biopsy and the initiation of study treatment.  Tumor tissue should 
be of good quality based on total and viable tumor content.  Fine needle aspiration, 
brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are 
not acceptable.  For core-needle biopsy specimens, at least three cores should be 
submitted for evaluation. 
• Patients who do not have tissue specimens meeting eligibility requirements will be 
required to undergo a biopsy during the screening period.  Acceptable samples 
include core needle biopsies for deep tumor tissue (minimum of three cores) or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. 
• Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable. 
 
9.1.2 Tumor Samples at the Time of Radiographic Progression 
 
Patients who are treated with atezolizumab may undergo an optional tumor biopsy to obtain a 
tumor sample ≤ 4 weeks from the date of disease progression.   Determination of PD-L1 status at 
the time of progression and additional exploratory biomarkers may be evaluated, based on the 
availability of rationale and funding. 
 
Acceptable samples include: 
 
• Core needle biopsies for deep tumor tissue; at least three cores, embedded into a 
single paraffin block, should be submitted for evaluation. 
• Excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous or 
mucosal lesions 
• Tumor tissue resection 
 
9.1.3 Tumor Samples at Other Time Points 
 
If a patient undergoes a medically indicated procedure (e.g., bronchoscopy, 
esophagogastroduodenoscopy, colonoscopy) any time during the course of the study that has the 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
49 
likelihood of yielding tumor tissue, any remaining samples or a portion of the sample not 
necessary for medical diagnosis (leftover tumor tissue) may be obtained for exploratory analysis. 
Tissue samples obtained at multiple times for individual patients will greatly contribute to an 
improved understanding of the dynamics of PD-L1 expression and implications for immune 
checkpoint blockade. 
 
9.1.4 Blood collection  
 
Additional studies may be performed on peripheral blood in order to understand mechanisms of 
immune escape and assess biomarkers of response.  These studies may include but are not 
limited to whole exome sequencing.  In order to facilitate these studies, blood will be collected at 
the following time points: 
 
Venous blood will be collected prior to treatment on C1D1 (mandatory).  Optional venous blood 
will be collected on C2D1, C3D1, C4D1, and C5D1.  
  
9.1.4.1 
Sample Collection in EDTA tubes: 
  
Separate plasma and PBMCs from whole blood at collection site:  
 
• Collect two10ml purple top EDTA tubes per collection time point. 
• Fill each of the two 10 ml EDTA tubes completely with whole blood. 
• Mix each EDTA tube thoroughly by slowly inverting the collection tube at least 10 
times. 
• Plasma and PBMC isolations as per lab protocol with cell count.  
• Ensure to label tubes sufficiently: 
o Subject ID 
o Gender 
o Specimen type (plasma or PBMC) 
o Specimen collection date 
 
An additional 3 ml of whole blood will also be collected for germline DNA isolation to be used 
as normal control for whole exome sequencing: 
 
• Collect 3 ml blood in one 6ml K3EDTA purple top tube at C1D1.  
• Mix the tube thoroughly by slowly inverting the collection tube at least 10 times.  
• Ensure to label tubes sufficiently: 
o Subject ID  
o Specimen type (whole blood/ WB)  
o Specimen collection date and time 
o The samples will be shipped on date of collection to Genentech Designated 
Vendor from collection site 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
50 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. Scans 
and x-rays must be done <4 weeks prior to the start of therapy. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
 
Pre- 
Study 
Cycle 1  
Cycle 2 
Subsequent 
Cycles 
Off 
Treatmentk 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Atezolizumab 
 
X 
 
 
X 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-------------------------------------------------------X 
X 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signsa 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Performance statusb 
X 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, pltsc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Serum chemistryd 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Coagulatione 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Urine β-HCGf 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysisg 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Thyroid function 
testingh 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Amylase and Lipase 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Viral Serologiesi 
X 
 
 
 
 
 
 
 
 
 
 
Biomarker Analysis and 
DNA sequencing 
 
Xn 
 
 
Xo 
 
 
Xo 
 
 
 
Adverse event 
evaluation 
X 
X-------------------------------------------------------X 
X 
Tumor measurements 
X 
X-------------------------------------------------------X 
 
