Conditions: Urothelial Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This is a single arm phase II study assessing the activity of atezolizumab in combination with carboplatin + gemcitabine or docetaxel compared to historical controls of chemotherapy only in metastatic or recurrent urothelial carcinoma subjects. Subjects that received a PD 1 or PD-L1 inhibitor with no prior platinum chemotherapy for metastatic disease will be treated with atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab + docetaxel on trial.

Detailed description:

Arms:
arm 1: Subjects that received a PD 1 or PD-L1 inhibitor with no prior platinum chemotherapy for metastatic disease will be treated with atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab + docetaxel on trial.

Interventions: intervention 1: Carboplatin intervention 2: Gemcitabine intervention 3: Atezolizumab intervention 4: Docetaxel
Intervention descriptions: intervention 1: Carboplatin AUC 4 IV Day 1 of each 21 day cycle intervention 2: Gemcitabine 1,000 mg/m2 IV Day 1 and Day 8 of each 21 day cycle intervention 3: Atezolizumab 1,200 mg IV Day 1 of each 21 day cycle intervention 4: Docetaxel 75 mg/m2 IV Day 1 of each 21 day Cycle.

Protocol document:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN GU17-295 
 
 
A Phase II Trial of Atezolizumab plus Chemotherapy after Progression on PD-1 or PD-L1 
Inhibitor in Cisplatin-ineligible Patients with Advanced Urothelial Carcinoma  
HCRN GU17-295 
 
 
Sponsor Investigator 
Nabil Adra, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
 
Statistician 
Yong Zang, PhD 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
7676 Interactive Way Suite 120 
Indianapolis, IN 46278 
 
 
Trial Supported by  
Genentech ML40231 
 
Investigational New Drug (IND) #:141032 
 
 
 
 
Initial Protocol Version Date: 04JUL2018 
Protocol Amendment Version Date:  
15MAR2019 
02OCT2019 
09JUN2021 
04FEB2022 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
A Phase II Trial of Atezolizumab plus Chemotherapy after Progression on PD-1 or PD-L1 
Inhibitor in Cisplatin-ineligible Patients with Advanced Urothelial Carcinoma  
HCRN GU17-295 
 
 
VERSION DATE:04FEB2022 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 


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SYNOPSIS 
 
TITLE 
A Phase II Trial of Atezolizumab plus Chemotherapy after 
Progression on PD-1 or PD-L1 Inhibitor in Cisplatin-ineligible 
Patients with Advanced Urothelial Carcinoma  
SHORT TITLE 
Chemotherapy plus atezolizumab in patients with advanced cisplatin-
ineligible urothelial carcinoma  
PHASE  
Phase 2, single arm 
CONCEPT AND 
RATIONALE 
The PD-L1 inhibitor, Atezolizumab, is FDA approved for first-line 
treatment in patients with metastatic urothelial carcinoma who are 
cisplatin ineligible. Patients who progress after first-line immune 
checkpoint inhibitors (Programmed cell death 1 [PD-1] or 
Programmed death-ligand 1 [PD-L1] inhibitors) have limited further 
treatment options. The concept of maintenance therapy with targeted 
agents and adding onto it at the time of disease progression is a 
proven effective strategy in several disease settings. Preclinical data 
indicates that cytotoxic chemotherapy can have an 
immunomodulatory effect and can potentially augment immune 
response. Based on these data, we hypothesize that in patients with 
cisplatin-ineligible urothelial carcinoma the use of atezolizumab in 
combination with chemotherapy after progression on PD-1 or PD-L1 
inhibitor will result in clinical benefit.
OBJECTIVES 
Primary Objective 
Evaluate PFS among patients to be treated with atezolizumab in 
combination with carboplatin + gemcitabine or docetaxel, who have 
cisplatin-ineligible metastatic urothelial carcinoma and who have 
progressed on prior PD-1 or PD-L1 inhibitor. 
 
Secondary Objectives 
 Assess the safety and tolerability of the combination of 
atezolizumab plus chemotherapy (carboplatin + gemcitabine or 
docetaxel)  
 Evaluate objective response rate (ORR) and clinical benefit rate 
(CBR), with RECIST 1.1 and irRECIST 
 Evaluate PFS with irRECIST 
 Evaluate overall survival (OS) 
 Compare PFS to historical controls. 
 Evaluate PFS among the subgroup treated with atezolizumab + 
carboplatin and gemcitabine 
 Evaluate PFS among the subgroup treated with atezolizumab + 
docetaxel  
 
 
 


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Exploratory Objectives 
 Compare the efficacy of atezolizumab post disease progression 
with carboplatin + gemcitabine or docetaxel vs. treating with 
carboplatin + gemcitabine alone in a virtual control arm  
 Assess PD-L1 status at the following time-points: 
o REQUIRED, if available: Baseline from archival tissue (prior 
to treatment with PD-1 or PD-L1 inhibitor) 
o OPTIONAL (RECOMMENDED): From new biopsy prior to 
C1D1
KEY 
ELIGIBILITY 
CRITERIA 
 
See Section 3 for a 
full set of eligibility 
criteria 
Inclusion Criteria 
1. ECOG Performance status (PS) of 0-2 
2. Histologically or cytologically confirmed metastatic or 
unresectable locally advanced urothelial carcinoma (primary 
tumor: renal pelvis, ureters, urinary bladder, or urethra) 
3. Patients with mixed histologies are eligible  
4. Cisplatin ineligible at the time of diagnosis with metastatic 
urothelial carcinoma based on consensus definition with any of 
the following criteria: ECOG PS 2, creatinine clearance 
<60mL/min, CTCAE v4 grade≥2 hearing loss, CTCAE v4 
grade≥2 peripheral neuropathy, New York Heart Association 
(NYHA) class≥3 heart failure 
5. Must have had progressive metastatic disease after previous 
treatment with PD-1 or PD-L1 inhibitor (in the adjuvant or 
metastatic setting). Treatment regimen will be determined based 
on prior treatment: 
o PD1 or PDL1 inhibitor with no prior platinum 
chemotherapy for metastatic disease  patients should be 
treated with atezolizumab + carboplatin + gemcitabine 
o Sequential or concurrent PD1/PDL1 inhibitor and 
carboplatin-based regimen  patients should be treated 
with atezolizumab + docetaxel 
6. Most recent therapy does not have to have been a checkpoint 
inhibitor. Intercurrent treatment is acceptable as long as subjects 
meet all other inclusion criteria.  
7. Previous neoadjuvant or adjuvant chemotherapy completed ≥ 6 
months prior to enrollment is allowed 
 
Exclusion Criteria 
8. Previous autoimmune complication from PD-1 or PD-L1 
inhibitor requiring permanent discontinuation of therapy


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INTERVENTION  
Atezolizumab 1,200 mg IV Day 1, Carboplatin AUC 4 IV Day 1 and 
Gemcitabine 1,000 mg/m2 IV Days 1 and 8  
 
OR 
 
Atezolizumab 1,200mg IV Day 1 and Docetaxel 75mg/m2 IV Day 1.  
 
Patients will be treated with Q21 day cycles until progressive disease 
or intolerable toxicity. Chemotherapy may be discontinued after 4-6 
cycles per site investigator and/or patient’s choice. 
STATISTICAL 
METHODS 
 
Definition of primary endpoint 
PFS is defined as the time from date of treatment start until the criteria 
for disease progression is met as defined by RECIST 1.1 criteria or 
death as a result of any cause; in the absence of an event, PFS will be 
censored at date of last disease assessment. 
 
Definition of secondary endpoints 
 ORR refers to the proportion of subjects with reduction in tumor 
burden of CR or PR according to RECIST 1.1 and immune-
related response criteria (irRECIST) criteria 
 CBR is defined by stable disease (SD) for at least 3 months, PR, 
or CR by both RECIST 1.1 and irRECIST criteria 
 OS defined by the date of treatment start to date of death from any 
cause 
 PFS is defined as the time from date of treatment start until the 
criteria for disease progression is met as defined by RECIST 1.1 
criteria or death as a result of any cause; in the absence of an 
event, PFS will be censored at date of last disease assessment. 
 
Analytic Plan 
The PFS along with 95% CI will be estimated using the Kaplan-Meier 
method using the Efficacy population. 
 ORR and clinical benefit rate will be estimated with two-sided 
95% exact binomial confidence intervals.  
 Toxicities will be tabulated. Change in tumor levels of PD-L1 will 
be descriptively summarized and compared over time using paired 
t-tests. Proportional hazards regression (for PFS) and logistic 
regression (for ORR and clinical benefit rate) will be used to 
explore the association between biomarkers with clinical 
outcomes. 
TOTAL  
NUMBER OF 
SUBJECTS 
N=37 to achieve 30 events (an event is defined as a patient with 
progression or death). We hypothesize that patients receiving 
atezolizumab plus chemotherapy (carboplatin + gemcitabine or 
docetaxel) will have a median PFS of 0.6 year (7.2 months). 


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Under the exponential distribution assumption, this corresponds to 
an annual hazard rate of 1.155. The number of events is 30 
required to obtain a 95% confidence interval of [0.79, 1.60] for 
estimating the hazard rate. Of note, the historical data suggest a 
median PFS of 4 months, which corresponds to a hazard rate of 
2.08, well outside the anticipated 95% CI.  A sample size of 33 is 
expected to yield 30 events, assuming an accrual period of 24 
months (1.375 per month) and maximum follow-up of 18 months 
after the last patient is enrolled. To allow for replacement of 
patients who are not evaluable for efficacy (estimated to be 10%), 
up to 37 patients will be enrolled. 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 24 months 
ESTIMATED 
STUDY 
DURATION  
Estimated 42 months 
  
 
 


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TABLE OF CONTENTS 
 
SYNOPSIS ..................................................................................................................................... 3 
SCHEMA ....................................................................................................................................... 8 
1. 
BACKGROUND AND RATIONALE ............................................................................ 9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................. 14 
3. 
ELIGIBILITY CRITERIA ............................................................................................ 16 
4. 
SUBJECT REGISTRATION ........................................................................................ 19 
5. 
TREATMENT PLAN ..................................................................................................... 19 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS ............................. 23 
7. 
STUDY CALENDAR & EVALUATIONS ................................................................... 31 
8. 
BIOSPECIMEN STUDIES AND PROCEDURES ...................................................... 34 
9. 
CRITERIA FOR DISEASE EVALUATION ............................................................... 35 
10 
DRUG INFORMATION ................................................................................................ 41 
11 
ADVERSE EVENTS ...................................................................................................... 48 
12 
STATISTICAL METHODS .......................................................................................... 53 
13. 
TRIAL MANAGEMENT ............................................................................................... 56 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................... 58 
15. 
ETHICS ........................................................................................................................... 59 
16. 
REFERENCES ................................................................................................................ 61 
APPENDIX 1: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE EVENTS
 
65 
 
 
 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Background of urothelial carcinoma 
Urothelial bladder cancer is the most common cancer of the urinary system worldwide, with 
transitional cell carcinoma (TCC) of the bladder being the predominant histologic type and 
location. Urothelial cancers may less commonly originate in the renal pelvis, ureters, or urethra.  
Urothelial carcinoma is the ninth most common cancer worldwide and more than 165,000 
patients die from this disease annually.1 
 
1.2 
Current Standard of Care in the treatment of advanced urothelial carcinoma  
The current standard of care for treatment of patients with metastatic urothelial carcinoma is 
cisplatin-based combination chemotherapy. Nonetheless, a significant number of patients are not 
appropriate candidates for cisplatin-based combination chemotherapy because of comorbidities 
and impaired functional status.2 A consensus-working group has defined medically frail patients 
as those with the following criteria predisposing them to increased risks of toxicity with 
cisplatin-based chemotherapy3:  
 World Health Organization (WHO)/ECOG performance status ≥ 2 or a KPS of 60% to 
70% 
 Creatinine clearance < 60 mL/min 
 A hearing loss of 25 dB at two contiguous frequencies 
 Grade ≥ 2 peripheral neuropathy 
 New York Heart Association Class ≥ III heart failure 
 
For cisplatin-ineligible patients, treatment options include carboplatin-based, non−platinum-
based, single-agent chemotherapy regimens, or even best supportive care (BSC). 
 
1.2.1 Cisplatin-based Regimens 
Patients with previously untreated urothelial bladder cancer typically receive platinum-based 
chemotherapy. The first evidence that chemotherapy produced a significant survival benefit in 
patients with advanced urothelial carcinoma came in the mid-1980s; two studies showed that the 
combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) produced overall 
response rates greater than 70%, with approximately 35% of patients achieving a complete 
response (CR).4,5 Subsequently, two prospective, randomized, Phase III trials demonstrated the 
superiority of MVAC in patients with advanced disease. MVAC was tested against single-agent 
cisplatin in a multicenter U.S. Intergroup trial.6 Compared with cisplatin, MVAC demonstrated 
significant improvements in the overall response rate (39% vs. 12%) and median overall survival 
(OS; 13 vs. 8 months). MVAC was also compared with the combination of cisplatin, 
cyclophosphamide, and doxorubicin (CISCA) in patients with advanced UBC.7 The objective 
response rate (ORR) of MVAC was 65% versus 46% for the CISCA arm and demonstrated a 
superior median OS (62.6 vs. 40.4 weeks). In an effort to develop a less toxic regimen, the 
combination of gemcitabine and cisplatin was tested against MVAC in the Phase III setting 
following the demonstration of activity in earlier phase trials. In the Phase III trial, 405 patients 
with advanced TCC of the urothelium were randomly assigned to GC versus MVAC for a 
maximum of six cycles. Patients allocated to gemcitabine and cisplatin had a similar OS to those 
randomized to MVAC (14.0 months for GC vs. 15.2 months for MVAC; hazard ratio [HR] = 
1.09; 95% CI: 0.88, 1.34, p = 0.66) with less Grade 3 or 4 toxicity (including neutropenia, 


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neutropenic sepsis, and mucositis) and, as a result, GC has largely displaced MVAC as the 
standard of care.8 The benefit conferred by cisplatin-based chemotherapy regimens appears to 
have reached a plateau in median OS (13−15 months) and leaves a significant population in need 
of salvage therapy options. 
 
