Clinical trial NCT03206203
Conditions: Triple Negative Breast Cancer Stage IV Breast Cancer HER2 Negative Invasive Breast Cancer
Sponsor: Vanderbilt-Ingram Cancer Center
Start date: 2017-08-29; Completion date: 2023-10-04
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This randomized phase II trial studies how well carboplatin with or without atezolizumab works in treating patients with stage IV triple negative breast cancer. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Giving carboplatin with atezolizumab may work better in treating patients with stage IV triple negative breast cancer

Detailed description:
Primary objective:

To evaluate the efficacy, as measured by progression free survival (PFS) of carboplatin + atezolizumab (using irRECIST) versus carboplatin alone (using RECIST) in patients with triple negative metastatic breast cancer

Secondary objectives:

* To determine overall response rate.
* To evaluate the efficacy, as measured by clinical benefit rate, of carboplatin + atezolizumab (using irRECIST) versus carboplatin (using RECIST) alone in patients with triple negative metastatic breast cancer. Clinical benefit rate is defined as complete response plus partial response plus stable disease for 6 months.
* To determine the duration of response for patients achieving a partial or complete response.
* To evaluate the overall survival (OS) of carboplatin + atezolizumab versus carboplatin alone in patients with triple negative metastatic breast cancer.

TERTIARY OBJECTIVES:

* To perform the following correlative studies from biopsies taken at baseline:

  1. Tumor infiltrating lymphocyte frequency and phenotype (TILs) at baseline
  2. PD-L1 expression from the baseline pre-treatment tissue and at progression lesion, performed by IHC (SP142 clone)
  3. HER2 (IHC, FISH) and ER/PR levels (IHC) from a metastatic site
  4. Perform RNA-seq to determine non-synonymous mutation burden in expressed genes and gene expression to assign a triple negative subtype at baseline for correlations with clinic outcome
  5. Immune phenotyping (IHC) for markers of T cell subsets and activation (CD4, CD8, FoxP3, CD25, Glut1) and exhaustion (PD1, CTLA4) and test feasibility of flow cytometric analyses to include additional markers
* To assess the effect of BRCA mutations on response to the study drugs
* To evaluate the effect of steroids on the efficacy of atezolizumab To assess the prognostic effects of TILs on PFS and CBR in patients receiving atezolizumab

Arms: arm 1: Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression.
Interventions: intervention 1: Atezolizumab intervention 2: Carboplatin intervention 3: Laboratory Biomarker intervention 4: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given by vein intervention 2: Given by vein intervention 3: Correlative study intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
A Phase II trial of Atezolizumab (anti-PDLl) with Carboplatin in 
Patients with Metastatic Triple Negative Breast Cancer 
Protocol Number 
Protocol Chair 
TBCRC Protocol 
GNE ML30041 / TBCRC 043 
VICC BRE 15136 
Laboratory Correlatives: 
Pathology: 
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Pagel o/103 
NCT03206203




 
Atezolizumab/Carboplatin 
Protocol Chair:  V. Abramson  
TBCRC 043 
 
 
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VICC  BRE 15136: A Phase II trial of Atezolizumab (anti-PDL1) with Carboplatin in 
Patients with Metastatic Triple Negative Breast Cancer 
 
- Protocol Revision Record - 
 
 
Original Protocol: 
 
4/4/2016 
 
Protocol Revision 1:  
 6/22/2017 
 
Protocol Revision 2:   
 8/04/2017 
 
Protocol Revision 3:   
 11/19/2018 
 
Protocol Revision 4:   
04/06/2020 
 
Protocol Revision 5:              07/30/2020 
 
Protocol Revision 6:              11/13/2020 
 
 
 
 


Atezolizumab/Carboplatin
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Table of Contents
SCHEMA............................................................................................................................................................. 6
STUDY DESIGN/SUMMARY .......................................................................................................................... 7
OBJECTIVES..................................................................................................................................................... 7
PRIMARY OBJECTIVE .................................................................................................................................... 7
SECONDARY OBJECTIVES.............................................................................................................................. 7
EXPLORATORY OBJECTIVES.......................................................................................................................... 7
BACKGROUND................................................................................................................................................. 8
INVESTIGATIONAL AGENTS.........................................................................................................................12
RATIONALE.................................................................................................................................................18
PARTICIPANT SELECTION ........................................................................................................................18
INCLUSION CRITERIA ..................................................................................................................................18
EXCLUSION CRITERIA................................................................................................................................. 20
INCLUSION OF UNDERREPRESENTED POPULATIONS....................................................................................23
REGISTRATION PROCEDURES.................................................................................................................23
GUIDELINES FOR ALL PARTICIPATING INSTITUTIONS...................................................................................23
BIOPSY OF METASTATIC LESION..................................................................................................................25
STUDY CALENDARS.....................................................................................................................................26
STUDY CALENDAR:  CARBOPLATIN  +/-  ATEZOLIZUMAB ..........................................................26
STUDY CALENDAR:  ATEZOLIZUMAB (CROSSOVER) ...................................................................29
TREATMENT PLAN.......................................................................................................................................31
OVERVIEW..................................................................................................................................................31
CONCOMITANT TREATMENT AND SUPPORTIVE CARE GUIDELINES.............................................................31
ASSESSMENTS DURING TREATMENT ...........................................................................................................32
CROSS-OVER POST-PROGRESSION ...............................................................................................................32
DURATION OF THERAPY..............................................................................................................................33
DURATION OF FOLLOW-UP.........................................................................................................................33
CRITERIA FOR REMOVAL FROM STUDY.......................................................................................................33
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS.....................................35
ANTICIPATED TOXICITIES OF ATEZOLIZUMAB (ATEZOLIZUMAB) AND DOSE MODIFICATIONS....................35
GENERAL GUIDELINES FOR DOSAGE MODIFICATION AND TREATMENT INTERRUPTION OR 
DISCONTINUATION ..................................................................................................................................................36
ANTICIPATED TOXICITIES OF CARBOPLATIN AND DOSE MODIFICATIONS...................................................60
SPECIAL CONSIDERATIONS .........................................................................................................................63
DRUG FORMULATION/STORAGE/SUPPLY............................................................................................64
ATEZOLIZUMAB (MPDL3280A).................................................................................................................64
CARBOPLATIN.............................................................................................................................................65
DRUG ACCOUNTABILITY.............................................................................................................................66
CORRELATIVE/SPECIAL STUDIES ..........................................................................................................67
ARCHIVED TISSUE SAMPLES.......................................................................................................................67
BLOOD/PLASMA COLLECTION .....................................................................................................................70


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TISSUE SPECIMEN AND BLOOD/PLASMA LABELING AND DOCUMENTATION .................................................70
PERIPHERAL BLOOD MONONUCLEAR CELL COLLECTION...........................................................................70
GENETIC TESTING.......................................................................................................................................70
SPECIMEN BANKING ...................................................................................................................................71
BIOPSY QUESTIONNAIRE.............................................................................................................................71
IMAGING CORRELATIVE STUDY .................................................................................................................71
MEASUREMENT OF EFFECT .....................................................................................................................71
DEFINITIONS ...............................................................................................................................................73
DISEASE PARAMETERS................................................................................................................................73
RESPONSE CRITERIA ...................................................................................................................................75
DURATION OF RESPONSE ............................................................................................................................77
IMMUNE-RELATED RESPONSE CRITERIA.....................................................................................................77
RESPONSE REVIEW AND CENTRAL TUMOR MEASUREMENTS......................................................................79
ASSESSMENT OF SAFETY ADVERSE EVENT REPORTING ...............................................................80
GENERAL ....................................................................................................................................................80
RISKS ASSOCIATED WITH ATEZOLIZUMAB ..................................................................................................80
13.3
SAFETY PARAMETERS AND DEFINITIONS....................................................................................................81
ASSESSMENT OF ADVERSE EVENTS ............................................................................................................82
REPORTING PROCEDURES ...........................................................................................................................83
COORDINATING CENTER REPORTING PROCEDURES....................................................................................91
DATA SAFETY AND MONITORING ..........................................................................................................97
DATA MANAGEMENT AND REPORTING.......................................................................................................97
MEETINGS...................................................................................................................................................97
MONITORING ..............................................................................................................................................98
DATA HANDLING AND RECORD KEEPING ...................................................................................................98
REGULATORY CONSIDERATIONS...........................................................................................................99
PROTOCOL REVIEW AND AMENDMENTS .....................................................................................................99
INFORMED CONSENT...................................................................................................................................99
ETHICS AND GCP......................................................................................................................................100
MULTI-CENTER GUIDELINES.................................................................................................................100
PROTOCOL REVIEW AND AMENDMENTS ...................................................................................................100
STUDY DOCUMENTATION .........................................................................................................................100
RECORDS RETENTION ...............................................................................................................................101
PUBLICATION............................................................................................................................................101
STATISTICAL CONSIDERATIONS ..........................................................................................................101
STUDY DESIGN/ ENDPOINTS .....................................................................................................................101
SAMPLE SIZE/ ACCRUAL RATE .................................................................................................................102
INTERIM ANALYSIS....................................................................................................................................102
ANALYSIS OF SECONDARY AND EXPLORATORY ENDPOINTS.....................................................................102
STATISTICAL ANALYSIS PLAN ..................................................................................................................103
REPORTING AND EXCLUSIONS ..................................................................................................................103
REFERENCES ........................................................................................................................................................103


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SCHEMA


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STUDY DESIGN/SUMMARY
The primary objective of this phase II multiple institution trial is to evaluate the efficacy of 
carboplatin + atezolizumab versus carboplatin alone in patients with metastatic triple negative 
breast cancer.  Patients with an ECOG performance status of 0-1 who have received either zero 
or one prior regimen for metastatic disease are eligible. Patients will be randomized to one of 
two arms. In arm 1, patients will receive combination therapy with carboplatin and atezolizumab
and in arm 2 patients will receive carboplatin monotherapy. All patients will undergo core biopsy 
of a metastatic lesion (if reasonably safe) at baseline and at the time of progression.  If a fresh 
biopsy is deemed not safe, a paraffin block from a prior biopsy or surgery must be available for 
enrollment.  Standard staging radiology scans will be performed at baseline and every 9 weeks 
thereafter.  Upon progression of disease (clinically or by RECIST), patients on the carboplatin 
alone arm may cross over to arm 1 to receive atezolizumab.  All patients with progression of 
disease who want to cross over to receive atezolizumab are required to undergo a biopsy of a 
metastatic site at progression if reasonably safe.  Patients who were receiving carboplatin + 
atezolizumab will be discontinued from study medications upon disease progression by RECIST.  
Patients will be screened and enrolled from the oncology practice at the Vanderbilt-Ingram 
Cancer Center and from participating member centers of the Translational Breast Cancer 
Research Consortium (TBCRC).
OBJECTIVES
Primary Objective
•
To evaluate the efficacy, as measured by median progression free survival (PFS) of 
carboplatin + atezolizumab (using RECIST) versus carboplatin alone (using RECIST) in 
patients with triple negative metastatic breast cancer
Secondary Objectives
•
To determine overall response rate (ORR) 
•
To evaluate the efficacy, as measured by clinical benefit rate (CBR), of carboplatin + 
atezolizumab versus carboplatin alone in patients with triple negative metastatic breast 
cancer.  CBR is defined as complete response (CR) plus partial response (PR) plus stable 
disease (SD) for 6 months.
•
To determine the duration of response (DOR) for patients achieving a partial or complete 
response 
•
To evaluate the overall survival (OS) of carboplatin + atezolizumab versus carboplatin 
alone in patients with triple negative metastatic breast cancer
•
To evaluate PFS, ORR, and DOR based on irRECIST as assessed by central imaging 
review.
Exploratory Objectives
•
To perform the following correlative studies from biopsies taken at baseline:
a) Tumor infiltrating lymphocyte frequency and phenotype (TILs) at baseline 


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TBCRC 043
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b) PD-L1 expression from the baseline pre-treatment tissue and at progression lesion, 
performed by IHC (SP142 clone) using a facility designated by the Supporter 
(Genentech) 
c) HER2 (IHC, FISH) and ER/PR levels (IHC) from a metastatic site
d) Perform RNA-seq to determine non-synonymous mutation burden in expressed genes 
and gene expression to assign a triple negative subtype at baseline for correlations 
with clinic outcome 
e) Immune phenotyping (IHC) for markers of T cell subsets and activation (CD4, CD8, 
FoxP3, CD25, Glut1) and exhaustion (PD1, CTLA4) and test feasibility of flow 
cytometric analyses to include additional markers 
•
To assess the effect of BRCA mutations on response to the study drugs
•
To evaluate the effect of steroids on the efficacy of atezolizumab
To assess the prognostic effects of TILs on PFS and CBR in patients receiving 
atezolizumab
•
To determine the correlation between low muscle mass and tumor immunophenotype by 
PDL1 expression, TIL frequency, tumor mutation burden, T cell activation, and T cell 
exhaustion. 
•
To determine the correlation between low muscle attenuation and tumor
immunophenotype by PDL1 expression, TIL frequency, tumor mutation burden, T cell 
activation, and T cell exhaustion. 
•
To determine the correlation between adipose mass and tumor immunophenotype by 
PDL1 expression, TIL frequency, tumor mutation burden, T cell activation, and T cell 
exhaustion. 
•
To determine the prognostic impact of LMM, LMA, and adiposity on progression free 
survival in patients receiving atezolizumab (anti-PDL1).
BACKGROUND
Over the past decade, the term “triple negative breast cancer” has been used to classify tumors that 
lack expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2.  Triple 
negative breast cancers (TNBC) are generally more aggressive than their ER positive counterparts, 
with higher rates of relapse in the early stage and decreased overall survival in the metastatic 
setting.  TNBC is a pathologically, molecularly and clinically heterogeneous disease and the lack 
of recurrent targetable alterations makes this disease particularly difficult to treat. Using gene 
expression analyses from 386 tumors, we recently identified six distinct TNBC subtypes, each 
displaying unique biologies (Figure 1). The TNBC molecular subtypes include two basal-like 
(BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like 
(MSL), and a luminal androgen receptor (LAR) subtype [1]. More importantly, the inherent 
differences between the subtypes predict for differential responses to standard chemotherapy.  In 
a retrospective re-analysis of pretreatment biopsies, TNBC molecular subtypes have shown 
clinical utility and are predictive of response to neoadjuvant anthracycline and cyclophosphamide 
followed by taxane (PMID:23948975)[2]. This study showed BL1 had the highest pCR rate (50%) 
at time of surgery and BL2 and LAR the lowest (0 and 10%, respectively), deviating from the 
overall response of 32% for unselected TNBC [2]. The differing biologies of TNBC subtypes, as 
indicated by their gene expression signatures, are providing significant insight to differential 
response to therapies.


 
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Comparable subtyping 
results 
have 
been 
obtained 
from 
two 
independent analyses 
of 
gene 
expression 
arrays and each have 
identified 
similar 
subtypes, including a 
immune-activated or -associated biology [3, 4]. The IM subtype is composed of immune antigens 
and genes involved in cytokine and core immune signal transduction pathways (Figure 2).   The 
data from our work and others suggest that the IM subtype is composed of an immune-activated 
and associated signaling components contributed 
from both the tumor and the infiltrating 
lymphocytes.  Adams and colleagues recently 
reported that higher levels of tumor infiltrating 
lymphocytes (TILs), in evaluable TNBC tumors 
collected from patients enrolled in an adjuvant phase III trial, were prognostic for overall and 
disease-free survival [5]. Similarly, the presence of TILs in pretreatment biopsies was especially 
predictive of response to neoadjuvant chemotherapy in the carboplatin arm of the GeparSixto trial 
[6].  These preliminary data suggesting that TILs are predictive markers of response, specifically 
to neoadjuvant platinum agent compared to liposomal-doxorubicin, suggest that cell death induced 
by platinum agents may “prime” or generate neoantigens to stimulate nearby lymphocytes.  
 
Figure 1. IM TNBC 
subtype is enriched in 
immune genes that are 
involved 
in 
cytokine 
signaling, 
immune 
signal transduction and 
antigen 
presentation.  
Heatmap shows relative 
expression of immune 
related 
genes 
across 
TNBC 
molecular 
subtypes from 386 tumor 
gene expression arrays.     
Figure 2. Immune regulatory genes that are 
indicative of tumor immune cell infiltrate are 
enriched in the IM TNBC subtype.  Heatmap shows 
unsupervised clustering of immune panel of genes that 
highly correlate with pathological evaluation of tumor 
infiltrating lymphocytes using RNA-seq expression 
from TNBC tumor samples from TCGA.    


 
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Analysis of the gene expression data from the IM subtype and identification of transcripts 
associated with lymphocytes further supports that the IM tumor samples contain tumor-infiltrating 
lymphocytes (TILs).  This is illustrated by observed enrichment of immune markers in the RNA-
seq data from TNBC samples in The Cancer Genome Atlas (TCGA) [6].  Unsupervised 
hierarchical clustering showed a strong correlation of TIL-associated immune signatures in TNBC 
tumors of the IM subtype compared to all other TNBC tumors (Figure 3). 
 
Given the recent efficacy of anti-PDL1 compounds in TNBC [7], we examined the levels of known 
immune checkpoint regulatory genes (PDL1, PD1 and CTLA4) to determine if these targets are 
differentially expressed in TNBC subtypes. Breast cancer RNA-seq data (RSEM) was downloaded 
(Broad Firehose) and TNBC samples subtyped as previously described [1, 8]. PDL1, PD1 and 
CTLA4 expression were significantly higher in the IM TNBC subtype (4437.4 vs. 784.1, 
p=0.0001; 144.3 vs. 31.4, p=0.001 and 167.8 v. 39.5, p=0.0001, respectively) compared to all other 
breast cancers (Figure 3A-3C). These data demonstrate that the IM TNBC subtype is significantly 
enriched in the expression of genes involved in immune checkpoint signaling.  Assessment of the 
IM signature in relation to spatial localization of T cells may identify a subset of TNBC in which 
immune cells may be present and checkpoint inhibitors have efficacy. 
 
 
Figure 3. Expression of immune signaling components is enriched in immunomodulatory (IM) TNBC.  
Boxplots show mRNA expression (RSEM counts) for (A) PD-L1, (B) PD1 and (C) CTLA4 across TNBC 
molecular subtypes (BL1, BL2, IM, M, MSL and LAR) or ER-positive (ER) and HER2-amplified (HER2) breast. 
cancer from TGCA. 


 
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Since there has been a strong correlation between non-synonymous mutation burden and response 
to anti PD-1 therapy in non–small cell lung cancer (NSCLC), and anti-PD-L1 antibodies have 
efficacy in TNBC, we examined non-synonymous mutation burden in TNBC and non-TNBC 
tumors from the TCGA [9].  The number of non-synonymous mutations per sample was higher for 
TNBC (n=69) than non-TNBC (n=38), suggesting the possibility that TNBC tumors may be more 
immunogenic and express more neoantigens (Figure 4B).  In addition, the mutational burden was 
differential among TNBC molecular subtypes, with significantly more amino acid coding 
mutations in the BL1 (138.2 vs. 70.0, p=0.0093) and M subtypes (133.9 vs. 70.0, p=0.036) 
compared to all other subtypes (Figure 4 B). 
 
 
 
A better understanding of the clinical and pathologic factors associated with benefit to 
immunotherapy in metastatic breast cancer could improve personalized therapy and provide 
insight into mechanisms of resistance.  One such factor may be the body composition of the host. 
Obesity is associated with systemic inflammation and suppression of adaptive immunity, yet 
augmented T cell responses after PD1/PDL1 blockade11; lower muscle mass is associated with 
pro-inflammatory cytokines that may promote tumor growth and impair response to immune 
checkpoint blockade12,13.  Low muscle mass (LMM), or sarcopenia, is associated with poorer 
outcome and increased toxicity in advanced cancer14.  Low muscle attenuation (LMA), reflecting 
muscle “quality” and intramuscular fat infiltration, is also associated with poor outcome and 
reflects physical functioning15.  To date, there has been no evaluation of how muscle or adiposity 
impact immune phenotype and outcome in patients with metastatic breast cancer receiving 
immunotherapy.  TBCRC043 offers a homogeneous population of patients with metastatic TNBC 
with baseline biopsies for immunophenotyping, centrally collected body imaging, and outcome 
follow up to investigate this question.  Using transverse cuts at the third lumbar vertebrae on 
abdominal CT scans as a reflection of total body composition16,17, we will quantify muscle mass, 
muscle attenuation, and adiposity.  Low muscle mass is defined as skeletal muscle index (SMI, 
lean muscle area/height, cm2/m2) less than 41 and low muscle attenuation will be defined as 
average muscle density less than 25 HU, or less than 33 HU if the patient is overweight/obese by 
BMI18.  Total adiposity will be defined as the sum of visceral adipose tissue, subcutaneous adipose 
tissue, and intramuscular adipose tissue and evaluated by tertiles.  Regarding the impact of body 
composition on immune phenotype and prognosis in patients receiving PDL1 blockade for 
metastatic triple negative breast cancer in TBCRC-043, our primary hypothesis is that LMM 
Figure 4. TNBC tumors in 
TCGA have a higher non-
synonymous 
mutation 
burden.  (A) Beeswarm 
plot shows the number of 
coding amino acid changing 
mutations in TNBC (red) 
and 
non-TNBC 
tumors 
(black). (B) Boxplot show 
mutational 
burden 
by 
TNBCytype 


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(sarcopenia) is associated with T cell exhaustion (PD1 and CTLA4 expression) and worse 
progression free survival in patients with metastatic breast cancer receiving anti-PDL1 therapy, 
attenuating the prognostic effect of tumor infiltrating lymphocytes.
Investigational Agents
4.1.1
Atezolizumab (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 is being investigated as a potential therapy against solid tumors and hematologic 
malignancies in humans. 
4.1.1.1
Summary of Nonclinical Experience 
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in vivo 
activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an acceptable safety 
profile, and to identify a Phase I starting dose.  Comprehensive pharmacology, PK, and toxicology 
evaluations were thus undertaken with atezolizumab. 
The safety, pharmacokinetics, and toxicokinetics of atezolizumab were investigated in mice and 
cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the 
appropriate starting dose in humans.  Given the similar binding of atezolizumab for cynomolgus 
monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, pharmacokinetics, and toxicokinetics of 
atezolizumab.  
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab supported 
entry into clinical studies, including providing adequate safety factors for the proposed Phase I 
starting doses.  The results of the toxicology program were consistent with the anticipated 
pharmacologic activity of down-modulating the PD-L1/PD-1 pathway and supported entry into 
clinical trials in patients.
Refer to the atezolizumab Investigator’s Brochure for details on the nonclinical studies. 
4.1.1.2
Clinical Experience with atezolizumab
4.1.1.2.1 Onoging Clinical Studies 


 
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Current studies of atezolizumab include one ongoing Phase Ia monotherapy study, three ongoing 
combination studies, five Phase II studies, and one Phase III study.  Details of all ongoing studies 
can be found in the atezolizumab Investigator’s Brochure. 
Phase Ia Study PCD4989g 
Study PCD4989g is a multicenter, first-in-human, open-label, dose-escalation study evaluating the 
safety, tolerability, immunogenicity, pharmacokinetics, exploratory pharmacodynamics, and 
preliminary evidence of biologic activity of atezolizumab administered as a single agent by IV 
infusion every 3 weeks to patients with locally advanced or metastatic solid malignancies or 
hematologic malignancies.  Ongoing expansion cohorts are studying the efficacy in patients with 
pancreatic cancer, bladder cancer, breast cancer, esophageal cancer, prostate cancer, small-cell 
lung cancer, malignant lymphoma, multiple myeloma, and other less common tumor types. 
Phase Ib Study GP28328    
Ongoing Phase Ib Study GP28328 is evaluating the safety and pharmacology of atezolizumab 
administered with bevacizumab alone (Arm A) or with bevacizumab plus leucovorin, 5-
fluorouracil, and oxaliplatin (FOLFOX; Arm B) in patients with advanced solid tumors.  
Additional cohorts have been included to investigate atezolizumab in combination with 
carboplatin plus paclitaxel, in combination with carboplatin plus pemetrexed, and in combination 
with carboplatin plus nab paclitaxel, pemetrexed, and cisplatin in patients with advanced or 
metastatic non-small cell lung cancer (NSCLC).  
 
Phase Ib Study GP28384 
Ongoing Phase Ib Study GP28384 is evaluating the safety and pharmacology of atezolizumab 
administered in combination with vemurafenib in patients with previously untreated BRAFV600-
mutation−positive metastatic melanoma. 
Phase Ib Study GP28363 
Ongoing Phase Ib Study GP28363 is evaluating the safety and pharmacology of atezolizumab 
administered in combination with cobimetinib (MEK inhibitor) in locally advanced or metastatic 
solid tumors. 
Phase II Study GO28625 (FIR) 
Ongoing, single-arm, Phase II Study GO28625 is evaluating the safety and efficacy of 
atezolizumab monotherapy in PD-L1−positive patients with NSCLC.  In particular, this study is 
evaluating whether archival or fresh tumor tissue is more predictive of response to atezolizumab.  
Safety and efficacy data are not yet available for this study.  
Phase II Study GO28753 (POPLAR) 
Study GO28753 is a randomized, open-label, phase II study in patients with locally advanced or 
metastatic NSCLC who have failed a prior platinum-containing regimen.  Patients in the control 
arm of Study GO28753 will receive docetaxel alone.  Eligible patients will be enrolled regardless 
of PD-L1 status and will be stratified by PD-L1 expression.  The primary endpoint is overall 
survival (OS) for both the PD-L1−positive population and the overall study population. 
Phase II Study GO28754 (BIRCH) 


 
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Ongoing, single-arm, Phase II Study GO28754 is evaluating the safety and efficacy of 
atezolizumab monotherapy in PD-L1−positive patients with NSCLC.  Safety and efficacy data are 
not yet available for this study. 
Phase II Study WO29074 
Ongoing Phase II Study WO29074 is evaluating the safety and efficacy of atezolizumab 
monotherapy or the combination of atezolizumab and bevacizumab versus sunitinib in treatment-
naïve patients with renal cell carcinoma (RCC).  As of the clinical cutoff date (CCOD) of 17 
October 2016, safety data was available from 304 patients in the safety-evaluable population, of 
whom 101 were treated with ATZ+BEV, 103 with atezolizumab alone, and 100 with sunitinib.  
The safety of atezolizumab in combination with bevacizumab was consistent with the known 
safety profile of individual treatment components; no new safety signals were identified.  Safety 
of atezolizumab monotherapy was also consistent with the known profile of atezolizumab.  The 
safety data demonstrated a more favorable safety profile for atezolizumab monotherapy compared 
to sunitinib.  No new safety signals were identified. 
 
Phase II Study GO29293 
Ongoing Study GO29293 is a single-arm, open label, Phase II study to assess the clinical benefit 
of atezolizumab as a single agent in patients with locally advanced or metastatic UBC.  The 
co-primary endpoints of this study are independent review facility (IRF)−assessed objective 
response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) and investigator-assessed ORR according to modified Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria. 
Phase III Study GO28915 (OAK) 
Study GO28915 is a randomized, open-label, Phase III study in patients with locally advanced or 
metastatic NSCLC who have failed a prior platinum-containing regimen.  Patients in the control 
arm of Study GO28915 will receive docetaxel alone.  Eligible patients will be enrolled regardless 
of PD-L1 status and will be stratified by PD-L1 expression.  The primary endpoint is OS for both 
the PD-L1−positive population and the overall study population. 
For further details, see the atezolizumab Investigator’s Brochure. 
4.1.1.2.2   Clinical Safety 
As of the clinical cutoff date (CCOD) of 17 May 2019 > 21,000 patients with solid tumors or 
hematologic malignancies have received atezolizumab as a single agent or in combination with 
cytotoxic chemotherapy and/or targeted therapy through participation in a clinical trial. 
Safety findings of single-agent atezolizumab across multiple tumor types in the clinical 
development program are consistent with the known mechanism of action of atezolizumab and the 
underlying disease. Overall, treatment with atezolizumab is well tolerated with a manageable 
adverse event profile. Currently, no maximum tolerated dose, no dose-limiting toxicities (DLTs), 
and no clear dose-related trends in the incidence of adverse events (AEs) have been determined. 
Among 3178 patients treated with single-agent atezolizumab for whom pooled safety data are 
available, the most commonly reported AEs (≥ 10%) include fatigue, decreased appetite, nausea, 


 
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cough, dyspnea, constipation, pyrexia, diarrhea, anemia, back pain, vomiting, asthenia, arthralgia, 
pruritus, rash, headache, urinary tract infection, and peripheral edema. 
The AEs observed with atezolizumab in combination with chemotherapy and/or targeted therapies 
are consistent with the known risks of the individual study treatment. 
Atezolizumab-related AEs were comparable between patients who received atezolizumab 
monotherapy and those who were treated with atezolizumab in combination with targeted therapy 
and/or chemotherapy. 
 