Radiologic evaluationj 
X 
X-------------------------------------------------------X 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
51 
Tumor Biopsyl 
X 
 
 
 
 
 
 
 
 
 
X 
(optional) 
Archival tissue pre-PD1 
therapy, if availablel 
X 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood 
Sample Collectionm 
 
Xn 
 
 
Xo 
 
 
Xo 
 
 
 
 
a Heart rate, respiratory rate, systolic and diastolic blood pressure while the patient is in a seated position, and 
temperature. For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressure, and 
temperature) should be determined within 60 minutes before, during (every 15 [± 5] minutes), and 30 (± 10) minutes 
after the infusion.  For subsequent infusions, vital signs will be collected within 60 minutes before and within 30 
minutes after the infusion.  Vital signs should be collected during the infusion only if clinically indicated.  Patients 
will be informed about the possibility of delayed post infusion symptoms and instructed to contact their study 
physician if they develop such symptoms. 
b Appendix A. 
c Hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count 
(neutrophils, bands, eosinophils, lymphocytes, monocytes, basophils, other cells). 
d Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and 
direct bilirubin, total protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatinine phosphokinase, and uric 
acid. 
e aPTT and INR 
f For women of childbearing potential and who are premenopausal.  To be performed at screening and otherwise, if 
clinically indicated. 
g Specific gravity, pH, glucose, protein, ketones, and blood. 
h TSH, free T3, free T4 
i Epstein-Barr virus (EBV) serology (EBNA IgG), hepatitis B virus (HBV) serology (HBsAg, antibodies against 
HBsAg, hepatitis B core antigen), and HCV serology (anti-HCV) 
j Radiographic evaluations must be performed every 6 weeks ± 1 weeks.  Confirmatory scans will also be obtained 
≥4 weeks following initial documentation of an objective response or progressive disease. 
k Patients who discontinue from treatment will be asked to return to the clinic no more than 30 days after the last 
treatment for a treatment discontinuation visit.  The visit at which a response assessment shows progressive disease 
may be used as the treatment discontinuation visit. Patients who have an ongoing study treatment-related AE upon 
study completion or at discontinuation from treatment will be followed until the event has resolved to baseline 
grade, the event is assessed by the investigator as stable, new anticancer treatment is initiated, the patient is lost to 
follow-up, the patient withdraws consent, or until it has been determined that study treatment or participation is not 
the cause of the AE. 
l Baseline archival tissue is acceptable if obtained within the protocol specified period (≤6 weeks prior to the 
initiation of atezolizumab) and if there is no intervening therapy between the tumor biopsy and the initiation of study 
treatment.  Additional details regarding submission of baseline tumor specimens and archival pre-PD-1 tumor 
tissues are provided in Section 3.1.5 and Section 9.   
m Additional details regarding sample collection are provided in Section 9.  
n  Mandatory. 
o  Optional, through C5D1. 
 
Note: There is a window of ± 1 week available for rescheduling treatment and/or procedures at 
the discretion of the treating investigator, and as discussed with the Sponsor-Investigator if a 
course is missed or a subject's treatment and/or testing day(s) need to be rescheduled due to the 
subject’s inability to comply with the study calendar (i.e., hospitalizations, business, vacation 
plans, travel from long distances for study treatment, in advance of the scheduled date to allow 
ready access to the result(s), reduce financial burden on the subject [i.e. non-UPMC insurance 
coverage] or reduce travel inconvenience, illness, transportation issues, holidays, family 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
52 
emergencies, etc.). 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks ±1 
week. In addition to a baseline scan, confirmatory scans should be obtained ≥ 4 weeks following 
initial documentation of objective response or progressive disease. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. 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. 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with atezolizumab.  
 
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.  
 
11.1.2 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) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or 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 may be considered 
measurable after discussion with the Sponsor-Investigator.  
 
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 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
53 
thickness 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) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same 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. 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.  
 
11.1.3 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 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
54 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. 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 site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. 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 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 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
55 
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: 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. 
 
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:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 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. 
c. 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. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
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. 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
56 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (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 (i.e., 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-
No 
PR 
≥4 wks. Confirmation 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
57 
PD 
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 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
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. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 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.  