1.2.2 Carboplatin-based Regimens 
Poor performance status, impaired renal function, advanced age, and multiple comorbidities 
(e.g., neuropathy, congestive heart failure, and hearing loss) are fairly common in patients with 
advanced urothelial carcinoma and can prohibit the use of cisplatin-based regimens. Carboplatin-
based regimens are feasible in these patients, but trials suggest they are less effective than 
cisplatin-based regimen.9 The benefit of carboplatin-based therapy in medically “unfit” patients 
was demonstrated in the European Organization for the Research and Treatment of Cancer 
(EORTC) Trial 30986. In this study, 238 patients with previously untreated advanced UBC and 
either a poor performance status and/or impaired renal function (glomerular filtration rate [GFR] 
< 60 but > 30 mL/min) were enrolled to gemcitabine and carboplatin (CarboGem) or 
methotrexate, carboplatin, and vincristine (M-CAVI).10 The ORR of CarboGem was 41% versus 
30% for the M-CAVI arm and demonstrated no difference in the median OS (9.3 vs. 8.1 
months). Notably, those with both impaired renal function and poor performance status had 
especially poor outcomes and increased acute toxicity with combination chemotherapy in this 
trial. 
 
1.2.3 Immunotherapy in urothelial carcinoma 
Immunotherapy was first found to be effective in non-muscle invasive bladder cancer in 1976 
with the introduction of BCG.11 Recently immunotherapy, in particular the immune checkpoint 
inhibitor for programmed death ligand-1 (PD-L1), atezolizumab, has been found to be clinically 
active in patients with locally and advanced and metastatic urothelial carcinoma who progressed 
after treatment with platinum-based chemotherapy. PD-1 is a T-cell co-receptor that, when 
activated, suppresses antitumor immunity by its interaction with its ligands, PD-L1 and PD-L2. 
 
In a single arm multicenter phase II trial, 310 patients with advanced urothelial carcinoma were 
treated with atezolizumab in the second line setting at a dose of 1200 mg, given every 3 weeks.12 
This study demonstrated durable activity and good tolerability in patients with urothelial 
carcinoma who had progressed after platinum-based first line therapy. The overall objective 
response rate was 15% (95% CI, 11 to 19). Moreover, increased expression of PD-L1 on immune 
cells was associated with increased response: patients with high PD-L1 expression had higher 
response rates 26% (95% CI, 18 to 36) compared to patients with lower PD-L1 expression 18% 
(95% CI, 13 to 24). Based on this study, the food and drug administration (FDA) granted 
atezolizumab accelerated approval for second-line therapy of metastatic urothelial carcinoma in 
May 2016.  
 
In a single arm multicenter phase II trial, 123 previously untreated patients with locally advanced 
or metastatic urothelial cancer who were cisplatin-ineligible were treated with atezolizumab 
1200 mg every 21 days until disease progression.13 At a median follow-up of 17.2 months, the 
objective response rate was 23% (95% CI, 16 to 31) and the complete response rate was 9% (11 
complete responses). Atezolizumab achieved durable responses and was generally tolerated by 


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patients. Based on these results, atezolizumab was granted accelerated FDA approval in first-line 
treatment of patients with urothelial carcinoma who are cisplatin-ineligible in April 2017.  
 
In addition to studies with atezolizumab, 2 recently reported phase 2 trials and 1 phase 3 trial 
have shown efficacy of programmed death receptor 1 (PD-1) inhibitors in metastatic urothelial 
carcinoma. CheckMate 275 was a single arm phase II study of Nivolumab in patients with 
urothelial carcinoma that progressed after platinum-based chemotherapy.14 At a median follow-
up of 7 months, overall response rate was 19.6% (95% CI 15 to 24.9). KEYNOTE-052 was a 
single arm phase II study of pembrolizumab as first line in patients with cisplatin-ineligible 
urothelial carcinoma.15 With a median follow-up of 8 months, overall response rate was 24% 
(95% CI, 16-33.6). Patients with higher PD-L1 expression had more response rates. KEYNOTE-
045 was a phase III study of pembrolizumab vs. investigator’s choice chemotherapy in 2nd line 
metastatic urothelial carcinoma.16 Median overall survival was 10.3 months in the 
pembrolizumab group compared to 7.4 months in the in the chemotherapy group.  
 
In patients with cisplatin-ineligible urothelial carcinoma who progress after first-line PD-1 or 
PD-L1 inhibitor, cytotoxic chemotherapy will have modest response rates and improvement in 
survival. Several phase II trials have evaluated a variety of non-cisplatin based chemotherapy 
regimens for patients with urothelial carcinoma who are not eligible for cisplatin. These 
regimens included carboplatin/gemcitabine, single agent gemcitabine, carboplatin/paclitaxel, and 
gemcitabine/paclitaxel. Average response rates ranged between 20-40% and median progression-
free survival (PFS) ranged between 3-5 months.10,17-21  
  
1.3 
Background of Atezolizumab 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 
and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as 
CD80), both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD L1 binding by atezolizumab has been shown to enhance the magnitude and 
quality of tumor specific T cell responses, resulting in improved anti-tumor activity.12,22 
Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc effector 
function and associated antibody-mediated clearance of activated effector T cells. Atezolizumab 
shows anti-tumor activity in both nonclinical models and cancer patients and is being 
investigated as a potential therapy in a wide variety of malignancies.  Atezolizumab is being 
studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy. Atezolizumab is 
approved in the United States for the treatment of locally advanced or metastatic urothelial 
carcinoma. 
 
Please refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
 
 
 


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1.4 
Background and rationale of combination chemotherapy and atezolizumab in 
patients with advanced urothelial carcinoma 
Currently, metastatic urothelial carcinoma in cisplatin-ineligible patients is optimally treated 
with single agent checkpoint inhibition (atezolizumab and pembrolizumab are FDA approved in 
this setting) or combination chemotherapy with carboplatin + gemcitabine. This regimen has 
well known ‘macro’ effects on the immune system such as neutropenia and lymphopenia; 
however, the effects on tumor-specific immune responses are becoming better appreciated. The 
ability to augment immune effector and suppressor cells and cytokine milieu can be taken 
advantage of to beneficially modulate atezolizumab immune checkpoint therapy.23-26 
 
Active Bladder Cancer Agent
Immune Effects
Cisplatin or Carboplatin 
Class I HLA expression 
Inhibits STAT6 expression of PD-L2 (B7-DC) 
Enhance Fas/ICAM-1 expression for Ag specific CTL killing
Gemcitabine 
Increased Ag presentation 
Inhibit and reduce myeloid derived suppressor cells 
Enhance Fas expression 
CD40 based T cell stimulation 
Prevent PD-1 dependent CD4+ T-cell tolerization
Immune modulating effects of cytotoxic chemotherapy for bladder cancer. 
ENREF_43 DC, dendritic cell; HLA, human leukocyte antigen; Ag, antigen; CTL, cytotoxic T 
lymphocyte; MHC, major histocompatibility complex
 
Cisplatin or carboplatin can stimulate antigen presentation, increase HLA expression, and 
improve factors for cytotoxic T lymphocyte kill. It also inhibits STAT6 expression of PD-L2 
which has unknown effects on PD-1 inhibition and tumor surveillance, though likely does not 
impede it.24,25 
 
Gemcitabine has been shown in vivo and in clinical trials to favorably augment tumor specific 
CD4+ and CD8+ ratios and to induce responses through effects it also has on the B-
lymphocytes.27,28 Gemcitabine, reduces myeloid-derived suppressor cells (MDSCs) to enhance 
immune surveillance23 and also prevents PD-1 dependent CD4+ T cell tolerization.26  
 
Several ongoing clinical trials combining immune checkpoint inhibitors with platinum-based 
chemotherapy in non-small cell lung cancer have demonstrated manageable toxicities.29-31 In an 
interim report of the Phase I multi-arm trial of an anti-PD-1 inhibitor in combination with 3 
different platinum doublet regimens for NSCLC, the cisplatin + gemcitabine combination arm 
showed good tolerability without any treatment discontinuations and grade 3-4 toxicity limited to 
anemia, thrombocytopenia, and 1 event of pneumonitis.29 Ongoing studies in metastatic colon 
cancer demonstrated safety of combining immune checkpoint inhibitor therapy with 5-fu, 
oxaliplatin, and leucovorin.32    
 
In metastatic urothelial carcinoma, the combination of checkpoint inhibition with cytotoxic 
chemotherapy has been shown to be feasible.33 A phase 3 study is underway comparing 
atezolizumab as monotherapy or in combination with platinum-based chemotherapy in patients 
with untreated locally advanced or metastatic urothelial carcinoma (NCT02807636). A phase IB 


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trial is evaluating the combination of atezolizumab with bevacizumab and/or cytotoxic 
chemotherapy in patients with advanced solid tumors (NCT01633970). 
 
Treatment with carboplatin and gemcitabine is a standard of care option for cisplatin-ineligible 
patients with metastatic urothelial carcinoma. Myelosuppression/cytopenias is a dose limiting 
toxicity of gemcitabine; and myelosuppression/nausea are the most common and/or serious 
adverse events for carboplatin. The most common adverse events identified (~10%) to date for 
atezolizumab are fatigue, nausea, and less commonly, flu-like symptoms and are often grade 1-2. 
Hematologic toxicity has not been noted. As atezolizumab toxicities are infrequent and mild, 
there is very little expectation for overlapping toxicities. 
 
1.5 
Rationale of combination Chemotherapy and Atezolizumab after progression on 
PD1 or PDL1 inhibitor  
The concept of maintenance therapy with targeted agents and adding onto it at the time of 
disease progression is a proven effective strategy in several disease settings.  For example, in 
patients with metastatic colon cancer the continued use of Bevacizumab (combined with a new 
chemotherapy agent) beyond progression has resulted in improved survival when compared with 
abandoning Bevacizumab and changing to a new chemotherapy agent alone.34 Similarly, the 
continued use of Trastuzumab in combination with chemotherapy after progression on 
Trastuzumab in HER2neu positive metastatic breast cancer improves outcomes in patients with 
breast cancer compared with abandoning HER-2 therapy and switching to chemotherapy alone.35 
 
The combination of immunotherapy with checkpoint inhibitors and cytotoxic chemotherapy has 
been shown to be safe and feasible in early studies with urothelial carcinoma.36 
 
The mechanism of resistance to PD-1 and PD-L1 inhibitors after prior response is poorly 
understood. As seen in prior trials evaluating PD-1 and PD-L1 inhibitors in urothelial carcinoma, 
there are patients whose tumors express PD-L1 that do not respond, and patients without PD-L1 
expression who have sustained response to PD-1 or PD-L1 inhibitors. Although data are lacking 
in this area, there are many theories about both the intrinsic and acquired resistance to immune 
checkpoint inhibitors. 
 
It has been shown in many tumor types that the presence of lymphocytic infiltrates with CD4 and 
CD8 T-cells within the tumor correlates with better outcomes. The principle of immune 
checkpoint inhibitors is to reactivate the endogenous tumor-specific T-cell immune response 
leading to tumoricidal activity. However, there is a subset of patients whose tumors lack 
lymphocytic infiltrates or who fail to produce a T-cell response with immune therapy thereby 
having intrinsic resistance. Tumors with low mutational burden have also been shown to have 
intrinsic resistance to the immune checkpoint inhibitors, likely by expressing fewer antigens that 
are recognized as foreign by the immune system, hence more likely to evade immune detection 
compared to tumors with a higher mutational load such as smoking-related urothelial carcinoma. 
The last theory is that the tumor microenvironment may prevent T-cells from exerting their 
effector function leading to intrinsic resistance. TGF-b, IL-10 and IDO are inhibitory molecules 
that have a direct negative effect on T-cell function in the microenvironment. The immature 
dendritic cells, myeloid derived suppressor cells or (inducible) regulatory CD4 T-cells within the 
microenvironment may also have an indirect effect on immune therapy. Additionally, the loss of 


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MHC class 1 expression in certain tumor cell population/subclones or other defects in antigen 
processing cascade may cloak the tumor cells from the immune system. 
 
Therapy-induced resistance, occurs when patients initially respond to immunotherapy then 
relapse or progress. This may be a result of immune-editing. This occurs when a heterogeneous 
tumor selects out clones that lack antigens that stimulate the immune response resulting in 
immune evasion. To overcome resistance, it is possible that pre-conditioning of the tumor in the 
form of chemotherapy, or radiation therapy may promote an immune supportive tumor 
microenvironment that may re-sensitize the tumors to the effects of immune therapy.37 
 
Based on these data, we hypothesize that in patients with cisplatin-ineligible urothelial 
carcinoma, the continued use of immune checkpoint inhibition with atezolizumab in combination 
with chemotherapy after progression on  PD-1 or PD-L1 inhibitor will result in clinical benefit.  
 
The combination of carboplatin and gemcitabine was the standard first-line therapy for patients 
with cisplatin-ineligible metastatic urothelial carcinoma until the FDA approval of atezolizumab 
and pembrolizumab in the first-line setting. For patients treated with first-line atezolizumab or 
pembrolizumab, the combination of carboplatin and gemcitabine has now become second-line 
therapy. Docetaxel remains a treatment option in patients who progress after platinum-based 
chemotherapy and immune checkpoint inhibitors.47  
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
Evaluate PFS among patients to be treated with atezolizumab in combination with carboplatin + 
gemcitabine or docetaxel, who have cisplatin-ineligible metastatic urothelial carcinoma and who 
have progressed on prior PD-1 or PD-L1 inhibitor.  
 
2.1.2 Secondary Objectives 
 Assess the safety and tolerability of the combination of atezolizumab plus chemotherapy 
(carboplatin + gemcitabine or docetaxel)  
 Evaluate objective response rate (ORR) with RECIST 1.1 and irRECIST 
 Evaluate clinical benefit rate (CBR) with RECIST 1.1 and irRECIST 
 Evaluate PFS with irRECIST 
 Evaluate overall survival (OS)  
 Compare PFS compared to historical controls. 
 Evaluate PFS for atezolizumab + carboplatin and gemcitabine 
 Evaluate PFS for atezolizumab + docetaxel  
 
 
 


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2.1.3 Correlative/Exploratory Objectives 
 Compare the efficacy of atezolizumab post disease progression with carboplatin + 
gemcitabine or docetaxel vs. treating with carboplatin + gemcitabine alone in a virtual 
control arm  
 Assess the PD-L1 status of the tumor at the following time points: 
o REQUIRED, if available: Baseline from archival tissue (prior to treatment with 
PD-1 or PD-L1 inhibitor) 
o OPTIONAL (RECOMMENDED): From new biopsy (prior to C1D1) 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
PFS is defined as the time from date of treatment start until the criteria for disease progression is 
met as defined by RECIST 1.1 criteria or death as a result of any cause; in the absence of an 
event, PFS will be censored at date of last disease assessment. 
 