Adverse Events 
The following adverse events are considered known risks of atezolizumab treatment: 
Very Common 
 
(occurs in  
> 10%  
of patients) 
 
• Fatigue 
• Arthralgia 
• Asthenia 
• Decreased appetite 
• Diarrhea 
• Dyspnea 
• Urinary tract infection 
• Cough 
 
• Pruritus 
• Nausea 
• Fever 
• Rash 
• Vomiting 
• Musculoskeletal pain 
Common 
 
(occurs in  
1% - 10% 
of patients) 
 
• Chills 
• Dysphagia 
• Increase in liver enzymes 
• Hypersensitivity 
• Hypokalemia 
• Hyponatremia 
• Hypotension 
• Hypothyroidism 
• Nasal congestion 
 
• Colitis 
• Hypoxia 
• Flu-like symptoms 
• Infusion-related reaction 
• Pneumonitis 
• Thrombocytopenia 
• Hepatitis 
• Abdominal pain 
Less Common  
but important 
 
(occurs in  
< 1%  
of patients) 
 
 
 
 
 
• Adrenal insufficiency 
• Diabetes 
• Hyperthyroidism 
• Meningoencephalitis 
• Hypophysitis 
• Myocarditis 
• Nephritis 
 
• Guillain-Barré syndrome 
• Myasthenic syndrome / 
myasthenia gravis 
• Pancreatitis 
• Increase in amylase and lipase 
• Diabetic ketoacidosis 
• Myositis 


 
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• Severe Cutaneous Adverse 
Reactions (SCARs)(erythema 
• multiforme, acute generalised 
exanthematous pustulosis, 
Stevens-Johnson syndrome 
• (SJS), Toxic Epidermal 
Necrolysis (TEN) and drug rash 
with eosinophilia and systemic 
• symptoms (DRESS). 
Immune-Mediated Adverse Events 
Immune-mediated AEs are consistent with the role of the PD-L1/PD-1 pathway in 
regulating peripheral tolerance.  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.  As of investigator’s brochure document date 15 
July 2019 (clinical cutoff date 17 May 2019), based on pooled data from 3178 monotherapy 
patients with multiple tumor types, with supporting data from the estimated cumulative 
exposure in > 21,000 patients across all clinical trials, the overall immune-mediated adverse 
drug reaction (ADR) monotherapy rate for atezolizumab is 12.7%, the majority of which 
were Grade 1- 2 immune-mediated ADRs.  In addition to infusion-related reactions, 
expected immune-mediated adverse drug reactions associated with atezolizumab include 
pneumonitis, hepatitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic 
syndrome/myasthenia gravis, meningoencephalitis, myocarditis, nephritis, and myositis, 
severe cutaneous adverse reactions  (erythema multiforme, acute generalised exanthematous 
pustulosis, Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and drug 
rash with eosinophilia and systemic symptoms (DRESS). 
 
 
For further details, see the atezolizumab Investigator’s Brochure. 
4.1.1.2.3 Clinical Activity 
As of the clinical cutoff date (CCOD) 17 May 2019, efficacy data are most extensive for 
patients with non-small cell lung cancer (NSCLC; 1636 atezolizumab treated patients enrolled 
in BIRCH, POPLAR, OAK, IMpower150, IMpower131, GO28625, and the NSCLC cohort 
of PCD4989g) and patients with metastatic urothelial carcinoma (mUC; 983 atezolizumab-
treated efficacy-evaluable patients in studies PCD4989g, IMvigor210, and IMvigor211) who 
were administered atezolizumab. 
 
Results from studies evaluating atezolizumab as monotherapy in patients with locally 
advanced or metastatic NSCLC (PCD4989g, FIR, OAK, POPLAR, and BIRCH) single-agent 
treatment with atezolizumab indicated clinically meaningful overall survival (OS) 
improvement in the 2L/3L NSCLC intent to treat (ITT) population, in comparison with 


 
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standard of care, in both non-squamous and squamous histologies, and across all PD-L1 
expression subgroups. 
 
Atezolizumab in combination with chemotherapy and other therapeutic agents was 
demonstrated to have benefit in the settings of small cell lung cancer (SCLC; IMpower133) 
and NSCLC (IMpower132). 
 
Clinical benefit was observed in patients with renal cell carcinoma (RCC) with the 
combination of atezolizumab and bevacizumab in IMmotion151. Additionally, in 
IMmotion150, a clinically meaningful improvement in IRC-assessed progression-free 
survival (PFS) was observed with atezolizumab and bevacizumab compared with sunitinib in 
the IC1/2/3 population, and no difference in treatment effect was observed with atezolizumab 
monotherapy compared with sunitinib in either the IC1/2/3 or ITT populations. 
 
The study IMpassion130 (WO29522) demonstrated improved OS and PFS in patients with 
triple-negative breast cancer (TNBC) who were treated with atezolizumab and nabpaclitaxel.  
Updated PFS analysis results were consistent with the primary analysis, confirming long-term 
benefit. However, study GO30182 (IMblaze370) did not meet its objectives of improved in 
OS or PFS versus regorafenib in patients with colorectal cancer (CRC) who were treated with 
atezolizumab and cobimetinib. 
 
Other available efficacy data suggested that treatment with atezolizumab as a single agent or 
in combination with other therapeutic agents resulted in anti-tumor activity across a range of 
other tumor types and hematologic malignancies (including pediatric-type tumors), across 
lines of therapy, and across PD-L1 expression subgroups. 
 
For further details, see the atezolizumab Investigator’s Brochure. 
4.1.1.2.4 Clinical Pharmacokinetics and Immunogenicity 
On the basis of available preliminary PK data (0.03−20 mg/kg), atezolizumab appeared to 
show linear pharmacokinetics at doses ≥ 1 mg/kg.  For the 1-mg/kg and 20-mg/kg dose 
groups, the mean 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. 


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Rationale 
Therapies for breast cancer should be guided by biologic features of the tumor, such as 
expression of steroid hormone receptors and hormone dependence and/or HER2/neu 
overexpression. Notable examples are the successful use of hormonal therapy (e.g. tamoxifen 
or aromatase inhibitors) for patients with hormone-sensitive (estrogen receptor [ER] and/or 
progesterone receptor [PR] expressing) tumors32, and the use of trastuzumab (Herceptin™), a 
monoclonal antibody against HER2/neu, for
patients
with overexpression of the 
aforementioned protein33. These are excellent examples of where appropriate patient selection 
is instrumental on the success of these therapies. An issue with triple negative breast cancer 
is that the key drivers of this disease are not well understood, and thus molecular targets for 
therapeutic intervention have not been identified.   
We have identified distinct subtypes of triple negative breast cancer to better understand 
potential drivers of disease progression and to help identify potential therapeutic targets. The 
presence of immune cells and expression of immune checkpoint genes in the IM subtype may 
identify patient populations that benefit from immune checkpoint inhibitors. In addition, 
carboplatin may induce an increase in mutational burden, which may increase response to 
immunotherapy. Considering all of our preclinical data, in this study patients with metastatic 
TNBC will be randomized to carboplatin with or without atezolizumab. We hypothesize that 
the combination of carboplatin and atezolizumab will be superior to carboplatin alone in 
efficacy, as measured by median progression free survival. We anticipate that high levels of 
pretreatment TILs or the IM subtype will correlate with better outcomes. In addition we 
hypothesize that the mutational burden in non-synonymous coding mutations will be 
predictive of response to anti-PD-L1 therapy.   
PARTICIPANT SELECTION
Inclusion Criteria
•
Patients must provide informed written consent. 
•
Patients must be ≥18 years of age. 
•
ECOG performance status 0-1. 
•
Clinical stage IV (metastatic) ER, PR, HER2 negative  invasive mammary 
carcinoma, previously documented by histological analysis and that meets the 
following criteria:
o
HER2 negativity is defined as any of the following by local laboratory 
assessment: In-situ hybridization (ISH) non-amplified (ratio of HER2 to 
CEP17 < 2.0 or single probe average HER2 gene copy number < 4 
signals/cell), or IHC 0 or IHC 1+ (if more than one test result is available 
and not all results meet the inclusion criterion definition, all results 
should be discussed with the Protocol Chair to establish eligibility of the 
patient)


 
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o ER and PR negativity are defined as < 10% of cells expressing hormonal 
receptors via IHC analysis. 
 
• Willing to undergo biopsy of a metastatic lesion (in patients with reasonably 
accessible metastatic lesions such aschest wall, skin, subcutaneous tissue, lymph 
nodes, bones, peripheral lung, and liver metastases). 
 
• Measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension by RECIST criteria v1.1. 
 
• Zero or one prior chemotherapy regimens for metastatic disease.   
 
• No prior treatment with carboplatin in the metastatic setting.  Carboplatin in 
neoadjuvant/adjuvant setting may be allowed if prior treatment with carboplatin 
was completed at least one year prior to initiation of this study and after 
discussion with the study chair. 
 
• Patients must have adequate hematologic, hepatic, and renal function. All tests 
must be obtained less than 28 days from initiation of study drug (C1D1).  This 
includes: 
o ANC ≥1000/mm3  
o Platelet count ≥100,000/mm3  
o Calculated creatinine clearance > 30 mL/min using the Cockcroft and 
Gault Formula (see Section 10.2)  
o Bilirubin, SGOT, SGPT, alkaline phosphatase ≤ 2.5x upper limits of 
normal if no liver metastases present. Serum total bilirubin must be < 3x 
upper limits of normal for patients with Gilbert disease.  Total bilirubin, 
SGOT, SGPT ≤ 5x upper limits of normal if liver metastases present.  
• 
For patients who are not postmenopausal (women) or surgically sterile (absence of 
ovaries and/or uterus or vasectomy), agreement to remain abstinent or to use two 
adequate 
methods 
of 
contraception 
(e.g., 
condoms, 
diaphragm, 
vasectomy/vasectomized partner, tubal ligation), during the treatment period and for 
at least 30 days after the last dose of study treatment. Hormone based oral 
contraceptives are not allowed on study. Postmenopausal is defined as: 
o Age ≥ 55 years  
o Age ≤ 55 years and amenorrheic for 12 months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression; or follicle 
stimulating hormone and estradiol in the postmenopausal range  
 
• Subjects must complete all baseline screening assessments.  The biopsy may be 
obtained before or after the patient is deemed eligible by administrative review, 
but must be before administration of study drugs on cycle 1, day 1.  


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Exclusion Criteria
Patients who meet any of the following criteria will be excluded from registration: 
Cancer-Specific Exclusion Criteria 
•
Spinal cord compression not definitively treated with surgery and/or radiation, or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for > 2 weeks prior to randomization
  
•
Known CNS disease, except for treated asymptomatic CNS metastases, provided all 
of the following criteria are met: measurable disease outside the CNS, only 
supratentorial and cerebellar metastases are allowed (i.e., no metastases to midbrain, 
pons, medulla, or spinal cord), no evidence of progression or hemorrhage after 
completion of CNS-directed therapy, no ongoing requirement for dexamethasone as 
therapy for CNS disease (anticonvulsants at a stable dose are allowed), no 
stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to 
randomization.  
• Leptomeningeal disease 
• Uncontrolled tumor-related pain: patients requiring narcotic pain medication must be 
on a stable regimen at registration. Symptomatic lesions (e.g., bone metastases or 
metastases causing nerve impingement) amenable to palliative radiotherapy should 
be treated prior to randomization. Patients should be recovered from the effects of 
radiation. There is no required minimum recovery period. Asymptomatic metastatic 
lesions whose further growth would likely cause functional deficits or intractable 
pain (e.g., epidural metastasis that is not presently associated with spinal cord 
compression) should be considered for loco-regional therapy if appropriate prior to 
randomization.  
•
Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL 
or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring 
continued use of bisphosphonate therapy. Patients who are receiving denosumab 
must discontinue denosumab use and replace it with a bisphosphonate instead while 
on study.  Patients receiving a bisphosphonate for skeletal metastases are not 
excluded and can continue treatment.   
•
Malignancies other than TNBC within 5 years prior to randomization, with the 
exception of those with a negligible risk of metastasis or death and treated with 
expected curative outcome (such as adequately treated carcinoma in situ of the 
cervix or basal or squamous cell skin cancer). 
•
Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, hormonal therapy, biological therapy) other than the ones specified 


 
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in the protocol. Any standard or investigational drugs should be discontinued 2 
weeks prior to the first dose of study medication. 
 
General Medical Exclusion Criteria 
• Women only: pregnancy or lactation  
 
• Evidence of significant uncontrolled concomitant disease that in the opinion of the 
investigator could affect compliance with the protocol or interpretation of results, 
including significant liver disease (such as cirrhosis, uncontrolled major seizure 
disorder, or superior vena cava syndrome)  
 
• Significant cardiovascular disease, such as New York Heart Association (NYHA) 
cardiac disease (Class II or greater), myocardial infarction within 3 months prior to 
randomization, unstable arrhythmias, or unstable angina. Patients with a known left 
ventricular ejection fraction (LVEF) < 40% will be excluded. Patients with known 
coronary artery disease, congestive heart failure not meeting the above criteria, or 
LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of 
the treating physician, in consultation with a cardiologist if appropriate. 
  
• Severe infection requiring systemic treatment within 4 weeks prior to randomization, 
including but not limited to hospitalization for complications of infection, 
bacteremia, or severe pneumonia  
 
• Major surgical procedure within 4 weeks prior to randomization or anticipation of 
the need for a major surgical procedure during the course of the study other than for 
diagnosis. Placement of central venous access catheter(s) (e.g., port or similar) is not 
considered a major surgical procedure and is therefore permitted. 
  
• History of severe reactions (e.g. allergic, anaphylactic, or other hypersensitivity)  to 
chimeric or humanized antibodies or fusion proteins 
  
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary cells or any component of the atezolizumab formulation 
  
• History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a 
history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible for this study. Patients with controlled Type 1 
diabetes mellitus on a stable insulin regimen are eligible for this study. 
  


 
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• Prior allogeneic stem cell or solid organ transplantation 
  
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on screening chest CT 
scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
  
• Positive test for HIV (testing required prior to registration) 
  
• Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] 
test at screening) or hepatitis C 
 
• Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive antibody to hepatitis B core 
antigen [anti-HBc] 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. 
 
• Active tuberculosis 
  
• Receipt of a live, attenuated vaccine within 4 weeks prior to initiation of study drug 
(C1D1) or anticipation  that such a live, attenuated vaccine will be required during 
the study 
  
• Prior treatment with CD137 agonists, anti−PD-1, or anti−PD-L1 therapeutic 
antibody or pathway-targeting agents 
  
• Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is 
shorter) prior to randomization 
  
• Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis 
factor [TNF] agents) within 2 weeks prior to cycle 1, day 1, or anticipated 
requirement for systemic immunosuppressive medications during the trial.  Patients 
who have received acute, low-dose, systemic immunosuppressant medications (e.g., 
a one-time dose of dexamethasone for nausea) may be enrolled in the study. Patients 
on a stable low dose (< 10 mg) daily prednisone or equivalent are allowed on study. 
Patients with a history of allergic reaction to IV contrast requiring steroid pre-
treatment should have baseline and subsequent tumor assessments performed using 
MRI.  The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, 
and low-dose supplemental corticosteroids for adrenocortical insufficiency are 




 
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• VICC Patient Enrollment Form 
The Coordinating Center will then provide a subject ID number via email. 
3) Once the patient has been deemed eligible by the site, an email with the following 
documents must be sent to the Coordinating Center for eligibility review and patient 
enrollment 
: 
• Copy of the patient’s signed and dated Informed Consent, including 
documentation of the consent process. 
• HIPAA authorization form (if separate from the main consent form) 
• VICC Patient Enrollment Form 
• Eligibility supporting documents such as pathology reports, laboratory 
tests, etc. or EMR access. Note: all source documents should be de-
identified and screening/subject ID number added prior to sending. 
• Tissue Block Registration Form (see the Lab Manual) 
• Signed and completed Eligibility Checklist. To be eligible for registration to 
the study, the participant must meet each inclusion and exclusion criterion 
listed in the eligibility checklist.  
 
Note: All study documents should be received 24-48 hours prior to the patient’s 
anticipated start date. Same day treatment registrations will only be accepted with 
prior notice and discussion with the Coordinating Center. Please email the 
Coordinating Center if enrollment is needed sooner. 
Upon satisfactory review of eligibility documents submitted, the Coordinating Center will 
approve enrollment and issue a subject ID number if one was not issued at screening. Once 
registration/enrollment confirmation from Coordinating Center is received, the site may 
proceed with protocol procedures.  
Please contact the assigned Study Contact with any questions regarding this process. You 
can also reach out to your assigned CRA once the study is activated.  
 
The VICC Coordinating Center will assign sequence numbers to all patients in screening. 
Only patients deemed eligible will be randomized to a treatment arm. Sequence numbers 
will only be re-used if a patient screen fails and then re-screens.  The Coordinating Center 
will randomize eligible patients to carboplatin + atezolizumab or carboplatin alone.  
Following registration and randomization, eligible participants should begin protocol 
treatment within 1 week. Issues that would cause treatment delays should be discussed with 
the Protocol Chair. If a participant does not receive protocol therapy following 
randomization within allowed time period, the participant will become ineligible and will 
not be  enrolled on study. Such patients will have to undergo screening again to participate 
in the study in the future. Any requests for eligibility exceptions and/or deviations must be 
approved in writing by the Protocol Chair, as well as any committees required by local 




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STUDY CALENDARS
STUDY CALENDAR:  CARBOPLATIN  +/-  ATEZOLIZUMAB
Procedure
Screening
Day -28 to 
Day 1b 
Cycle 1 
(21-days)
Day 1a,b 
Additional cyclesa 
Day 1
End-of-
treatmentd
30 day 
(+/- 3 days) 
follow-upd
1, 2 & 3 year
follow-upn 
Informed consent
X
Inclusion/exclusion criteria 
X
Demographics/ medical history (SOC)
X
Physical exam/signs/symptomse (SOC)
X
X
X
X
Vital signs (including oxygen sat)c (SOC)
X
X
X
X
Single 12-lead ECG
X
ECOG Performance Status (SOC)
X
X
X
X
Blood 
collection
Clinical laboratory testsf (SOC)
X
X
X
X
Serum pregnancy test (SOC)f
X
TSH, free T3, T4g (After screening, 
atezolizumab arm only)
X 
X (every 4th cycle)
X 
PT (or INR) and PTT 
X
HIV, HBV, HCV serologyh
X
Circulating tumor DNA
X
X (Cycle 2 only)
X
Mononuclear Cell Collection
X
X (Cycle 2 only)
X
Tumor assessment CTs, bone scani (SOC)
X
X (every 3 cycles)
Archived tumor blocks/slidesj
X
Tumor biopsy (metastatic site)k
X
X
Carboplatin administration (IV) (SOC)
X
Xl
Atezolizumab administration (IV): if on 
atezolizumab arm
X 
X 
Concomitant medicationsm
X
X
X
Adverse events
X
X
X
X
Xn
Biopsy questionnaireo
X (cycle 2, day 1)
BRCA 1 and 2 testingp (SOC)
X


 
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AE = adverse event; BSA = body surface area; CX = Cycle X, where X is the cycle number; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; HbA1C = glycosylated hemoglobin; IMP = investigational medicinal product; INR = international normalized ratio; PT = prothrombin time; 
PTT = partial prothrombin time; SAE = serious adverse event  SOC = Standard of Care; all tests not indicated as SOC are research-related. 
a Evaluation assessments should be performed prior to administration of IMP unless otherwise indicated. Results should be reviewed by the Investigator prior to the 
administration of the next dose. All visits must occur within + 3 days from the scheduled date unless otherwise noted. Delays up to 7 days will be considered by 
Study Chair.  
b Screening must occur within 28days of dosing. The following procedures must be repeated at the day 1 visit if they were previously done >7 days prior to study treatment 
administration: Medical and cancer history, physical examination, weight measurement, vital signs, hematology, serum chemistry panel. Tumor assessments must be 
repeated at the baseline visit only if determined to be changed by clinical exam or other clinical observations. SOC procedures performed prior to consent but within the 
protocol defined screening window for each assessment can be used for study purposes. All research only procedures must be performed after the consent date.  
c See section 10.1.2 for vital sign information during atezolizumab infusion. 
d The 30-day follow-up assessments should be done 30 (±3 days) days after the last dose of study drugs.  30 day follow-up can be done by phone or by a clinic visit.  Any 
ongoing toxicities should be documented.  Any ongoing serious adverse events will be followed every 3 months (in person or by phone) until resolution. Any AEs or 
SAEs considered possibly or probably related to IMP that have not stabilized, returned to baseline, or are considered irreversible will continue to be monitored as per the 
protocol .   
e The physical examination will include measurements of height and weight at screening.  Weight will be measured on day 1 of each cycle and at the End-of-treatment 
visit.  Dosing changes are only required if the weight changes 10% or more. Physical examination will include examination of major body systems including neurologic, 
cardiac, respiratory, gastrointestinal, and skin. Clinically relevant signs and symptoms will be reported as AEs. 
f Clinical laboratory tests will include hematology and serum chemistry panel including white blood cell count, differential, hemoglobin, platelet count, sodium, potassium, 
chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium, AST (SGOT), ALT (SGPT), and total serum bilirubin, albumin, and total protein. Additional 
tests will be performed when clinically appropriate. In case of Grade 3 or higher AST/ALT, additional testing will be done weekly until recovery to baseline value (see 
protocol section 9.1.2 and 9.2.2.1).  Labs do not have to be repeated on cycle 1, day 1 if they were done up to 7 days prior to day 1.  For all other timepoints, labs can be 
performed up to 3 days prior to each timepoint indicated in the study calendar. Results from labs obtained on C1D1 (up to -7 days) must meet eligibility criteria.  At 
the start of each cycle, the ANC must be ≥1000/mm3 and the platelet count must be ≥ 80,000/mm3 (see section 9.2.1) for carboplatin to be administered.  
Atezolizumab may be administered if these criteria are not met at the discretion of the treating physician.   Serum pregnancy test does not need to be performed 
for patients > 55 years old, those who are known to be post-menopausal, or who have had a hysterectomy. 
g Thyroid function studies: see section 9.1.4 for abnormal results 
h All patients will be tested for HIV and HIV-positive patients will be excluded from the clinical trial. Please note that this result must be back by the time patient starts 
study so it is advised this be drawn prior to day 1 if the result may take some time to obtain.   HBV serology includes Hepatitis B surface antigen, anti-HBc, and anti-HBs.  
As above, it is advised the HBV serology be obtained in advance if results may be delayed.   Hepatitis B virus (HBV) DNA must be collected on or before Cycle 1, Day 1 
in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HBc.  
i Tumor assessment should be performed approximately every 3 cycles (up to -5 days) while on study treatment (i.e. on or up to 5 days prior to Day 1 of Cycles 4, 7, 10 
etc)  and at End-of-treatment visit if not obtained within the past 6 weeks.  Scans should consist of CT scan of the chest, abdomen, and pelvis and a bone scan at baseline.  
Of note, if the prior bone scan did not show metastases, it does not need to be repeated if the bone scan was obtained within 8 weeks of C1D1.  Subsequent scans should 
consist of CT chest, abdomen and pelvis, and bone scan if bone metastases were present on the baseline studies.  MRI is also an acceptable form of imaging.  At the end 
of treatment, all scans (baseline and through disease progression) should be sent on a CD to the Vanderbilt Cancer Imaging Support Laboratory for central review and 
assessment.  See Section 12.6 for details and address.   
j Archived tumor biopsy specimen:  Archived biopsy block (unstained slides) will be requested at the time of registration prior to initiation of treatment. See Section 11.1 
for details.  If archived tissue is not available, the VICC coordinating center should be contacted. 
k After signing consent, a fresh tumor biopsy from a metastatic site amenable to a reasonably safe biopsy will be obtained prior to day 1 and upon progression of disease 
(see Section 11).  The second biopsy will not be required for patients who are removed from study for reasons other than disease progression.  A patient who undergoes a 
research biopsy procedure for the purpose of this protocol,  in whom inadequate tissue is obtained, is not obligated to undergo a repeat biopsy.  


 
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l After cycle 6, at the discretion of the treating physician, carboplatin can be stopped and atezolizumab can be continued as a single agent. 
m The dose of steroids before each carboplatin injection should be recorded.  Prohibited medications (section 8) must be discontinued at least 7 days prior to initiation of 
study drug (C1D1). 
n 1, 2, and 3 year follow-up can be done by phone or chart review to document survival status, and if applicate, the date of death and cause of death. Surveillance for 
Adverse Events of Special Interest (AESIs) (see section 13.5.12) should be included. 
o Biopsy questionnaire should be filled out by the patient on C2D1. Form can be found in the packet of supplemental forms. 
BRCA 1/2 testing and results are not required prior to enrollment.  However, all patients in whom BRCA status is unknown must be referred for testing during the 
screening period.  Testing must be sent for analysis prior to C3D1, although results need not be available.  This is a standard procedure as per NCCN guidelines.  The 
VICC coordinating center should be contacted if a patient’s insurance will not pay for testing and an exception my be granted.   
 