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
58 
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
12.1 
Data Safety Monitoring Plan 
 
Sponsor-Investigator, Sub-investigators, regulatory, CRS management, clinical research 
coordinators, clinical research associates, data managers, and clinic staff meet monthly in disease 
center Data Safety Monitoring Boards (DSMB) to review and discuss study data to include, but 
not limited to, the following: 
 
• serious adverse events 
• subject safety issues 
• recruitment issues 
• accrual 
• protocol deviations 
• unanticipated problems 
• breaches of confidentiality 
 
Minutes from the DSMB meetings are available to anyone unable to attend the center DSMB. 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 
the NCI Common Toxicity Criteria version 4. All study treatment associated adverse events that 
are serious, at least possibly related and unexpected will be reported to the IRB. Any 
modifications necessary to ensure subject safety and decisions to continue, or close the trial to 
accrual are also discussed during these meetings. If any literature becomes available which 
changes the risk/benefit ratio or suggests that conducting the trial is no longer ethical, the IRB 
will be notified in the form of an Unanticipated Problem submission and the study may be 
terminated. 
 
All study data reviewed and discussed during these meetings will be kept confidential. Any 
breach in subject confidentiality will be reported to the IRB in the form of an Unanticipated 
Problem submission. The summaries of these meetings are forwarded to the HCC DSMC which 
also meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, 
and approval will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will 
be reviewed twice a year rather than monthly by the disease center DSMB. 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
59 
 
Both the HCC DSMC as well as the individual disease center DSMB have the authority to 
suspend accrual or further investigate treatment on any trial based on information discussed at 
these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research 
records. 
 
12.2 
Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and Guidelines on Good Clinical 
Practice compliance will be conducted periodically (i.e., at a minimum of annually) by qualified 
staff of the Education and Compliance Office – Human Subject Research, Research Conduct and 
Compliance Office, University of Pittsburgh. 
 
The Investigator (i.e., the study site principal investigator) and the University of Pittsburgh and 
University of Pittsburgh 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. 
 
12.3 
Data Handling and Record-Keeping 
 
The Investigator (i.e., the study site principal investigator) will maintain records in accordance 
with Good Clinical Practice. 
 
The investigator will retain the specified records and reports for up to 2 years after the marketing 
application is approved for the investigational drug; or, if a marketing application is not 
submitted or approved for the investigational drug, until 2 years after investigations under the 
IND have been discontinued and the FDA so notified. 
 
12.4 
Institutional Review Board (IRB) Approval 
 
The investigator (i.e., the study site principal investigator) will obtain, from the University of 
Pittsburgh Institutional Review Board (IRB), prospective approval of the clinical protocol and 
corresponding informed consent form(s); modifications to the clinical protocol and 
corresponding informed consent forms, and advertisements (i.e., directed at potential research 
subjects) for study recruitment, if applicable. 
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). In such circumstances, the 
investigator will promptly notify the University of Pittsburgh IRB of the deviation. 
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 
50 and 21 CFR 56, and in conformance with applicable International Conference on 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
60 
Harmonization (ICH) Guidelines on Good Clinical Practice. 
 
In the event that the University of Pittsburgh IRB requires, as a condition of approval, substantial 
changes to a clinical protocol submitted under an FDA-accepted IND application, or in the event 
of an sponsor’s decision to modify the previously accepted clinical protocol, the sponsor will 
submit (i.e., in advance of implementing the change) a Protocol Amendment to the IND 
describing any change that significantly affects the safety of subjects, the scope of the 
investigation, or the scientific quality of the study. Examples of protocol changes requiring the 
submission of a Protocol Amendment include: 
 
• Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any significant 
increase in the number of subjects under study. 
• Any significant change in the design of the protocol (such as the addition or deletion of a 
control group). 
• The addition of a new test or procedure that is intended to improve monitoring for, or 
reduce the risk of, a side effect or AE; or the dropping of a test intended to monitor the 
safety of the investigational drug. 
 
12.5 
Ethical and Scientific Conduct of the Clinical Study 
 
The clinical study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH Guidelines on Guidelines on Good Clinical Practice; and relevant policies, 
requirements, and regulations of the University of Pittsburgh IRB, University of Pittsburgh and 
University of Pittsburgh Medical Center, Commonwealth of Pennsylvania, and applicable federal 
agencies. 
 