2.2.2 Secondary Endpoints (See Section 9 for definitions) 
 Toxicity will be assessed using CTCAE v4.03 
 Objective response rate (ORR) using RECIST 1.1 defined as the proportion of all 
subjects with confirmed PR or CR according to RECIST 1.1, from the start of treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the start of treatment). 
 ORR defined as the proportion of all subjects with confirmed PR or CR using immune-
related response criteria (irRECIST), from the start of treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the start of treatment). 
 Clinical benefit rate (CBR) of treatment (defined by proportion of all subjects with stable 
disease for at least 3 months, partial response, or complete response) using RECIST 1.1 
from the start of treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of treatment). 
 CBR of treatment (defined by proportion of all subjects with stable disease for at least 3 
months, partial response, or complete response) using irRECIST from the start of 
treatment until disease progression/recurrence (taking as reference for progressive disease 
the smallest measurements recorded since the start of treatment). 
 PFS defined as duration from date of treatment start until progression according to 
irRECIST criteria or death from any cause 
 OS defined by the date of treatment start to date of death from any cause 
 
2.2.3 Exploratory Endpoints 
 Efficacy of atezolizumab+carboplatin+gemcitabine in this trial compared to 
carboplatin+gemcitabine in the virtual control arm will be compared using OS defined by 
the date of treatment start to date of death from any cause.  
 Assess PD-L1 status of tissue samples (archived tissue and new biopsy after progression 
on PD-1 or PD-L1 inhibitor) using PD-L1 immunohistochemistry assay. 
 


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2.2.4 Virtual Control Arm 
Flatiron Electronic Health Records will serve as data source for a retrospective real-world 
analysis of patient level data. The data source will be queried for patients with metastatic 
urothelial carcinoma who received first-line treatment with atezolizumab and then had 
progressive disease treated with carboplatin+gemcitabine. This data source will be queried for 
OS analysis and hence serve as a virtual control arm to the single arm phase II trial in this 
protocol. Data exports will be performed at 2 time-points by HCRN staff. OS analysis of data 
exports in the virtual control arm will be the responsibility of the sponsor investigator and the 
Biostatistics and Data Management Core at Indiana University Melvin and Bren Simon Cancer 
Center (IUSCC). 
 
3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of 0-2 within 28 days prior to registration. 
 
4. Histological or cytological confirmed metastatic or unresectable locally advanced urothelial 
carcinoma (primary tumor: renal pelvis, ureters, urinary bladder, or urethra). 
 
5. Patients with mixed histologies are eligible. 
 
6. Cisplatin ineligible at the time of diagnosis with metastatic urothelial carcinoma based on 
consensus definition with any of the following criteria: ECOG PS 2, creatinine clearance < 
60mL/min, CTCAE v4 grade ≥ 2 hearing loss, CTCAE v4 grade ≥ 2 peripheral neuropathy, 
New York Heart Association (NYHA) class ≥ 3 heart failure. 
 
7. Measurable disease according to RECIST 1.1 within 28 days prior to registration. 
 
8. Must have had progressive metastatic disease after previous treatment with PD-1 or PD-L1 
inhibitor (in the adjuvant or metastatic setting). Treatment regimen will be determined based 
on prior treatment: 
 PD1 or PDL1 inhibitor with no prior platinum chemotherapy for metastatic disease  
patients should be treated with atezolizumab + carboplatin + gemcitabine on trial. 
 Sequential or concurrent PD1/PDL1 inhibitor and carboplatin-based regimen  
patients should be treated with atezolizumab + docetaxel on trial. 
 
9. Most recent therapy does not have to have been a checkpoint inhibitor. Intercurrent treatment 
is acceptable if subjects meet all other inclusion criteria.  


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10. A subject with prior brain metastasis may be considered if they have completed their 
treatment for brain metastasis at least 4 weeks prior to study registration, have been off of 
corticosteroids for ≥ 2 weeks, and are asymptomatic. 
 
11. Previous neoadjuvant or adjuvant chemotherapy that was completed ≥ 6 months prior to 
study enrollment is allowed.  
 
12. Demonstrate adequate organ function as defined in the table below. All screening labs to be 
obtained within 28 days prior to registration. 
 
System 
Laboratory Value 
Hematological
White blood cell (WBC)
≥ 2 k/mm3
Absolute Neutrophil Count (ANC)
≥ 1.5 K/mm3
Hemoglobin (Hgb)
≥ 9 g/dL  
Platelet
>100k
Renal
Estimated creatinine clearance1 
≥ 30 mL/min 
Hepatic
Bilirubin
1.5 ≤ (ULN)2
Aspartate aminotransferase (AST) 
≤1.5 × ULN
Alanine aminotransferase (ALT) 
≤1.5 × ULN
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT) Activated Partial 
Thromboplastin Time (aPTT) 
≤ 2 × ULN (NOTE: This applies only to 
patients who are not receiving therapeutic 
anticoagulation; patients receiving 
therapeutic anticoagulation should be on a 
stable dose)
 
1 Cockcroft-Gault formula will be used to calculate creatinine clearance  
 
2 Except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL 
 
13. Females of childbearing potential (FOCBP) must have a negative serum pregnancy test 
within 28 days prior to registration. These women must also have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of atezolizumab then every 6 weeks thereafter. NOTE: Females are 
considered of child bearing potential unless they are surgically sterile (have undergone a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is post-menopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the 
absence of other biological or physiological causes. In addition, women under the age of 62 
must have a documented serum follicle stimulating hormone (FSH) level less than 40 
mIU/mL. 
 
14. Females of childbearing potential and males must be willing to abstain from heterosexual 
activity or to use 2 forms of effective methods of contraception from the time of informed 
consent until 150 days (5 months) after treatment discontinuation. The two contraception 
methods can be comprised of two barrier methods, or a barrier method plus a hormonal 
method.  


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15. Men who are sexually active with FOCBP must use any contraceptive method with a failure 
rate of less than 1% per year. Men receiving atezolizumab and who are sexually active with 
WOCBP will be instructed to adhere to contraception for a period of 150 days (5 months) 
after the last dose of investigational product. 
 
16. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study. 
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Previous autoimmune complication from PD-1 or PD-L1 inhibitor requiring permanent 
discontinuation of therapy. 
 
2. Previous permanent discontinuation from PD-1 or PD-L1 inhibitor due to an adverse event 
(patients who had temporary holds or discontinuation of PD-1 or PD-L1 inhibitor and then 
re-treated are eligible). 
 
3. Any serious or uncontrolled medical disorder or active infection that would impair the ability 
of the subject to receive protocol therapy. 
 
4. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study). 
 
5. Has a known additional malignancy that is progressing or required treatment ≤ 48 months of 
study registration.  Exceptions: include malignancies with negligible risk of metastasis or 
death treated with expected curative outcome or undergoing surveillance per investigator’s 
discretion (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell 
skin cancer,  ductal carcinoma in situ treated surgically with curative intent, or very low risk 
or low risk prostate cancer per NCCN guidelines). 
 
6. Active central nervous system (CNS) metastases. Subjects with brain metastases are eligible 
if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence 
of progression within 28 days prior to the first dose of atezolizumab administration. There 
must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 
mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. 
 
7. Treatment with any investigational drug within 30 days prior to registration.  
 
8. Subjects with an active or recent history of a known or suspected autoimmune disease or 
recent history of a syndrome that required systemic corticosteroids/immunosuppressive 
medications EXCEPT for syndromes which would not be expected to recur in the absence of 
an external trigger. (Subjects with vitiligo, autoimmune thyroiditis, or type I diabetes mellitus 
are permitted to enroll.). 
 


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9. As there is potential for hepatic toxicity with atezolizumab, drugs with a predisposition to 
hepatoxicity should be used with caution in subjects treated with atezolizumab-containing 
regimen. 
 
10. Subjects should be excluded if they have known history of testing positive for hepatitis B 
virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) 
indicating acute or chronic infection. Testing is not required. 
 
11. Subjects should be excluded if they have known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 
Testing is not required. 
 
12. History of allergy to atezolizumab or respective chemotherapy regimen (carboplatin + 
gemcitabine or docetaxel).  
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. A subject 
is considered registered when an “On Study” date is entered into the EDC system. Subjects must 
be registered prior to starting protocol therapy. Subjects must begin therapy within 5 business 
days of registration.  
 
5. 
TREATMENT PLAN 
This is a single arm phase II study assessing the activity of atezolizumab in combination with 
carboplatin + gemcitabine or docetaxel compared to historical controls of chemotherapy only in 
metastatic or recurrent urothelial carcinoma subjects. Subjects that received a PD 1 or PD-L1 
inhibitor with no prior platinum chemotherapy for metastatic disease will be treated with 
atezolizumab + carboplatin + gemcitabine on trial. Subjects that received sequential or 
concurrent PD1/PDL1 inhibitor and carboplatin-based regimen will be treated with atezolizumab 
+ docetaxel on trial. 
 
5.1 
Pre-medications and Hydration 
There are no required pre-medications or intravenous hydration for treatment with carboplatin, 
gemcitabine, docetaxel, or atezolizumab.  Institutional standards will be followed for pre-
medications and/or intravenous hydration for treatment with either carboplatin, gemcitabine, 
docetaxel, or atezolizumab.   
 
 
 


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5.2 
Treatment Administration  
 
5.2.1 Carboplatin, Gemcitabine, and Atezolizumab Administration 
 
Drug1 
Dose2 
Route 
Schedule 
Cycle 
Length 
Carboplatin 
AUC 4  
Intravenously (IV) per 
institutional standards
Day 1 
3 weeks 
(21 days) 
Gemcitabine 
1,000 mg/m2 
IV per institutional standards 
Day 1 and 8  
Atezolizumab 
1,200 mg 
IV over 1 hour  
Day 1 
1 Carboplatin will be infused first followed by gemcitabine then atezolizumab. Atezolizumab will be 
administered a minimum of 5 minutes after carboplatin and gemcitabine  
2 Medication dose will not be changed for reasons other than weight change per institutional policy
NOTE: * Infusions may be given ± 3 days for reasons such as observed holidays, inclement 
weather, scheduling conflicts, etc. It should be clearly documented in patient’s chart and case 
report forms. 
 
5.2.2 Docetaxel and Atezolizumab Administration 
 
Drug1
Dose2
Route
Schedule 
Cycle Length 
Docetaxel  
75mg/m2  
IV per institutional standards 
Day 1 
3 weeks 
(21 days) 
Atezolizumab3 
1,200 mg 
IV over 1 hour  
Day 1 
1 Docetaxel will be infused first followed by atezolizumab. Atezolizumab will be administered a 
minimum of 5 minutes after docetaxel. 
2 Medication dose will not be changed for reasons other than weight change per institutional 
policy.
 
5.2.3 Carboplatin Administration 
Carboplatin AUC 4 will be administered intravenously per institutional standards on Day 1 of 
each 21 day Cycle. Please see package insert for additional details regarding this medication.   
 
5.2.4 Gemcitabine Administration 
Gemcitabine 1,000mg/m2 will be administered intravenously per institutional standards on Days 
1 and 8 of each 21 day Cycle. Please see package insert for additional details regarding this 
medication.   
 
5.2.5 Docetaxel Administration  
Docetaxel 75 mg/m2 will be administered intravenously per institutional standards on Day 1 of 
each 21 day Cycle.  Please see package insert for additional details regarding this medication.   
 


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5.2.6 Atezolizumab Administration 
Atezolizumab will be delivered over 60 minutes (± 15) intravenously on Day 1 of each 21 day 
Cycle. Institutional standards will be used regarding the infusion. If the first infusion is tolerated, 
all subsequent infusions may be delivered over 30 minutes. Guidelines for management of 
atezolizumab-specific adverse events can be found in Appendix 1. Please see the investigator’s 
brochure for additional details regarding this medication. 
 
5.3 
Study Treatment Adjustments 
Chemotherapy (carboplatin + gemcitabine or docetaxel) may be discontinued after 4-6 cycles per 
site investigator and/or patient’s choice.  
 
Atezolizumab should be continued until disease progression per RECIST v1.1 or loss of clinical 
benefit, unacceptable toxicity, or consent withdrawal. NOTE: 
 Patients with progression by RECIST 1.1 may continue treatment with atezolizumab if 
they demonstrate clinical benefit per investigator’s assessment.  
 Patients who have achieved a PR or CR of target lesions and who develop new lesions 
that are amenable to surgery or ablative techniques (e.g., radiotherapy, radiofrequency 
ablation) may continue to receive study treatment if they demonstrate no further 
progression of disease at the next assessment and continue to demonstrate clinical benefit 
per investigator. 
 
5.4 
Concomitant Medications 
All concomitant medications should be reported to the site investigator and recorded on the 
appropriate eCRF. 
 
5.4.1 Allowed Concomitant Medications 
Patients are permitted to use the following therapies during the study: 
 Growth factor support may be delivered at the site investigator's discretion 
 Oral contraceptives 
 Hormone-replacement therapy 
 Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose or 
low-molecular-weight heparin) 
 Inactivated influenza vaccinations 
 Megestrol acetate administered as an appetite stimulant  
 Mineralocorticoids (e.g., fludrocortisone) 
 Corticosteroids administered for COPD or asthma 
 Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic relief 
of pain) as outlined below: 
o Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be the 
only site of measurable disease).  If clinical benefit is observed, treatment with 
atezolizumab may be continued during palliative radiotherapy. Details of 
palliative radiotherapy should be documented in the source records and electronic 
case report form (eCRF). Details in the source records should include: dates of 


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treatment, anatomical site, dose administered and fractionation schedule, and 
adverse events.    
 Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency 
ablation) as outlined below: 
o Patients who receive local therapy directed at a target lesion will no longer be 
evaluable for radiographic response but will remain evaluable for progression. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered for the 
second and subsequent atezolizumab infusions only, at the discretion of the site investigator. In 
general, site investigators should manage a patient’s care with supportive therapies as clinically 
indicated, per local standard practice.  Patients who experience infusion-associated symptoms 
may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-
receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 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. Retreating with medication will be at discretion of investigator.   
 