 
 
 


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STUDY CALENDAR: ATEZOLIZUMAB (CROSSOVER)
Crossover therapy (atezolizumab) must begin no later than 21 days after the clinic visit at which progression is determined.  
Procedure
Cycle 1 a
(21-days)
Additional cyclesa
End-of-
treatmentc
30 day 
follow-upb
1, 2, 3 year 
follow-upi 
Day 1 
Day 1 
Physical exam/signs and symptomsc
X
X
X
Vital signs (including oxygen sat)
X
X
X
ECOG Performance Status
X
X
X
Blood
collection
Clinical laboratory testsd
X
X
X
TSH, free T3, T4e 
X 
X (every 4th
cycle)
Circulating tumor DNA
X
X (Cycle 2 only)
X
Mononuclear Cell Collection
X
X (Cycle 2 only)
X
Tumor assessment CTs, bone scanf
X (every 3 cycles)
Tumor biopsy (metastatic site) at crossoverg
X
Atezolizumab administration (IV)
X
X
Concomitant medicationsh
X
X
Adverse events
X
X
X
Xi
a
Evaluation assessments should be performed prior to administration of IMP unless otherwise indicated. Results should be reviewed by the Investigator prior to the 
administration of the next dose. All visits should occur within 3 days of scheduled visit unless otherwise noted.  Delays up to 7 days will be considered by study chair.
Crossover therapy (atezolizumab) must begin no later than 21 days after the clinic visit at which progression is determined. Exceptions must be discussed with the 
Protocol Chair.
b
The 30-day follow-up assessments should be done 30 (±3 days) days after the last dose of study drugs.  30 day follow-up can be done by phone or by a clinic visit.  Any 
ongoing toxicities should be documented.  Any ongoing serious adverse events will be followed every 3 months until resolution. Any AEs or SAEs considered possibly or 
probably related to IMP that have not stabilized, returned to baseline, or are considered irreversible will continue to be monitored as per the protocol.  
c
The physical examination will include measurements of height and weight at screening.  Weight will be measured on day 1 of each cycle and at the End-of-treatment 
visit. Physical examination will include examination of major body systems including neurologic, cardiac, respiratory, gastrointestinal, and skin. Clinically relevant signs 
and symptoms will be reported as AEs.
d
Clinical laboratory tests will include hematology and serum chemistry panel including white blood cell count, differential, hemoglobin, platelet count, sodium, potassium, 
chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium, AST (SGOT), ALT (SGPT), and total serum bilirubin, albumin, and total protein. Additional 
tests will be performed when clinically appropriate. In case of Grade 3 or higher abnormal AST/ALT, additional testing will be done weekly until recovery to baseline 
value.  Labs can be performed up to 3 days prior to each timepoint indicated in the study calendar.  
e
See section 9.1.4 for abnormal results


 
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f Tumor assessment should be performed approximately every 3 cycles (up to -5 days) while on study treatment and at End-of-treatment visit if not obtained within the past 
6 weeks.  Scans should consist of CT scan of the chest, abdomen, and pelvis and a bone scan at baseline.  Subsequent scans should consist of CT chest, abdomen and 
pelvis, and bone scan if bone metastases were present on the baseline studies.  At the end of treatment, all scans (baseline and through disease progression) should be sent 
on a CD to the Vanderbilt Cancer Imaging Support Laboratory for central review and assessment.  See Section 12 for details and address.   
g Tumor biopsies from a metastatic site will be obtained from patients prior to day 1 (this will be the biopsy obtained at disease progression on the carboplatin only arm).  
h The dose of steroids before each carboplatin injection should be recorded.  See protocol for concomitant medications that are prohibited (section 8). 
i 1, 2, and 3 year follow-up can be done by phone or chart review to document survival status, and if applicate, the date of death and cause of death.  Surveillance for 
Adverse Events of Special Interest (AESIs) – see section 13.5.12 should be included. 
 


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TREATMENT PLAN
Overview
This is an open-label phase II multi-institution trial that evaluates the safety profile and anti-
tumor activity of carboplatin +/- atezolizumab in patients with metastatic triple negative (ER 
negative, PR negative, HER2neu negative by IHC or FISH) breast cancer.  Patients will be 
treated with carboplatin AUC 6 IV on day 1 and atezolizumab 1200 mg IV on day 1 of a 21 day 
cycle or carboplatin AUC 6 IV on day 1 of a 21 day cycle For patients on the combination arm, 
atezolizumab is to be administered prior to carboplatin.  For patients on the combination arm, 
carboplatin can be stopped after cycle 6 and atezolizumab can be continued as a single-agent at 
the discretion of the treating physician.
Concomitant Treatment and Supportive Care Guidelines
8.2.1
Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding Cycle 1, day 1 and the treatment 
discontinuation visit. 
Neulasta (pegfilgrastim) may be given prophylactically per treating investigator discretion.  
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor 
antagonist, as per standard practice.  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.  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 prophylactic or therapeutic anticoagulation therapy (such as low-molecular-
weight heparin or warfarin at a stable dose level), or other allowed maintenance therapy can
continue their use.  Males and females of reproductive potential should use highly effective 
means of contraception. 


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8.2.2
Excluded Therapy 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited.  This includes but is not limited to the 
following:
•
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational agents, 
or herbal therapy  
–
After Cycle 1, certain forms of radiotherapy may be considered for pain palliation if 
patients are deriving benefit (e.g., treatment of known bony metastases); 
atezolizumab administration may be suspended during radiotherapy. 
Patients must discontinue: 
•
Traditional herbal medicines 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); this agent could potentially alter the activity 
and the safety of atezolizumab.  Bisphophonates may be used in lieu of RANKL 
inhibitors. 
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 during the course of treatment at the discretion of 
the treating physician after discussion with the Protocol Chair.  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. 
Assessments during Treatment
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted. Please 
see the Study Calendar at the beginning of this protocol for the schedule of treatment period 
assessments. 
Cross-over post-progression
Patients who are randomized to carboplatin alone can cross over to receive atezolizumab upon 
disease progression based on clinical progression or radiographic progression.  Patients who 
are randomized to carboplatin alone and who discontinue carboplatin for toxicity cannot cross
over to receive single agent atezolizumab.  There may be exceptions to this based on 
discussion with the Protocol Chair.  However, patients on the carboplatin + atezolizumab arm
can continue to receive single agent atezolizumab if they discontinue carboplatin due to 
toxicity. Patients who cross over to receive atezolizumab will follow the assessments and 
procedures as outlined in the study calendar. The duration of each cycle will continue to be 21 


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days and the cycle numbers will "reset" to 1 and will be followed by the “X” suffix (e.g., 
Cycles 1X, 2X, etc.). Crossover therapy (atezolizumab) must begin no later than 21 days after 
the clinic visit at which progression is determined. 
Patients must have labs and procedures performed as outlined in the cross-over study calendar 
and must meet the values as described in the Inclusion Criteria, prior to receiving 
atezolizumab based on assessments and procedures performed within 21 days prior to Day 1 
of Cycle 1X.  Labs and procedures not included in the cross-over study calendar do not have 
to be repeated.  Patients must also agree to a tumor biopsy, as outlined in the eligibility 
criteria, prior to initiating atezolizumab. Patients will receive crossover treatment until 
progression, intolerable toxicity, or elective withdrawal from the study. Patients who cross
over will be evaluated with radiologic assessments every 3 cycles until disease progression.
Duration of Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
until one of criteria in Section 8.7 applies.
Duration of Follow-Up 
Participants will be followed for 30 days for toxicity after the final dose of study drug. The 30 
day follow-up can be done by phone or through a clinic visit. Patients who at the treatment 
completion visit have an ongoing serious adverse event or an adverse event leading to 
treatment discontinuation will be followed every 3 months until the event resolves, the 
investigator assesses the event as stable, or the patient is lost to follow-up. Participants will 
also be followed for disease progression by chart review yearly for 3 years from the date of 
last study drug administration.  If the patient is no longer coming to the institution for care, 
then the patient may be called as needed for follow-up. 
Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed below apply. All patients 
who initiate protocol treatment will be included in the overall evaluation of response (intent-
to-treat analysis). All reasons for discontinuation of therapy should be documented clearly in 
the medical record. 
If a subject discontinues or withdraws from the study, every reasonable attempt will be made 
to get a tissue/tumor biopsy, along with blood, at the end of treatment, if the subject is able 
and willing. 
   Patients may be withdrawn from the study if they experience any of the following: 
• Disease progression, per investigator assessment by RECIST (or irRECIST for 
atezolizumab arm)
• Intolerable toxicity to atezolizumab or carboplatin.  Patients assigned to carboplatin + 
atezolizumab who experience toxicity to atezolizumab or carboplatin can continue on 
study with single agent carboplatin or atezolizumab, respectively, at the discretion of the 
treating physician.  Patients will be followed for disease progression and should continue 
radiologic assessments every 3 cycles as per the study.  
     Other reasons for patient discontinuation may include, but are not limited to, the following:


 
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• Non-compliance with the study protocol, including, but not limited to not attending the 
majority of scheduled visits. The Protocol Chair will determine when non-compliance 
should lead to removal from study. Note: The patients will still be included  in the overall 
evaluation of response (intent-to-treat analysis). 
• Patient personal decision. The reason for discontinuation from the study must be 
documented. The patients will be included in the overall evaluation of response (intent-
to-treat analysis) if any protocol therapy was administered prior to withdrawal. 
• If the patient becomes pregnant 
• Patient is lost to follow-up 
• Study is terminated for any reason 
 
 
The investigator has the right to discontinue a patient from the study for any medical condition  
that the investigator determines may jeopardize the patient’s safety if he or she continues in the 
study; for reasons of noncompliance (e.g., missed doses, visits); or if the investigator determines 
it is in the best interest of the patient.  The Protocol Chair should be notified in such cases. 
 


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EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
Anticipated Toxicities of atezolizumab (Atezolizumab) and 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, should be used to evaluate for a possible immunogenic etiology, when clinically 
indicated. Although most immune-mediated adverse events observed with atezolizumab 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-mediated toxicities may require 
acute management with topical corticosteroids, systemic corticosteroids, or other
immunosuppressive agents. 
The investigator should consider the benefitrisk balance for a given patient prior to further 
administration of atezolizumab. In patients who have met the criteria for permanent 
iscontinuation, resumption of atezolizumab may be considered if the patient is deriving benefit 
and has fully recovered from the immune-mediated event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. Guidelines for managing patients who 
experience selected adverse events are provided in the following sections. Management 
guidelines are presented by adverse event severity based on the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) and in some instances 
may vary by CTCAE version (4.0 vs. 
5.0). 
Management Guidelines for Renal Events
 Event
    Management
Renal 
event, 
Grade 1
• Continue atezolizumab.
• Monitor kidney function, including creatinine, 
closely until values resolve to within normal limits or 
to baseline values.
Renal 
event, 
Grade 2
• Withhold atezolizumab for up to 12 weeks after event 
onset. a
• Refer patient to renal specialist.
• Initiate treatment with corticosteroids 
equivalent to 1-2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab.
b
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair. c


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Renal 
event, 
Grade 3 or 
4 
• Permanently discontinue atezolizumab and contact
Study Chair. 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids 
equivalent to 1-2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper corticosteroids
over 
≥1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of ≤10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event. Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Study Chair. 
General Guidelines for Dosage Modification and Treatment Interruption or 
Discontinuation
Atezolizumab treatment will be given as long as the patient continues to experience clinical 
benefit in the opinion of the investigator until the earlier of unacceptable toxicity, 
symptomatic deterioration attributed to disease progression, or any of the other reasons for 
treatment discontinuation listed above. 
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 
the protocol. 
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 Protocol Chair. 
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. 


 
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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.  
9.2.1 Gastrointestinal Toxicity 
Immune-mediated colitis has been associated with the administration of atezolizumab. 
Patients should be advised to inform the investigator if any diarrhea occurs, even if it is mild. 
If the event is of significant duration or magnitude, or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased CRP or platelet count or bandemia), it is 
recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy with 
three to five specimens for standard paraffin block be performed.  If possible, one or two 
biopsy specimens should be snap frozen and stored.     
Treatment may be restarted following the resolution of colitis.  In addition, if the patient is 
being managed with corticosteroids, treatment should not be restarted until the steroids have 
been tapered down to a prednisone dose ≤ 10 mg/day.  Patients who resume treatment should 
be monitored closely for signs of renewed diarrhea.   
 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for > 7 days. 
• Monitor closely. 
Diarrhea or 
colitis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist > 5 days, initiate 
treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair. c 


 
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Diarrhea or 
colitis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory 
biopsy. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day 
oral prednisone or equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair. c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Study Chair. 
9.2.2 Hepatotoxicity 
Immune-mediated hepatitis has been associated with the administration of atezolizumab. 
While in this study, patients presenting with right upper-quadrant abdominal pain felt by the 
investigator to be possibly related to study treatment and/or unexplained nausea or vomiting 
should have LFTs performed immediately, and LFTs (AST/ALT) should be reviewed before 
administration of the next dose of study drug. 
In the presence of LFT abnormalities, 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 suspected. 
Patients with LFT abnormalities should be managed according to the guidelines in table 
below. 
Dose Modification Guidelines for Hepatic Events 
Event 
Management 
Hepatic 
event, Grade 
1 
CTCAE v4.0 guidelines 
• Continue atezolizumab. 
• 
Monitor LFTs until values resolve to within normal limits. 


 
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CTCAE v5.0 guidelines 
• Continue atezolizumab. 
• Monitor LFTs until values resolve to within normal limits 
or to baseline values. 
Hepatic 
event, Grade 
2 
All events: 
• Monitor LFTs more frequently until return to baseline values. 
Events of > 5 days’ duration: 
• Withhold atezolizumab for up to 12 weeks after event onset. 
aa 
• Initiate treatment with corticosteroids equivalent 
to 1-2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair. c 
Event 
Management 
Hepatic 
event, Grade 
3 or 4 
• Permanently discontinue atezolizumab and contact Study 
Chair. c 
• Consider patient referral to gastrointestinal specialist 
for evaluation and liver biopsy to establish etiology of 
hepatic injury. 
• Initiate treatment with corticosteroids equivalent 
to 1-2 mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over 
≥ 1 month. 
LFT = liver function tests. CTCAE =Common Terminology Criteria for Adverse Events 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 
mg/day oral prednisone. The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Study Chair. 
 


 
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9.2.3 Dermatologic Toxicity 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of 
rash were mild in severity and self-limited, with or without pruritus. 
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should be 
performed unless contraindicated.  Low-grade rash and pruritus irAEs have been treated with 
symptomatic therapy (e.g., antihistamines).  Topical or parenteral corticosteroids may be 
required for more severe symptoms. 
Dermatologic toxicity and rash should be managed according to the guidelines in table below. 
Dose Modification Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, 
Grade 1 
• Continue atezolizumab. 
• Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g. antihistamines). 
Dermatologic event, 
Grade 2 
• Continue atezolizumab. 
• Consider patient referral to dermatologist. 
• Initiate treatment with topical corticosteroids. 
• Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
• Initiate treatment with higher-potency topical corticosteroids if 
event does not improve. 
Dermatologic event, 
Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to dermatologist. 
• Initiate treatment with corticosteroids equivalent to 10mg/day 
oral prednisone, increasing dose to 1-2 mg/kg/day if event does 
not improve within 48-72 hours. 
• If event resolves to Grade 1 or better, resume atezolizumab.b 
• If event does not resolved to Grade 1 or better while withholding 
atezolizumab, permanently discontinue ateazolizumab and 
contact Study Chair.c 
Dermatologic event, 
Grade 4 
• Permanently discontinue atezolizumab and contact Study Chair.c 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Stud Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 
mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event. Patients can be re- challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Study Chair. 


 
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9.2.4 Endocrine Toxicity 
Hypothyroidism has been associated with the administration of atezolizumab. 
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental status 
changes, or constipation should be investigated for the presence of thyroid, pituitary, or 
adrenal endocrinopathies, as well as for hyponatremia or hyperkalemia.  An endocrinologist 
should be consulted if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free T4 levels should be obtained to determine whether thyroid abnormalities are present.  
TSH, prolactin, and a morning cortisol level will help to differentiate primary adrenal 
insufficiency from primary pituitary insufficiency. 
Hypothyroidism should be managed according to the guidelines in the table below. 
Management Guidelines for Endocrine Events 
 
 
 
 
 
 
 
 
 
 
 
  
MRI=magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
         Note: Management guidelines are presented by adverse event severity based on 
NCI CTCAE and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
 Event 
Management 
Asymptomatic 
hypothyroidism 
• Continue atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
Symptomatic 
hypothyroidism 
• Withhold atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled 
and thyroid function is improving. 
Asymptomatic 
hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• Continue atezolizumab. 
• Monitor TSH every 4 weeks. 
TSH < 0.1 mU/L: 
• Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled 
and thyroid function is improving. 
• Permanently discontinue atezolizumab and contact Study 
Chair for life-threatening immune-related 
hyperthyroidism. c 


 
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investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the 
equivalent of ≤10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Study Chair. 
 
Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Symptomatic 
adrenal 
insufficiency, 
Grade 2-4 
• Withhold atezolizumab for up to 12 weeks after event onset. 
a 
• Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day IV methylprednisolone and convert 
to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• If event resolves to Grade 1 or better and patient is stable 
on replacement therapy, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better or patient is 
not stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Study Chair. C 
Hyperglycemia, 
Grade 1 or 2 
• Continue atezolizumab. 
• Investigate for diabetes. If patient has Type 1 diabetes, 
treat as a Grade 3 event. If patient does not have Type 1 
diabetes, treat as per institutional guidelines. 
• Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Resume atezolizumab when symptoms resolve and 
glucose levels are stable. 
Hypophysitis 
(pan-
hypopituitarism), 
Grade 2 or 3 
• Withhold atezolizumab for up to 12 weeks after event onset. 
a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day IV methylprednisolone and convert 
to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 


 
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MRI=magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Study Chair. 
 
Management Guidelines for Endocrine Events (cont.) 
 
Event 
Management 
Hypophysitis 
(pan-
hypopituitarism), 
Grade 4 
• Permanently discontinue atezolizumab and contact Study 
Chair. c 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day IV methylprednisolone and convert 
to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the  Study Chair. 
 
 
9.2.5 Pulmonary Toxicity 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab and have primarily been observed in 
patients with underlying NSCLC. 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 


 
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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: 
• 
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 the table below. 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
 
  Event 
                    Management 
Pulmonary 
event, Grade 1 
• Continue atezolizumab and monitor closely. 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
Pulmonary 
event, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to pulmonary and infectious disease 
specialists and consider bronchoscopy or BAL. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair. c 
• For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
• Permanently discontinue atezolizumab and contact Study Chair. 
c 
• Bronchoscopy or BAL is recommended. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
BAL = bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) 


 
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to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Study Chair 
 
9.2.6 Potential Pancreatic Toxicity 
Management Guidelines for Pancreatic Events, Including Pancreatitis 
 
Event 
Management 
Amylase and/or 
lipase elevation, 
Grade 2 
Amylase and/or lipase > 1.5-2.0 x ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., >3 weeks), consider 
treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0-5.0 
xULN: 
• Treat as a Grade 3 event. 
Amylase and/or 
lipase elevation, 
Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event 
onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with 
corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, 
resume atezolizumab. b 
• If event does not resolve to Grade 1 or better 
while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Study 
Chair. c 
• For recurrent events, permanently discontinue 
atezolizumab and contact Study Chair. c 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 


 
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10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Study Chair. 


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


 
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9.2.7 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. 
Potential eye toxicity should be managed according to the guidelines in the table below. 
Management Guidelines for Ocular Events 
 
   Event 
          Management 
Ocular 
event, 
Grade 1 
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular 
event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair. c 
Ocular 
event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact 
Study Chair. c 
• Refer patient to ophthalmologist. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤ 10 mg/day oral prednisone. The acceptable length of the extended period of time must be agreed 
upon by the investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent 
of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Study 
Chair. 
 


 
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9.2.8 Immune-mediated Myocarditis 
Immune-mediated myocarditis has been associated with the administration of atezolizumab. 
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to,  laboratory (e.g., BNP [B-
Natriuretic Peptide]) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope. 
 
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), ischemic 
events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of 
malignancy. 
 
All patients with possible myocarditis should be urgently evaluated by performing cardiac enzyme 
assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 
 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines provided below. 
 
Management Guidelines for Immune-Mediated Myocarditis 
Event 
Management 
Immune-mediated 
myocarditis, Grade 1 
(CTCAE v4.0 
guidelines only) 
CTCAE v4.0 guidelines 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines. 
Immune-mediated 
myocarditis,  
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onseta 
and contact Study Chair. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional  guidelines and 
consider antiarrhythmic drugs, temporary pacemaker, 
ECMO, or VAD as appropriate. 
• Consider treatment with corticosteroids equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 1-2 
mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab.b  
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair.c  


 
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Event 
Management 
Immune-mediated 
myocarditis, Grade 1 
(CTCAE v4.0 
guidelines only) 
CTCAE v4.0 guidelines 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines. 
Immune-mediated 
myocarditis, Grade 3-4 
• Permanently discontinue atezolizumab and contact Study 
Chair.c  
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or 
VAD as appropriate. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 1-2 
mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper  corticosteroids 
over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
 
a Atezolizumab may be withheld for longer period of time (i.e., >12 weeks after event onset) to allow for corticosteroids 
(if       
  initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period 
of    
  time must be agreed upon by the investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone  
 before ateolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the  
 immune-mediated event. Patients can be re-challenged with atezolizumab only after approval has been documented by 
both  
 the investigator (or an appropriate delegate) and the Study Chair. 
 
9.2.9      Infusion-related reactions and Cytokine-Release Syndrome 
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab. However, patients 
who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) with 
atezolizumab may receive premedication with antihistamines, antipyretics, and/or analgesics (e.g., 
acetaminophen) for subsequent infusions. Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
IRRs are known to occur with the administration of monoclonal antibodies and have been reported 
with atezolizumab. These reactions, which are thought to be due to release of cytokines and/or other 


 
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chemical mediators, occur within 24 hours of atezolizumab administration and are generally mild to 
moderate in severity.  
 
CRS is defined as a supraphysiologic response following administration of any immune therapy that 
results in activation or engagement of endogenous or infused T cells and/or other immune effector 
cells. Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al. 2019). CRS has been 
well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell engager 
antibody therapies but has also been reported with immunotherapies that target PD-1 or PD-L1 
(Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of the 
challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in the table below. 
 
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome 
 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
• If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. Administer 
symptomatic treatment, c including maintenance of IV fluids for 
hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in 
patients with significant symptoms and/or comorbidities, onsider 
managing as per Grade 2. 
• For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygen d 
by nasal cannula or 
blow-by 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely (in 
the ICU, if appropriate). Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ 
toxicities as per institutional practice. 


 
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• Rule out other inflammatory conditions that can mimic CRS 
• (e.g., sepsis). If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS. 
• Consider IV corticosteroids (e.g., methylprednisolone 2 
mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. e 
• Consider hospitalization until complete resolution of symptoms. 
If no improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Study Chair. 
• If symptoms resolve to Grade 1 or better for 3 consecutive days, 
the next dose of atezolizumab may be administered. For 
subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 3 
consecutive days, contact Study Chair. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table. Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.) 
 
Event 
      Management 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia requiring 
• Permanently discontinue atezolizumab and contact 
Study Chair. f 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus and 
vasopressor as needed. 
• Monitor cardiopulmonary and other organ function 
closely; monitoring in the ICU is recommended. 
Administer IV fluids as clinically indicated, and 
manage constitutional symptoms and organ toxicities 


 
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high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or venturi 
mask 
 
as per institutional practice. 
• Rule out other inflammatory conditions that can 
mimic CRS (e.g., sepsis). If no improvement within 
24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
• Administer IV corticosteroids (e.g., 
methylprednisolone 2 mg/kg/day or dexamethasone 
10 mg every 6 hours). 
• Consider anti-cytokine therapy. e 
• Hospitalize patient until complete resolution of 
symptoms. If no improvement within 24 hours, 
manage as per Grade 4, that is, admit patient to ICU 
and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as 
needed; for patients who are refractory to anti-
cytokine therapy, experimental treatments may be 
considered at the discretion of 
the investigator and in consultation with the Study 
Chair. 
Grade 4 a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
• Permanently discontinue atezolizumab and contact 
Study Chair. f 
• Administer symptomatic treatment. c 
• Admit patient to ICU and initiate hemodynamic 
monitoring, mechanical ventilation, and/or IV fluids 
and vasopressors as 
• needed. Monitor other organ function closely. 
Manage 
• constitutional symptoms and organ toxicities as per 
institutional practice. 
• Rule out other inflammatory conditions that can 
mimic CRS 
• (e.g., sepsis). If no improvement within 24 hours, 
initiate workup and assess for signs and symptoms of 
HLH or MAS. 
• Administer IV corticosteroids (e.g., 
methylprednisolone 2 mg/kg/day or dexamethasone 
10 mg every 6 hours). 
• Consider anti-cytokine therapy. e For patients who 
are refractory to anti-cytokine therapy, experimental 
treatments g may be considered at the discretion of 
the investigator and in consultation with the Study 
Chair 
• Hospitalize patient until complete resolution of 
symptoms 


 
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ASTCT =American Society for Transplantation and Cellular Therapy; BiPAP =bi-level 
positive airway pressure; CAR =chimeric antigen receptor; CPAP =continuous positive 
airway pressure; CRS =cytokine-release syndrome; CTCAE =Common Terminology 
Criteria for Adverse Events; eCRF =electronic Case Report Form; HLH =hemophagocytic 
lymphohistiocytosis; ICU =intensive care unit; IRR =infusion-related reaction; 
MAS =macrophage activation syndrome; NCCN =National Cancer Comprehensive 
Network; NCI =National Cancer Institute. 
Note: The management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cell-related toxicities (Version 2.2019).  
a Grading system for management guidelines is based on ASTCT consensus grading for 
CRS. NCI CTCAE (version as specified in the protocol) should be used when reporting 
severity of IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event 
eCRF. Organ toxicities associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients 
who develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, 
fever is no longer required when subsequently determining event severity (grade). In 
this case, the grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as 
oxygen delivered at  > 6 L/min. 
e There are case reports where anti-cytokine therapy has been used for treatment of 
CRS with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), 
but data are limited, and the role of such treatment in the setting of antibody-associated 
CRS has not been established. 
f Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Study Chair. For subsequent infusions, administer 
oral premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor 
closely for IRRs and/or CRS. Premedication with corticosteroids and extending the 
infusion time may also be considered after consulting the Study Chair and 
considering the benefit-risk ratio. 
        g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.  
9.2.10 Neurologic Disorders 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies. Management guidelines for neurologic disorders are provided below. 
 
 
 
 
 


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Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated neuropathy,
Grade 1
Continue atezolizumab.
Investigate etiology.
Immune-mediated neuropathy,
Grade 2
Withhold atezolizumab for up to 12 weeks after 
event onset.a
Investigate etiology.
Initiate treatment as per institutional guidelines.
If event resolves to Grade 1 or better, resume 
atezolizumab.b
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently 
discontinue atezolizumab and contact Study Chair.
Immune-mediated neuropathy,
Grade 3 or 4 
Permanently discontinue atezolizumab and contact 
Study Chair.c
Initiate treatment as per institutional guidelines.
Myasthenia gravis and Guillain-Barré 
syndrome (any grade)
Permanently discontinue atezolizumab and contact 
Study Chair.c
Refer patient to neurologist. 
Initiate treatment as per institutional guidelines.
Consider initiation of corticosteroids equivalent to 
1-2 mg/kg/day oral or IV prednisone.
a Atezolizumab may be withheld for longer period of time (i.e., >12 weeks after event onset) to allow for corticosteroids 
(if      
  initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period 
of   
  time must be agreed upon by the investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone 
before ateolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event. Patients can be re-challenged with atezolizumab only after approval has been documented by 
both 
the investigator (or an appropriate delegate) and the Study Chair. 
9.2.11 Immune-mediated Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not limited to, 
headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed 
level of consciousness.


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Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from potential 
meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression of 
malignancy, or secondary to a paraneoplastic process.
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If 
deemed safe by the treating physician, a lumbar puncture should be performed and a neurologist 
should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines below. 
Management Guidelines for Immune-Mediated Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades
Permanently discontinue atezolizumab and contact 
Study Chair. 
Refer patient to neurologist.
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day IV methylprednisolone and convert 
to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
If event resolves to Grade 1 or better, taper 
corticosteroids over ≥1 month. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully  
  recovered from the immune-mediated event. Patients can be re-challenged with atezolizumab only 
after 
 approval has been documented by both investigator (or an appropriate delegate) and the Study 
Chair.
9.2.12 Immune-Mediated Myositis
Immune-mediated myositis has been associated with the administration of atezolizumab.
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are amongst the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatine-kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle-biopsy. Patients with signs and 
symptoms of myositis, in the absence of an identified alternate etiology, should be treated according 
to the guidelines below. 
Management guidelines for Immune-Mediated Myositis 


 
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Event 
Management 
Immune-mediated 
myositis,  
Grade 1 
• Continue atezolizumab 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines 
Immune-mediated 
myositis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onseta 
and contact Study Chair. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines . 
• Consider treatment with corticosteroid equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 1-2 
mg/kg/day oral prednisone or equivalent upon improvement. 
• If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab.b  
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair. 
Immune-mediated 
myositis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onseta 
and contact Study Chair. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines . 
• Respiratory support may be required in more severe cases . 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day IV methylprednisolone or higher-dose bolus if 
patient is severely compromised (e.g. cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1-2 mg/kg/day oral prednisolone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab.b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Study Chair.c 
• For recurrent events, treat as a Grade 4 event. 