12.6 
Informed Consent 
 
The investigator (i.e., the study site principal investigator) will make certain that an appropriate 
informed consent process is in place to ensure that potential research subjects, or their authorized 
representatives, are fully informed about the nature and objectives of the clinical study, the 
potential risks and benefits of study participation, and their rights as research subjects. The 
investigator, or a sub-investigator(s) designated by the sponsor, will obtain the written, signed 
informed consent of each subject, or the subject’s authorized representative, prior to performing 
any study-specific procedures on the subject. The date and time that the subject, or the subject’s 
authorized representative, signs the informed consent form and a narrative of the issues discussed 
during the informed consent process will be documented in the subject’s case history. The 
investigator or sub-investigator will retain the original copy of the signed informed consent form, 
and a copy will be provided to the subject, or to the subject’s authorized representative. 
 
The investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study. In the event of substantial changes to the clinical study or the 
risk-to-benefit ratio of study participation, the investigator will obtain the informed consent of 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
61 
enrolled subjects for continued participation in the clinical study. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
For each of the 3 cohorts, Simon's optimal two-stage design is used to minimize the expected 
sample size if the treatment is not effective.  The primary endpoint is best overall response 
(BOR) by RECIST 1.1 (Complete Response or Partial Response, vs. Stable Disease or 
Progressive Disease).  Patients who are lost to follow-up without achieving CR or PR are 
considered non-responders for the primary analysis, with the exception of patients who withdraw 
from the study before C2D1 for reasons explicitly unrelated to disease or toxicity.   
(Occasionally a patient may withdraw because of insurance concerns or to avoid additional travel 
required to receive study treatment.) 
 
Progression-free survival (PFS) is measured in months from start of treatment to time of 
progression or death, with date of progression the date of first radiographic evidence of 
progression that is later confirmed as PD (rather than pseudo-progression).   If progression or 
death is not observed on study, PFS is censored at the date of last radiographic assessment 
without PD.  If the first evidence of PD is from a radiographic assessment that is ≥12 weeks 
overdue, PFS is censored at the date of last radiographic assessment without PD. 
 
Duration of response is measured as time in months from CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented (using the 
same criteria for PD as for PFS with respect to timing and censoring) 
 
Overall survival (OS) is measured as months from first study treatment until death or last contact 
confirming that the patient is alive. 
 
13.2 
Sample Size 
 
For each cohort, a BOR rate of 15% would be promising compared to a null rate of 2%.  The 
target enrollment is 37 evaluable patients within each cohort.  A stopping rule for futility is 
implemented if none of the first 11 evaluable patients within a cohort have a confirmed objective 
response.   Accrual may continue during follow-up for these patients. If 1 or more responses are 
observed in the first 11 evaluable patients in a cohort, an additional 26 patients will be enrolled.  
Importantly, if one cohort meets criteria for futility in stage 1, the other cohort(s) may proceed to 
stage 2, if indicated.  A promising study result would be if 3 or more responses are seen at the 
conclusion of stage 2.  This design has 80% power for each cohort to detect a true response rate 
of 15% (compared with a null rate of 2%). The one-sided type 1 error rate is 0.05 for each 
cohort. 
 
Thus, the minimum sample size is 33 for the study (3 cohorts), and the maximum sample size is  
111.    
 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
62 
 
13.3 
Analysis cohorts 
 
All enrolled patients who receive at least one dose of study therapy will be included in primary 
assessments of both efficacy and safety, with the exception of patients not evaluable for the 
primary analysis (see 13.1).  Secondary analyses may examine subsets of patients based on the 
delivered dose of therapy. 
 
13.4 
Analysis plans 
 
13.4.1 Primary objective 
 
Futility stopping rules for the Simon optimal two-stage design are described above (Section 
13.2).  A promising study result is 3 or more responses (PR or CR as BOR) in 37 patients.  For 
each cohort, the overall response rate (ORR) for best overall response and 90% and 95% 
confidence intervals will be estimated using a uniformly minimum variance unbiased estimator 
appropriate for a two-stage trial (Jung et al, 2004 and Jung, 2015). 
 