5.4.2 Prohibited Concomitant Medications 
Use of the following concomitant therapies is prohibited as described below: 
 Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy) 
whether health authority-approved or experimental, is prohibited until disease 
progression is documented and the patient has discontinued study treatment (with the 
exception of palliative radiotherapy and local therapy under certain circumstances – see 
Section 5.3.1 for details). 
 Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 30 days prior to initiation of study treatment and during study treatment. 
 Denosumab (a RANKL inhibitor) is prohibited during the atezolizumab treatment 
because it could potentially alter the efficacy and safety of atezolizumab.  Patients who 
are receiving denosumab prior to enrollment must be willing and eligible to receive a 
bisphosphonate instead during atezolizumab treatment. 
 Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation 
of study treatment, during treatment with atezolizumab, and for 5 months after the last 
dose of atezolizumab. 
 Systemic immunostimulatory agents (including, but not limited to, interferons and IL 2) 
are prohibited within 4 weeks or five half-lives of the drug (whichever is longer) prior to 
initiation of study treatment and during study treatment because these agents could 
potentially increase the risk for autoimmune conditions when given in combination with 
atezolizumab. 
 Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited during 
study treatment because these agents could potentially alter the efficacy and safety of 
atezolizumab. 
 
 
 


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6 
Toxicities and Dose Delays/Dose Modifications 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 will be used to grade 
adverse events. Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study as specified 
in Study Calendar & Evaluations. Subjects will be evaluated for adverse events (all grades), 
serious adverse events, and adverse events requiring study drug interruption or discontinuation as 
specified in Study Calendar & Evaluations.   
 
6.1 
Dose Delays for Atezolizumab 
Management of atezolizumab-specific adverse events can be found in Appendix 1. Dose delay 
criteria apply for all drug-related adverse events (regardless of whether or not the event is 
attributed to atezolizumab). All study drugs must be delayed until treatment can resume.  
 
Atezolizumab administration should be delayed for the following: 
 
Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
 Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay 
 Grade 3 skin, drug-related AE 
 
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
 Grade ≤ 3 lymphopenia or leukopenia does not require dose delay. 
 If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥ 2 toxicity. 
 If a subject has a baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥ 3 toxicity. 
 Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. The 
sponsor-investigator should be consulted for such Grade ≥ 3 amylase or lipase 
abnormalities. 
 
Any AE, laboratory abnormality, or inter-current illness which, in the judgment of the site 
investigator, warrants delaying the dose of study medication. 
 
Subjects who require delay of atezolizumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume atezolizumab dosing when re-treatment criteria are met. 
 
Patients may temporarily suspend study treatment for up to 42 days beyond the last dose if they 
experience adverse events that require a dose to be held. If atezolizumab is held because of 
adverse events for > 42 days beyond the last dose, then the patient will be discontinued from 
atezolizumab and will be followed for safety and efficacy.  
 
If, in the judgment of the site investigator, the patient is likely to derive clinical benefit from 
atezolizumab after a hold of > 42 days, study drug may be restarted with the approval of the 
sponsor-investigator. If a patient must be tapered off steroids used to treat adverse events, 
atezolizumab may be held for additional time beyond 42 days from the last dose until steroids are 
discontinued or reduced to prednisone dose (or dose equivalent) ≤ 10 mg/day. The acceptable 


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length of interruption will depend on an agreement between the site investigator and sponsor-
investigator. 
 
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be allowed 
with sponsor-investigator approval. The acceptable length of interruption will depend on 
agreement between the site investigator and the sponsor-investigator. 
 
6.1.1 Criteria to Resume Treatment with Atezolizumab 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 
or baseline value, with the following exceptions: 
 Subjects may resume treatment in the presence of Grade 2 fatigue  
 Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
 Subjects with baseline Grade 1 AST, ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST, ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST, ALT OR total bilirubin 
 Subjects with combined Grade 2 AST, ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 
 Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed. Subjects with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month will be eligible to restart treatment at 
the discretion of the treating physician. 
 Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment at the discretion of the treating physician. 
 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled time-point per protocol. However, if the treatment is delayed past the next scheduled 
time-point per protocol, the next scheduled time-point will be delayed until dosing resumes. 
 
If treatment is delayed or interrupted for > 6 weeks, the subject must be permanently 
discontinued from study therapy, except as specified abpve 
 
6.1.2 Discontinuation Criteria for Atezolizumab 
Patients must permanently discontinue study treatment (atezolizumab and/or carboplatin plus 
gemcitabine) if they experience any of the following: 
 Intolerable toxicity related to study treatment, including development of an immune 
mediated adverse event determined by the site investigator to be unacceptable given the 
individual patient’s potential response to therapy and severity of the event 
 Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment 
 Site investigator determines it is in the best interest of the patient 
 Use of another non-protocol anti-cancer therapy 
 Pregnancy 
 Loss of clinical benefit as determined by the site investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), and 
clinical status (e.g., symptomatic deterioration such as pain secondary to disease). 


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Patients will discontinue treatment at occurrence of progression with the following 
exception:  Patients who have achieved a PR or CR of target lesions and who develop 
new lesions that are amenable to surgery or ablative techniques (e.g., radiotherapy, 
radiofrequency ablation) may continue to receive study treatment if they demonstrate no 
further progression of disease at the next assessment and continue to demonstrate clinical 
benefit per investigator. 
 
The primary reason for study treatment discontinuation should be documented in the patient’s 
medical records.  
 
Patients will return to the clinic for a treatment discontinuation visit around 30 days after the last 
dose of study treatment.  The visit at which response assessment shows progressive disease may 
be used as the treatment discontinuation visit.  Patients who discontinue study treatment for any 
reason other than progressive disease or loss of clinical benefit will continue to undergo tumor 
response assessments as outlined in the schedule of activities. 
 
Subjects will be followed up to 18 months after the last patient is enrolled onto the study. 
Information on survival follow-up and new anti-cancer therapy will be collected via telephone 
calls, patient medical records, and/or clinic visits. 
 
6.1.3 Dose Modifications for Atezolizumab Dose modifications on Day 1 
Dose reductions or dose escalations of atezolizumab are not permitted. If treatment with 
carboplatin+gemcitabine or docetaxel is delayed, atezolizumab dosing should be delayed as well 
and should resume to stay “in-sequence” with carboplatin + gemcitabine or docetaxel cycles.  
 
6.1.4 Management of Atezolizumab-Specific Adverse Events 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology. Although most immune-
mediated adverse events observed with immunomodulatory agents have been mild and self-
limiting, such events should be recognized early and treated promptly to avoid potential major 
complications. Discontinuation of atezolizumab may not have an immediate therapeutic effect 
and in severe cases, immune-mediated toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, or other immunosuppressive agents. 
 
The primary approach to Grade 1−2 immune-mediated adverse events is supportive and 
symptomatic care with continued treatment with atezolizumab; for higher grade immune-
mediated adverse events, atezolizumab should be held and oral/parenteral steroids administered. 
Recurrent Grade 2 immune-mediated adverse events may also mandate withholding 
atezolizumab or the use of steroids. Consideration for benefit-risk balance should be made by the 
site investigator, with consideration of the totality of information as it pertains to the nature of 
the toxicity and the degree of clinical benefit a given patient may be experiencing prior to further 
administration of atezolizumab. Atezolizumab should be permanently discontinued in patients 
with life-threatening immune-mediated adverse events. 
 


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Management of systemic immune activation is presented below. See the Atezolizumab 
Investigator’s Brochure for details on management of gastrointestinal, dermatologic, endocrine, 
pulmonary toxicity, hepatotoxicity, potential pancreatic or eye toxicity and other immune-
mediated adverse events. 
 
6.2 
Dose Modifications for Carboplatin and Gemcitabine 
 
6.2.1 Hematologic adjustments 
Complete white blood cell (WBC) and platelet count weekly on days 1 and 8 in every cycle. 
Absolute neutrophils count (ANC) is recommended and is mandatory whenever WBC < 3.0 x 
109/l. Grade 3 febrile neutropenia should be retreated after recovery. 
 
Dose modifications on Day 1 
WBC x 109/l 
 
ANC x 109/l 
 
Platelets x 109/l
% dose of 
Gemcitabine
% dose of 
Carboplatin 
≥ 3.0 
and 
≥ 1.5 
and
≥ 100 
100 
100 
< 3.0 
and 
≥ 1.5 
and
≥ 100 
100 
100 
< 3.0 
or 
< 1.5 
or 
< 100 
Delay 1 week
Delay 1 week 
 
Dose modifications on Day 8 
WBC x 109/l 
 
ANC x 109/l 
 
Platelets x 109/l
% dose of Gemcitabine 
≥ 3.0 
and 
≥ 1.5 
and 
≥ 100 
100 
≥ 2.0 – 3.0 
and 
≥ 1.0 
and 
> 100 
100 
1.0 – 1.9 
or 
>0.5 - <1.0 
or 
50-99 
50 
< 1.0 
or 
<0.5 
or 
< 50 
Withhold 
NOTE: If treatment with carboplatin and gemcitabine is delayed per guidelines in 6.1.6.1, 
atezolizumab dosing should be delayed as well and should resume to stay “in-sequence” with 
carboplatin + gemcitabine cycles. 
 
Dose modifications for subsequent cycles 
At day 1, 25% dose reduction of carboplatin and gemcitabine if during the nadir one or more of 
the following occurs: 
 grade IV neutropenia (ANC < 0.5 x 109/l) with fever > 38.5 C or 
 grade IV thrombocytopenia (<10.0 x 109/l) for more than 3 days or 
 thrombocytopenia with active bleeding during the nadir. 
 
If a patient requires more than 2 weeks for hematologic recovery (defined as at least WBC is ≥ 
2.0 x 109/l, ANC ≥ 1.0 x 109/l and platelets ≥ 75 x 109/l), treatment should be continued with 
75% of both drugs.  
 


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6.2.2 Renal Toxicity 
 Carboplatin will be adjusted every cycle using Calvert’s formula. 
 For gemcitabine, no dose modification is necessary if the GFR is ≥ 30 ml/min. 
Gemcitabine is withheld if the GFR is less than 30 ml/min. 
 
6.2.3 Hypersensitivity reaction adjustments 
 No dose reductions will be made for any hypersensitivity reactions.  If a subject 
experiences a hypersensitivity reaction, treatment should be as indicated below: 
o Grade 1 symptoms (eg., mild flushing, rash, pruritis) = complete infusion.  
Supervise at bedside.  No treatment required. 
o Grade 2 symptoms (e.g., moderate rash, flushing, mild dyspnea, chest discomfort) 
= Stop infusion.  Give intravenous diphenhydramine 25 mg and intravenous 
dexamethasone 10 mg.  Resume infusion after recovery of symptoms at a slower 
rate, then increased incrementally to the initial planned rate.  Depending on the 
intensity of the reaction observed, additional oral or IV premedication with an 
antihistamine should also be given for the next cycle of treatment and the rate of 
infusion should be decreased initially and then increased back to the 
recommended 1 hour infusion.   
o Grade 3 symptoms (e.g., hypotension requiring pressor therapy, angioedema, 
respiratory distress requiring bronchodilation therapy, generalized urticaria) = 
Stop infusion.  Give intravenous diphenhydramine and dexamethasone as above.  
Add epinephrine or bronchodilators if indicated.  If wheezing is present, that is 
not responsive to administration of 0.35 cc of nebulized salbutamol solution (or 
equivalent), epinephrine is recommended.  The subject will go off study 
o Grade 4 symptoms = Anaphylaxis—Discontinue protocol treatment. 
 
6.2.4 Other non-hematologic toxicities 
 Grade ≥ 3 AE = carboplatin and gemcitabine should be held until resolution to Grade 1 or 
less, then reinstituted, if medically appropriate, after recovery. 
 Subjects requiring a > 2 week delay in starting Cycle 2 or 3 due to non-hematologic 
toxicity will be removed from protocol treatment. 
 
6.3 
Dose Modifications for Docetaxel  
 
Drug 
Dose Level 
Dose 
Docetaxel
Full Dose
75 mg/m2/d
Docetaxel
Dose Level –1
55 mg/m2/d
Docetaxel
Dose Level –2 
35 mg/m2/d
 
NOTE: If treatment with docetaxel is delayed, atezolizumab dosing should be delayed as well 
and should resume to stay “in-sequence” with docetaxel cycles. 
 
6.3.1 Hematologic adjustments 
 Grade 3 febrile neutropenia should be retreated after recovery with a one level dose 
reduction. 


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 Grade 4 neutropenia lasting > 7 days should be retreated after recovery with a one level 
dose reduction. 
 Grade 4 thrombocytopenia or thrombocytopenic bleeding should be retreated after 
recovery with a one level dose reduction. 
 
6.3.2 Peripheral neuropathy adjustments 
 Grade 2 = subsequent retreatment after recovery should be with a one level dose 
reduction. 
 Grade 3 or higher peripheral neuropathy toxicity = discontinuation of study treatment. 
 
6.3.3 Hypersensitivity reaction adjustments 
 No dose reductions will be made for any hypersensitivity reactions.  If, despite proper 
pretreatment with dexamethasone, the subject experiences a hypersensitivity reaction, 
treatment should be as indicated below: 
o Grade 1 symptoms (eg., mild flushing, rash, pruritis) = complete infusion.  
Supervise at bedside.  No treatment required. 
o Grade 2 symptoms (e.g., moderate rash, flushing, mild dyspnea, chest discomfort) 
= Stop infusion.  Give intravenous diphenhydramine 25 mg and intravenous 
dexamethasone 10 mg.  Resume infusion after recovery of symptoms at a slower 
rate, then increased incrementally to the initial planned rate.  Depending on the 
intensity of the reaction observed, additional oral or IV premedication with an 
antihistamine should also be given for the next cycle of treatment and the rate of 
infusion should be decreased initially and then increased back to the 
recommended 1 hour infusion.   
o Grade 3 symptoms (e.g., hypotension requiring pressor therapy, angioedema, 
respiratory distress requiring bronchodilation therapy, generalized urticaria) = 
Stop infusion.  Give intravenous diphenhydramine and dexamethasone as above.  
Add epinephrine or bronchodilators if indicated.  If wheezing is present, that is 
not responsive to administration of 0.35 cc of nebulized salbutamol solution (or 
equivalent), epinephrine is recommended.  The subject will go off study 
o Grade 4 symptoms = Anaphylaxis—Discontinue protocol treatment. 
 