 
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Event 
Management 
Immune-mediated 
myositis, Grade 4 
• Permanently discontinue atezolizumab and contact Study 
Chair.c  
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. Respiratory 
support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day IV methylprednisolone or higher-dose bolus if 
patient is severely compromised (e.g. cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limiting 
mobility); convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab may be withheld for longer period of time (i.e., >12 weeks after event onset) to allow for corticosteroids 
(if       
  initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period 
of    
  time must be agreed upon by the investigator and the Study Chair. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone  
 before ateolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the  
 immune-mediated event. Patients can be re-challenged with atezolizumab only after approval has been documented by 
both  
 the investigator (or an appropriate delegate) and the Study Chair. 
 
9.2.13 Severe Cutaneous Adverse Reactions (SCARs) 
 
Severe Cutaneous Adverse Reactions (SCARs) are rare but potentially fatal skin toxicities 
frequently associated with drug use including immune checkpoint inhibitor as a class. A 
comprehensive analysis of the data available across the TECENTRIQ® (atezolizumab) program has 
identified cases of SCARs following atezolizumab use.  SCARs were previously a potential risk of 
atezolizumab, and have been monitored continuously.  
Based upon the totality of evidence in a recent analysis, SCARs are now  considered to be an 
identified risk for atezolizumab.   
SCARs are a heterogeneous group of immunologically mediated skin eruptions. 
Although rare, these events are potentially fatal, and mainly constituted by erythema 
multiforme, acute generalised exanthematous pustulosis, Stevens-Johnson syndrome 
(SJS), Toxic Epidermal Necrolysis (TEN) and drug rash with eosinophilia and systemic 
symptoms (DRESS). 
As per epidemiology data, the incidence of SJS and TEN ranges from 0.8 to 5.3 and 1.2 to 6 per 
million person-years respectively (19, 20) 


 
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A cumulative analysis of the company safety database across the TECENTRIQ 
(atezolizumab) program identified at total of 99 cases of SCARs, of which 36 were 
confirmed by histopathology or specialist diagnosis, in patients who have received 
TECENTRIQ (atezolizumab). Approximately 23,654 clinical trial patients and 106,316 
patients in post-marketing settings have been exposed to TECENTRIQ (atezolizumab) 
as of 17 May 2020. The incidence rates of SCAR, regardless of severity, from pooled 
atezolizumab monotherapy (N=3178) and combination therapy (N=4371) companysponsored 
clinical studies were 0.7% and 0.6% respectively. One fatal case of TEN was 
reported in a 77 year old female patient who received atezolizumab monotherapy. 
 
Management guidelines for  SCARs 
 
● For suspected SCARs the patients should be referred to a dermatologist for 
further diagnosis and management 
● Atezolizumab should be withheld for patients with suspected SJS or TEN 
● Atezolizumab should be permanently withdrawn for any grade confirmed SJS or 
TEN 
● Caution should be used when considering the use of atezolizumab in a patient 
who has previously experienced a severe or life-threatening skin adverse 
reaction on prior treatment with other immune-stimulatory anticancer agents 
9.2.14 Overdose 
In clinical trials with atezolizumab, doses of up to 20 mg/kg have been administered. 
The standard fixed dose of 1200 mg is equivalent to 15 mg/kg in a typical patient. No 
dose-limiting toxicities were observed at the 20 mg/kg dose level and the incidence and 
intensity of AEs reported have not been shown to be dependent on dose. A maximum 
tolerated dose has not been established. 
 
Atezolizumab is supplied in vials containing the fixed 1200 mg dose of drug substance, 
which minimizes the chance of overdose. Because the dose per patient is not based on 
weight or body surface area, and no dose calculation is required, the risk of overdose 
due to medication errors is minimal. 
The data available to date suggest that the potential for harm from overdose is very low. 
 
 
 
 
 
 
 
 
 
 
 


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Anticipated Toxicities of Carboplatin and Dose Modifications 
Carboplatin is known to cause bone marrow suppression including myelosuppression,
anemia, and thrombocytopenia. Carboplatin-based chemotherapy is considered to be
moderately emetogenic. Patients will be monitored for carboplatin-related adverse
events.
9.3.1
Hematologic Toxicity
At the start of each cycle if the patient is receiving carboplatin, the ANC must be ≥1000/mm3
and the platelet count must be ≥ 80,000/mm3. Platelets must be > 100,000 for study entry. 
Growth factors may be used in accordance with American Society of Clinical Oncology (ASCO) 
and National Comprehensive Cancer Network (NCCN) guidelines (Smith et al. 2006; NCCN 2012). 
Upon recovery, dose adjustments at the start of a subsequent cycle will be made on the basis of the 
lowest platelet and
neutrophil values from the previous cycle (see Table below).
9.3.1.1
Carboplatin Dose Modification for Hematologic Toxicities
Toxicity
Carboplatin Dose
ANC <500/mm3 and platelets ≥ 50,000/mm3
Decrease AUC by 1
Platelets < 50,000/mm3, regardless of ANC
Decrease AUC by 1
Platelets < 50,000/mm3 with Grade ≥ 2 
bleeding, regardless of ANC
Decrease AUC by 2
ANC < 1000/mm3 plus fever of ≥ 38.5°C
Decrease AUC by 1
All dose reductions for the first episode of neutropenic fever or thrombocytopenia (platelet count < 
25,000 or < 50,000 with bleeding or that requires transfusion) are permanent. If a second episode of 
neutropenic fever or thrombocytopenia requiring dose reduction occurs, the dose of carboplatin will 
be reduced according to physician judgment and local standard practice. Colony-stimulating factors, 
such as granulocyte colony-stimulating factor, may be used instead of dose reduction for 
neutropenic fever or Grade 4 neutropenia, according to the local standard practice and ASCO 
guideline. Patients who require a third dose reduction will immediately discontinue chemotherapy. 
In the event that dose adjustments are needed for both ANC and platelets, patients are to receive the 
lower dose. 
For Grade 3 ANC toxicity ( ANC <1000-500/ml), carboplatin should be withheld until the patient 
recovers completely or to Grade 1 toxicity. The treatment should then be resumed at 50% dose 
(permanent dose reduction). If recovery to Grade 1 toxicity does not occur within 3 weeks, the 
patient’s chemotherapy will be discontinued.  
Treatment with carboplatin can be delayed for up to 3 weeks until the Day 1 ANC is ≥1000/mm3
and the platelet count is ≥ 80,000/mm3. However, if the counts have not recovered in 3 weeks, the 
patient’s chemotherapy will be dose-reduced, held until adequate neutrophil recovery, or 


 
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discontinued, according to physician judgment and local standard practice. If chemotherapy is held 
longer than 42 days, all study treatment should be discontinued. 
 
Investigators should be vigilant and alert to early and overt signs of myelosuppression, infection, or 
febrile neutropenia so that these complications can be promptly and appropriately managed. Patients 
should be made aware of these signs and encouraged to seek medical attention at the earliest 
opportunity. If chemotherapy must be withheld because of hematologic toxicity, full blood counts 
(including differential WBC) should be obtained weekly until the counts reach the lower limits for 
treatment as outlined. The treatment schedule will then proceed in the usual sequence. 
 
No dose reductions will be made for anemia. Patients should be supported per the treating 
physician’s institution’s guidelines. 
 
9.3.2 Non-Hematologic Toxicity 
For Grade 3 or 4 non-hematologic toxicities, treatment should be delayed until resolution to less 
than or equal to the patient’s baseline value. Dose reductions at the start of the subsequent cycle will 
be made on the basis of non-hematologic toxicities from the dose administered in the preceding 
cycle. The table below provides the relevant dose adjustments for non-hematologic toxicities. 
 
9.3.2.1 Carboplatin Dose Modification on the Basis of Non-Hematologic 
 
Toxicities in the Preceding Cycle 
 
Toxicity 
Adjusted Carboplatin Dosea 
Diarrhea   
Grade 3 or 4b:  100% of dose 
Oral mucositis  
Grade 3 or 4:     Decrease AUC by 1 
Nausea/Vomiting  
Grade 3 or 4:     Decrease AUC by 1 
Neurotoxicity (motor or sensory) 
Grade 2: 100% of dose 
Grade 3 or 4:  Decrease AUC by 1 
Transaminase Elevation 
Grade 3:    Decrease AUC by 1 
Grade 4:    discontinue 
Other 
Grade 3 or 4:  Decrease AUC by 1 
AUCarea under the concentration curve. 
a If deemed appropriate by the treating physician, adjust carboplatin dose to the specified 
percentage of the previous AUC. 
b Or any grade of diarrhea requiring hospitalization. 
 
Nausea and/or vomiting should be controlled with adequate anti-emetics. If Grade 3 or 4 
nausea/vomiting occurs in spite of anti-emetics, the dose should be reduced by 25% for the next 
course. If tolerated, the dose should be increased back to 100% as soon as possible. 
 


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If, on Day 1 of any treatment cycle, the patient has grade 2 oral mucositis, the treatment can be 
withheld until the oral mucositis is cleared. If the oral mucositis has not cleared in 3 weeks, the 
patient’s chemotherapy will be discontinued. If acute Grade 3 oral mucositis occurs at any time, the 
dose should be given at a 75% dose when the oral mucositis is completely cleared. This is a permanent 
dose reduction. 
9.3.3
Special Considerations
•
For toxicities which are considered by the treating investigator unlikely to develop into 
serious or life–threatening events (e.g. alopecia, altered taste etc.), treatment may be 
continued at the same dose without reduction or interruption. 
•
The treating investigator may reduce a subject’s dose for a toxicity of any grade/duration 
where s/he believes it to be in the best interests of the subject.
•
Any consideration to modification of the above dose modification guidelines should be 
discussed with the Principal Investigator for approval or disapproval in advance. 


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DRUG FORMULATION/STORAGE/SUPPLY
Atezolizumab (MPDL3280A) 
Atezolizumab is an investigational agent and will be supplied free-of-charge from Genentech. 
10.1.1 Formulation
The atezolizumab drug product is typically provided in a single-use 15 mL or 20 mL USP/Ph. Eur. 
Type 1 glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution 
intended for IV administration.  Other excipients of the atezolizumab drug product include histidine 
acetate, sucrose and polysorbate 20. 
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 or the diluent; 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.  Once prepared, atezolizumab 
can be stored for up to 8 hours at room temperature. 
For further details, see the atezolizumab Investigator’s Brochure.
10.1.2 Dosage, Administration, and Storage 
The dose level of atezolizumab to be tested in this study is 1200 mg (equivalent to an average body 
weight−based dose of 15 mg/kg) administered by IV infusion every 3 weeks (21 [± 2] days).  
Atezolizumab will be delivered in infusion bags with IV infusion lines that have product contacting 
surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 µm in-line filters (filter membrane of 
polyethersulfone [PES]).  No incompatibilities have been observed between atezolizumab and PVC 
or polyolefin infusion materials (bags or infusion lines).  
Administration of atezolizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
The initial dose of atezolizumab will be delivered over 60 (± 15) minutes.  If the first infusion is 
tolerated without infusion-associated AEs, the second infusion may be delivered over 30 (± 10) 
minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 
30 (± 10) minutes.  For the first infusion, the patient’s vital signs (heart rate, 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.  Atezolizumab should be administered prior to carboplatin.


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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 
infusion-related reactions (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 the appendices. 
Guidelines for dosage modification, treatment interruption, or discontinuation and the management 
of specific adverse events are provided in the protocol.
Carboplatin 
Carboplatin is commercially available.  Carboplatin should be administered intravenously according 
to local practice.  Carboplatin should be administered after atezolizumab if the patient is 
receving atezolizumab.  
The carboplatin dose will be calculated using the Cockcroft and Gault formula.   
For the purposes of this protocol, the GFR is considered to be equivalent to the 
creatinine clearance (CrCl). The CrCl is calculated by institutional guidelines or by the
method of Cockcroft and Gault (1976) using the following formula: 
     (140−age) (wt)   (× 0.85 if female)
CrCl =            72 × Scr           
Where: CrCl = creatinine clearance in mL/min
age = patient's age in years
wt = patient’s weight in kg
Scr = serum creatinine in mg/dL
If a patient’s GFR is estimated on the basis of serum creatinine measurements by the
isotope dilution mass spectroscopy method, the U.S. Food and Drug Administration 
(FDA) recommends that physicians consider capping the dose of carboplatin for desired 


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exposure (AUC) to avoid potential toxicity caused by overdosing.  
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for
patients with normal renal function. No higher estimated GFR values should be used. 
For a target AUC = 6, the maximum dose is 6 × 150 = 900 mg. 
For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg. 
For a target AUC = 4, the maximum dose is 4 × 150 = 600 mg. 
See the FDA’s communication regarding carboplatin dosing for more details at 
http://www fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974 htm
Drug Accountability
Accountability for the drug at all study sites is the responsibility of the site Principal Investigator 
and designated Pharmacy representative. The investigator will ensure that the investigational drug is 
used only in accordance with this protocol. Drug accountability records indicating the drug’s 
delivery date to the site, inventory at the site, use by each patient, and destruction locally will be 
maintained by the clinical site.  Atezolizumab should be destroyed locally as per local policy.  
Accountability records will include dates, quantities, lot numbers, expiration dates, and patient 
numbers.  These records should be sent to Genentech for filing.  


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exposure (AUC) to avoid potential toxicity caused by overdosing.  
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for
patients with normal renal function. No higher estimated GFR values should be used. 
For a target AUC = 6, the maximum dose is 6 × 150 = 900 mg. 
For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg. 
For a target AUC = 4, the maximum dose is 4 × 150 = 600 mg. 
See the FDA’s communication regarding carboplatin dosing for more details at 
http://www fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm228974 htm
Drug Accountability
Accountability for the drug at all study sites is the responsibility of the site Principal Investigator 
and designated Pharmacy representative. The investigator will ensure that the investigational drug is 
used only in accordance with this protocol. Drug accountability records indicating the drug’s 
delivery date to the site, inventory at the site, use by each patient, and destruction locally will be 
maintained by the clinical site.  Atezolizumab should be destroyed locally as per local policy.  
Accountability records will include dates, quantities, lot numbers, expiration dates, and patient 
numbers.  These records should be sent to Genentech for filing.  


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CORRELATIVE/SPECIAL STUDIES
Archived Tissue Samples
Metastatic tissue is the preferred sample; however, if the remaining tissue is insufficient to fit the 
requirements below, tissue from the patient’s primary tumor is acceptable.
Formalin-fixed paraffin embedded tissue blocks from the patient’s metastatic lesion collected for 
diagnostic and therapeutic purposes is requested for all patients enrolled in the study at the time of 
registration. They will be returned within 8 weeks (or earlier if requested); tissue taken from these 
blocks will not be returned.    
In case the participating institutions are not allowed to release clinical paraffin embedded blocks 
from prior surgeries/biopsies, ideally we will need the following cut in this order: 
A. If sending prior metastatic biopsy (performed pre-enrollment for diagnostic purposes) then 
send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, 
levels 2-5 to Genentech for PDL-1 IHC) 
2. Six (6) 10 µm unstained sections on non-charged slides (Vanderbilt DNA/RNA isolation)
3. Twelve (12) 4 µm unstained slides on charged slides (level 1 and 12 to be H&E stained upon 
receipt)
If remaining tissue is insufficient for the complete request, please send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate 
assessment, levels 2-5 to Genentech for PDL-1 IHC)
2. Two 5 x 10 μm peels in a DNAse-free/RNAse-free tube 
If remaining tissue is very limited, please send:
Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, 
levels 2,3,4,5 to Genentech for PDL-1 IHC)
B.  If sending primary tumor send: 
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, 
levels 2-5 to Genentech for PDL-1 IHC)
2. Six (6) 10 µm unstained sections on non-charged slides (Vanderbilt DNA/RNA isolation)
3. Two (2) 4 µm unstained slides on charged slides (last will be H&E stained upon receipt)
If remaining tissue is insufficient for the complete request, please send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate 
assessment, levels 2-5 to Genentech for PDL-1 IHC)
If remaining tissue is very limited, please send:


 
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Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, 
levels 2,3,4,5 to Genentech for PDL-1 IHC) 
After removing all stray tissue from the area, the microtome blade and surrounding area should be 
wiped with 70% ETOH before starting to section the block and between patients to prevent 
contamination with extraneous tissue. 
 
All formalin-fixed paraffin embedded tissue and/or slides should be sent with a cold pack to 
avoid melting that could damage tissue analysis. 
 
Once a patient meets all other eligibility, and registers for the study, collection of tissue from a 
metastatic site, if reasonably safe, is also a requirement for entry to this study.  Pre-trial and 
post-progression biopsies should be collected. Research tissue blocks prepared from these 
metastatic biopsies will not be returned.  All patients must have a biopsy of a metastatic site (if 
reasonably safe) at the end of treatment if the patient is removed for disease progression, or if 
on the carboplatin only arm and crossing over to atezolizumab.  
11.1.1 Guidelines for Tissue Acquisition on Biopsies of Metastatic Lesions 
Tissue specimens, when feasible, will be collected from recurrent or metastatic lesions using 
standard institutional procedures. The amount of tissue collected will follow the guidelines listed 
below. If a patient has more than one site of disease, only one site needs to be biopsied, and the site 
is left to the discretion of the patient and the treating physician. If a patient is undergoing resection 
of a lesion for clinical reasons (i.e. wedge resection of a new lung lesion for confirmation of 
diagnosis or re-testing of hormone receptor or HER2 status; or, resection of a chest wall lesion; or, 
resection of a lymph node), then the patient may opt to have a portion of that tissue (roughly 
equivalent to the goal amount of tissue listed in the guidelines above, i.e. the equivalent of two 5-
mm punch biopsies of the skin, or 3-6 18-gauge core biopsies) stored for research at the time of the 
procedure. 
 
Listed below are the goal amounts of tissue for patients who undergo core biopsy or punch biopsy, 
or who have either ascites fluid or pleural fluid accessible for collection. Please note that the below 
are guidelines for the amount of tissue to be obtained at the baseline biopsy, and are not meant to 
replace clinical judgment at the time the procedure is performed. Less than the goal quantity of 
tissue is accepted for each type of biopsy, and will be left to the clinical judgment of the physician 
performing the procedure. 
• Breast: A goal of 3-6 core biopsy specimens will be obtained using standard institutional 
guidelines for a diagnostic core biopsy of a breast mass  
• Skin/chest wall: A goal of one to two 5-mm punch biops(ies)  
• Lymph node: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge 
needle  
• Liver: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle  
• Lung: A goal of 3 core biopsy specimens will be obtained using an 18-gauge needle.  Due to 
the risk of pneumothorax associated with core needle biopsies of lung nodules, peripheral 
lesions should be carefully selected.    


 
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• Bone: Because the yield of malignant tissue from bone biopsies tends to be relatively low, if 
a patient has another accessible site of disease (i.e. skin, lymph node, liver), that site should 
be biopsied preferentially. If bone is the only biopsy-accessible site, then a goal of 3-6 core 
biopsy specimens will be obtained using an 18-gauge needle.  
• Pleural Fluid (known or suspected to be due to malignancy): This should only be used if 
there is no other site noted above that can be biopsied and this should be discussed with the 
VICC coordinating center.  A goal of 500 cc of pleural fluid will be obtained with a standard 
thoracentesis procedure, with or without image guidance, according to the clinical judgment 
of the treating physician and clinician performing the procedure. Less than the goal amount 
is acceptable, and should be based upon the clinical judgment of the Investigator and the 
clinician performing the procedure. If more than the goal amount of fluid is obtained, then 
the entire specimen (with the exception of what is needed for clinical purposes, if 
applicable) will be stored at Vanderbilt.  
• Ascites fluid: This should only be used if there is no other site noted above that can be 
biopsied and this should be verified by the VICC coordinating center. A goal of 500 cc of 
ascites fluid will be obtained with a standard paracentesis procedure, with or without image 
guidance, according to the clinical judgment of the treating physician and clinician 
performing the procedure. Less than the goal amount is acceptable, and should be based 
upon the clinical judgment of the Investigator and the clinician performing the procedure.  
11.1.2 Instructions on fresh tissue specimen handling 
*Tissue obtained at Vanderbilt will be handled differently as it does not need to be shipped.  Please 
see the Vanderbilt lab manual for handing if obtaining a biopsy at Vanderbilt* 
• First core biopsy should be suspended in 10% buffered formalin. 
• Second core biopsy should be suspended in 5-10 volumes “RNAlater” solution*  
• Third core biopsy should be suspended in 10% buffered formalin. 
• Fourth core biopsy should be suspended in 5-10 volumes “RNAlater” solution* 
• Fifth core biopsy should be suspended in 10% buffered formalin 
*RNAlater kits will be provided.  1 core should be placed in one 1.5ml specimen tube. All samples 
should be shipped immediately, according to the lab manual. 
 
For patients in whom a core biopsy is not possible and who thus undergo fine needle aspiration 
(FNA), 3 passes should be collected.  
• First pass should be evacuated and rinsed directly into 10% buffered formalin  
• Second pass should be evacuated and rinsed directly into 5-10 volumes “RNAlater” 
solution*  
• Last pass should be evacuated and rinsed directly into 10% buffered formalin. 


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Blood/plasma collection
Streck Cell-Free DNA BCT kits will be provided for circulating tumor DNA.  One vial of whole 
blood should be collected in a Cell-Free DNA BCT tube (Streck tube).  Fill the tube completely.  
Remove the tube from the adapter and immediately mix by gentle inversion 8 to 10 times.  
Collection times are: cycle 1/day 1, cycle 2/day 1, and end-of-treatment, see study calendar.  
Tube should be packed and shipped according to the lab manual and sent immediately (within 24 
hours) to VICC at the address provided. Do not freeze specimens collected in Streck tube.
Tissue specimen and blood/plasma labeling and documentation 
Label each collection containers with Patient ID sequence number/code letter, site and location of 
biopsy, date and time. 
If sample comes in contact with contaminate, make note in information section of paperwork.
Enter time core biopsy was collected on paperwork. 
Outside sites should ship specimens along with Tissue Registration Form as directed in the lab 
manual.   
The specimens will be logged in as a consented specimen and available for molecular pathology 
studies.  
Peripheral Blood Mononuclear Cell Collection
Blood will be collected on Cycle 1/ Day 1, Cycle 2/ Day 1, and at the end-of-treatment (also Cycle 
1/Day 1, Cycle 2/Day 1, and end-of-treatment for those crossing over to carboplatin + 
atezolizumab).
BD Vacutainer® CPT™ Mononuclear Cell Preparation Tubes are included to collect blood. One 
vial of whole blood should be collected in a BD Vacutainer® CPT™ (CPT tube).   
Whole blood is drawn directly into the CPT™ using standard phlebotomy techniques and in 
accordance with the lab manual. Samples should be shipped according to the lab manaul.  
Genetic Testing
Participants will be given information as part of the informed consent process that samples will be 
used for research tests that will include genetic studies and testing.  The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may or 
may not already be aware.  In the case that an incidental genetic finding is identified, the Protocol 
Chair of this project will be notified.  The possible decisions for handling incidental findings may 
include notification of the participant (and provider); recommendation for genetic counseling, 
which may or may not include genetic testing (e.g., if the finding was not done in a CLIA certified 
laboratory); or, neither.  In general, a member of the participant’s treating team will be given the 
information to help with notification.  In all cases, the current policy of the Vanderbilt and 


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local/participating site IRB, as applicable, will be followed and any additional approvals that may 
be required prior to participant notification will be secured in advance.
Specimen Banking
Any leftover study tissue or blood samples may be stored for future research studies.  The subjects 
will consent to the future use of samples in the consent form for the study, which includes the 
transfer of specimens to Genentech for product development.  The study PI and collaborators have 
approval by the TBCRC, which has custodial oversight of all biospecimens collected as part of a 
TBCRC trial, to address the research questions described in the protocol document.  All future use 
as part of residual or repository specimens collected in this trial for purposes not prospectively 
defined will require review and approval by the TBCRC according to its established policies, 
whether the specimens are stored in a central site or at a local institution or in a virtual repository.  
Secondary use of bio-specimens for new endpoints must be submitted to the TBCRC Central Office 
for possible review by the TBCRC Correlative Science Review Committee.
Biopsy Questionnaire
A questionnaire will be given to each participant to complete at cycle 2, day 1.  This questionnaire 
is designed to assess the impact of the biopsy on the patient’s quality of life and overall experience 
with the study.  
Imaging Correlative Study
Evaluation of muscle mass, muscle attenuation, and adipose mass will be determined using baseline 
abdominal CT scans collected for central review. A transverse cut at the L3 level will be extracted, 
as muscle and adipose area at this level is linearly related to whole body mass16.  SliceOmatic 
software (version 5, Tomovision) will be used to process images, providing a highly accurate 
estimation of cross-sectional skeletal muscle area and muscle attenuation with high inter-observer 
reliability17.  The software is semi-automated and will be run by two independent investigators, with 
a subset of images read by both investigators to determine a coefficient of variation.  Muscle mass, 
muscle attenuation, and adiposity will be evaluated both as continuous and categorical variables 
(LMM: yes/no, LMA: yes/no, adipose: tertiles). LMM is defined as skeletal muscle index (SMI, 
lean muscle area/height, cm2/m2) less than 41 and LMA will be defined as average muscle density 
less than 25 HU, or less than 33 HU if the patient is overweight/obese by BMI.  These cut-points are 
based on previously determined thresholds associated with reduced survival in patients with 
metastatic solid tumors18.  We will also explore whether there are alternate cut-points predictive of 
survival in this particular population based on optimal stratification.  Total adiposity will be defined 
as the sum of visceral adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue 
and evaluated by tertiles. 
MEASUREMENT OF EFFECT
For the purposes of this study, patients should be re-evaluated for response after every 3 cycles. 
Response and progression will be evaluated in this study using the international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1).   
Any evaluable or measurable disease must be documented at screening and reassessed at each 
subsequent tumor evaluation.  For PFS analysis, patients will be considered to have disease 
progression if their tumor assseessment shows PD by RECIST.  However, as conventional response 


 
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criteria may not adequately assess the activity of immunotherapeutic agents because radiographic 
progressive disease does not necessarily reflect therapeutic failure, for patients on the carboplatin + 
atezolizumab arm, if a patient is found to have disease progression by RECIST, at the discretion of 
the treating physician, the patient may remain on study and managed by irRECIST (see section 
12.5) provided he/she meets the following criteria: 
• Evidence of clinical benefit as assessed by the investigator. 
• Absence of symptoms and signs (including worsening laboratory values [e.g., new or 
worsening hypercalcemia]) indicating clinically significant progression of disase 
• No decline in ECOG performance status that can be attributed to disease progression 
• Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) and 
no other signs/symptoms of unequivocal disease progression.  This includes tumor 
progression that cannot be managed by protocol-allowed medical interventions (ie., pain 
secondary to disease or unmanageable ascites, etc.), as determined by the investigator after 
an integrated review of radiographic data and clinical status. 
Scans should be repeated after 6 weeks, and if progression is confirmed by irRECIST, the patient 
should be removed from study.  If scans by irRECIST show the patient to not have disease 
progression, the patient may remain on study after discussion with the Protocol Chair.  Patients on 
the carboplatin alone arm who show progression by RECIST must either be removed from study or 
cross over to receive atezolizumab. 
Conventional response criteria may not adequately assess the activity of immunotherapeutic agents 
because radiographic progressive disease does not necessarily reflect therapeutic failure. In Phase Ia 
Study PCD4989g, several patients who progressed per RECIST v1.1 continued on atezolizumab 
treatment and subsequently demonstrated durable anti-tumor activity. Of the 21 patients with TNBC 
in the study who were evaluable for response 3 patients with IC2/3 TNBC showed evidence of 
target lesion shrinkage after an initial increase in tumor burden or following the appearance of new 
lesions. These patients likely experienced pseudoprogression or delayed response (Emens et al. 
2014). Additionally, in some responding patients with NSCLC in Study PCD4989g, the growth of 
known lesions or the appearance of new radiographic lesions were shown to contain immune cells 
and no viable cancer cells on biopsy (Gettinger et al. 2013). The expected rate of pseudoprogression 
or delayed anti-tumor immunity when atezolizumab is administered in combination with carboplatin 
is not known. On the other hand, radiographic progression when carboplatin is given alone is likely 
to represent true disease progression requiring a change in therapy.  Although the primary endpoint 
measures of efficacy (PFS) will be performed using RECIST v1.1, noncomparative analyses of 
these measures will be performed with use of immune-modified RECIST for patients who continue 
treatment beyond radiographic progression. The immune-modified RECIST allows the 
incorporation of new lesions into the calculation of total tumor burden after baseline.  