13.4.2 Secondary objectives 
 
For patients experiencing complete or partial tumor responses, the distribution of response 
duration will be characterized by the median and quartiles, , and graphical display of Kaplan-
Meier estimates of response duration, separately for each cohort and for all responders. 
 
Progression-free survival (PFS, months from start of treatment to time of progression, death or 
last radiographic assessment without PD, whichever occurs first) and overall survival (OS, 
months from first study treatment to death or last contact) will be summarized separately for 
each cohort.  The PFS function and median PFS will be estimated by the Kaplan-Meier method, 
with a 90% confidence interval using the Greenwood variance formula applied to log-
transformed survival. 
 
Adverse events will be graded using the Cancer Therapy Evaluation Program (CTEP) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4. Adverse events of grade 3 or 
greater determined to be possibly, probably or definitely related to treatment, or that result in 
dose holds or reductions, will be collected and reported. Adverse events and serious adverse 
events will be tabulated in order of prevalence, with the highest grade reported by each patient. 
The number and percent of subjects reporting adverse events will be summarized by category 
(i.e., “Blood and lymphatic system disorders”), for the most common adverse event 
subcategories (i.e., “anemia”), and for serious adverse events (defined in section 7.2). Narratives 
of all serious adverse events and deaths on-study will be provided.  All safety data will be 
tabulated separately by cohort, and for the full study sample. 
 
13.4.3 Exploratory objectives   
 
PD-L1 expression will be measured in tissue from a mandatory biopsy conducted after 
discontinuation of the prior therapy and before initiation of study therapy. The primary analysis 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
63 
will examine associations between PD-L1 expression and best overall response by RECIST 1.1, 
for all cohorts combined.  These two ordinal variables (immunohistochemistry and response) 
will first be described graphically in a mosaic plot, which may suggest a clinically relevant 
dichotomization of PD-L1 expression and/or best overall response.  Further analysis may use 
generalized linear model approaches for ordinal regression, or treat response as dichotomous or 
continuous, with limited models fit to avoid “p-hacking”. 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
64 
 
 
REFERENCES 
 
Borghaei H., Paz-Ares L, Horn L., et al. Nivolumab versus docetaxel in advanced nonsquamous 
non-small-cell lung cancer. N Eng J Med 2015; 373:1627-39. DOI: 10.1056/NEJMoa1507643.  
 
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 
(MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and 
immunologic correlates. J Clin Oncol 2010; 28: 3167-75.  
 
Brahmer JR, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-
cell non-small-cell lung cancer. N Eng J Med 2015; 373:123-35. DOI:10.1056/NEJMoa1504627. 
 
Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression 
in patients with non-small cell lung cancer; a 5-year follow-up study. Tumori 2012; 94:107-16.  
 
Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, et al. Non-small cell lung 
cancer. J Natl Compr Canc Netw 2010;8:740-801. 
 
The Federal Drug Administration. FDA approves Keytruda for advanced non-small cell lung 
Cancer. October 2nd, 2015. 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm 
 
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, 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. 
2016;387(10030):1837-46. 
 
Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus doctaxel as second-line treatment 
of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a 
randomized controlled trial. Lancet Oncol 2013; 14:981-8. 
 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung 
Cancer. N Eng J Med 2015; 372: 2018-2028.  
 
Garon, EB. Current Perspectives in Immunotherapy for Non-Small Cell Lung Cancer. Seminars 
in Oncology 2015; 42 (suppl 2): s11-s18.  
 
Gettinger SN, Horn L, Gandhi L, et al. Overall survival and long term safety of nivolumab (anti-
programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated 
advanced non-small-cell lung cancer. J Clin Oncol 2015; 33: 2004-12.  
 
Gettinger SN, Kowanetz M, Koeppen H, Wistuba II, Kockx M, Kadel EE, Rizvi NA, Spira AI, 
Hirsch FR, Boyd Z, Denker M, Minn A, Shames DS, Sandler A, Chen DS, Hegde PS, Spigel 
DR; Yale School of Medicine, New Haven, CT; Genentech, Inc., South San Francisco, CA; The 
University of Texas MD Anderson Cancer Center, Houston, TX; Histogenex, Berchem, 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
65 
Belgium; Columbia University Medical Center, New York, NY; Virginia Cancer Specialists 
Research Institute, US Oncology Research, Fairfax, VA; University of Colorado Cancer Center, 
Denver, CO; Sarah Cannon Research Institute, Nashville, TN. Molecular, immune and 
histopathological characterization of NSCLC based on PDL1 expression on tumor and immune 
cells and association with response to the anti-PDL1 antibody MPDL3280A. J Clin Oncol 33, 
2015 (suppl; abstr 3015). 
 
Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus 
docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J 
Clin Oncol 2004; 22:1589-97.  
 
Herbst RS, Baas P., Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, 
PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized 
controlled trial. The Lancet. Epub December 18th 2015; DOI: 10.1016/s0140-6736(15)01281-7 
 
Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 
antibody MPDL3280A in cancer patients. Nature 2014;515:563-7. doi: 10.1038/nature14011. 
 
Horn L, Spiegel D, Gettinger S. Clinical activity, safety and predictive biomarkers of the 
engineered antibody atezolizumab (anti-PDL1) in non-small cell lung cancer (NSCLC): update 
from a phase Ia study. J Clin Oncol 2015; 33 (suppl; abstr 8029). 
 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J 
Clin 2011;61:69-90. 
 
Jung SH. Statistical issues for design and analysis of single-arm multi-stage phase II cancer 
clinical trials. Contemp Clin Trials. 2015 May;42:9-17.  
 
Jung SH, Kim KM. On the estimation of the binomial probability in multistage clinical trials. 
Stat Med. 2004 Mar 30;23(6):881-96.  
 
Kowanetz, Marcin, et al. "Abstract A017: PD-L1 as a predictive biomarker for atezolizumab 
(MPDL3280A; anti-PDL1) in non-small cell lung cancer (NSCLC)." Cancer Immunology 
Research 4.1 Supplement (2016): A017-A017. 
 
Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive 
resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune 
checkpoints. Nat Commun. 2016 Feb 17;7:10501. 
 
Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba, II, et al. Using 
multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 
2014;311:1998-2006. 
 
McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal 
neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. 
Science. 2016 Mar 25;351(6280):1463-9. 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
66 
 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
2012; 12:252-64.  
 
Rizvi NA, Brahmer JR, Ou S-HI, et al. Safety and clinical activity of MEDI4736, an anti-
programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer 
(NSCLC). J Clin Oncol 2015;33 (suppl; abstr 8032).  
 
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-8. 
 
Shepherd FA, Dancey J, Ramlau R et al. Prospective randomized trial of docetaxel versus best 
supportive care in patients with non-small-cell lung cancer previously treated with platinum-
based chemotherapy. J Clin Oncol 2000; 18:2095-103.  
 
Somasundaram A, Socinski MA, Burns TF. Personalized treatment of EGFR mutant and ALK-
positive patients in NSCLC. Expert Opin Pharmacother 2014;15:2693-708. 
 
Spira AI, Park K, Mazieres, J. et al. Efficacy, safety and predictive biomarkers results from a 
randomized phase II study comparing PDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). J 
Clin Oncol 2015; 33 (suppl; abstr 8010).  
 
Sui X, Ma J, Han W, et al. The anticancer immune response of anti-PD-1/PD-L1 and the genetic 
determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget 2015; 6: 
19393–19404. 
 
Topalian SL, Hodi FS, Brahmer JR. et al. Safety, activity and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med 2012; 366: 2443-54.  
 
Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression in non-
small cell lung cancer. Lab Invest 2014; 94:107-16.  
 
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: 
Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016 Mar 
2;8(328):328rv4.  
 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
67 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 


HCC #:16-153 
Version 9 Dated 8/17/2020 
 
68 
APPENDIX B 
ANAPHYLAXIS PRECAUTIONS 
 
EQUIPMENT NEEDED 
 
• 
Tourniquet 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice  
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
 
In the event of a suspected anaphylactic reaction during study drug infusion, the following 
procedures should be performed: 
 
1. Stop the study drug infusion. 
2. Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug.  Do not obstruct arterial flow in the limb. 
3. Maintain an adequate airway. 
4. Administer antihistamines, epinephrine, or other medications as required by patient status 
and directed by the physician in charge. 
5. Continue to observe the patient and document observation. 


 
1 
 
 
 
 
 
 
APPENDIX C  
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