6.3.4 Hepatic adjustments 
Subjects who develop abnormal liver function tests for any reason while on the study will have 
the following docetaxel dose reductions: 
 
Abnormal Liver Function Dose Modifications for Docetaxel 
Bilirubin 
Alkaline 
Phosphatase 
SGOT (AST) 
Action 
> ULN 
 
or > 5 X ULN 
or > 5 X ULN 
 
Wait <2 weeks.  If 
recovered*, reduce 
docetaxel dose by –
1 dose level.  If not, 
off study.  


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< ULN 
and < 5 X ULN 
and 1.6-5 X ULN 
Reduce docetaxel 
dose by –1 dose 
level. 
*Bilirubin < ULN and alkaline phosphatase < 5 X ULN and SGOT (AST) < 5 X ULN. 
NOTE:  A maximum of two dose reductions per patient are allowed. 
ULN= upper limit of normal for institution 
 
6.3.5 Fluid retention adjustments: 
 If symptomatic, subjects developing fluid retention may be treated with diuretics at the 
investigator’s discretion.   
 Grade 3 = Docetaxel should be held until resolution to < Grade 1, then reinstituted, if 
medically appropriate, after recovery, with a one level dose reduction. 
 
6.3.6 Stomatitis adjustments: 
Grade 3 or 4 stomatitis = retreatment after recovery to ≤ Grade 1 with a one level dose reduction. 
 
6.3.7 Other non-hematologic toxicities: 
 Grade > 3 AE = Docetaxel should be held until resolution to ≤ Grade 1 or less, then 
reinstituted, if medically appropriate, after recovery, with a one level dose reduction. 
 Subjects requiring a > 2 week delay in starting Cycle 2 or 3 due to non-hematologic 
toxicity will be removed from protocol treatment. 
 
6.4 Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in Section 6.1, a 
subject will also be discontinued from protocol therapy and followed per protocol under the 
following circumstances: 
 Documented disease progression NOTE: patients who demonstrate clinical benefit per 
investigator’s assessment may continue on atezolizumab treatment at the treating 
investigator's discretion. See Section 5 for additional detail. 
 Site investigator determines a change of therapy would be in the best interest of the 
subject. 
 Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
 Female subject becomes pregnant.  
 Protocol therapy is interrupted for ≥ 6 weeks unless requiring steroid taper  
 
Subjects will be removed from protocol therapy and the site investigator notified when any of the 
criteria listed above apply. The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF).  The subject will continue to be followed 
per Section 7. 


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6.5 Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
 
 


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7 
STUDY CALENDAR & EVALUATIONS 
Study Evaluation 
 
Cycle = 21 days 
Screening 
On Treatment 
Safety follow 
up visit10 
Safety follow 
up evaluation10 
Long-term 
Follow up11 
-28 days 
Day 1 
(± 3 days) 
Day 8 
(± 3 days) 
30 days 
(± 7 days) 
post last dose
100 days 
(± 7 days) 
post last dose
(± 14 days) 
REQUIRED ASSESSMENTS 
Informed Consent
X
Medical History1
X
Physical Exam
X
X
X
Vital signs and ECOG Performance Status2
X
X
X
AEs & concomitant medications
X
X
X
X
LABORATORY ASSESSMENTS 
Complete Blood Cell Count with diff (CBC)3 
X
X3
X
X
Comprehensive Metabolic Profile (CMP)3
X
X3
X
Thyroid Function (TSH, T4, T3)4 
X
X4 
Pregnancy test (serum or urine) (WOCBP)5 
X
X5 
DISEASE ASSESSMENT 
CT of chest6 
X
X6 
 
X11 
CT or MRI of abdomen and pelvis6 
X6 
X6 
 
X11 
MRI Brain6
X
X6 
X11 
TREATMENT EXPOSURE12
Atezolizumab
X
 
Carboplatin, Gemcitabine OR
CARBO/GEM
GEM
Docetaxel
DOCETAXEL
SPECIMEN COLLECTION  
REQUIRED: Archival Tumor Tissue7 
X
OPTIONAL: Pre-Treatment Biopsy8 
X8 
REQUIRED: Whole Blood, Serum, Plasma9
X9 
X
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X
 
 
 
 


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Key to Footnotes  
1: Medical History to include: smoking history, trial awareness question, diagnosis and staging (to include pathology report and Tumor Node 
Metastasis (TNM) staging) and prior treatment history.   
 
2: Vital signs to include blood pressure, weight, and height (screening only) and ECOG performance status. 
 
3: If screening CBC and CMP were performed within 7 days of Cycle 1 Day 1 of treatment, these do not need to be repeated.  Day 8 CBC is 
applicable to only those subjects receiving gemcitabine. CBC with differential to include Hgb, Hct, WBC, ANC platelet count.  CMP to include 
sodium, potassium, chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline 
phosphatase.   
 
4: Thyroid function to be checked at screening. During treatment, monitoring of thyroid function is at the site investigator’s discretion- TSH, T3 
and T4. Free versus total for T3 and T4 is at the site investigator’s discretion. 
 
5: Females of childbearing potential (FOCBP) must have a negative serum pregnancy test within 28 days prior to registration. FOCBP must also 
have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of 
atezolizumab then every 6 weeks during treatment.  
 
6: Radiology Imaging:  Screening tests should be done -28 days from registration.  Pelvic CT or MRI should be done if it is a known disease site.  
MRI of brain should be performed at screening only if the site investigator suspects the presence of brain metastases.  Tumor response assessment 
will consist of evaluation by CT scans of chest and abdomen (pelvis if known disease site) every odd numbered cycle starting after screening 
with Cycle 3 (imaging selected for each subject should remain the same throughout the study).  During follow up, tumor imaging is at the 
discretion of the investigator. Radiology imaging may take place within 7 days prior to a study visit.   
 
7: REQUIRED IF AVAILABLE. Archival tumor tissue (prior to treatment with PD-1 or PD-L1 inhibitor) must be identified during the 
screening period and obtained prior to registration. Confirmation of acquisition should occur prior to C1D1 treatment. Sample requirement is 
FFPE block + 2 H&E stained slides or 17 unstained slides + 2 H&E stained slides.  Sample will be used for PD-L1 status and genetic analyses.  
Subjects will be consented to optional storage of any remaining tumor samples after protocol-specified studies are complete. Stored samples will 
be reserved for future unspecified cancer-related research. See Correlative Laboratory Manual (CLM) for additional details. 
 
8: OPTIONAL (RECOMMENDED). A biopsy after registration and prior to C1D1 treatment for PD-L1 status and other correlative studies should 
be from the primary tumor or a metastatic lesion.  Biopsy should be excisional, incisional or core needle. Fine needle aspiration is insufficient. 
Sample requirement is block + 2 H&E stained slides or 17 unstained slides and 2 H&E stained slides.  Sample will be used for PD-L1 and genetic 
analyses.  Subjects will be consented to optional storage of any remaining tumor samples after protocol-specified studies are complete. Stored 
samples will be reserved for future unspecified cancer-related research. See CLM for additional details. 
 


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9: REQUIRED: whole blood, serum, and plasma for cell-free DNA and proteomic correlative analysis. Obtain during screening or prior to 
treatment C1D1 and at time of progression/D30 safety visit.  Subjects will be consented to optional storage of any remaining blood samples after 
protocol-specified studies are complete. Stored samples will be reserved for future unspecified cancer-related research. See CLM for additional 
details. 
 
10: Safety follow-up visit should occur when subjects permanently stop study treatment for whatever reasons (toxicity, progression, or at 
discretion of site investigator) and should be performed 30 days (±7 days) after the last dose of study treatment. The visit at which response 
assessment shows progressive disease may be used as the treatment discontinuation visit. A safety follow up call, email or other avenues as 
appropriate will be made 100 days (±7 days) after the last dose of study treatment for AE assessment. Subjects who have an ongoing ≥ grade 2 or 
serious AE (SAE) at this visit will continue to be followed until the AE resolves to ≤ Grade 1 or baseline, deemed clinically insignificant, and/or 
until a new anti-cancer treatment starts, whichever is earlier.  
 
11: Long Term Follow Up: Subjects will be followed every 6 months up to 18 months after the last patient is enrolled onto the study. Radiology 
imaging should be done at the site investigator’s discretion during this time and results made available to the research staff. Follow up may be 
accomplished via clinic visit, phone call, or other avenues as appropriate.  
 
12: A cycle is equal to 21 days. All subjects will receive atezolizumab on Day 1. Chemotherapy is based on prior platinum therapy.  If no prior 
platinum therapy: carboplatin (Day 1) and gemcitabine (Day 1 and 8). If prior platinum therapy: docetaxel (Day 1).  
 
 
 
  
 


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8 
BIOSPECIMEN STUDIES AND PROCEDURES 
For tumor specimens or blood collected in the protocol, please see the CLM for additional 
information regarding collection, labeling and shipping. 
 
Published results suggest that the expression of PD-L1 in tumors correlates with response to anti-
PD-1 and anti-PD-L1 therapy.22,38,39 In the current study, archival or baseline tumor specimens 
will be collected from patients and tested for PD-L1 expression by a central laboratory. In 
addition to the assessment of PD-L1 status, other exploratory biomarkers, such as potential 
predictive and prognostic biomarkers related to the clinical benefit of PD-1 or PD-L1 inhibitor, 
tumor immunobiology, mechanisms of resistance, or tumor type, may be analyzed. 
 
Archival tumor tissue will be collected at baseline (REQUIRED, if available). Tumor tissue will 
also be collected by biopsy prior to C1D1 treatment (OPTIONAL) to enable analysis of tumor 
tissue biomarkers related to resistance, disease progression, and clinical benefit of PD-1 or PD-
L1 inhibitors. 
 
Blood samples will be collected at baseline (REQUIRED) and at the time of progression on 
study therapy to evaluate changes in surrogate biomarkers. Changes in biomarkers such as 
cytokines associated with T cell activation and lymphocyte subpopulations may provide 
evidence of biologic activity of PD-1 or PD-L1 inhibitors in humans.  Correlations between these 
biomarkers and safety and efficacy endpoints may be explored in a future analysis to identify 
blood-based biomarkers that might predict which patients are more likely to benefit from PD-1 
or PD-L1 inhibitors.   
 
8.1 
REQUIRED IF AVAILABLE: Archived Tumor Sample  
Formalin-fixed, paraffin-embedded archival tumor tissue block for biomarker evaluation should 
be obtained (required if available) at screening for all subjects prior to C1D1 treatment. These 
biopsy samples should be from an excisional, incisional, punch or core needle biopsy. Fine 
needle aspirates or other cytology specimens are insufficient for downstream biomarker analyses. 
Sample requirement is FFPE block + 2 H&E stained slides or 17 unstained slides + 2 H&E 
stained slides.  Sample should have been obtained prior to treatment with PD-1 or PD-L1 
inhibitor.  
 
8.1.1 PD-L1 Analysis 
Specimens will be submitted for central PD-L1 immunohistochemistry (IHC) assessment. PD-L1 
stained tissue sections will be assessed by a pathologist and scored as PD-L1 positive if 
membrane staining is observed. PD-L1 expression will be evaluated on tumor cells and tumor-
infiltrating immune cells with standard PD-L1 immunohistochemistry assay.  
. 
Scoring will be performed for tumor cells expressing PD-L1 as a percentage of total tumor cells 
and tumor-infiltrating immune cells expressing PD-L1 as a percentage of tumor area, as 
previously described (tumor cells scored as percentage of PD-L1-expressing tumor cells: 
TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%; tumor infiltrating immune 
cells scored as percentage of tumor area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and 
IC0<1%).40 


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8.2 
OPTIONAL (RECOMMENDED): Biopsy Prior to C1D1 treatment 
A fresh or formalin-fixed, paraffin-embedded tumor tissue block or unstained slides of tumor 
sample (recent, after progression on PD-1 or PD-L1 inhibitor therapy) for biomarker evaluation 
is optional but if performed should be done prior to C1D1 treatment and received prior to C2D1. 
Fine needle aspirates or other cytology specimens are insufficient for downstream biomarker 
analyses. Sample requirement is FFPE block + 2 H&E stained slides or 17 unstained slides + 2 
H&E stained slides. 
 
Specimens will be submitted for central PD-L1 immunohistochemistry (IHC) assessment. These 
biopsy samples should be excisional, incisional, punch or core needle. PD-L1 stained tissue 
sections will be assessed by a pathologist and scored as PD-L1 positive if membrane staining is 
observed. Please refer to section 8.1.1 for details regarding PD-L1 testing.   
 
8.3 
REQUIRED: Blood Draw Prior to C1D1 Treatment and at Progression 
Whole blood, serum, and plasma will be collected prior to C1D1 and at the time of 
progression/D30 safety visit. Blood samples will be utilized for cell-free DNA and proteomic 
analysis by the sponsor-investigator to evaluate clonal evolution and mechanisms of resistance to 
therapy.  
 
8.4 
Storage of Biospecimens 
Any remaining bio-specimens (tissue or blood) will be stored for future unspecified cancer 
related research once protocol described biospecimen-based studies are completed. Permission 
for storage will be obtained from subjects during informed consent. 
 
8.5 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s sequence ID assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and 
only identified by the subject’s sequence ID. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
 
9.2 
RECIST 1.1 Criteria  
Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (see Eisenhauer EA et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Can, 
2009.45:p.228-247).  Refer to the RECIST 1.1 publication for complete details on these criteria. 
 
9.1.1 Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam (lesions which cannot be accurately measured with calipers should be 
recorded as non-measurable). All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 


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9.1.2 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
9.1.3 Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable.  NOTE:  Cystic lesions that meet the criteria for 
radiographically defined simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ 
thought to represent cystic metastases can be considered as measurable lesions, if they meet the 
definition of measurability described above. However, if non-cystic lesions are present in the 
same subject, these are preferred for selection as target lesions. 
 