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Definitions
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with atezolizumab and/or carboplatin. 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.) 
Disease Parameters
12.2.1 Measurable
12.2.1.1 Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:
•
10mm by CT scan (CT scan slice thickness no greater than 5 mm).
•
10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
•
20mm by chest X-ray. 
12.2.1.2 Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed.  
12.2.2 Non-measurable
All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes 
with ≥10 to <15mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion,
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
12.2.3 Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment:
12.2.3.1 Bone lesions:
•
Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions.
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as


 
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CTor MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
12.2.3.2 Cystic lesions: 
• 
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. 
 Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated active tumor. 
• 
Progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
12.2.4 Specifications by methods of measurements 
12.2.4.1 Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 21 days before the beginning of the treatment. 
12.2.4.2 Method of assessment 
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than 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 
and ≥10mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by colour photography including a ruler to estimate the size of the 
lesion is suggested. When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed 
at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
 


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CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Guidelines have defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5mm or less. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
MRI is also acceptable in certain situations (e.g. for bodyscans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.
PET/CT may not be used for RECIST or irRECIST measurements.
Endoscopy, laparoscopy: The utilisation of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers: tumor markers alone cannot be used to assess objective  tumor response. If 
markers are initially above the upper normal limit, however, they must normalise for a patient 
to be considered in complete response.  
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign  tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.
Response Criteria
12.3.1 Target lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).


 
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12.3.2 Evaluation of Target Lesions 
12.3.2.1 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. 
12.3.2.2 Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
12.3.2.3 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression). 
12.3.2.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 
12.3.3 Non-target lesions:  
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. 
In addition, it is possible to record multiple nontarget lesions involving the same organ as a single 
item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
12.3.4 Evaluation of Non-Target Lesions 
12.3.4.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of  
tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis). 
12.3.4.2 Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits. 
12.3.4.3 Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: 
the appearance of one or more new lesions is also considered progression). 
12.3.5 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment.   
 
Table 3: Time point response 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non CR/Non PD 
No 
PR 


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CR
Not evaluated
No
PR
PR
Non PD or not all evaluated
No
PR
SD
Non PD or not all evaluated
No
SD
Not all 
evaluated
Non PD
No
NE
PD
Any
Yes or 
no
PD
Any
PD
Yes or 
no
PD
Any
Any
Yes
PD
CR= completeresponse, PR= partial response, PD= progressive disease, SD= stable disease, NE= 
not evaluable. 
* 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. 
Duration of Response
12.4.1 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 recurrent disease is objectively documented.
12.4.2 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.
Immune-Related Response Criteria
12.5.1 Introduction 
Increasing clinical experience indicates that traditional response criteria (e.g., Response Evaluation 
Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization [WHO]) may 
not be sufficient to characterize fully activity in the new era of target therapies and/or biologics.  In 
studies with cytokines, cancer vaccines, and monoclonal antibodies, complete response, partial 
response, or stable disease has been shown to occur after an increase in tumor burden as 
characterized by progressive disease by traditional response criteria.  Therefore, conventional 
response criteria may not adequately assess the activity of immunotherapeutic agents because 
progressive disease (by initial radiographic evaluation) does not necessarily reflect therapeutic 


 
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failure.  Long-term effect on the target disease must also be captured.  The immune-related response 
criteria (irRC) are criteria that attempt to do that by enhancing characterization of new response 
patterns that have been observed with immunotherapeutic agents (i.e., ipilimumab).  (Note:  The 
irRC only index and measurable new lesions are taken into account.) 
12.5.2 Glossary 
Term 
Definition 
SPD 
sum of the products of the two largest perpendicular diameters 
Tumor burden 
SPDindex lesions + SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irBOR 
immune-related best overall response 
12.5.3 Baseline Assessment Using irRC 
Step 1. Identify the index lesions (five lesions per organ, up to ten visceral lesions and 
five cutaneous lesions).   
Step 2. Calculate the SPD of all of these index lesions: 
SPD = 
(Largest diameter of lesion i) × (Second largest diameter of lesion i). 
12.5.4 Post-baseline Assessments Using irRC 
Step 1. Calculate the SPD of the index lesions.   
Step 2. Identify new, measurable lesions (≥ 5 × 5 mm; up to five new lesions per organ:  five new 
cutaneous lesions and ten visceral lesions).   
Step 3. Calculate the SPD of the new, measurable lesions. 
Step 4. Calculate the tumor burden: 
Tumor burden =  SPDindex lesions + SPDnew, measurable lesions 
Step 5. Calculate the change in tumor burden relative to baseline and the change in tumor burden 
relative to nadir. 
Step 6. Derive the overall response using the table below. 
Overall Response 
Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or not, and 
no new lesions) confirmed by a repeat, consecutive assessment ≥ 4 
weeks from the date first documented 
∑
i




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ASSESSMENT OF SAFETY ADVERSE EVENT REPORTING 
Safety assessments will consist of monitoring and reporting AEs and SAEs, all events of death, and 
any study-specific issue of concern.
General
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events version 5.0 (CTCAE v.5.0) that is available at http://ctep.cancer.gov/reporting//ctc.html.  
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections.  
Adverse events experienced by participants will be collected and reported from initiation of study 
medication, throughout the study, and within 30 days of the last dose of study medication. 
Participants who experience an ongoing adverse event related to a study procedure and/or study 
medication beyond 30 days will continue to be contacted by a member of the study team until the 
event is resolved, stabilized, or determined to be irreversible by the participating investigator.  
Participants should be instructed to report any serious post-study event(s) that might reasonably be 
related to participation in this study. The investigator should notify the IRB and any other 
applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to the 
study.  
Risks Associated with atezolizumab
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase 
the risk of immune-related AEs, specifically the induction or enhancement of autoimmune 
conditions.  AEs with potentially immune-related causes, including rash, hypothyroidism, 
hepatitis/transaminitis, colitis, myositis, and myasthenia gravis, have been observed in Study 
PCD4989g.  
Although most immune-related AEs observed with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid potential major 
complications (Di Giacomo et al. 2010).  
A more detailed safety profile of atezolizumab is provided in the atezolizumab Investigator’s 
Brochure. 


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Safety Parameters and Definitions
13.3.1 Adverse Event (AE) 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
This includes the following: 
•
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE reporting 
period 
•
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations)
•
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention
•
Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period 
•
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
13.3.2 Serious adverse event (SAE)
An AE should be classified as an SAE if any of the following criteria are met: 
•
It results in death (i.e., the AE actually causes or leads to death)
•
It is life threatening (i.e., the AE, in the view of the investigator, places the patient at immediate 
risk of death.  It does not include an AE that, had it occurred in a more severe form, might have 
caused death.) 
•
It requires or prolongs inpatient hospitalization
•
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions) 
•
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the IMP
•
It is considered a significant medical event by the investigator based on medical judgment (e.g., 
may jeopardize the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
•
If a patient is hospitalized to undergo a medical or surgical procedure as a result of an AE, the 
event responsible for the procedure, not the procedure itself, should be reported as the SAE.  
For example, if a patient is hospitalized to undergo coronary bypass surgery, record the heart 
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Events not considered to be serious adverse events (and therefore do not require reporting) are 
hospitalizations or prolonged hospitalizations for:
•
routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition, or for elective procedures 
•
diagnostic, elective or pre-planned surgical procedures/treatment for a pre-existing condition that 
did not worsen 
•
efficacy measurement for the study
•
emergency outpatient treatment for an event not fulfilling the serious criteria outlined above and 
not resulting in inpatient admission
•
respite care
Assessment of Adverse Events
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
atezolizumab (, and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes
There is a plausible temporal relationship between the onset of the AE and administration of 
atezolizumab or carboplatin, and the AE cannot be readily explained by the patient’s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to atezolizumab or carboplatin; and/or the AE abates or resolves upon discontinuation 
of atezolizumab or carboplatin or dose reduction and, if applicable, reappears upon re-
challenge.
No
Evidence exists that the AE has an etiology other than atezolizumab or carboplatin (e.g., 
pre-existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to atezolizumab
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
13.4.1 Expectedness 
•
Expected:  Expected adverse events are those that have been previously identified 
as resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk. 
•
Unexpected: An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, 
the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk 


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•
For patients receiving combination therapy, causality will be assessed individually 
for each protocol-mandated therapy. 
13.4.2 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
•
Definite – The AE is clearly related to the study treatment. 
•
Probable – The AE is likely related to the study treatment.
•
Possible – The AE may be related to the study treatment.  
•
Unlikely - The AE is doubtfully related to the study treatment.
•
Unrelated - The AE is clearly NOT related to the study treatment.
Procedures for Eliciting, Recording, and Reporting Adverse Events
Eliciting Adverse Events  
A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. 
Examples of non-directive questions include: 
·  “How have you felt since your last clinical visit?”
·  “Have you had any new or changed health problems since you were last here?” 
13.5.1 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  Avoid 
colloquialisms and abbreviations. All adverse events will be captured on the appropriate study-
specific case report forms (CRFs). 
13.5.2 Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report the 
information that is currently available.  If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
13.5.3 Deaths
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, report “Unexplained 
Death.”  Deaths that occur during the protocol-specified adverse event reporting period that are 
attributed by the investigator solely to progression of disease should be recorded only in the study 
CRF.


 
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13.5.4 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be reported as medical and surgical history.  A pre-existing medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study.  When reporting such events, it is important to 
convey the concept that the pre-existing condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
13.5.5 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. 
13.5.6 Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0 Update current versions) will be 
used for assessing adverse event severity. Below Table should be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age‑appropriate instrumental activities of daily living a 


 
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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 v.5.0 which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a.      Instrumental activities of daily living refer to preparing meals, shopping for groceries 
or clothes, using the telephone, managing money, etc. 
b.      Examples of self-care activities of daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as performed by 
patients who are not bedridden. 
c.      If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event 
d.      Grade 4 and 5 events must be reported as serious adverse events 
 
 
Case Transmission Verification of Single Case Reports 
 
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech via the Investigator emailing Genentech a 
Quarterly line-listing documenting single case reports sent by the Investigator to Genentech in the 
preceding time period. 
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 and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-case 


 
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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 the Investigator 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 
 
13.5.7 Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the investigator if 
they become pregnant during the study or within 90 days after the last dose of study drug.  A 
Pregnancy Report should be submitted to the VICC Coordinating Center (i.e., no more than 
24 hours after learning of the pregnancy).  Pregnancy should not be recorded as an adverse event.  
The investigator should discontinue study drug and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any SAEs associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported appropriately (see SAE reporting section 13.5.11.2). 
13.5.8 Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the ICF to immediately inform the investigator if their 
partner becomes pregnant during the study or within 90 days after completing treatment with 
atezolizumab.  Male patients who received study treatment should not attempt to father a child until 
after this 90 day period. A Pregnancy Report should be completed by the investigator immediately 
(i.e., no more than 24 hours after learning of the pregnancy) and submitted to the VICC 
Coordinating Center for processing.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study drug.  The 
pregnant partner will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  Once the authorization has been signed, the 
investigator will update the Pregnancy Report with additional information on the course and 
outcome of the pregnancy.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or obstetrician. 
13.5.9 Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsors consider spontaneous 
abortions to be medically significant events), recorded as such , and reported to the Vanderbilt 
Coordinating Center (i.e., no more than 24 hours after learning of the event). 


 
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13.5.10Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a male 
patient exposed to study drug should be classified as an SAE, recorded as such,  and reported to the 
Vanderbilt Coordinating Center  (i.e., no more than 24 hours after learning of the event). 
13.5.11  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. 
 
Adverse events of special interest (AESIs) are defined as a potential safety problem, identified as a 
result of safety monitoring of the IMP. 
The following AEs are considered of special interest  for Atezolizumab and must be reported to the 
Coordinating Center expeditiously (following the SAE reporting procedure), irrespective of 
regulatory seriousness criteria:  
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, hyperthyroidism or  hypophysitis  
● 
Hepatitis, including AST or ALT >10x ULN 
• 
Systemic lupus erythematosus 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
and meningoencephalitis 
• 
Events suggestive of hypersensitivity, cytokine release syndrome, influenza-like illness, 
systemic inflammatory response syndrome, or infusion-reaction syndromes 
• 
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)  
 




 
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Email: kaiseraugst.global impcomplaint management@roche.com 
 
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs/SAEs, 
AESIs, Special Situation Reports (including pregnancy reports) and Product Complaints (with or 
without an AE) originating from the study. 
These single case reports will be exchanged between the parties as outlined below so that regulatory 
obligations are met. 
 
 
13.5.13  Serious Adverse Events 
All serious adverse events, regardless of causality to study drug, occurring after the patient’s first 
dose of study treatment will be reported to the Principal Investigator and/or the Study Coordinator 
at each institution, and also to the Coordinating Center. Serious adverse events that occur during 
screening do not require reporting unless they are due to a screening procedure (eg biopsy).  
 
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports (including 
pregnancy occurring in the partner of a male study subject), other Special Situation Reports and 
Product Complaints (with or without an AE), where the patient has been exposed to the Genentech 
Product, will be sent on a MedWatch form or CIOMS I form or on Genentech approved reporting 
forms to Genentech Drug Safety. Transmission of these reports (initial and follow-up) will be either 
electronically or by fax and within the timelines specified below: 
·      SADRs 
Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen 
(15) calendar days of the awareness date. 
  
·      Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty 
(30) calendar days of the awareness date. 
  
·    AESIs 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date. 
  
·       Special Situation Reports 
Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined 
herein, any reports of pregnancy (including pregnancy occurring in the partner of a male study 
subject), where the fetus may have been exposed to the Product, shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. Pregnancies will be followed up until the 
outcome of the pregnancy is known, whenever possible, based upon due diligence taken to obtain 
the follow-up information. 
  




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Coordinating Center within 1 business day after the treating institution becomes aware of the event, 
according to SAE reporting instructions in protocol Section 13.5.11.2. 
13.5.15  Institutional Review Board
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent or the protocol, these 
modifications will be provided to the IRB, as will the report of the adverse event.  
Coordinating Center Reporting Procedures
        Reporting to Regulatory Authorities, Ethics Committees and Investigators 
Genentech as the Marketing Authorization Holder will be responsible for the reporting of individual 
case safety reports from the study to the regulatory authority in compliance with applicable 
regulations. 
The Investigator as the Sponsor of the Study, will be responsible for the expedited reporting of 
safety reports originating from the study to the EMA through Eudravigilance Clinical Trial Module 
(EVCTM), where applicable.
The Investigator will be responsible for the expedited reporting of safety reports originating from 
the Study to the Ethics Committees and Institutional Review Boards (IRB), where applicable.
The Investigator will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
13.6.1  Food and Drug Administration (FDA) 
Unexpected serious adverse events believed to be definitely, probably, or possibly related to the 
medications will be reported to the Food and Drug Administration via MedWatch Form 3500A 
(http://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm ) by telephone 1-
800-FDA-1088; or by fax 1-800-FDA-0178.The Coordinating Center will be responsible for 
correspondence regarding adverse events with the FDA for all participating sites.
13.6.2 Additional Reporting Requirements for IND 
IND Safety Reports
Events meeting the following criteria need to be submitted to the 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 AE that is unexpected 
and assessed by the investigator to be possibly related to the use of atezolizumab.  An unexpected 
AE is one that is not already described in the atezolizumab Investigator’s Brochure.  Such reports 
are to be telephoned or faxed to the FDA and Genentech within 7 calendar days of first learning of 
the event.


 
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15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related 
to the use of atezolizumab.  An unexpected AE is one that is not already described in the 
atezolizumab Investigator’s Brochure.  
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of the 
previous, similar reports commented on. 
Written IND safety reports with analysis of similar events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the event.  
The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are acceptable 
(e.g., summary letter).  
Contact Information for IND Safety Reports 
FDA fax number for IND safety reports: 
Fax:  (800) FDA-0178 
 
All written IND safety reports submitted to the FDA by the investigator must also be faxed to 
the local site IRB and Genentech at: 
Fax: (650) 225-4682 or (650) 225-4630 
Genentech Drug Safety CTV mailbox: ctvist_drugsafety@gene.com 
 
And the Investigator will be responsible for the distribution of safety information to Site IRB. 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel:  (888) 835-2555 
Fax:  (650) 225-4682 or (650) 225-4630 
 
IND Annual Reports 
 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech 
  
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail 
box:  
 
ctvist_drugsafety@gene.com 


 
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Other Reports 
The Sponsor will forward a copy of the Final Study Report to Genentech upon completion of the 
Study. 
 
 
All FDA Reports 
Any study report submitted to the FDA by the Sponsor-investigator should be copied to Genentech.  
This includes all IND annual reports and the Clinical Study Report (final study report).  
Additionally, any literature articles that are a result of the study should be sent to Genentech.  
Copies of such reports should be mailed to the assigned Clinical Operations contact for the study. 
 
13.6.3  Genentech 
The Sponsor-investigator must report all SAEs to Genentech within the timelines described below.  
The completed MedWatch or comparable SAE form should be faxed or emailed immediately upon 
completion to Genentech Drug Safety at: 
(650) 225-4682  or  (650) 225-4360 
usds_aereporting-d@gene.com 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available 
Additional reporting requirements to Genentech include the following: 
• 
Any reports of pregnancy following the start of administration with the atezolizumab and 
within the follow-up period (for female patients within one year after the last dose of 
atezolizumab or the partner of a male patient within three months of completing therapy)  This 
includes reports of abortions and congenital anomalies /birth defects. Pregnancies will be 
followed up until the outcome of the pregnancy is known, whenever possible, based upon due 
diligence taken to obtain the follow-up information. 
• 
All non-serious atezolizumab AEs originating from the study will be forwarded Genentech 
quarterly. 
 
Note:  Investigators should also report events to their IRB as required. 
In addition to SAEs, pregnancy reports and AESIs, the following safety reports  should be collected 
and transmitted to Genentech/Roche even in the absence of an Adverse Event within thirty (30) 
calendar days: 
• 
Data related to product usage during pregnancy or breastfeeding 


 
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• 
Data related to overdose, abuse, misuse, inadvertent/erroneous administration, medication error 
or occupational exposure, with or without association with an AE/SAE unless otherwise 
specified in the protocol 
• 
Data related to a suspected transmission of an infectious agent via a medicinal product 
(STIAMP) 
• 
Lack of therapeutic efficacy 
In addition, reasonable attempts should 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 
. 
Safety Reconciliation 
The Sponsor-investigator agrees to conduct reconciliation for the product.  Genentech and the 
Sponsor-investigator will agree to the reconciliation periodicity and format, but agree at minimum 
to exchange quarterly line listings of cases received by the other party.  If discrepancies are 
identified, the Sponsor-investigator and Genentech will cooperate in resolving the discrepancies.  
The responsible individuals for each party shall handle the matter on a case-by-case basis until 
satisfactory resolution. The sponsor shall receive reconciliation guidance documents within the 
‘Activation Package.’ 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include the following information within the Event Description (item 5) of the 
MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the AE to each investigational product and 
suspect medication 
 
Follow-Up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e., date of birth, initial, patient number), protocol description and number, if assigned, brief 
AE description, and notation that additional or follow-up information is being submitted.  (The 
patient identifiers are important so that the new information is added to the correct initial 
report.) 


 
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Occasionally Genentech may contact the reporter for additional information, clarification, or current 
status of the patient for whom and AE was reported.  For questions regarding SAE reporting, you 
may contact a Genentech Drug Safety representative.  Relevant follow-up information should be 
submitted to Genentech Drug Safety as soon as it becomes available and/or upon request. 
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download 
 
 
 
 
 
 
STUDY CLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech/Roche. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech/Roche. Copies of such reports should be mailed to the assigned Clinical Operations 
contact for the study: 
              anti-pdl-1-mpd3280a-gsur@gene.com 
  
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
QUERIES 
  
Queries related to the Study will be answered by the Investigator. However, responses to all  safety  
queries  from  regulatory  authorities  or  for publications will be discussed and coordinated between 
the Parties. The Parties agree that Genentech/Roche shall have the final say and control over safety 
queries relating to the Product. The Investigator agrees that it shall not answer such queries from 
regulatory authorities and other sources relating to the Product independently but shall redirect such 
queries to Genentech/Roche. 
  
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests 
for information or review of data are met. The Parties will clearly indicate on the request the reason 
for urgency and the date by which a response is required. 
  
SAFETY CRISIS MANAGEMENT 
  
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. 


 
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The Parties agree that Genentech/Roche shall have the final say and control over safety crisis 
management issues relating to the Product. The Investigator agrees that it shall not answer such 
queries from media and other sources relating to the Product but shall redirect such queries to 
Genentech/Roche. 
 
 


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DATA SAFETY AND MONITORING
Data Management and Reporting
Participating institutions will be collaborating with Vanderbilt in patient accrual. Data will be 
collected using a centralized electronic case report form called ON-line Clinical Oncology Research 
Environment = 
Oncore is a highly secure, 
web based, cancer specific, and customizable system that provides fully integrative clinical data 
management and study administration capabilities developed in an ongoing collaborative effort with 
NCI designated Comprehensive Cancer Centers.  It fully integrates study administration 
functionality including protocol tracking, patient registration, NCI reporting, review committee 
tracking, and SAE tracking, with clinical data management functionality including electronic case 
report forms (eCRF) design, clinical data capture, protocol and regulatory compliance monitoring.  
Also the system is capable in storing basic protocol information (e.g., IRB approval dates, dates for 
annual renewals,) and clinical trials research data.  Oncore allows the investigator to define specific 
protocol requirements and generate data collection forms.  Creation of the data collection form is 
done with a single button click after the parameters of an individual protocol have been specified. 
Oncore permits specification of study protocols, management of patient enrollment, clinical data 
entry and viewing, and the generation of patient or study-specific reports based on time stamping.  
OnCore is embedded with a comprehensive domain repository of standard reference codes and 
forms to promote standardization. The sources for the repository include CDUS, CTC, CDEs from 
NCI, ICD, MedDRA and various best practices from contributing NCI-designated Comprehensive 
Cancer Centers. OnCore provides several reporting features specifically addressing NCI Summary 3 
and Summary 4 and other reporting requirements. Data may also be exported in a format suitable 
for import into other database, spreadsheets or analysis systems (such as SPSS). This system will be 
used to manage all VICCC clinical trials data. OnCore is maintained and supported in the VICC 
Clinical and Research Informatics Resource. 
Specified members at each participating site will submit all pertinent regulatory documents to the 
Coordinating Center, who will store it in a secure location. 
The Principal Investigator or designee will inform Genentech as defined in the Safety and Data 
Exchange Agreement (SDEA) of any serious adverse event, and will inform the IRB in accordance 
with each institution’s IRB policy.  The investigator is responsible for the detection and 
documentation of events meeting the criteria and definition of an AE or SAE, as provided in this 
protocol.  During the study when there is a safety evaluation, the treating investigator or site staff 
will be responsible for detecting, documenting, and report AEs and SAEs, as detailed in the 
protocol.  If any problem is identified related to the conduct of this research, the VICC Data Safety 
and Monitoring Committee (DSMC) will be formally asked to review the study and the situation 
that required DSMC intervention. 
Meetings
This trial will be monitored by the VICC Breast Cancer Research Team. The Breast Cancer 
Research Team is composed of the Clinical Core Director of the Breast Cancer Program and Team 
Leader, Surgical Oncologists, Radiation Oncologists, Medical Oncologists, Research Nurses, the 
Data Manager, and our Regulatory Specialist. The Breast Cancer Research Team meets on a 


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monthly basis to discuss all AEs/SAEs, accrual, compliance, safety issues, adherence to protocol, 
reviews, etc. pertaining to all breast cancer studies. This particular study will be thoroughly 
reviewed during these meetings. These monthly meetings have minutes recorded each time and 
those are also reviewed on a monthly basis by the Breast Cancer Research Team Physician Leader.
Monitoring
This trial will be monitored continuously by the study’s Protocol Chair and by the Breast Cancer 
Research Team at VUMC.  The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety 
and data monitoring for its investigator-initiated and NIH-NCI funded clinical trials through its Data 
and Safety Monitoring Committee (DSMC).  The purpose of the DSMC is to ensure the efficient 
implementation and management of the VICC Data and Safety Monitoring Plan (DSMP).  The 
Committee maintains authority to intervene in the conduct of studies as necessary to ensure clinical 
research performed at VICC achieves the highest quality standards.
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP.  Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk.  The committee reviews all serious 
adverse events (SAE) on Vanderbilt sponsored investigator-initiated studies on a quarterly basis and 
provides DSMC SAE review reports to the Vanderbilt IRB.
Additionally, regular interim monitoring will be conducted by the Coordinating Center remotely. 
Data Handling and Record Keeping
14.4.1 Case Report Forms
An electronic case report form (eCRF) is required and must be completed for each included 
participant. The completed dataset should not be made available in any form to third parties, except 
for authorized representatives of appropriate Health/Regulatory Authorities, without written 
permission from Vanderbilt.
14.4.2 Record Retention 
To enable evaluations and/or audits from Health Authorities and Vanderbilt, each site investigator 
agrees to keep records including: The identity of all participants (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition. To comply with international regulations, the 
records should be retained by the investigator in compliance with regulations.  
During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRF's will 
be generated for each site and transmitted to the site and the site monitor. Corrections will be made 
by the study site personnel. This will be done on an ongoing basis. 


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REGULATORY CONSIDERATIONS 
Protocol Review and Amendments
Information regarding study conduct and progress will be reported to the Institutional Review Board 
(IRB) per the current institutional standards of each participating center.
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB of each institution prior to local implementation.   
The Protocol Chair (or her designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the participating centers.
Informed Consent
The investigator (or his/her designee) will explain to each subject the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits involved 
and any discomfort it may entail.  Each subject will be informed that participation in the study is 
voluntary, that s/he may withdraw from the study at any time, and that withdrawal of consent will 
not affect her subsequent medical treatment or relationship with the treating physician(s) or 
institution.  The informed consent will be given by means of a standard written statement, written in 
non-technical language, which will be IRB approved.  The subject should read and consider the 
statement before signing and dating it, and will be given a copy of the signed document.  No subject 
will enter the study or have study-specific procedures done before his/her informed consent has 
been obtained. 
Confidentiality and security will be maintained for the tissue collection within this study. All tissue 
samples obtained for this study will be assigned a code and this code used to identify the sample. 
The samples will not be labeled with the patient’s name, address or other information that would 
identify them.  All information will be coded to maintain privacy. Research data, including the data 
collected from the medical charts will be entered into a password-protected database.  The database 
(Breast Cancer Program Database) in which this study data is going to be stored has a firewall (in 
addition to the institutional firewall) with the highest level of protection, i.e. the same level of 
protection as the on-line hospital information system at Vanderbilt.  This means that users must log 
on to a web server that sits between the institutional firewall and the firewall to the database, and 
only this application server is allowed to query the database.   Information, including the identifier 
and password for the authorized users, is transmitted via a secure shell protocol using 128k 
encryption. Only Dr. Vandana Abramson, the PI, and the Breast Team Data Manager, approved 
through our institutional review board will be allowed access to patient identifiers. Other levels of 
authorization may exist for approved users, e.g. access to de-identified data. This database will store 
a de-identified link to the patient data and will not otherwise store patient data, even de-identified.  
The safety monitoring will be performed by the groups deemed appropriate by the Vanderbilt 
University Medical Center Institutional Review Board for reviewing the clinical trials procedure.  
Safety monitoring for the database is also performed by the Networking and Security Services of 
the Vanderbilt University Medical Center. Audit trails for access to the web server and the 
databases behind the dual firewall system are maintained in accordance with the practices of the 
Networking and Security Services of the Vanderbilt University Medical Center.


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In accordance with the Health Information Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the consent 
document) will include a subject authorization to release medical information to the study sponsor 
and supporting agencies and/or allow these bodies, a regulatory authority, or Institutional Review 
Board access to subjects’ medical information that includes all hospital records relevant to the 
study, including subjects’ medical history. 
Ethics and GCP
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to.
MULTI-CENTER GUIDELINES
Protocol Review and Amendments
Information regarding study conduct and progress will be reported to the Institutional Review Board 
(IRB) per the current institutional standards of each participating center.
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB of each institution prior to local implementation.   
The Protocol Chair (or her designee) is responsible for the coordination and development of all 
protocol amendments.  Once approved by the Protocol Chair, Vanderbilt will disseminate this 
information to the participating centers.
Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory documentation 
to the Coordinating Center. The required documents include, but are not limited to the following: 
local IRB approvals (i.e., protocol, consent form, amendments, patient brochures and recruitment 
material, etc.), IRB membership rosters, summary of unanticipated problems or protocol deviations, 
and documentation of expertise of the investigators. The Coordinating Center will provide each 
participating site with a comprehensive list of the necessary documents. It is the responsibility of 
the participating sites to maintain copies of all documentation submitted to the Coordinating Center.


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The requirements for data management, submissions, and monitoring are outlined below. The 
participating sites will submit all the research related information (source documents and research 
records – IRB approval documents, patient registration list, CRF info, toxicity assessments, tumor 
measurements/ responses, etc.) to the Coordinating Center.Personnel from the VICC Clinical Trial 
Shared Resource will monitor the trial remotely and may periodically visit the investigative site to 
assure proper conduct of the trial and proper collection of the data.  The investigators at other sites 
will allow the monitor to review all source documents used in the preparation of the case reports, 
whether it be in person or remotely. 
Records Retention
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by each Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these records 
must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable national 
and local health authorities are notified.  
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location.  The Coordinating Center will inform the investigator at each 
site at such time that the records may be destroyed.
Publication
It is understood that any manuscript or releases resulting from the collaborative research must be 
approved by the Protocol Chair and will be circulated to both Genentech and applicable
participating sites/investigators prior to submission for publication or presentation. 
Additionally, any publication of study data and results must conform to the publications policy as 
stated the Translational Breast Cancer Research Consortium’s (TBCRC) “Policies and Procedures”.
STATISTICAL CONSIDERATIONS 
Study Design/ Endpoints
The primary endpoint of this trial is the median PFS of carboplatin + atezolizumab versus 
carboplatin alone in patients with metastatic triple negative (ER/PR/HER2 negative) breast cancer. 
Prior studies have shown a median progression free survival of 2.9 months in patients with triple 
negative breast cancer receiving cisplatin or carboplatin who have received up to one prior 
chemotherapy regimen and a stable disease rate of approximately 5% at 6 months.  We therefore 
propose that an improvement in median PFS of 2.9 months for single agent carboplatin to 4.4 
months  for the combination of carboplatin with atezolizumab would render this therapy worthy of 
further study.   The overall PFS data will be estimated using the Kaplan-Meier method with 95% 
confidence intervals.


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Sample Size/ Accrual Rate
The sample size estimation was completed using the log-rank test. A total sample size of 106 (n=53 
in each arm) provides  80% power to detect a 1.5 month improvement in the median PFS, i.e. 2.9 
months vs. 4.4 months,   with a one-sided significance level equal to .10 (type I error).  This 
estimation is based on the assumptions that accrual time is 24 months, additional follow-up time is 
12 months, , and the ratio randomization is 1:1.  
Analysis of Secondary and Exploratory Endpoints
We will calculate the ORR, CBR, DOR, and OS and corresponding 95% confidence intervals. PFS, 
ORR, and DOR will also be analyzed using irRECIST.  
RNA-seq will be performed on all biopsies to assign a triple negative subtype, to determine baseline 
and treatment-induced changes in GE after therapy and define mutations present in the tumors both 
at baseline and upon progression of the disease.  We expect an enrichment of drug resistance-
associated mutations/gene amplifications particularly in tumors that regress and later recur while on 
therapy.  Somatic SNPs and structural variants will be validated by whole exome sequencing (WES) 
of genomic DNA from the tumor and matched blood.  We will validate mutations by targeted 
capture approaches that allow high-level coverage (greater than 200X) and analysis of clonality. 
The status of p53, BRCA1/2, PIK3CA, PTEN, INPP4B and other mutations associated with TNBC, 
along with PDL1 expression and TILs in the tumor tissue is critical for testing our hypothesis.  We 
anticipate significant opportunity for discovery of novel mutations as well as those arising from 
selection during resistance to the therapies under investigation.  Statistics on the correlative endpoints 
(tissue assays) will be primarily descriptive. Therefore, these studies are considered to be exploratory 
and potentially hypothesis-generating. 
Regarding the impact of body composition on immune phenotype and prognosis in patients 
receiving PDL1 blockade for metastatic triple negative breast cancer in this study, data analysis will 
be primarily exploratory.  Pearson’s rho will be used to estimate the correlation between low muscle 
mass (sarcopenia) and T cell exhaustion (PD1 and CTLA4 expression).  Additional exploratory 
analysis will include the linear regression model to adjust for the potential confounders such as age 
and gender.  It is anticipated this sudy would provide data from 106 patients.  Assuming about 10% 
may not be able to provide evaluable data, we will have the complete data from 95 patients.  A 
sample size of 95 would have 84.7% power to detect a true correlation rho=0.3 versus the null 
hypothesis rho=0, with a type-I error of 0.05.  To evaluate the impact of body composition on 
prognosis by progression free survival in patients receiving immunotherapy, we will evaluate only 
the study cohort receiving atezolizumab (n = 53).  A Cox regression will be used to investigate the 
association between low muscle mass and PFS, while including T cell exhaustion (PD1 and CTLA4 
expression) as the additional covariates as well as other potential confounders. 
Statistical Analysis Plan  
Demographic information, such as age and race, will be tabulated. Descriptive statistics, including 
means, standard deviations, and ranges for continuous parameters, as well as percents and 
frequencies for categorical parameters, will be presented.  Investigation for outliers and assumptions 
for statistical analysis, e.g., normality and homoscedasticity, will be made. If necessary, data will be 


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transformed by utilizing appropriate transformations such as log or square root. Adverse medical 
events will be tabulated.  NCI toxicity Grade 3 and Grade 4, and laboratory abnormalities will be 
listed.  
Reporting and Exclusions
All patients included in the study must be assessed for safety, tolerability, and response to 
treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient 
will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 
7) early death because of other cause, or 9) unknown (not assessable, insufficient data).  
All of the patients who met the eligibility criteria and received study drugs for 4 weeks should be 
included in the main analysis of the clinical benefit rate. Patients in response categories 4-9 should 
be considered to have a treatment failure (disease progression). Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of the response and 
clinical benefit rate.
REFERENCES
1. 
Lehmann, B.D., et al., Identification of human triple-negative breast cancer subtypes and 
preclinical models for selection of targeted therapies. J Clin Invest, 2011. 121(7): p. 2750-
67. 
2. 
Masuda, H., et al., Differential response to neoadjuvant chemotherapy among 7 triple-
negative breast cancer molecular subtypes. Clin Cancer Res, 2013. 19(19): p. 5533-40.
3. 
Jezequel, P., et al., Gene-expression molecular subtyping of triple-negative breast cancer 
tumours: importance of immune response. Breast Cancer Res, 2015. 17(1): p. 43. 
4. 
Burstein, M.D., et al., Comprehensive genomic analysis identifies novel subtypes and targets 
of triple-negative breast cancer. Clin Cancer Res, 2015. 21(7): p. 1688-98. 
5. 
Adams, S., et al., Prognostic value of tumor-infiltrating lymphocytes in triple-negative 
breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 
and ECOG 1199. J Clin Oncol, 2014. 32(27): p. 2959-66. 
6. 
Denkert, C., et al., Tumor-infiltrating lymphocytes and response to neoadjuvant 
chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-
positive and triple-negative primary breast cancers. J Clin Oncol, 2015. 33(9): p. 983-91. 
7. 
Pembrolizumab shows potential in breast cancer. Cancer Discov, 2015. 5(2): p. 100-1. 
8. 
Chen, X., et al., TNBCtype: A Subtyping Tool for Triple-Negative Breast Cancer. Cancer 
Inform, 2012. 11: p. 147-56. 
9. 
Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-
1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8. 
10.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Can Res 2009;15:7412−20. 
11. 
Wang Z, Aguilar EG, Luna JI, et al: Paradoxical effects of obesity on T cell function during 
tumor progression and PD-1 checkpoint blockade. Nat Med 25:141-151, 2019
12. 
Mariathasan S, Turley SJ, Nickles D, et al: TGFbeta attenuates tumour response to PD-L1 
blockade by contributing to exclusion of T cells. Nature 554:544-548, 2018 


 
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13. 
Tsukamoto H, Fujieda K, Miyashita A, et al: Combined Blockade of IL6 and PD-1/PD-L1 
Signaling Abrogates Mutual Regulation of Their Immunosuppressive Effects in the Tumor 
Microenvironment. Cancer Res 78:5011-5022, 2018 
14. 
Shachar SS, Williams GR, Muss HB, et al: Prognostic value of sarcopenia in adults with 
solid tumours: A meta-analysis and systematic review. Eur J Cancer 57:58-67, 2016 
15. 
Williams GR, Deal AM, Muss HB, et al: Skeletal muscle measures and physical function in 
older adults with cancer: sarcopenia or myopenia? Oncotarget 8:33658-33665, 2017 
16. 
Mourtzakis M, Prado CM, Lieffers JR, et al: A practical and precise approach to 
quantification of body composition in cancer patients using computed tomography images 
acquired during routine care. Appl Physiol Nutr Metab 33:997-1006, 2008 
17. 
van Vugt JL, Levolger S, Gharbharan A, et al: A comparative study of software programmes 
for cross-sectional skeletal muscle and adipose tissue measurements on abdominal computed 
tomography scans of rectal cancer patients. J Cachexia Sarcopenia Muscle 8:285-297, 2017 
18. 
Martin L, Birdsell L, Macdonald N, et al: Cancer cachexia in the age of obesity: skeletal 
muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin 
Oncol 31:1539-47, 2013 
 19.       Li LF, Ma C. Epidemiological study of severe cutaneous adverse drug reactions in a city 
district of China. Clin Exp Dermatol. 2006;31(5):642-647 
20.        Yang MS, Lee JY, Kim J, et al. Incidence of Stevens-Johnson Syndrome and Toxic 
Epidermal Necrolysis: A Nationwide Population-Based Study Using National Health 
Insurance Database in Korea. PLoS One. 2016;11(11):e0165933 
 
 
 
 
 
 
 
 
 
 
 
 


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CORRELATIVE/SPECIAL STUDIES
Archived Tissue Samples
Metastatic tissue is the preferred sample; however, if the remaining tissue is insufficient to fit the 
requirements below, tissue from the patient’s primary tumor is acceptable.
Formalin-fixed paraffin embedded tissue blocks from the patient’s metastatic lesion collected for 
diagnostic and therapeutic purposes is requested for all patients enrolled in the study at the time of 
registration. They will be returned within 8 weeks (or earlier if requested); tissue taken from these 
blocks will not be returned.    
In case the participating institutions are not allowed to release clinical paraffin embedded blocks 
from prior surgeries/biopsies, ideally we will need the following cut in this order: 
A. If sending prior metastatic biopsy (performed pre-enrollment for diagnostic purposes) then 
send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, 
levels 2-5 to Genentech for PDL-1 IHC) 
2. Six (6) 10 µm unstained sections on non-charged slides (Vanderbilt DNA/RNA isolation)
3. Twelve (12) 4 µm unstained slides on charged slides (level 1 and 12 to be H&E stained upon 
receipt)
If remaining tissue is insufficient for the complete request, please send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate 
assessment, levels 2-5 to Genentech for PDL-1 IHC)
2. Two 5 x 10 μm peels in a DNAse-free/RNAse-free tube 
If remaining tissue is very limited, please send:
Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, 
levels 2,3,4,5 to Genentech for PDL-1 IHC)
B.  If sending primary tumor send: 
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate assessment, 
levels 2-5 to Genentech for PDL-1 IHC)
2. Six (6) 10 µm unstained sections on non-charged slides (Vanderbilt DNA/RNA isolation)
3. Two (2) 4 µm unstained slides on charged slides (last will be H&E stained upon receipt)
If remaining tissue is insufficient for the complete request, please send:
1. Six (6) 4 µm unstained sections on charged slides (levels 1,6 for immune infiltrate 
assessment, levels 2-5 to Genentech for PDL-1 IHC)
If remaining tissue is very limited, please send:


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Blood/plasma collection
Streck Cell-Free DNA BCT kits will be provided for circulating tumor DNA.  One vial of whole 
blood should be collected in a Cell-Free DNA BCT tube (Streck tube).  Fill the tube completely.  
Remove the tube from the adapter and immediately mix by gentle inversion 8 to 10 times.  
Collection times are: cycle 1/day 1, cycle 2/day 1, and end-of-treatment, see study calendar.  
Tube should be packed and shipped according to the lab manual and sent immediately (within 24 
hours) to VICC at the address provided. Do not freeze specimens collected in Streck tube.
Tissue specimen and blood/plasma labeling and documentation 
Label each collection containers with Patient ID sequence number/code letter, site and location of 
biopsy, date and time. 
If sample comes in contact with contaminate, make note in information section of paperwork.
Enter time core biopsy was collected on paperwork. 
Outside sites should ship specimens along with Tissue Registration Form as directed in the lab 
manual.   
The specimens will be logged in as a consented specimen and available for molecular pathology 
studies.  
Peripheral Blood Mononuclear Cell Collection
Blood will be collected on Cycle 1/ Day 1, Cycle 2/ Day 1, and at the end-of-treatment (also Cycle 
1/Day 1, Cycle 2/Day 1, and end-of-treatment for those crossing over to carboplatin + 
atezolizumab).
BD Vacutainer® CPT™ Mononuclear Cell Preparation Tubes are included to collect blood. One 
vial of whole blood should be collected in a BD Vacutainer® CPT™ (CPT tube).   
Whole blood is drawn directly into the CPT™ using standard phlebotomy techniques and in 
accordance with the lab manual. Samples should be shipped according to the lab manaul.  
Genetic Testing
Participants will be given information as part of the informed consent process that samples will be 
used for research tests that will include genetic studies and testing.  The intent is not to give 
participants (or his/her medical providers) the results of any testing done for research purposes; 
however, incidental germline (heritable) mutations may be identified of which a participant may or 
may not already be aware.  In the case that an incidental genetic finding is identified, the Protocol 
Chair of this project will be notified.  The possible decisions for handling incidental findings may 
include notification of the participant (and provider); recommendation for genetic counseling, 
which may or may not include genetic testing (e.g., if the finding was not done in a CLIA certified 
laboratory); or, neither.  In general, a member of the participant’s treating team will be given the 
information to help with notification.  In all cases, the current policy of the Vanderbilt and 


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local/participating site IRB, as applicable, will be followed and any additional approvals that may 
be required prior to participant notification will be secured in advance.
Specimen Banking
Any leftover study tissue or blood samples may be stored for future research studies.  The subjects 
will consent to the future use of samples in the consent form for the study, which includes the 
transfer of specimens to Genentech for product development.  The study PI and collaborators have 
approval by the TBCRC, which has custodial oversight of all biospecimens collected as part of a 
TBCRC trial, to address the research questions described in the protocol document.  All future use 
as part of residual or repository specimens collected in this trial for purposes not prospectively 
defined will require review and approval by the TBCRC according to its established policies, 
whether the specimens are stored in a central site or at a local institution or in a virtual repository.  
Secondary use of bio-specimens for new endpoints must be submitted to the TBCRC Central Office 
for possible review by the TBCRC Correlative Science Review Committee.
Biopsy Questionnaire
A questionnaire will be given to each participant to complete at cycle 2, day 1.  This questionnaire 
is designed to assess the impact of the biopsy on the patient’s quality of life and overall experience 
with the study.  
Imaging Correlative Study
Evaluation of muscle mass, muscle attenuation, and adipose mass will be determined using baseline 
abdominal CT scans collected for central review. A transverse cut at the L3 level will be extracted, 
as muscle and adipose area at this level is linearly related to whole body mass16.  SliceOmatic 
software (version 5, Tomovision) will be used to process images, providing a highly accurate 
estimation of cross-sectional skeletal muscle area and muscle attenuation with high inter-observer 
reliability17.  The software is semi-automated and will be run by two independent investigators, with 
a subset of images read by both investigators to determine a coefficient of variation.  Muscle mass, 
muscle attenuation, and adiposity will be evaluated both as continuous and categorical variables 
(LMM: yes/no, LMA: yes/no, adipose: tertiles). LMM is defined as skeletal muscle index (SMI, 
lean muscle area/height, cm2/m2) less than 41 and LMA will be defined as average muscle density 
less than 25 HU, or less than 33 HU if the patient is overweight/obese by BMI.  These cut-points are 
based on previously determined thresholds associated with reduced survival in patients with 
metastatic solid tumors18.  We will also explore whether there are alternate cut-points predictive of 
survival in this particular population based on optimal stratification.  Total adiposity will be defined 
as the sum of visceral adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue 
and evaluated by tertiles. 
MEASUREMENT OF EFFECT
For the purposes of this study, patients should be re-evaluated for response after every 3 cycles. 
Response and progression will be evaluated in this study using the international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1).   
Any evaluable or measurable disease must be documented at screening and reassessed at each 
subsequent tumor evaluation.  For PFS analysis, patients will be considered to have disease 
progression if their tumor assseessment shows PD by RECIST.  However, as conventional response 


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Definitions
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with atezolizumab and/or carboplatin. 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.) 
Disease Parameters
12.2.1 Measurable
12.2.1.1 Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:
•
10mm by CT scan (CT scan slice thickness no greater than 5 mm).
•
10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).
•
20mm by chest X-ray. 
12.2.1.2 Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed.  
12.2.2 Non-measurable
All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes 
with ≥10 to <15mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion,
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
12.2.3 Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment:
12.2.3.1 Bone lesions:
•
Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions.
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as


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CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Guidelines have defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5mm or less. When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.
MRI is also acceptable in certain situations (e.g. for bodyscans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.
PET/CT may not be used for RECIST or irRECIST measurements.
Endoscopy, laparoscopy: The utilisation of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers: tumor markers alone cannot be used to assess objective  tumor response. If 
markers are initially above the upper normal limit, however, they must normalise for a patient 
to be considered in complete response.  
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign  tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.
Response Criteria
12.3.1 Target lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).


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CR
Not evaluated
No
PR
PR
Non PD or not all evaluated
No
PR
SD
Non PD or not all evaluated
No
SD
Not all 
evaluated
Non PD
No
NE
PD
Any
Yes or 
no
PD
Any
PD
Yes or 
no
PD
Any
Any
Yes
PD
CR= completeresponse, PR= partial response, PD= progressive disease, SD= stable disease, NE= 
not evaluable. 
* 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. 
Duration of Response
12.4.1 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 recurrent disease is objectively documented.
12.4.2 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.
Immune-Related Response Criteria
12.5.1 Introduction 
Increasing clinical experience indicates that traditional response criteria (e.g., Response Evaluation 
Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health Organization [WHO]) may 
not be sufficient to characterize fully activity in the new era of target therapies and/or biologics.  In 
studies with cytokines, cancer vaccines, and monoclonal antibodies, complete response, partial 
response, or stable disease has been shown to occur after an increase in tumor burden as 
characterized by progressive disease by traditional response criteria.  Therefore, conventional 
response criteria may not adequately assess the activity of immunotherapeutic agents because 
progressive disease (by initial radiographic evaluation) does not necessarily reflect therapeutic 


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ASSESSMENT OF SAFETY ADVERSE EVENT REPORTING 
Safety assessments will consist of monitoring and reporting AEs and SAEs, all events of death, and 
any study-specific issue of concern.
General
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events version 5.0 (CTCAE v.5.0) that is available at http://ctep.cancer.gov/reporting//ctc.html.  
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections.  
Adverse events experienced by participants will be collected and reported from initiation of study 
medication, throughout the study, and within 30 days of the last dose of study medication. 
Participants who experience an ongoing adverse event related to a study procedure and/or study 
medication beyond 30 days will continue to be contacted by a member of the study team until the 
event is resolved, stabilized, or determined to be irreversible by the participating investigator.  
Participants should be instructed to report any serious post-study event(s) that might reasonably be 
related to participation in this study. The investigator should notify the IRB and any other 
applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to the 
study.  
Risks Associated with atezolizumab
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase 
the risk of immune-related AEs, specifically the induction or enhancement of autoimmune 
conditions.  AEs with potentially immune-related causes, including rash, hypothyroidism, 
hepatitis/transaminitis, colitis, myositis, and myasthenia gravis, have been observed in Study 
PCD4989g.  
Although most immune-related AEs observed with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid potential major 
complications (Di Giacomo et al. 2010).  
A more detailed safety profile of atezolizumab is provided in the atezolizumab Investigator’s 
Brochure. 


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Safety Parameters and Definitions
13.3.1 Adverse Event (AE) 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
This includes the following: 
•
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE reporting 
period 
•
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations)
•
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention
•
Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period 
•
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
13.3.2 Serious adverse event (SAE)
An AE should be classified as an SAE if any of the following criteria are met: 
•
It results in death (i.e., the AE actually causes or leads to death)
•
It is life threatening (i.e., the AE, in the view of the investigator, places the patient at immediate 
risk of death.  It does not include an AE that, had it occurred in a more severe form, might have 
caused death.) 
•
It requires or prolongs inpatient hospitalization
•
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions) 
•
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the IMP
•
It is considered a significant medical event by the investigator based on medical judgment (e.g., 
may jeopardize the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
•
If a patient is hospitalized to undergo a medical or surgical procedure as a result of an AE, the 
event responsible for the procedure, not the procedure itself, should be reported as the SAE.  
For example, if a patient is hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE


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Events not considered to be serious adverse events (and therefore do not require reporting) are 
hospitalizations or prolonged hospitalizations for:
•
routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition, or for elective procedures 
•
diagnostic, elective or pre-planned surgical procedures/treatment for a pre-existing condition that 
did not worsen 
•
efficacy measurement for the study
•
emergency outpatient treatment for an event not fulfilling the serious criteria outlined above and 
not resulting in inpatient admission
•
respite care
Assessment of Adverse Events
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
atezolizumab (, and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes
There is a plausible temporal relationship between the onset of the AE and administration of 
atezolizumab or carboplatin, and the AE cannot be readily explained by the patient’s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to atezolizumab or carboplatin; and/or the AE abates or resolves upon discontinuation 
of atezolizumab or carboplatin or dose reduction and, if applicable, reappears upon re-
challenge.
No
Evidence exists that the AE has an etiology other than atezolizumab or carboplatin (e.g., 
pre-existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to atezolizumab
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
13.4.1 Expectedness 
•
Expected:  Expected adverse events are those that have been previously identified 
as resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk. 
•
Unexpected: An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, 
the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk 


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•
For patients receiving combination therapy, causality will be assessed individually 
for each protocol-mandated therapy. 
13.4.2 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
•
Definite – The AE is clearly related to the study treatment. 
•
Probable – The AE is likely related to the study treatment.
•
Possible – The AE may be related to the study treatment.  
•
Unlikely - The AE is doubtfully related to the study treatment.
•
Unrelated - The AE is clearly NOT related to the study treatment.
Procedures for Eliciting, Recording, and Reporting Adverse Events
Eliciting Adverse Events  
A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. 
Examples of non-directive questions include: 
·  “How have you felt since your last clinical visit?”
·  “Have you had any new or changed health problems since you were last here?” 
13.5.1 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  Avoid 
colloquialisms and abbreviations. All adverse events will be captured on the appropriate study-
specific case report forms (CRFs). 
13.5.2 Diagnosis versus Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is acceptable to report the 
information that is currently available.  If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
13.5.3 Deaths
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 
will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, report “Unexplained 
Death.”  Deaths that occur during the protocol-specified adverse event reporting period that are 
attributed by the investigator solely to progression of disease should be recorded only in the study 
CRF.


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Coordinating Center within 1 business day after the treating institution becomes aware of the event, 
according to SAE reporting instructions in protocol Section 13.5.11.2. 
13.5.15  Institutional Review Board
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent or the protocol, these 
modifications will be provided to the IRB, as will the report of the adverse event.  
Coordinating Center Reporting Procedures
        Reporting to Regulatory Authorities, Ethics Committees and Investigators 
Genentech as the Marketing Authorization Holder will be responsible for the reporting of individual 
case safety reports from the study to the regulatory authority in compliance with applicable 
regulations. 
The Investigator as the Sponsor of the Study, will be responsible for the expedited reporting of 
safety reports originating from the study to the EMA through Eudravigilance Clinical Trial Module 
(EVCTM), where applicable.
The Investigator will be responsible for the expedited reporting of safety reports originating from 
the Study to the Ethics Committees and Institutional Review Boards (IRB), where applicable.
The Investigator will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
13.6.1  Food and Drug Administration (FDA) 
Unexpected serious adverse events believed to be definitely, probably, or possibly related to the 
medications will be reported to the Food and Drug Administration via MedWatch Form 3500A 
(http://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm ) by telephone 1-
800-FDA-1088; or by fax 1-800-FDA-0178.The Coordinating Center will be responsible for 
correspondence regarding adverse events with the FDA for all participating sites.
13.6.2 Additional Reporting Requirements for IND 
IND Safety Reports
Events meeting the following criteria need to be submitted to the 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 AE that is unexpected 
and assessed by the investigator to be possibly related to the use of atezolizumab.  An unexpected 
AE is one that is not already described in the atezolizumab Investigator’s Brochure.  Such reports 
are to be telephoned or faxed to the FDA and Genentech within 7 calendar days of first learning of 
the event.