9.1.4 Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
9.1.5 Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
 
 


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9.1.6 Evaluation of Target Lesions 
NOTE: In addition to the information below, also see in the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 (Eur J 
Cancer 45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm.
Partial 
Response (PR)
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note:  the 
appearance of one or more new lesions is also considered 
progressions).
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study
 
9.1.7 Evaluation of Non-Target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a subject to be 
considered in complete clinical response.
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of 
overall disease status change, not a single lesion 
increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
 
 
 


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9.1.8 Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD/ or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
Non-evaluable
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
n exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
9.2 
Definitions for Response Evaluation – RECIST 1.1 
 
9.2.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.2.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 
9.2.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
 
9.2.4 Duration of Overall Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 


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9.2.5 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
 
9.2.6 Clinical Benefit Rate 
The clinical benefit rate is the proportion of all subjects with stable disease (SD) for at least 3 
months, or partial response (PR), or complete response (CR) according to RECIST 1.1, from the 
start of treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the start of treatment). 
 
9.2.7 Progression Free Survival 
A measurement from the date of treatment start until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-censored 
at the date of the last disease evaluation. 
 
9.2.8 Overall Survival 
Overall survival is defined by the date of treatment start to date of death from any cause. 
 
9.3 
Immune- Related RECIST Criteria  
Immune-related RECIST criteria (see Bohnsack O. et al. Adaptation of the immune-related 
response criteria: irRECIST. ESMO 2014 Abstract 4958. http://www.irrecist.com/  
Refer to the publication for complete details on these criteria. 
 
9.3.1 Measurable lesion definitions and target lesion selection 
Follow the definitions from RECIST 1.1. Measurable lesions must be accurately  measured in at 
least one dimension with a minimum size of: 
 10 mm in the longest diameter by CT or MRI scan (or no less than double the slice 
thickness) for non-nodal lesions and ≥15 mm in short axis for nodal lesions 
 10 mm caliper measurement by clinical exam 
 20 mm by chest X-ray 
 At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 
visceral lesions and five cutaneous index lesions) is calculated. 
 Baseline: Target and Non-Target Lymph Node Lesion Definitions - Follow the 
definitions from RECIST 1.1 
 Baseline: Bone Lesions- Follow the definitions from RECIST 1.1. Regardless of the 
imaging modality blastic bone lesions will not be selected as target lesions. Lytic or 
mixed lytic-blastic lesions with a measurable soft tissue component ≥10 mm can be 
selected as target lesions. 
 Baseline: Cystic and necrotic lesions as target lesions that are partially cystic or necrotic 
can be selected as target lesions. The longest diameter of such a lesion will be added to 
the Total Measured Tumor Burden (TMTB) of all target lesions at baseline. If other 
lesions with a non-liquid/non-necrotic component are present, those should be preferred. 


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 Baseline: Lesions with prior local treatment during target lesion selection the radiologist 
will consider information on the anatomical sites of previous intervention (e.g. previous 
irradiation, RF-ablation, TACE, surgery, etc.). Lesions undergoing prior intervention will 
not be selected as target lesions unless there has been a demonstration of progress in the 
lesion. 
 
9.3.2 Follow-up 
 Only index and measurable new lesions are taken into account. The longest diameters of 
non-nodal target and new non-nodal measurable lesions, and short axes of nodal target 
and new nodal measurable lesions will be recorded. Together they determine the Total 
Measured Tumor Burden (TMTB) at follow-up. 
 Definition of Measurable New Lesions: In order to be selected as new measurable lesions 
(≤ 2 lesions per organ, ≤ 5 lesions total, per timepoint), new lesions must meet criteria as 
defined for baseline target lesion selection and meet the same minimum size requirements 
of 10 mm in long diameter and minimum 15 mm in short axis for new measurable lymph 
nodes. New measurable lesions shall be prioritized according to size, and the largest 
lesions shall be selected as new measured lesions. 
 Non-Target Lesion Assessment- The RECIST 1.1 definitions for the assessment of non-
target lesions apply. The response of non-target lesions primarily contributes to the 
overall response assessments of irCR and irNon-CR/Non-PD (irNN). Non-target lesions 
do not affect irPR and irSD assessments. Only a massive and unequivocal worsening of 
non-target lesions alone, even without progress in the TMTB is indicative of irPD. 
 New Non-Measurable Lesions Definition and Assessment: All new lesions not selected 
as new measurable lesions are considered new non-measurable lesions and are followed 
qualitatively. Only a massive and unequivocal progression of new non-measurable 
lesions leads to an overall assessment of irPD for the timepoint. Persisting new non-
measurable lesions prevent irCR. 
 
9.3.3 Best overall response using the irRECIST 
The overall response according to the irRECIST is derived from time-point response assessments 
(based on tumor burden) as follows: 
 Complete response (irCR) is defined by the complete disappearance of all lesions. Lymph 
nodes must decrease to < 10 mm in short axis. Confirmation of response is not 
mandatory. 
 Partial response (irPR) is defined by the decrease of ≥ 30% in TMTB relative to baseline, 
non-target lesions are irNN, and no unequivocal progression of new non-measurable 
lesions. Stable disease (irSD) is when the measurements do not meet criteria for irCR or 
irPR, in absence of progressive disease (irPD). 
 irPD is defined by a minimum 20% increase and minimum 5 mm absolute increase in 
TMTB compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first irPD 
assessment.  
 
 
 


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10 DRUG INFORMATION 
 
10.1 
Atezolizumab 
Atezolizumab lacks the N-linked oligosaccharides typically observed on other CHO-derived 
monoclonal antibodies because it incorporates an amino acid substitution (asparagine to alanine) 
at position 298 in the CH2 domain of each heavy chain, resulting in a non-glycosylated antibody. 
This non-glycosylated antibody has minimal binding to Fcγ receptors and, consequently, 
prevents Fc-effector function and depletion of cells expressing PD-L1 at expected concentrations 
in humans. 
 
 
Early Phase I/II Material (F01) 
Late Phase I/II and Phase III Material 
(F03)
Generic name
Atezolizumab
Atezolizumab
Code number
RO5541267/F01
RO5541267/F03
Chemical name 
Humanized monoclonal antibody 
based on a human IgG1 framework 
containing heavy chain VHIII and 
light chain VκI subgroup sequences.
Humanized monoclonal antibody based 
on a human IgG1 framework containing 
heavy chain VHIII and light chain VκI 
subgroup sequences.
Chemical structure
The recombinant antibody consists 
of two heavy chains and two light 
chains with inter and intra chain 
disulfide bonds that are typical of 
IgG1 antibodies. 
The recombinant antibody consists of two 
heavy chains and two light chains with 
inter and intra chain disulfide bonds that 
are typical of IgG1 antibodies. 
Molecular weight 
150 KD 
150 KD 
Description 
Colorless to slightly yellow solution 
Colorless to slightly yellow solution 
 
10.1.1 Supplier/How Supplied 
Atezolizumab Injection, 1200 mg/20 mL (60 mg/mL)  
 
The atezolizumab Drug Product in Formulation F03 (late Phase I/II and Phase III clinical 
studies) is provided in a single-use, 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. 
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more 
than the stated volume to enable delivery of the entire 20 mL volume. The atezolizumab Drug 
Product is formulated as 60 mg/mL atezolizumab in a solution containing histidine acetate, 
sucrose, and polysorbate 20 at pH 5.8. 
 
GNE will supply atezolizumab at no charge to subjects participating in this clinical trial.  
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
 
 


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10.1.2 Preparation  
Atezolizumab Injection, 1200 mg/20 mL (60 mg/mL) 
Atezolizumab in Formulation F03 (1200 mg per vial) will be administered in 250-mL 0.9% NaCl 
IV infusion bags and infusion lines equipped with 0.2 μm in-line filters. The IV bag may be 
constructed of polyvinyl chloride or polyolefin, the IV infusion line may be constructed of 
polyvinyl chloride or polyethylene, and the 0.2 μm in-line filter may be constructed of 
polyethersulfone. The use of administration supplies composed of materials other than those 
listed should be avoided if possible. Atezolizumab must be prepared/diluted under appropriate 
aseptic conditions as it does not contain antimicrobial preservatives. The prepared solution for 
infusion should be used immediately to limit microbial growth in case of potential accidental 
contamination. If not used immediately, in-use storage time and conditions prior to use are the 
responsibility of the user. The dose solution should be stored at 2°C–25°C (36°F–77°F). The 
total storage time prior to administration should not exceed 8 hours. 
 
10.1.3 Storage and Stability 
Atezolizumab Injection, 1200 mg/20 mL (60 mg/mL)  
Atezolizumab (F03) and the diluent must be refrigerated at 2°C−8°C (36°F−46°F) upon receipt 
until use. Atezolizumab and the diluent 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, the vial is intended for single use only. Discard any unused portion of drug 
remaining in a vial. Vial contents should not be frozen or shaken and should be protected from 
light. 
 
10.1.4 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
10.1.5 Dispensing 
Atezolizumab must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Atezolizumab should be stored in a secure area according to 
local regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
10.1.6 Adverse Events 
The most common side effects of atezolizumab are: Fatigue, decreased appetite, diarrhea, 
vomiting, arthralgia, asthenia, dyspnea, urinary tract infection, cough, pruritis, rash, nausea, fever 
and musculoskeletal pain. Please see current IB for a detailed list of side effects. 
 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated adverse events have been closely monitored during the atezolizumab clinical 
program. These include potential dermatologic, hepatic, endocrine, and respiratory events, as 
well as events of hepatitis/elevated liver function tests (LFTs) and influenza-like illness that are 
considered potential adverse drug reactions associated with atezolizumab. There is also a 
potential for immune activation being associated with generalized systemic features (e.g., 
hypotension, respiratory failure, and other organ impairment). 
 


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Atezolizumab has been associated with risks such as the following:  IRRs and immunerelated 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, meningoencephalitis, myocarditis, nephritis, myositis, and severe cutaneous 
adverse reactions.  Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome.  Refer to the 
Atezolizumab Investigator’s Brochure for a detailed description of anticipated safety risks for 
atezolizumab.   
 
10.2 
Carboplatin 
Please see package insert for detailed information regarding this medication 
 
10.2.1 Other Names 
Carboplatin (carboplatin for injection or platinum diamine [1,1-cyclobutane-decarbozxylate (2—
0,0’)-,(SP-4-2)]) 
 
10.2.2 Classification 
Platinum compound chemotherapeutic agent 
 
10.2.3 Mode of Action 
Carboplatin is a second generation platinum compound and acts by covalently binding to DNA. 
It can react with 2 different sites on DNA to produce cross-links, either intra-stand (>90% of the 
time) or inter-strand (<5% of the time). Formation of DNA adducts results in inhibition of DNA 
synthesis and function as well as inhibition of transcription. Carboplatin can form complexes 
with nuclear and/or cytoplasmic proteins which may contribute to anti-tumor activity as well as 
toxicity.  
 
10.2.4 Storage and Stability 
Intact vials of carboplatin are stable for the period indicated on the package when stored at room 
temperature (15-30°C or 59-86°F) and protected from light. When prepared as described above, 
carboplatin solutions are stable for 8 hours at room temperature if protected from light. The 
solution should be discarded after 8 hours since no antibacterial preservative is contained in the 
formulation. 
 
10.2.5 Dose Specifics and Administration 
All patients on protocol treatment will receive Carboplatin at AUC 4 IV infusion over 30-60 
minutes, every 21 days for a total of 4 cycles. Carboplatin dosing is by the Calvert formula: Total 
Dose (mg) = (target AUC) x (CrCl+ 25). 
 
10.2.6 Preparation 
Immediately before use, the contents of a carboplatin vial must be reconstituted with either 
sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP. 
The following shows the proper diluent volumes to be used to obtain a carboplatin concentration 
of 10 mg/mL. Carboplatin solution can be further diluted to concentrations as low as 0.5 mg/mL 
with D5W or 0.9% normal saline. 
 


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Vial Size
Diluent Volume
50 mg 
5 mL
150 mg
15 mL
450 mg
45 mL
 
Carboplatin reacts with aluminum to form a precipitate and cause a loss of potency. Therefore, 
needles or intravenous sets containing aluminum parts that may come in contact with the drug 
must not be used for the preparation or administration of carboplatin. 
 
10.2.7 Route of Administration 
IV infusion. 
 
10.2.8 Availability 
Carboplatin is commercially available 
 
10.2.9 Side Effects 
Please see package insert for detailed information regarding side effects related to this drug. 
 
Below are some common side effects related to Carboplatin.  
 
Hematologic: Myelosuppression is the major dose-limiting toxicity. Thrombocytopenia, 
neutropenia, leukopenia, and anemia are common, but typically resolve by Day 28 when 
carboplatin is given as a single agent. 
 
Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of patients receiving 
the drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely bronchospasm and 
hypotension. The reactions can be successfully managed with standard epinephrine, 
corticosteroid, and antihistamine therapy. 
 
Neurologic: Peripheral neuropathies have been observed in 4% of patients receiving carboplatin 
with mild paresthesia being the most common.  
 
Gastrointestinal: Nausea and vomiting are the most common GI events; both usually resolve 
within 24 hours and respond to antiemetics. Other GI events include diarrhea, weight loss, 
constipation, and gastrointestinal pain. 
 
Hepatic Toxicity: Elevated alkaline phosphatase, total bilirubin, and SGOT have been observed. 
 
Other: Pain and asthenia are the most common miscellaneous adverse events. Alopecia has 
been reported in 3% of the patients taking carboplatin. 
 
10.3 
Gemcitabine 
Please see package insert for detailed information regarding this medication 
 
10.3.1 Other Names 
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar 
 


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10.3.2 Classification 
Antimetabolite (nucleoside pyrimidine analogue) 
 
10.3.3 Mode of Action 
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S 
phase) and also blocking the progression of cells through the G1/S phase boundary. Gemcitabine 
is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and 
triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a 
combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to 
inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, 
which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates 
for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction 
in the concentrations of deoxynucleotides, including dCTP. Second, gemcitabine triphosphate 
competes with dCTP for incorporation into DNA. The reduction in the intracellular 
concentration of dCTP (by the action of the diphosphate) enhances the incorporation of 
gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is 
incorporated into DNA, only one additional nucleotide is added to the growing DNA strands. 
After this addition, there is inhibition of further DNA synthesis. DNA polymerase epsilon is 
unable to remove the gemcitabine nucleotide and repair the growing DNA strands (masked chain 
termination). 
 