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DATA SAFETY AND MONITORING
Data Management and Reporting
Participating institutions will be collaborating with Vanderbilt in patient accrual. Data will be 
collected using a centralized electronic case report form called ON-line Clinical Oncology Research 
Environment = 
Oncore is a highly secure, 
web based, cancer specific, and customizable system that provides fully integrative clinical data 
management and study administration capabilities developed in an ongoing collaborative effort with 
NCI designated Comprehensive Cancer Centers.  It fully integrates study administration 
functionality including protocol tracking, patient registration, NCI reporting, review committee 
tracking, and SAE tracking, with clinical data management functionality including electronic case 
report forms (eCRF) design, clinical data capture, protocol and regulatory compliance monitoring.  
Also the system is capable in storing basic protocol information (e.g., IRB approval dates, dates for 
annual renewals,) and clinical trials research data.  Oncore allows the investigator to define specific 
protocol requirements and generate data collection forms.  Creation of the data collection form is 
done with a single button click after the parameters of an individual protocol have been specified. 
Oncore permits specification of study protocols, management of patient enrollment, clinical data 
entry and viewing, and the generation of patient or study-specific reports based on time stamping.  
OnCore is embedded with a comprehensive domain repository of standard reference codes and 
forms to promote standardization. The sources for the repository include CDUS, CTC, CDEs from 
NCI, ICD, MedDRA and various best practices from contributing NCI-designated Comprehensive 
Cancer Centers. OnCore provides several reporting features specifically addressing NCI Summary 3 
and Summary 4 and other reporting requirements. Data may also be exported in a format suitable 
for import into other database, spreadsheets or analysis systems (such as SPSS). This system will be 
used to manage all VICCC clinical trials data. OnCore is maintained and supported in the VICC 
Clinical and Research Informatics Resource. 
Specified members at each participating site will submit all pertinent regulatory documents to the 
Coordinating Center, who will store it in a secure location. 
The Principal Investigator or designee will inform Genentech as defined in the Safety and Data 
Exchange Agreement (SDEA) of any serious adverse event, and will inform the IRB in accordance 
with each institution’s IRB policy.  The investigator is responsible for the detection and 
documentation of events meeting the criteria and definition of an AE or SAE, as provided in this 
protocol.  During the study when there is a safety evaluation, the treating investigator or site staff 
will be responsible for detecting, documenting, and report AEs and SAEs, as detailed in the 
protocol.  If any problem is identified related to the conduct of this research, the VICC Data Safety 
and Monitoring Committee (DSMC) will be formally asked to review the study and the situation 
that required DSMC intervention. 
Meetings
This trial will be monitored by the VICC Breast Cancer Research Team. The Breast Cancer 
Research Team is composed of the Clinical Core Director of the Breast Cancer Program and Team 
Leader, Surgical Oncologists, Radiation Oncologists, Medical Oncologists, Research Nurses, the 
Data Manager, and our Regulatory Specialist. The Breast Cancer Research Team meets on a 


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monthly basis to discuss all AEs/SAEs, accrual, compliance, safety issues, adherence to protocol, 
reviews, etc. pertaining to all breast cancer studies. This particular study will be thoroughly 
reviewed during these meetings. These monthly meetings have minutes recorded each time and 
those are also reviewed on a monthly basis by the Breast Cancer Research Team Physician Leader.
Monitoring
This trial will be monitored continuously by the study’s Protocol Chair and by the Breast Cancer 
Research Team at VUMC.  The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety 
and data monitoring for its investigator-initiated and NIH-NCI funded clinical trials through its Data 
and Safety Monitoring Committee (DSMC).  The purpose of the DSMC is to ensure the efficient 
implementation and management of the VICC Data and Safety Monitoring Plan (DSMP).  The 
Committee maintains authority to intervene in the conduct of studies as necessary to ensure clinical 
research performed at VICC achieves the highest quality standards.
The VICC DSMC meets on a quarterly basis and ad hoc to discuss data and safety monitoring of 
clinical trials and to oversee the VICC DSMP.  Internal audits for compliance with adverse event 
reporting, regulatory and study requirements, and data accuracy and completion are conducted 
according to the VICC DSMP according to study phase and risk.  The committee reviews all serious 
adverse events (SAE) on Vanderbilt sponsored investigator-initiated studies on a quarterly basis and 
provides DSMC SAE review reports to the Vanderbilt IRB.
Additionally, regular interim monitoring will be conducted by the Coordinating Center remotely. 
Data Handling and Record Keeping
14.4.1 Case Report Forms
An electronic case report form (eCRF) is required and must be completed for each included 
participant. The completed dataset should not be made available in any form to third parties, except 
for authorized representatives of appropriate Health/Regulatory Authorities, without written 
permission from Vanderbilt.
14.4.2 Record Retention 
To enable evaluations and/or audits from Health Authorities and Vanderbilt, each site investigator 
agrees to keep records including: The identity of all participants (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition. To comply with international regulations, the 
records should be retained by the investigator in compliance with regulations.  
During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRF's will 
be generated for each site and transmitted to the site and the site monitor. Corrections will be made 
by the study site personnel. This will be done on an ongoing basis. 


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REGULATORY CONSIDERATIONS 
Protocol Review and Amendments
Information regarding study conduct and progress will be reported to the Institutional Review Board 
(IRB) per the current institutional standards of each participating center.
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB of each institution prior to local implementation.   
The Protocol Chair (or her designee) is responsible for the coordination and development of all 
protocol amendments, and will disseminate this information to the participating centers.
Informed Consent
The investigator (or his/her designee) will explain to each subject the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits involved 
and any discomfort it may entail.  Each subject will be informed that participation in the study is 
voluntary, that s/he may withdraw from the study at any time, and that withdrawal of consent will 
not affect her subsequent medical treatment or relationship with the treating physician(s) or 
institution.  The informed consent will be given by means of a standard written statement, written in 
non-technical language, which will be IRB approved.  The subject should read and consider the 
statement before signing and dating it, and will be given a copy of the signed document.  No subject 
will enter the study or have study-specific procedures done before his/her informed consent has 
been obtained. 
Confidentiality and security will be maintained for the tissue collection within this study. All tissue 
samples obtained for this study will be assigned a code and this code used to identify the sample. 
The samples will not be labeled with the patient’s name, address or other information that would 
identify them.  All information will be coded to maintain privacy. Research data, including the data 
collected from the medical charts will be entered into a password-protected database.  The database 
(Breast Cancer Program Database) in which this study data is going to be stored has a firewall (in 
addition to the institutional firewall) with the highest level of protection, i.e. the same level of 
protection as the on-line hospital information system at Vanderbilt.  This means that users must log 
on to a web server that sits between the institutional firewall and the firewall to the database, and 
only this application server is allowed to query the database.   Information, including the identifier 
and password for the authorized users, is transmitted via a secure shell protocol using 128k 
encryption. Only Dr. Vandana Abramson, the PI, and the Breast Team Data Manager, approved 
through our institutional review board will be allowed access to patient identifiers. Other levels of 
authorization may exist for approved users, e.g. access to de-identified data. This database will store 
a de-identified link to the patient data and will not otherwise store patient data, even de-identified.  
The safety monitoring will be performed by the groups deemed appropriate by the Vanderbilt 
University Medical Center Institutional Review Board for reviewing the clinical trials procedure.  
Safety monitoring for the database is also performed by the Networking and Security Services of 
the Vanderbilt University Medical Center. Audit trails for access to the web server and the 
databases behind the dual firewall system are maintained in accordance with the practices of the 
Networking and Security Services of the Vanderbilt University Medical Center.


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In accordance with the Health Information Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the consent 
document) will include a subject authorization to release medical information to the study sponsor 
and supporting agencies and/or allow these bodies, a regulatory authority, or Institutional Review 
Board access to subjects’ medical information that includes all hospital records relevant to the 
study, including subjects’ medical history. 
Ethics and GCP
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to.
MULTI-CENTER GUIDELINES
Protocol Review and Amendments
Information regarding study conduct and progress will be reported to the Institutional Review Board 
(IRB) per the current institutional standards of each participating center.
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB of each institution prior to local implementation.   
The Protocol Chair (or her designee) is responsible for the coordination and development of all 
protocol amendments.  Once approved by the Protocol Chair, Vanderbilt will disseminate this 
information to the participating centers.
Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory documentation 
to the Coordinating Center. The required documents include, but are not limited to the following: 
local IRB approvals (i.e., protocol, consent form, amendments, patient brochures and recruitment 
material, etc.), IRB membership rosters, summary of unanticipated problems or protocol deviations, 
and documentation of expertise of the investigators. The Coordinating Center will provide each 
participating site with a comprehensive list of the necessary documents. It is the responsibility of 
the participating sites to maintain copies of all documentation submitted to the Coordinating Center.


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The requirements for data management, submissions, and monitoring are outlined below. The 
participating sites will submit all the research related information (source documents and research 
records – IRB approval documents, patient registration list, CRF info, toxicity assessments, tumor 
measurements/ responses, etc.) to the Coordinating Center.Personnel from the VICC Clinical Trial 
Shared Resource will monitor the trial remotely and may periodically visit the investigative site to 
assure proper conduct of the trial and proper collection of the data.  The investigators at other sites 
will allow the monitor to review all source documents used in the preparation of the case reports, 
whether it be in person or remotely. 
Records Retention
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by each Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these records 
must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable national 
and local health authorities are notified.  
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location.  The Coordinating Center will inform the investigator at each 
site at such time that the records may be destroyed.
Publication
It is understood that any manuscript or releases resulting from the collaborative research must be 
approved by the Protocol Chair and will be circulated to both Genentech and applicable
participating sites/investigators prior to submission for publication or presentation. 
Additionally, any publication of study data and results must conform to the publications policy as 
stated the Translational Breast Cancer Research Consortium’s (TBCRC) “Policies and Procedures”.
STATISTICAL CONSIDERATIONS 
Study Design/ Endpoints
The primary endpoint of this trial is the median PFS of carboplatin + atezolizumab versus 
carboplatin alone in patients with metastatic triple negative (ER/PR/HER2 negative) breast cancer. 
Prior studies have shown a median progression free survival of 2.9 months in patients with triple 
negative breast cancer receiving cisplatin or carboplatin who have received up to one prior 
chemotherapy regimen and a stable disease rate of approximately 5% at 6 months.  We therefore 
propose that an improvement in median PFS of 2.9 months for single agent carboplatin to 4.4 
months  for the combination of carboplatin with atezolizumab would render this therapy worthy of 
further study.   The overall PFS data will be estimated using the Kaplan-Meier method with 95% 
confidence intervals.


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Sample Size/ Accrual Rate
The sample size estimation was completed using the log-rank test. A total sample size of 106 (n=53 
in each arm) provides  80% power to detect a 1.5 month improvement in the median PFS, i.e. 2.9 
months vs. 4.4 months,   with a one-sided significance level equal to .10 (type I error).  This 
estimation is based on the assumptions that accrual time is 24 months, additional follow-up time is 
12 months, , and the ratio randomization is 1:1.  
Analysis of Secondary and Exploratory Endpoints
We will calculate the ORR, CBR, DOR, and OS and corresponding 95% confidence intervals. PFS, 
ORR, and DOR will also be analyzed using irRECIST.  
RNA-seq will be performed on all biopsies to assign a triple negative subtype, to determine baseline 
and treatment-induced changes in GE after therapy and define mutations present in the tumors both 
at baseline and upon progression of the disease.  We expect an enrichment of drug resistance-
associated mutations/gene amplifications particularly in tumors that regress and later recur while on 
therapy.  Somatic SNPs and structural variants will be validated by whole exome sequencing (WES) 
of genomic DNA from the tumor and matched blood.  We will validate mutations by targeted 
capture approaches that allow high-level coverage (greater than 200X) and analysis of clonality. 
The status of p53, BRCA1/2, PIK3CA, PTEN, INPP4B and other mutations associated with TNBC, 
along with PDL1 expression and TILs in the tumor tissue is critical for testing our hypothesis.  We 
anticipate significant opportunity for discovery of novel mutations as well as those arising from 
selection during resistance to the therapies under investigation.  Statistics on the correlative endpoints 
(tissue assays) will be primarily descriptive. Therefore, these studies are considered to be exploratory 
and potentially hypothesis-generating. 
Regarding the impact of body composition on immune phenotype and prognosis in patients 
receiving PDL1 blockade for metastatic triple negative breast cancer in this study, data analysis will 
be primarily exploratory.  Pearson’s rho will be used to estimate the correlation between low muscle 
mass (sarcopenia) and T cell exhaustion (PD1 and CTLA4 expression).  Additional exploratory 
analysis will include the linear regression model to adjust for the potential confounders such as age 
and gender.  It is anticipated this sudy would provide data from 106 patients.  Assuming about 10% 
may not be able to provide evaluable data, we will have the complete data from 95 patients.  A 
sample size of 95 would have 84.7% power to detect a true correlation rho=0.3 versus the null 
hypothesis rho=0, with a type-I error of 0.05.  To evaluate the impact of body composition on 
prognosis by progression free survival in patients receiving immunotherapy, we will evaluate only 
the study cohort receiving atezolizumab (n = 53).  A Cox regression will be used to investigate the 
association between low muscle mass and PFS, while including T cell exhaustion (PD1 and CTLA4 
expression) as the additional covariates as well as other potential confounders. 
Statistical Analysis Plan  
Demographic information, such as age and race, will be tabulated. Descriptive statistics, including 
means, standard deviations, and ranges for continuous parameters, as well as percents and 
frequencies for categorical parameters, will be presented.  Investigation for outliers and assumptions 
for statistical analysis, e.g., normality and homoscedasticity, will be made. If necessary, data will be 


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transformed by utilizing appropriate transformations such as log or square root. Adverse medical 
events will be tabulated.  NCI toxicity Grade 3 and Grade 4, and laboratory abnormalities will be 
listed.  
Reporting and Exclusions
All patients included in the study must be assessed for safety, tolerability, and response to 
treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient 
will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 
7) early death because of other cause, or 9) unknown (not assessable, insufficient data).  
All of the patients who met the eligibility criteria and received study drugs for 4 weeks should be 
included in the main analysis of the clinical benefit rate. Patients in response categories 4-9 should 
be considered to have a treatment failure (disease progression). Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of the response and 
clinical benefit rate.
REFERENCES
1. 
Lehmann, B.D., et al., Identification of human triple-negative breast cancer subtypes and 
preclinical models for selection of targeted therapies. J Clin Invest, 2011. 121(7): p. 2750-
67. 
2. 
Masuda, H., et al., Differential response to neoadjuvant chemotherapy among 7 triple-
negative breast cancer molecular subtypes. Clin Cancer Res, 2013. 19(19): p. 5533-40.
3. 
Jezequel, P., et al., Gene-expression molecular subtyping of triple-negative breast cancer 
tumours: importance of immune response. Breast Cancer Res, 2015. 17(1): p. 43. 
4. 
Burstein, M.D., et al., Comprehensive genomic analysis identifies novel subtypes and targets 
of triple-negative breast cancer. Clin Cancer Res, 2015. 21(7): p. 1688-98. 
5. 
Adams, S., et al., Prognostic value of tumor-infiltrating lymphocytes in triple-negative 
breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 
and ECOG 1199. J Clin Oncol, 2014. 32(27): p. 2959-66. 
6. 
Denkert, C., et al., Tumor-infiltrating lymphocytes and response to neoadjuvant 
chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-
positive and triple-negative primary breast cancers. J Clin Oncol, 2015. 33(9): p. 983-91. 
7. 
Pembrolizumab shows potential in breast cancer. Cancer Discov, 2015. 5(2): p. 100-1. 
8. 
Chen, X., et al., TNBCtype: A Subtyping Tool for Triple-Negative Breast Cancer. Cancer 
Inform, 2012. 11: p. 147-56. 
9. 
Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to PD-
1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8. 
10.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Can Res 2009;15:7412−20. 
11. 
Wang Z, Aguilar EG, Luna JI, et al: Paradoxical effects of obesity on T cell function during 
tumor progression and PD-1 checkpoint blockade. Nat Med 25:141-151, 2019
12. 
Mariathasan S, Turley SJ, Nickles D, et al: TGFbeta attenuates tumour response to PD-L1 
blockade by contributing to exclusion of T cells. Nature 554:544-548, 2018 

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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research          
Principal Investigator: Vandana G. Abramson, MD  
        Revision Date: 9/11/2020 
Study Title: BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer                                 
Institution/Hospital: Vanderbilt University Medical Center                                              NCT03206203
This informed consent applies to Adults. 
Name of participant: _________________________________________________________ Age: ___________ 
The following is given to you to tell you about this research study.  Please read this form with care and ask any questions you may have 
about this study.  Your questions will be answered.  Also, you will be given a copy of this consent form. 
You do not have to be in this research study. You may choose not to be in this study and get other treatments without changing 
your healthcare, services or other rights. You can stop being in this study at any time.  If we learn something new that may 
affect the risks or benefits of this study, you will be told so that you can decide whether or not you still want to be in this study.   
Your medical record will contain a note saying you are in a research study. Anyone you authorize to receive your medical 
record will also get this note. 
1. What is the purpose of this study?
You are being asked to take part in this research study because you have breast cancer that has spread to areas of your 
body outside of your breast. 
The purpose of this study is to test how well the combination of study drugs, carboplatin and atezolizumab, keeps your 
cancer from growing compared to taking carboplatin only. You will be given carboplatin with atezolizumab or carboplatin 
alone (a computer decides).  If you receive only carboplatin, at some time in the future, if your cancer starts to grow, you 
may be able to receive atezolizumab. If you receive carboplatin and atezolizumab, you will be removed from the study if 
your cancer becomes worse.    
Carboplatin is an FDA approved drug that is administered intravenously. 
The study drug atezolizumab is an investigational drug.  This means that it has not been approved by the Food and Drug 
Administration (FDA) for breast cancer. Atezolizumab is also called MPDL3280A. Atezolizumab works to assist your 
immune system in fighting cancer cells. It is now being tested as a possible therapy against solid tumors and hematologic 
malignancies for humans.  
About 106 people will take part in this study. About 37 people from Vanderbilt will take part in this study. 
2. What will happen and how long will you be in the study?
If you give your consent to be in this study by signing this form, you will have tests and procedures (called “screening”) 
done. These are done to reduce the risks of taking part in this study and to make sure it is okay for you to be in the study. 
Biospecimens will be collected in this study.  Biospecimens may include any of the following: blood, tissue, saliva, urine, 
bone marrow, cells, etc.  Most biospecimens contain DNA, which is the genetic code for each person. 
It is possible that after these tests are reviewed, you will not be able to be in the study.  There may be other reasons why 
you cannot be in this study.  These reasons will be discussed with you by your study doctor or the clinic staff. 
Screening
After you have signed this consent, the screening tests listed below will be done within 28 days of your first dose of study 
drugs.  Some of the tests listed below must be done less than 7 days of your first dose of the study drugs.  If they were 
done too long before that, they may need to be repeated. Your doctor/study team will discuss this with you. 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
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 
You will have a complete physical exam and your current symptoms will be reviewed. Physical examination will 
include examination of major body systems including neurologic, cardiac, respiratory, gastrointestinal, and skin. 
You will be asked about your medical and cancer history including any past treatments or surgeries for your 
disease.  Your performance status (your ability to carry out your daily activities) will be assessed.  Your vital signs 
(height, weight, temperature, breathing rate, blood pressure, pulse and oxygen saturation) will also be recorded.  
You will be asked about any medicines you are taking including over-the-counter medicines, vitamins, or herbal 
treatments.  
 
You will have an ECG (electrocardiogram).  This is a test to measure how your heart beats and this test may detect 
some abnormal heart conditions.  Sticky pads will be put on your chest for this test and wires will be attached from 
the pads to an ECG machine.  It is possible the sticky pads will irritate your skin and may cause a small amount of 
pain upon removal.  You will be asked to lie still for about five minutes before the test.
 
You will have a body CT Scan of your chest, abdomen, and pelvis, and a bone scan.  These are described in the 
“scans” section of the consent.  

Blood Collection (4-5 tablespoons in total will be collected at the screening visit): 
o 
Blood will be drawn for the Vanderbilt lab to check your health and blood sugar levels (white blood cell 
count, differential, hemoglobin, platelet count, sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, and magnesium, SGOT, SGPT, and total serum bilirubin, albumin, total protein, and 
INR).  
o 
If you are randomized to receive atezolizumab, blood will be drawn to assess thyroid function after 
screening. About 1 teaspoon of blood will be drawn for this test. 
o 
Blood will be drawn to test your blood for HIV, active or past exposure to hepatitis B, and hepatitis C. About 
4 teaspoons of blood will be drawn for these tests.  
 
Only Women Able to Have Children: A pregnancy test will be done for women who can have children.  The test will 
be done using a blood sample. The test must be negative for you to take part in the study.  Women who are 
pregnant or breast feeding may not take part in the study.  About 1 teaspoon of blood will be drawn. 
 
You will be asked to provide a piece of stored breast tumor sample from previous biopsies or surgeries you may 
have had in the past before you joined this study. If archived tumor samples are unavailable, a new tumor biopsy 
will be required. These samples can be used to study breast cancer. They will help researchers better understand 
the reasons for cancer development, growth, spread, and its response to treatment.  
 
You will be asked to have a biopsy of your disease.  This biopsy will be done on an area of your body where your 
cancer has spread (area of disease outside of the breast).  These samples will be used to test the gene signature 
of your tumor and for other research purposes.  Having this biopsy is required to take part in this study. Your 
research doctor will tell you what area(s) of your body can be biopsied. Your research doctor, with your input and 
consent, will select only one area to biopsy. This is the case even if your breast cancer has spread to multiple 
areas. Before the biopsy, you will discuss the procedure with the doctor who will perform the biopsy. You will be 
asked to sign a separate consent form with the doctor that performs the procedure. You will sign only after an 
explanation of the potential risks.  If you do not have any disease that is safely accessible, you will not have to 
undergo a biopsy. Also, if enough tissue is not obtained during a biopsy, you will not have to have it repeated. 
Types of biopsy you may have depending on the location of your tumor: 
If your cancer has spread to your skin, you may be asked to provide a biopsy sample for research purposes. Skin 
biopsies can be performed by your research doctor or by a surgeon. For a skin biopsy, lidocaine will be injected in 
your skin to numb it. Lidocaine may burn or cause a rash, redness, or soreness where you get the shot. There is a 
risk that this drug may cause problems with heart rhythm. Then two small pieces of skin (about half a centimeter 
each) will be removed. Two to four stitches will be used to close the biopsy site. These will be taken out after a 
week.  The procedure will take about 15-20 minutes. 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
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If your cancer has spread to your lymph nodes, liver, or bone, you may be asked to provide three to six samples for 
research purposes. The biopsy will be done either by a surgeon or a radiologist. This is an outpatient procedure.  
You cannot to eat or drink anything starting the night before the procedure. Right before the procedure, a very small 
flexible hollow tube will be inserted into a vein in your arm. You will get medicines such as sedatives and painkillers 
through this tube. Depending upon the location of the cancer, a radiologist may use ultrasound or a CT scan to 
guide him/her to the correct place to take a piece of tissue. Next, a needle will be used to get samples. The 
procedure will take about 1 hour. Usually, no stitches are required. Afterwards, you will be observed in the recovery 
room for 2-6 hours, on average. You will also need to get a friend or family member to drive you home after the 
procedure.  
How the Study Drugs are Given 
If the screening tests show you can be in the study, then you will be asked to return to the cancer clinic for your first visit.  
The study doctor will let you know how much of each drug to take. A computer will decide whether you will go into the 
carboplatin only group or the carboplatin + atezolizumab group.  This process is called “randomization,” like flipping a coin 
to decide on a group. You and your doctor will be told which treatment you are assigned. For every 1 patient in the 
carboplatin + atezolizumab group, one patient will go to the carboplatin only group.  If your disease worsens and you are in 
the carboplatin only group, you can “cross-over” to receive atezolizumab. 
Carboplatin and atezolizumab are both a liquid solution given intravenously. 
You will be administered carboplatin or the carboplatin and atezolizumab (if in the carboplatin + atezolizumab group) on day 
1, cycle 1. 
Photography 
If you have skin rashes or lesions, the study doctor may take color photographs (digital images) and measurements to 
document your condition. Special care will be taken to shield your identity in these photographs, in accordance with local 
guidelines. If you have a tattoo(s), your tattoo(s) may be included and visible in the photographs (digital images). Tattoos 
may be considered unique and identifiable, so the photograph(s) (digital images) of your tattoo(s) may identify you in 
pictures. However, your eyes will be masked in an effort to protect your identity. All photographs will be treated in a secure 
and confidential manner at all times. If you choose not to allow photos to be taken of your lesions or rash, you will still be 
able to participate in the study
What will be done during Each Cycle
While you are taking part in the study, you will be asked to come to cancer clinic on day 1 of every cycle that you participate 
in this study. Each cycle is 21 days. When you come to the cancer clinic you may have the following things done: 
 
You will have a complete physical exam.   
 
Your performance status (your ability to carry out your daily activities) will be assessed.   
 
Your vital signs (weight, temperature, breathing rate, blood pressure, pulse and oxygen saturation) will be recorded. 
 
You will be asked about any medicines you are taking including over-the-counter medicines, vitamins, or herbal 
treatments. 
 
You will be asked about any changes in your health status that you may be experiencing. 

Blood Collection (4-5 tablespoons in total will be collected at these visits): 
o 
Blood will be drawn for the Vanderbilt lab to check your health and blood sugar levels (white blood cell 
count, differential, hemoglobin, platelet count, sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
Date of IRB Approval: 11/07/2020
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
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glucose, calcium, and magnesium, SGOT, SGPT, and total serum bilirubin, albumin, total protein, and 
INR).  .  
o 
If you are randomized to receive atezolizumab, blood will be drawn to assess thyroid function every 4 
cycles. 
o 
Blood will be drawn for the Vanderbilt lab to check your blood for tumor cells.  This test is called circulating 
tumor DNA.  This will only be done on day 1 of cycle 1, day 1 of cycle 2, and at the end of treatment.  
o 
Blood will be drawn at cycle 1, day 1 and cycle 2 day 1 to collect mononuclear cells (to look at how the cells 
in the body respond to the study immunotherapy). 
o 
Blood will be drawn to test your blood for HIV, active or past exposure to hepatitis B, and hepatitis C, once 
every year that you are on the study. About 4 teaspoons of blood will be drawn for this test.   
 
A CT scan will be completed every 3 cycles. In addition, if bone metastases were present on the baseline studies, a 
bone scan will also be completed every 3 cycles. 
 
Study drug administration 
 
You will complete a biopsy questionnaire regarding your experience with the biopsies on cycle 2, day 1.
End of Study Visit 
If your disease gets worse, you are having bad side effects, or you no longer wish to be in the study then you will have an 
end of study visit.  This is to make sure you are okay after taking the study drug.  The following things will be done at this 
visit: 
 
You will have a complete physical exam and your current symptoms will be reviewed.  Your performance status 
(your ability to carry out your daily activities) will be assessed.  Your vital signs (weight, temperature, breathing rate, 
blood pressure, oxygen saturation and pulse) will also be recorded.   

Blood Collection (3-4 tablespoons in total will be collected at the end of study visit): 
o 
Blood will be drawn for the Vanderbilt lab to check your health and blood sugar levels (white blood cell 
count, differential, hemoglobin, platelet count, sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, and magnesium, SGOT, SGPT, and total serum bilirubin, albumin, total protein, and 
INR).  
o 
If you are randomized to receive atezolizumab, blood will be drawn to assess thyroid function every 4 
cycles. About 1 teaspoon of blood will be drawn for this test.  
o 
Blood will be drawn for the Vanderbilt lab to check your blood for tumor cells.  This test is called circulating 
tumor DNA.  About 2 teaspoons of blood will be drawn for this test.  
o 
Blood will be drawn to collect mononuclear cells (to look at how the cells in the body respond to the study 
immunotherapy). 
 
You will have a biopsy of your disease if you are stopping the study. This biopsy will be done on an area of your 
body where your cancer has spread (area of disease outside of the breast).   
Study Duration and Follow-up
You will keep taking the study drugs until:
 Your disease gets worse, or  
 You get bad side effects from the treatment that you cannot tolerate, or  
 You wish to stop the study, or 
 You are not able to follow the requirements of the study 
 You become pregnant 
 The study is canceled 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
5 of 17
Because of these reasons, we cannot predict the length of time that you will be on study. You will be closely followed by the 
research nurse while on study and will be asked to come back to the cancer clinic for a follow up visit within 30 days (+/- 3 
days) from your last dose of study drugs. If you are not able to return to the cancer clinic, then the research nurse will call you 
for this follow up. Any ongoing side effects or problems will be reviewed. 
Please note that if you are in the carboplatin only group and your disease worsens, you can “cross-over” to receive 
atezolizumab.  
If you are still experiencing bad side effects from the treatment, then you may be followed by the research nurse every 3 
months until the side effect has gotten better. 
We may follow-up your health status by reviewing your medical charts annually for up to 3 years after participation in this 
study.
Scans While You are in the Study 
While you are in the study, you will have Computed tomography (CT) scans done to measure the disease in your body. A 
Magnetic Resonance Imaging (MRI) may be done if a CT is unable to be done or your doctor feels that is indicated.  You 
will have a CT/MRI scan with contrast. An IV (needle in your vein) will be used to give you the contrast. This contrast is 
used to help organs, blood vessels and other area show up more clearly on the scan.   
At screening you will have a CT or MRI of your body to measure your disease before you take the study drugs. You will also 
have a bone scan to check for disease in your bones.   
While you are taking the study drug, you will have a CT or MRI of your body every 3 cycles to measure your disease. You 
may need to have a bone scan of your body if the scan at screening showed that you have disease in your bones.  
What happens during a CT Scan: 
The CT scan will take a few minutes.  You will be asked to lie on a narrow table.  The table slides into the center of the CT 
scanner.  You will be asked to lie very still during the scan. You may be asked to hold your breath for short periods of time.   
What happens during an MRI Scan: 
The MRI scan will take a few hours.  An MRI scan is taken in a large machine that is shaped like a tunnel.  This scan does 
not use x-rays. Instead, they use a strong magnet and radio waves, like those used in an AM/FM radio to make pictures of 
your body.  
You may not be able to have this scan if you have a device in your body such as aneurysm clips in the brain, heart 
pacemakers or defibrillators, and cochlear implants. Also, you may not be able to have this scan if you have an iron-based 
tattoo, pieces of metal (bullet, BB, shrapnel) close to or in an important organ (such as the eye).  
Certain metal objects like watches, credit cards, hairpins, writing pens, etc. may be damaged by the machine or may be 
pulled away from the body when you are getting the scan.  Also, metal can sometimes cause poor pictures if it is close to 
the part of the body being scanned.  For these reasons, you will be asked to remove these objects before going into the 
room for the scan.   
You will hear “hammering”, clicking, or squealing noises during the scan.  You can ask the staff whether earplugs are 
available to reduce the noise.   
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
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During the scan, the MRI staff is able to hear and talk to you.  You will also be able to hear the staff.  They will be talking to 
you during your scan and may ask you to hold your breath, not move, or other simple tasks.  You may be asked to lie very 
still throughout the scan. 
What happens during a Bone Scan: 
The bone scan may take a few hours.  You will be given an injection of a radioactive material.  This is called a tracer.  The 
tracer sends out a type of radiation called a gamma ray.  A special camera then makes pictures from these gamma rays.  
A few hours after the injection you will be asked to lie still on a table while a machine with an arm-like device with the 
special camera passes over your body.   
After the scan, the tracer in your body does not stay radioactive for long.  You will be asked to drink extra water after the 
scan.  This will help remove any unabsorbed radioactive material from your system.  After two days all of the tracer should 
be out of your system. 
3. Costs to you if you take part in this study: 
If you agree to take part in this research study, you and/or your insurance will not have to pay for the tests and treatments 
that are being done only for research. Genentech will provide the study drug free of charge for your use in this study.  
However, you are still responsible for paying for the usual care you would normally receive for the treatment of your illness. 
This includes treatments and tests you would need even if you were not in this study. These costs will be billed to you 
and/or your insurance.  
You have the right to ask what it may cost you to take part in this study. If you would like assistance, financial counseling is 
available through the Vanderbilt Financial Assistance Program.  The study staff can help you contact this program. You 
have the right to contact your insurance company to discuss the costs of your routine care (non-research) further before 
choosing to be in the study. You may choose not to be in this study if your insurance does not pay for your routine care 
(non-research) costs and your doctor will discuss other treatment plans with you. 
The National Cancer Institute provides an online resource to help people participating in cancer clinical trials understand
which services their insurance company is required by law to pay.  This can be found at the website below or can be 
provided by the study team: 
http://www.cancer.gov/clinicaltrials/learning/insurance-coverage
4.
Biospecimens for Research
Your biospecimens (tissue and blood samples) are being used for this research study.  As part of the study, we may perform 
the following research studies on them.  In addition, we will ask your permission in the next section for the use of any leftover 
biospecimens (that is, samples remaining or “leftover” after the research for this study is completed) to be used for future 
research and the option to contact you in the future.  In order to perform additional research, some of your blood and tissue 
samples may be sent to Genentech for future product development.
We may use genetic analysis in some of the research we do on your samples. Researchers can learn a lot by studying genes. 
Genes are pieces of DNA that give instructions for building the proteins that make our bodies work. DNA stores these 
instructions in the form of a code. This is the code that you inherit from your parents and that you pass on to your children. 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
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One of the methods we might use to study your samples is called whole genome sequencing. This allows us to look at some 
or all of your genetic code. Researchers may also use other methods as they are developed. Studying genes along with your 
health information will help us to better understand what causes certain diseases. It may also help us to understand how 
different patients respond to treatment. This knowledge could help us to develop treatments for everyone.   
What we learn about you from your samples will not be put in your health record and will not be shared with you or your 
doctor.  No one else (like a relative, boss, or insurance company) will be given your test results.   
Your samples will only be used for research and will not be sold.  Health insurance companies and group health plans may 
not request your genetic information that comes from this research.  
We will remove your name and any other information that could directly identify you from your samples and information.  We 
will replace this information with codes.  We will keep a master list that links those codes to your materials.  Only certain study 
staff can access this master list.  We will keep the samples in locked freezers in locked buildings. We will keep health 
information and research data on secure computers.  These computers have many levels of protection. 
The Genetic Information Nondiscrimination Act (GINA) may help protect you from health insurance or health-related 
employment discrimination based on genetic information.  The law provides that health insurance companies and group 
health plans  
 
may not ask for genetic information from this research and  
 
may not use genetic information when making decision about eligibility or premiums 
The law will not stop health insurance companies from using genetic information to decide whether to pay claims. The law 
does not apply to other types of insurance (such as life, disability or long-term care).  
Despite the GINA protections and the best efforts of the research team to protect your information, you may still be at risk if 
information about you were to become known to people outside of this study. 
5. Side effects and risks that you can expect if you take part in this study:  
Because of your illness or the treatment, you may get for your illness, you may have complications or side effects from the 
drugs. These may be serious or could even threaten your life.  Complications from your illness may happen whether or not 
you are in this study.  We are not certain if being in this study affects the risks that come with your illness.  
Risks of carboplatin
During your participation in this study, you are at risk for the side effects described below. You should discuss these with 
the study doctor. 
Carboplatin as a Single Agent:  Side Effects in Clinical Studies 
The common side effects listed below were considered to be related to carboplatin: 
 
Anemia (low levels of red blood cells) 
 
Decreased blood platelets 
 
Decreased function of bone marrow 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
8 of 17
 
Decreased neutrophils (a type of white blood cell) 
 
Bleeding 
 
Nausea 
 
Vomiting  
 
Infection 
 
Signs and symptoms at injection site 
 
Feeling weak 
 
Hair loss 
 
Low amounts of calcium, magnesium, potassium, and sodium in the blood 
 
Numbness, tingling, or pain of hands and feet 
 
Stomach cramps 
 
Pain 
Less frequent side effects that were considered to be related to carboplatin: 
 
Bronchospasm 
 
Hives 
 
Inflammation of skin/reaction caused by an allergy 
 
Itching 
 
Hemorrhage 
 
Rash 
 
Toxic effect on brain or spinal cord function 
 
Toxicity to organs of hearing 
 
Trouble breathing 
 
Abnormal liver function tests 
 
Diarrhea 
 
Constipation 
 
Vision problems 
Rare side effects that were considered to be related to carboplatin: 
 
Blockage or closing off of blood vessels in the liver 
 
Life threatening allergic reaction 
 
Painful, red or swollen mouth 
 
Poor vision 
 
High blood pressure 
 
Loss of appetite 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
9 of 17
Risks of atezolizumab 
During your participation in this study, you are at risk for the side effects described below. You should discuss these with 
the study doctor. 
Very Common (more than 10% chance) 
 
Joint pain 
 
Lack of energy 
 
Vomiting 
 
Decreased appetite 
 
Diarrhea 
 
Cough 
 
Shortness of breath 
 
Fatigue 
 
Generalized pain and back pain 
 
Itching of the skin 
 
Nausea 
 
Fever 
 
Rash 
 
Urinary tract infection 
Common (between 1-10% chance) 
 
Chills 
 
Nasal congestion 
 
Inflammation of the large intestines (colitis) 
 
Abdominal pain 
 
Infusion-related reaction or hypersensitivity (allergic reaction) 
 
Hepatitis 
 
Difficulty swallowing 
 
Elevated liver enzymes, which may indicate inflammation of the liver 
 
Decreased potassium in the blood 
 
Decreased sodium in the blood 
 
Low blood pressure 
 
Decreased oxygen resulting in shortness of breath 
 
Influenza-like illness 
 
Inflammation of the lungs 
 
Low platelet count, which may make you more likely to bruise or bleed 
 
Hypothyroidism 
 
Immune-mediated pneumonitis (inflammation of the lungs) 
 
Immune-mediated hepatitis (inflammation of the liver) 
 
Immune-mediated colitis (inflammation of the large intestines) 
 
Immune-mediated hypothyroidism 
 
Infusion-related reactions within 24 hours of administration (such as flu-like symptoms, fever, and rash) 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
10 of 17
Less common but important (less than 1% chance) 
 
Decreased ability of your adrenal glands to produce hormones 
 
Elevated blood sugar (diabetes) 
 
Hyperthyroidism 
 
Inflammation of the brain and surrounding tissues usually caused by infection 
 
Inflammation of the pituitary gland or pituitary stalk (symptoms may include severe headaches, nausea and 
vomiting, producing large amounts of dilute urine and extreme thirst) 
 
Inflammation of the heart muscle 
 
Diabetic ketoacidosis (a life-threatening complication of diabetes) 
 
Guillain-Barre (auto-immune numbness and/or paralysis)  
 
Increase in amylase and lipase, which may indicate inflammation of the pancreas  
 
Myasthenia gravis (muscle weakness)  
 
Immune-mediated Myositis (inflammation of the muscle), which led to death in 4 cases  
 
Immune-mediated nephritis (inflammation of the kidneys) 
 
Immune-mediated pancreatitis (inflammation of the pancreas) 
 
Immune-mediated diabetes (elevated blood sugar) 
 
Immune-mediated hypothyroidism 
 
Immune-mediated adrenal insufficiency, (decreased ability of your adrenal glands to produce hormones), which led 
to death in 1 case 
 
Immune-mediated hypophysitis (inflammation of the pituitary gland)  
 
Immune-mediated Guillain-Barre syndrome (auto-immune numbness and/or paralysis), which led to death in 1 case 
 
Immune-mediated myasthenic syndrome/myasthenia gravis (muscle weakness) 
 
Immune-mediated meningoencephalitis (inflammation of the brain and surrounding tissues) 
 
Immune-mediated myocarditis (inflammation of the heart muscle) 
 
Decreased levels of red blood cells (anemia) 
 
Low white blood cell count (leukopenia) 
 
Inflammation of the lining of the bronchial tubes (bronchitis) 
 
Viral infection of the nerves (shingles) 
 
Lower respiratory tract infection
 
Lung infection (such as pneumonia) 
 
Increase in creatinine level in blood 
 
Decrease in neutrophils (a type of white blood cell)(neutropenia) 
 
Decrease in white blood cell count 
 
Low level of magnesium in blood (hypomagnesaemia) 
 
Autoimmune neuropathy 
 
Dizziness
 
Headache 
 
Weakness, numbness, and pain in the hands or feet (peripheral neuropathy) 
 
Peripheral sensory neuropathy (impedes ability to feel or sense your feet) 
 
Fainting (syncope) 
 
Inflammation of the muscle (myositis) 
 
Inflammation of the kidneys (nephritis) 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
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Pregnancy Risks 
You should not become pregnant or father a baby while in this study because the study drug may affect an unborn baby. 
Women should not breastfeed a baby while on this study. If you are a woman who can have children, you will have a 
pregnancy test before you can be in this study. If you are pregnant, you cannot be in this study. Tell one of the study 
doctors right away if you suspect that you have become pregnant while in the study. Whether you are a man or a woman, 
you need to use effective methods of birth control (e.g., abstinence, condoms, diaphragm, vasectomy/vasectomized
partner, tubal ligation) while in this study and for at least 3 months after your last dose of study drug. Check with your study 
doctor about the methods of birth control to use and how long to use them.
Risks of Blood Draw 
Pain, redness, soreness, bruising, or infection may occur at the needle stick site. Rarely some people faint.  The study 
doctor may put some cream (called EMLA) on your skin to numb the area so you will not feel the needle stick as much.  
The numbing cream may make your skin or the area have a change in skin color, but this is rare.   
Risks of HIV Testing 
You will be tested for HIV (AIDS virus) during this study.  If test results show that you have the virus that causes AIDS, the 
study staff will tell you the results and refer you to the health department to confirm the test results and give you someone 
to talk to about this disease.  We will talk with you before and after testing, and your test result will be given to you only in 
person.  You should know that the study staff must give your name to the Tennessee Department of Health if you test 
positive because this is the law. If others find out you have this virus, it may cause mental stress, unfair treatment from 
other people, problems with being able to get insurance or find a job, or other unknown problems.  It is important to seek 
medical care if you have HIV. 
Risks of Infusion 
You may experience symptoms associated with receiving an infusion. Serious infusion-associated events may include: 
 
Difficulty breathing (Dyspnea) 
 
Low blood pressure (Hypotension) 
 
Wheezing 
 
Tightening of the airways (Bronchospasm) 
 
Rapid heart rate (Tachycardia) 
 
Reduced oxygen saturation 
 
Respiratory distress 
Risks of an ECG 
The sticky pads used for the ECG may cause skin irritation. 
Risks of Tumor Biopsy 
Biopsies are normally performed under the guidance of an imaging technique. Each procedure requires a separate consent 
prior to the biopsy. The risks may include: 
 
Pain and discomfort. The amount of pain and discomfort will vary, depending on the location of the biopsy 
site. These risks can be discussed with the study doctor. 
 
Minor bleeding at the biopsy site. 
 
Tenderness at the biopsy site. 
 
Scarring at the biopsy site. 
 
Rarely, an infection at the biopsy site. 
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
12 of 17
 
Lidocaine, a numbing drug, may burn or cause a rash, redness or soreness where you get the shot.  There 
is a small risk that this drug may cause problems with heart rhythm. 
Although uncommon, problems from biopsies can be life threatening.  Some potentially serious problems from bleeding or 
organ damage may occur. These might require surgical repair. 
Skin or chest biopsy 
Likely: local discomfort and minor bleeding 
Rare: moderate or major bleeding.  Infection and allergic reaction to the numbing medicine also occur rarely. 
Lymph node biopsy 
Likely: local discomfort and minor bleeding 
Rare: moderate or major bleeding, need for blood transfusion, lung collapse, hospitalization due to bleeding or other 
complications, infection, damage to bowels, damage to nearby organs, allergic reaction to the numbing medicine. 
Liver biopsy 
Likely: local discomfort and minor bleeding 
Rare: moderate or major bleeding, need for blood transfusion, lung collapse, hospitalization due to bleeding or other 
complications, infection, damage to bowels, damage to nearby organs, allergic reaction to the numbing medicine 
Bone biopsy 
Likely: local discomfort and minor bleeding 
Rare: moderate or major bleeding, need for blood transfusion, lung collapse, hospitalization due to bleeding or other 
complications, infection, damage to bowels, damage to nearby organs, allergic reaction to the numbing medicine 
Some biopsy procedures, such as a liver biopsy, may require “intravenous conscious sedation” (IVCS).  For IVCS, a very 
small hollow flexible tube will be placed in your vein. You will get sedatives and painkillers before and during the procedure.  
You may become sleepy. However, you will be able to breathe on your own and respond to commands.  There is a very small 
risk of having allergic reactions to the medications, pneumonia, a heart attack, irregular heartbeat, low blood oxygen, and 
death with IVCS.  To minimize these risks, your doctor will review your medical history before the procedure.  If you have 
active heart problems (such as chest pains or a recent heart attack), you cannot take part in this procedure.  Your doctor or 
the IVCS personnel may feel that you would be at moderate or high risk of complications with IVCS.  If so, you cannot take 
part in this study if IVCS would be required for the biopsy.  You will be carefully watched during and after the procedure.  
Some biopsy procedures require imaging studies, such as a CT scan or ultrasound to plan or guide the procedure.  These 
studies would be done even if you were not donating samples for research purposes.  However, if the biopsy is done for 
research, the imaging studies would also be considered research. Your doctor will tell you whether imaging studies are 
required for your procedure.  If you have a CT scan, there is also a small risk of allergic reaction to the dye that may be used 
during the scan. You could have anxiety or claustrophobia in the scanning machine.  Talk to your doctor if you have had 
problems during a CT scan in the past.  There is no radiation from an ultrasound test. 
Risks of Radiation 
For your first year of participation in this study, you may be asked to undergo certain imaging procedures that are outside of 
your normal standard of care.  These procedures include the use of CT guidance to obtain tumor tissue biopsy samples.  In 
the first year of the study, you will only be asked to have two of the CT guided biopsy procedures.   
The above procedure exposes you to radiation that is in addition to your exposure from normal standard of care imaging.   
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
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We estimate your research radiation exposure for the first year to be approximately 12% more than that allowed annually 
for persons who are exposed to radiation as part of their work. 
Should you choose to continue in the study, you may have up to one more CT guided biopsy procedure.  This additional 
exposure to radiation increases your overall exposure to approximately twice that allowed annually for radiation workers. 
Additionally, to protect your bladder from the effects of the injected radioactive imaging substance, we encourage you to 
drink plenty of fluids before and after the CT procedures. You should urinate at least every two hours for up to six hours 
following the procedures. 
Risks of MRI
There are no known major risks with an MRI scan. But, it is possible that harmful effects could be found out in the future.  
Even though the tunnel is open, it may bother you to be placed in a tight space (claustrophobia), and to hear the noise 
made by the magnet during the scan. You may also feel the table vibrate and/or move slightly during the scan.  It may be 
hard to lie on the table during the scan. If you have any metal pieces in your body, they could move during the scan and 
damage nearby tissues or organs.  
If you use a transdermal patch (medicated patches applied to the skin), you may need to take it off during the MRI scan.  
Transdermal patches slowly deliver medicines through the skin.  Some patches have metal in the layer of the patch that is 
not in contact with the skin (the backing).  You may not be able to see the metal in the backing of these patches.  Patches 
that contain metal can overheat during an MRI scan and cause skin burns in the immediate area of the patch. Tell the study 
doctor that you are using a patch and why you are using it (such as, for pain, smoking cessation, hormones).  Ask your 
doctor for guidance about removing and disposing of the patch before having an MRI scan and replacing it after the 
procedure.  Tell the MRI facility that you are using a patch. You should do this when making your appointment and during 
the health history questions you are asked when you arrive for your appointment.  
The contrast dye you will receive is the standard dye used in these scans.  Getting the dye through the IV does not cause 
pain, but you may feel discomfort, tingling or warmth in the lips, metal taste in the mouth, tingling in the arm, nausea, or 
headache.  These symptoms occur in less than 1% (less than 1 in 100) of people and go away quickly.  Very rarely, there 
may be an allergic reaction, which may be severe.  This may cause you to have a rash, swelling, tightness in the throat, 
trouble breathing, low blood pressure, and very rarely death.  Placing the needle in your vein may also cause minor pain, 
bruising and/or infection where it goes into your arm.  There will be trained health workers and supplies on hand to treat you 
and keep you safe if you have any of these symptoms.  Also, a doctor will be on hand during the scan to provide any 
needed care if side effects do occur, and to decide when or if we should stop giving you the dye. 
Allergic reactions to the radioactive dye are rare. Most of the dye will be eliminated from your body (through your urine or 
stool) within a day, so be sure to promptly flush the toilet and thoroughly wash your hands with soap and water. The amount 
of radiation is so small that it is not a risk for the people you come in contact with after the test.
There are no known risks of having MRI scans without contrast while pregnant.  However, there may be risks that are 
unknown.
Risks of Drug Interaction with Foods and Other Medicines 
As with all drugs, there is a chance that some foods or medications can affect how the study drugs work.  Medications 
including some over-the-counter medications and common herbal supplements may cause bad effects, by making the study 
drug action stronger or weaker. You will be given more information about medicines and products that should be avoided.   
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
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For your safety, you must tell the study doctor or nurse about all the drugs you are taking, including over-the-counter drugs 
and herbals, before you start the study and before taking any new drugs while you are on the study. Your doctor and nurse 
will make sure that your prescription medications are not going to interfere with the study drugs and vice-versa. If you are 
visiting any other doctor who prescribes you any medication, it is important that you tell him/her that you are taking part in 
this study.  
6. Risks that are not known: 
Because this treatment is investigational, meaning non-FDA approved, there may be risks that we do not know about at this 
time.
7.  Payment in case you are injured because of this research study: 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of the tests or treatments that 
are done for research, then you and/or your insurance will not have to pay for the cost of immediate medical care provided 
at Vanderbilt to treat the injury.  
There are no plans for Vanderbilt or for the study supporters to pay for any injury caused by the usual care you would 
normally receive for treating your illness or the costs of any additional care. There are no plans for Vanderbilt or for the 
study supports to give you money for the injury  
8.  Good effects that might result from this study:
a) The benefits to science and humankind that might result from this study:  The information from this study will help doctors 
learn more about how atezolizumab affects patients’ bodies and cancers when combined with carboplatin. 
 
 
 
b) The benefits you might get from being in this study:  If you decide to take part in this study, there is no guarantee that your 
health will improve.  
9.  Other treatments you could get if you decide not to be in this study: 
  
Your other choices may include the following: 
 
Getting treatment or care for your cancer, such as other chemotherapy regimens or radiation therapy (in a few 
special circumstances), without being in a study 
 
Taking part in another study 
 
Getting no treatment 
 
Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite 
problems, and other problems caused by the cancer. It does not treat the cancer directly, but instead tries to 
improve how you feel. Comfort care tries to keep you as active and comfortable as possible.  
10.  Payments for your time spent taking part in this study or expenses: 
You will not be paid to take part in this study. 
Date of IRB Approval: 11/07/2020
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
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11. Reasons why the study doctor may take you out of this study:  
You may be taken out of the study if: 

staying in the study would be harmful to you 

you have side effects that you cannot tolerate 

you need treatment not allowed in the study 

your disease gets worse or progresses 

you fail to follow instructions 

you become pregnant 

the study is cancelled 
There may be other reasons to take you out of the study that we do not know at this time. If you are taken out of the study, 
you will be told the reason why, and your doctor will discuss other treatments with you. You will be followed for 30 days 
after stopping study drugs. If you stop taking study drugs due to bad side effects from the treatment that you cannot 
tolerate, you will be followed until these side effects are better or resolved. A medical chart review will be conducted 
annually for survival purposes.  
12. What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should tell your study doctor. Deciding to not be part of the study will not 
change your regular medical care in any way. Being in this study is voluntary. You can change your mind about being in this 
treatment program at any time. Your decision will not affect your future care. Deciding not to be in this study, or stopping 
participation in it, will cause no penalty or loss of benefits you otherwise would have. You may seek care from a doctor of 
your choice at any time. If you decide to no longer take part in the study, the study doctor may ask you to allow him/her to 
follow you and collect information from your medical records, if you agree. You will also be asked to return to clinic for a last 
visit to check blood work and your physical well-being.
If you decide to leave the study, please contact Dr. Abramson in writing and let her know that you are leaving. Her mailing 
address is:   
13. Who to call for any questions or in case you are injured: 
If you should have any questions about this research study or if you feel you have been hurt by being a part of this study, 
please feel free to contact 
For additional information about giving consent or your rights as a person in this study, to discuss problems, concerns, and 
questions, or to offer input, please feel free to call the Vanderbilt University Institutional Review Board Office at (615) 322-
2918 or toll free at (866) 224-8273. 
Date of IRB Approval: 11/07/2020
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
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14. Clinical Trials Registry.  
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law.  This Web site will not 
include information that can identify you.  At most, the Web site will include a summary of the results.  You can search this 
Web site at any time. 
15. Confidentiality:  
All efforts, within reason, will be made to keep your personal information in your research record confidential but total 
confidentiality cannot be guaranteed.  Your information and samples will be given a code.  Dr. Abramson, her staff, and 
other authorized people will be the only people who know your personal information.   
Study data will be recorded in the Vanderbilt ONCORE electronic database which is maintained by the research coordinator 
and data manager at Vanderbilt. The ONCORE electronic database is password protected in order to protect your identity. 
Your study records will be locked up in the clinical trials office. 
Vanderbilt may share your information, without identifiers, to others or use it for other research projects not listed in this 
form. Vanderbilt, Dr. Abramson and her staff will comply with any and all laws regarding the privacy of such information.  
There are no plans to pay you for the use or transfer of this de-identified information.
16. Authorization to Use/Disclose Protected Health Information
All efforts, within reason, will be made to keep your protected health information (PHI) private. PHI is your health 
information that is, or has been gathered or kept by Vanderbilt as a result of your healthcare.  This includes data gathered 
for research studies that can be traced back to you. Using or sharing (“disclosure”) such data must follow federal privacy 
rules. By signing the consent for this study, you are agreeing (“authorization”) to the uses and likely sharing of your PHI.  If 
you decide to be in this research study, you are also agreeing to let the study team use and share your PHI as described 
below.  
As part of the study, Dr. Abramson and her study team may share the results of your study and/or non-study linked physical 
exams, lab tests, ECG, radiology scans, tumor tissue testing, as well as parts of your medical record, to the groups named 
below. These groups may include people from the Federal Government Office for Human Research Protections, the 
Vanderbilt University Institutional Review Board and Scientific Review Committee, National Cancer Institute, Food and Drug 
Administration, representatives of Genentech and its authorized agents; Johns Hopkins University on behalf of the 
Translational Breast Cancer Consortium (TBCRC;),and insurance companies for billing purposes. Federal privacy rules 
may not apply to these groups; they have their own rules and codes to assure that all efforts, within reason, will be made to 
keep your PHI private.  
The study results will be kept in your research record for at least six years after the study is finished.  At that time, the 
research data that has not been put in your medical record will be kept for an unknown length of time.  Any research data 
that has been put into your medical record will be kept for an unknown length of time. 
Unless told otherwise, your consent to use or share your PHI does not expire. If you change your mind, we ask that you 
contact Dr. Abramson in writing and let her know that you withdraw your consent.  Her mailing address is Vanderbilt-Ingram 
Cancer Center, Attn:  
.  At 
that time, we will stop getting any more data about you.  But, the health data we stored before you withdrew your consent 
may still be used for reporting and research quality. 
Date of IRB Approval: 11/07/2020
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Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
Principal Investigator:  Vandana G. Abramson, MD   
        Revision Date: 9/11/2020   
Study Title:  BRE 15136: A Phase II trial of atezolizumab (anti-PDL1) with carboplatin in patients with metastatic triple negative breast 
cancer
Institution/Hospital:  Vanderbilt University Medical Center
Main ICF 
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You have the right to see and copy the PHI we gather on you for as long as the study doctor or research site holds this 
data.  To ensure the scientific quality of the research study, you will not be able to review some of your research data until 
after the research study is finished. 
If you decide not to take part in this research study, it will not affect your treatment, payment or enrollment in any health 
plans or affect your ability to get benefits. You will get a copy of this form after it is signed. 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY
 
I have read this consent form and the research study has been explained to me verbally.  All my questions 
have been answered, and I freely and voluntarily choose to take part in this study.    
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature of patient/volunteer 
 
 
 
 
Consent obtained by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name and Title 
Date of IRB Approval: 11/07/2020
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