10.3.4 Storage and Stability  
Unreconstituted drug vials are stored at controlled room temperature (15ºC to 30ºC, 59ºF to 
86ºF). Reconstituted solution should be stored at controlled room temperature and used within 24 
hours. Solutions of gemcitabine should not be refrigerated; as crystallization may occur. The 
unused portion should be discarded. 
 
10.3.5 Preparation  
Gemcitabine may be further diluted with normal saline as per institutional standards. 
 
10.3.6 Route of Administration 
IV infusion. 
 
10.3.7 Availability 
Gemcitabine is commercially available in 200 mg and 1 gm vials 
 
10.3.8 Side Effects 
Please see package insert for detailed information regarding side effects related to this drug. 
 
Below are some common side effects related to Gemcitabine: 
Neutropenia, anemia, thrombocytopenia, and leukopenia are reported. Rash with pruritis and 
injection-site reactions are can occur. Nausea and vomiting, diarrhea, constipation and mucositis 
have been reported. Abnormalities of hepatic transaminase enzymes occur in two-thirds of 
subjects, but they are usually mild, non-progressive, and rarely necessitate stopping treatment. 
Bronchospasm and/or dyspnea within a few hours of infusion of the drug, cough, rhinitis, 
pneumonitis may occur. Somnolence, insomnia, paresthesia, pain. Peripheral edema is reported 


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in about 30% of subjects. Flu-like symptoms are reported for about 20% of subjects. This 
includes fever, headache, back pain, chills, myalgia, asthenia, and anorexia. 
 
10.3 
Docetaxel 
Please refer to the latest version of the prescribing information that can be found at 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/, and/or on the manufacturer’s website. 
 
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by 
semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew 
plants.  Docetaxel acts by disrupting the microtubular network in cells that is essential for mitotic 
and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of 
tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to 
the production of microtubule bundles without normal function and to the stabilization of 
microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to 
microtubules does not alter the number of protofilaments in the bound microtubules, a feature 
which differs from most spindle poisons currently in clinical use. 
 
10.3.1 Supplier/How Supplied 
One-vial TAXOTERE (Injection Concentrate)  
TAXOTERE Injection Concentrate is supplied in a single use vial as a sterile, pyrogen-free, non-
aqueous solution.  
 
TAXOTERE (docetaxel) Injection Concentrate 20 mg/1 mL: 20 mg docetaxel in 1 mL in 50/50 
(v/v) ratio polysorbate 80/dehydrated alcohol. The vial is in a blister pack in one carton.  
 
TAXOTERE (docetaxel) Injection Concentrate 80 mg/4 mL: 80 mg docetaxel in 4 mL 50/50 
(v/v) ratio polysorbate 80/dehydrated alcohol. The vial is in a blister pack in one carton.  
 
TAXOTERE (docetaxel) Injection Concentrate 160 mg/8 mL: 160 mg docetaxel in 8 mL 50/50 
(v/v) ratio polysorbate 80/dehydrated alcohol. The vial is in a blister pack in one carton.  
Docetaxel (Taxotere) is commercially available and will not be supplied for this study. 
 
10.3.2 Preparation  
TAXOTERE Injection Concentrate (20 mg/mL) requires NO prior dilution with a diluent and is 
ready to add to the infusion solution. Use only a 21 gauge needle to withdraw TAXOTERE from 
the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and 
rubber particulates.  
1. TAXOTERE vials should be stored between 2 and 25°C (36 and 77°F). If the vials are 
stored under refrigeration, allow the appropriate number of vials of TAXOTERE 
Injection Concentrate vials to stand at room temperature for approximately 5 minutes 
before use.  
2. Using only a 21 gauge needle, aseptically withdraw the required amount of TAXOTERE 
injection concentrate (20 mg docetaxel/mL) with a calibrated syringe and inject via a 
single injection (one shot) into a 250 mL infusion bag or bottle of either 0.9% Sodium 
Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 mg/mL 
to 0.74 mg/mL.  


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If a dose greater than 200 mg of TAXOTERE is required, use a larger volume of the 
infusion vehicle so that a concentration of 0.74 mg/mL TAXOTERE is not exceeded.  
3. Thoroughly mix the infusion by gentle manual rotation.  
4. As with all parenteral products, TAXOTERE should be inspected visually for particulate 
matter or discoloration prior to administration whenever the solution and container 
permit. If the TAXOTERE dilution for intravenous infusion is not clear or appears to 
have precipitation, it should be discarded.  
5. TAXOTERE infusion solution is supersaturated, therefore may crystallize over time. If 
crystals appear, the solution must no longer be used and shall be discarded.  
 
The TAXOTERE dilution for infusion should be administered intravenously as a 1-hour infusion 
under ambient room temperature (below 25°C) and lighting conditions.  
 
10.3.3 Storage and Stability 
TAXOTERE final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is 
stable for 6 hours. TAXOTERE final dilution for infusion (in either 0.9% Sodium Chloride 
solution or 5% Dextrose solution) should be used within 6 hours (including the 1 hour 
intravenous administration). In addition, physical and chemical in-use stability of the infusion 
solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when 
stored between 2°C and 8°C (36 and 46°F). Retain in the original package to protect from light. 
Freezing does not adversely affect the product.  
 
10.3.4 Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to asepsis. 
 
10.3.5 Adverse Events 
The most common side effects of TAXOTERE include: 
 Changes in your sense of taste  
 Feeling short of breath  
 Constipation  
 Decreased appetite 
 Changes in your fingernails or toenails 
 Swelling of your hands, face or feet   
 Feeling weak or tired  
 Joint and muscle pain  
 Nausea and vomiting  
 Diarrhea  
 Mouth or lips sores  
 Hair loss   
 Rash  
 Redness of the eye, excess tearing  
 Skin reactions at the site of TAXOTERE administration such as increased skin 
pigmentation, redness, tenderness, swelling, warmth or dryness of the skin.  
 Tissue damage if TAXOTERE leaks out of the vein into the tissues 


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11 ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v4 will be utilized for AE 
assessment. A copy of the CTCAE v4 can be downloaded from the CTEP website at 
http://ctep.cancer.gov.  
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with urothelial carcinoma that 
were not present prior to the AE reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period.  
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 


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therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
 Results in persistent or significant disability/incapacity(i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
 
Is a congenital anomaly or birth defect defect in a neonate/infant born to a mother exposed 
to the IMP. 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 Pregnancy  
 Overdose 
 
11.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
 
11.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
To ensure consistency of AE and SAE causality assessments, site investigators should apply the 
following general guideline: 
 
Yes (definitive, probable, possible, unlikely) 
There is a plausible temporal relationship between the onset of the AE and administration of 
Atezolizumab, and the AE cannot be readily explained by the subject’s clinical state, inter-
current illness, or concomitant therapies; and/or the AE follows a known pattern of response to 
Atezolizumab; and/or the AE abates or resolves upon discontinuation of atezolizumab or dose 
reduction and, if applicable, reappears upon re- challenge. 
 


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No (unrelated) 
 
Evidence exists that the AE has an etiology other than the Atezolizumab (e.g., preexisting 
medical condition, underlying disease, inter-current 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 Atezolizumab. 
 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert (P.I) or current Investigator Brochure (I.B). 
 
Unexpected adverse events are those not listed in the P.I or current I.B or not identified. This 
includes adverse events for which the specificity or severity is not consistent with the 
description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be 
unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or hepatitis. 
 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
 
 


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11.1.5 AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product. AESIs shall be forwarded to Genentech/Roche within fifteen (15) 
calendar days of the awareness date. 
 
The Atezolizumab Events of Special Interest   
Adverse events of special interest for this study include the following: 
 Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
o Treatment-emergent ALT or AST > 3 x ULN in combination with total 
bilirubin > 2 x ULN (of which ≥ 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 x ULN in combination with clinical 
jaundice 
 Suspected transmission of an infectious agent by Atezolizumab, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal product.  
This term applies only when a contamination of the study drug is suspected. 
 Pneumonitis 
 Colitis 
 Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis 
 Hepatitis, including AST or ALT > 10 x ULN 
 Systemic lupus erythematosus 
 Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, influenza-like illness, macrophage activating syndrome and hemophagocytic 
lymphohistiocytosis . 
 Nephritis 
 Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 Myositis 
 Myopathies, including rhabdomyolysis 
 Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 Vasculitis 
 Autoimmune hemolytic anemia 
 Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
 
 
 


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11.2 
Reporting 
 
11.2.1 Adverse Events  
 AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
 AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever occurs first. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs to HCRN 
 SAEs will be reported from time of signed informed consent until 100 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first. 
 SAEs will be reported on the SAE Reporting Form within 1 business day of discovery 
of the event.  
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 
The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form may be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed in 11.2.2.1), sites must submit a 
follow-up SAE Submission Form within a reasonable timeframe to HCRN to 
safety@hoosiercancer.org.   
 
11.2.2.2 
HCRN Requirements for Reporting SAEs to Genentech (GNE) 
HCRN will report all SAEs to GNE within 1 business day of receipt of the SAE Submission 
Form from a site. Follow-up information will be provided to GNE as it is received from site. 
 


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11.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.4 
HCRN Responsibilities to FDA 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
Genentech’s parent IND at the time of submission. Additionally, All written IND Safety Reports 
submitted to the FDA by HCRN on behalf of the sponsor-investigator must also be faxed to 
Genentech/Roche Drug Safety: Fax: (650) 225-4682 or (650) 225-4630. 
 
HCRN will be responsible for all communication with the FDA in accordance with 21CFR312 
including but not limited to the 7 and 15 Day Reports, as well as an Annual Progress Report. 
Additionally, HCRN will submit a copy of these reports to GNE at the time of submission to 
FDA. 
 
11.5 
IND Safety Reports Unrelated to this Trial 
GNE will provide IND safety reports from external studies that involve the study drug(s) per 
their guidelines.  HCRN will forward safety reports to the sponsor-investigator who will review 
these reports and determine if revisions are needed to the protocol or consent. HCRN will 
forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review.  Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required).  All IND safety reports will 
also be made available to sites via the EDC system.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
12 
STATISTICAL METHODS 
General Considerations:  Statistical analysis of this study will be the responsibility of 
Biostatistics and Data Management Core at Indiana University Melvin and Bren Simon Cancer 
Center (IUSCC). Parameter estimates and relevant summary statistics will be reported where 
appropriate. For continuous variables, summary statistics will include number of subjects, mean, 
median, standard deviation, minimum and maximum. Categorical endpoints will be summarized 
using number of subjects, frequency, and percentages. Missing data will not be imputed. Data 
analysis will be performed in SAS. 
 
Additional exploratory analyses of the data will be conducted as deemed appropriate. Changes 
from this analysis plan will not require an amendment to the protocol unless it changes a 
significant feature of the protocol; however, all changes from the original analysis plan will be 
documented in the final study report. The statistical analysis methods are outline below.     
 
 
 


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12.1 
Study Design 
This is a single-arm phase II study of immunotherapy with atezolizumab plus addition of 
chemotherapy (carboplatin+gemcitabine or docetaxel) in patients with cisplatin-ineligible 
urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitor.       
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
The primary endpoint is PFS assessed by RECIST 1.1 and is defined as the time from date of 
treatment start until the criteria for disease progression is met as defined by RECIST 1.1 criteria 
or death as a result of any cause; in the absence of an event, the endpoint will be right-censored 
at the date of last disease assessment (see also section 9.2.8). 
 
12.2.2 Definition of Secondary Endpoints 
 Toxicity assessed by CTCAE Version 4.03. 
 ORR (CR+PR) assessed via RECIST 1.1 (Section 9.2.5) 
 ORR (iCR+iPR) assessed via irRECIST (Section 9.3.3) 
 CBR (CR+PR+SD > 3 months) assessed via RECIST 1.1 (Section 9.2.6) 
 CBR (iCR+iPR+iSD > 3 months) assessed via irRECIST (Section 9.3.3) 
 PFS assessed by irRECIST defined as the time from date of treatment start until the 
criteria for disease progression is met as defined by irRECIST criteria or death as a result 
of any cause; in the absence of an event, the endpoint will be right-censored at the date of 
last disease assessment. 
 OS defined by the date of treatment start to date of death from any cause 
 
12.3 
Sample Size and Accrual 
In historical data, the median PFS among patients who received chemotherapy in the 2nd or 3rd 
line setting in metastatic urothelial carcinoma is around 4 months.41-46 Therefore, for this study 
we will consider the historical control for 2nd line carboplatin + gemcitabine or 3rd line Docetaxel 
in metastatic urothelial carcinoma to be 4 months. To be further conservative, we will include 
analysis of a virtual control arm as an exploratory endpoint to analyze real-life data from patients 
receiving atezolizumab as first-line and then receive carboplatin + gemcitabine in the 2nd line 
setting. We are using the virtual control arm for this purpose because historical data in this 
particular setting is not available to date.  
 
The primary goal is to estimate PFS among patients to be treated with atezolizumab in 
combination with carboplatin + gemcitabine or docetaxel, who have cisplatin-ineligible 
metastatic urothelial carcinoma and who have progressed on prior PD-1 or PD-L1 inhibitor. We 
hypothesize that patients receiving atezolizumab plus chemotherapy (carboplatin + gemcitabine 
or docetaxel) will have a median PFS of 0.6 year (7.2 months). Under the exponential 
distribution assumption, this corresponds to an annual hazard rate of 1.155. The number of 
events is 30 required to obtain a 95% confidence interval of [0.79, 1.60] for estimating the 
hazard rate. Of note, the historical data suggest a median PFS of 4 months, which corresponds to 
a hazard rate of 2.08, well outside the anticipated 95% CI.  An event is defined as a patient with 
progression or death. Assuming an accrual period of 24 months (1.375 per month) and maximum 
follow-up of 18 months after the last patient is enrolled, an accrual of 33 is expected to yield 30 


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events. To allow for replacement of patients who are not evaluable for efficacy (estimated to be 
10%), up to 37 patients will be enrolled. 
 
12.4 
Assessment of Safety 
Safety will be assessed by the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE Version 4.03). Please refer to the Study Calendar for the schedule 
of toxicity assessment. The safety population will comprise all subjects who receive at least one 
dose of trial drug(s) 
 
12.5 
Assessment of Efficacy 
The analysis of PFS and other efficacy endpoints will use the efficacy population. This will 
comprise all subjects who receive at least one dose of trial treatment (atezolizumab plus 
carboplatin + gemcitabine or docetaxel) and either undergo at least one post-baseline assessment 
or die before any evaluation.  
 
12.6 
Data Analysis Plans 
 
12.6.1 Analysis Plans for Primary Objective 
The PFS along with 95% CI will be estimated using the Kaplan-Meier method in the Efficacy 
population. 
 
12.6.2 Analysis Plans for Secondary Objectives 
In the Efficacy population, median PFS by irRECIST will be estimated and tested similarly to 
the primary endpoint. Objective response rate and clinical benefit rate will be estimated with 
two-sided 95% exact binomial confidence intervals. OS will be estimated using Kaplan-Meier 
methodology. Toxicities will be tabulated in the Safety population. 
 
To compare PFS with the historical control, 
 Null hypothesis – Patients receiving atezolizumab plus chemotherapy (carboplatin + 
gemcitabine or docetaxel) will have a median PFS of 4 months. 
 Alternative hypothesis – Patients receiving atezolizumab plus chemotherapy (carboplatin 
+ gemcitabine or docetaxel) will have a median PFS of 7.2 months. 
 
With 1 sided alpha level of 0.1, the sample size of 33 will have 81.4% power to detect the 
hypothesized difference in median PFS, assuming an accrual period of approximately 24 months 
(1-2 per month) and maximum follow-up of 18 months after the last patient is enrolled. The 
power calculation is based the SWOG calculator “One Arm Nonparametric Survival Sample Size 
and Power”, based on the assumptions of uniform accrual over time, no loss to follow-up, 
exponentially distributed death times. As noted in Section 12.3, to allow for replacement of 
patients who are not evaluable for efficacy (estimated to be 10%), up to 37 patients will be 
enrolled. 
 
 


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12.6.3 Analysis Plans for Exploratory Objectives 
An exploratory analysis will compare OS in the Efficacy population of this study to the virtual 
control arm (per section 2.2.4) using a stratified log-rank test.  Kaplan-Meier plots will also be 
generated with two-sided 90% confidence intervals for estimated median OS.   
 
In the Efficacy population, % of PDL-1 cells positive in the tumors at baseline and at time of 
progression on PD-1 or PD-L1 inhibitor will be compared using paired t-tests.  For markers of 
checkpoint efficacy or resistance (positive or negative) and PDL-1 status, frequencies at each 
time point will be reported, and changes over time will be assessed with McNemar’s tests. 
 
12.6.4 Other Planned Analyses 
For the Enrolled population, descriptive statistics will be used the characterize subject 
demographic and clinical characteristics, disposition, and significant protocol violations.  In the 
safety population, concomitant medications and exposure will be described. 
 
13. 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the Indiana University Melvin and Bren Simon 
Cancer Center’s (IUSCC) DSMP for High Risk Phase II Trials.  
 
HCRN facilitated oversight activities for High Risk Phase II Trials include: 
 Review and processing of all AEs requiring expedited reporting as defined in the protocol 
 Provide trial accrual progress, safety information, and data summary reports to the 
sponsor-investigator, including a weekly update of aggregate AE data. For any increase 
in frequency of grade 3 or above adverse events (above the rate reported in the 
Investigator Brochure or package insert), the sponsor investigator will notify HCRN, who 
will notify the DSMC Chair and Compliance Officer immediately. The notification will 
include the incidence of study adverse events, grades, and attributions, as well as 
investigator statements regarding comparison with risks per the IB/ package insert. 
 Notify participating sites of adverse events potentially requiring expedited. 
reporting and subsequent DSMC recommendations for study modifications. 
 Investigators will conduct continuous review of data and patient safety. 
 Coordinate monthly (Phase II) meetings which will include each accruing site. 
o These meetings should include review of data, the number of subjects and 
significant toxicities as described in the protocol. HCRN should maintain 
meeting minutes and attendance for submission to the DSMC upon request. 
 Conduct the trial across all participating sites in accordance with the requirements set 
forth in the IUSCC DSMP. 
 
13.2 
IUSCC Data Safety Monitoring Committee Oversight 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of 
subject safety, regulatory compliance, and data integrity for this trial. The DSMC will review this 
study to assess toxicity, compliance, data integrity, and accrual per the Institutional DSMP. Trials 
managed by HCRN are not routinely audited or monitored by IUSCC; however, the IUSCC 
DSMC retains the right to audit HCRN trials on a for cause basis.  


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The IUSCC DSMC will review study data semi-annually during the active treatment and safety 
follow-up portion of the trial per the IUSCC DSMP.  
 
In preparation for the IUSCC DSMC review, HCRN will provide the following: 
 Monthly Summary Reports 
 Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary report (including serious adverse events) 
o Study accrual patterns 
o Protocol deviations 
 Audit and/or monitoring results, if applicable 
 HCRN month study update meeting minutes/ attendance 
 
Documentation of DSMC reviews will be provided to sponsor-investigator and HCRN.  The 
IUSCC DSMC will notify the sponsor-investigator and other regulatory bodies, as appropriate, 
for issues of immediate concern.  The sponsor-investigator will work with HCRN to address the 
DSMC’s concerns as appropriate.   
 
At any time during the conduct of the trial, if it is the opinion of the sponsor-investigator that the 
risks (or benefits) to the patient warrant early closure of the study, this recommendation should 
be made in writing to the DSMC Chair and Compliance Officer. Alternatively, the DSMC may 
initiate suspension or early closure of the study based on its review of the investigator reports. 
 
13.2.1 IND Annual Reports  
Since this study has an IND held locally by the IU principal investigator, the IND Annual Report 
will be prepared and submitted to the Compliance Team. This report will be reviewed by the 
DSMC at the time of FDA submission. 
 
13.3 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study.  A summary report (QC Report) of these checks together with any queries 
resulting from manual review of the eCRFs will be generated for each site and transmitted to the 
site. Corrections will be made by the study site personnel.  
 
13.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. For cause audits may occur as necessary. Source documents will be 
reviewed for verification of agreement with data entered into the EDC system.  It is important for 
the site investigator and their relevant personnel to be available for a sufficient amount of time 
during the monitoring visits or audit, if applicable. The site investigator and institution guarantee 
access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by GNE or its designee as well as 
inspection by appropriate regulatory agencies. 
 


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13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Office for this trial. Data will be collected through a 
web based clinical research platform, a system compliant with Good Clinical Practices and 
Federal Rules and Regulations.  HCRN personnel will coordinate and manage data for quality 
control assurance and integrity. All data will be collected and entered into the EDC system by 
study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database(s). If procedures on the study 
calendar are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system according to 
study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without written permission from the sponsor-investigator and 
HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 


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secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, GNE, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
14.5 
Aggregate Reports 
The sponsor-investigator (Nabil Adra) will forward a copy of the Final Study Report to 
Genentech/Roche upon completion of the study. 
 
14.6 
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: 
 
Atezolizumab IIS Clinical Operations  
Email: anti-pdl-1-mpd3280a-gsur@gene.com 
 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
15. 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 


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15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 


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16. 
REFERENCES 
 
1. Ferlay J, Soerjomataram I, Dikshit R, et al: Cancer incidence and mortality worldwide: 
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359-86, 
2015 
2. Dash A, Galsky MD, Vickers AJ, et al: Impact of renal impairment on eligibility for 
adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the 
bladder. Cancer 107:506-13, 2006 
3. Galsky MD, Hahn NM, Rosenberg J, et al: A consensus definition of patients with 
metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet 
Oncol 12:211-4, 2011 
4. Sternberg CN, Yagoda A, Scher HI, et al: Preliminary results of M-VAC (methotrexate, 
vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J 
Urol 133:403-7, 1985 
5. Sternberg CN, Yagoda A, Scher HI, et al: Methotrexate, vinblastine, doxorubicin, and 
cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns 
of response and relapse. Cancer 64:2448-58, 1989 
6. Loehrer PJ, Sr., Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone 
or in combination with methotrexate, vinblastine, and doxorubicin in patients with 
metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 10:1066-73, 
1992 
7. Logothetis CJ, Dexeus FH, Finn L, et al: A prospective randomized trial comparing 
MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin 
Oncol 8:1050-5, 1990 
8. von der Maase H, Sengelov L, Roberts JT, et al: Long-term survival results of a 
randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, 
doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 23:4602-8, 2005 
9. Dogliotti L, Carteni G, Siena S, et al: Gemcitabine plus cisplatin versus gemcitabine plus 
carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the 
urothelium: results of a randomized phase 2 trial. Eur Urol 52:134-41, 2007 
10. De Santis M, Bellmunt J, Mead G, et al: Randomized phase II/III trial assessing 
gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with 
advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC 
study 30986. J Clin Oncol 30:191-9, 2012 
11. Morales A, Eidinger D, Bruce AW: Intracavitary Bacillus Calmette-Guerin in the 
treatment of superficial bladder tumors. J Urol 116:180-3, 1976 
12. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment 
with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 
387:1909-20, 2016 
13. Balar AV, Galsky MD, Rosenberg JE, et al: Atezolizumab as first-line treatment in 
cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a 
single-arm, multicentre, phase 2 trial. Lancet 389:67-76, 2017 
14. Galsky MR, M; Siefker-Radtke, AO; Baron, A; Necchi, A; Bedke, J; Plimack E.R; 
Vaena, D; Grimm, M-O; Bracarda, S; Arranz Arija, J; Pal, S.K; Ohyama, C; Saci, A; 
Lambert, A; Krishnan, S; Azrilevich, A; Sharma, P: Efficacy and safety of nivolumab 


Clinical Study Protocol 
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Page 62 of 85 
monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior 
treatment: Results from the phase II CheckMate 275 study, EUROPEAN SOCIETY FOR 
MEDICAL ONCOLOGY, 2016 
15. Balar AB, J; O'Donnell, P.H; Castellano, D; Grivas, P; Vuky, J; Powles, T; Plimack, 
E.R.; Hahn, N.M.; de Wit, R; Pang, L; Savage, M.J.; Perini, R; Keefe, S; Bajorin, D: 
Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic 
urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study, 
EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY,, 2016 
16. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as Second-Line Therapy for 
Advanced Urothelial Carcinoma. N Engl J Med, 2017 
17. Bellmunt J, de Wit R, Albanell J, et al: A feasibility study of carboplatin with fixed dose 
of gemcitabine in "unfit" patients with advanced bladder cancer. Eur J Cancer 37:2212-5, 
2001 
18. Calabro F, Lorusso V, Rosati G, et al: Gemcitabine and paclitaxel every 2 weeks in 
patients with previously untreated urothelial carcinoma. Cancer 115:2652-9, 2009 
19. Linardou H, Aravantinos G, Efstathiou E, et al: Gemcitabine and carboplatin combination 
as first-line treatment in elderly patients and those unfit for cisplatin-based chemotherapy 
with advanced bladder carcinoma: Phase II study of the Hellenic Co-operative Oncology 
Group. Urology 64:479-84, 2004 
20. Stadler WM, Kuzel T, Roth B, et al: Phase II study of single-agent gemcitabine in 
previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15:3394-8, 
1997 
21. Vaughn DJ, Manola J, Dreicer R, et al: Phase II study of paclitaxel plus carboplatin in 
patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a 
trial of the Eastern Cooperative Oncology Group. Cancer 95:1022-7, 2002 
22. Fehrenbacher L, Spira A, Ballinger M, et al: Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, 
phase 2 randomised controlled trial. Lancet 387:1837-46, 2016 
23. Suzuki E, Kapoor V, Jassar AS, et al: Gemcitabine selectively eliminates splenic Gr-
1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor 
immune activity. Clin Cancer Res 11:6713-21, 2005 
24. Galluzzi L, Senovilla L, Zitvogel L, et al: The secret ally: immunostimulation by 
anticancer drugs. Nat Rev Drug Discov 11:215-33, 2012 
25. Kaneno R, Shurin GV, Tourkova IL, et al: Chemomodulation of human dendritic cell 
function by antineoplastic agents in low noncytotoxic concentrations. J Transl Med 7:58, 
2009 
26. Ding ZC, Lu X, Yu M, et al: Immunosuppressive myeloid cells induced by chemotherapy 
attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 
74:3441-53, 2014 
27. Soeda A, Morita-Hoshi Y, Makiyama H, et al: Regular dose of gemcitabine induces an 
increase in CD14+ monocytes and CD11c+ dendritic cells in patients with advanced 
pancreatic cancer. Jpn J Clin Oncol 39:797-806, 2009 
28. Nowak AK, Robinson BW, Lake RA: Gemcitabine exerts a selective effect on the 
humoral immune response: implications for combination chemo-immunotherapy. Cancer 
Res 62:2353-8, 2002 


Clinical Study Protocol 
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29. Rizvi NA, Hellmann MD, Brahmer JR, et al: Nivolumab in Combination With Platinum-
Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell 
Lung Cancer. J Clin Oncol 34:2969-79, 2016 
30. Lynch TJ, Bondarenko I, Luft A, et al: Ipilimumab in combination with paclitaxel and 
carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results 
from a randomized, double-blind, multicenter phase II study. J Clin Oncol 30:2046-54, 
2012 
31. Langer CJ, Gadgeel SM, Borghaei H, et al: Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, 
phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17:1497-1508, 
2016 
32. Shahda S, Noonan AM, Bekaii-Saab TS: A phase II study of pembrolizumab in 
combination with mFOLFOX6 for patients with advanced colorectal cancer., American 
Society of Clinical Oncology . Abstract No. 3541., 2017 
33. Lara P, Beckett L, Li Y, et al: Combination checkpoint immunotherapy and cytotoxic 
chemotherapy: Pembrolizumab (Pembro) plus either docetaxel or gemcitabine in patients 
with advanced or metastatic urothelial cancer., ASCO Genitourinary Cancer Symposium 
2017 
34. Grothey A, Sugrue MM, Purdie DM, et al: Bevacizumab beyond first progression is 
associated with prolonged overall survival in metastatic colorectal cancer: results from a 
large observational cohort study (BRiTE). J Clin Oncol 26:5326-34, 2008 
35. von Minckwitz G, du Bois A, Schmidt M, et al: Trastuzumab beyond progression in 
human epidermal growth factor receptor 2-positive advanced breast cancer: a german 
breast group 26/breast international group 03-05 study. J Clin Oncol 27:1999-2006, 2009 
36. Lara PB, L; Li, Y: Combination checkpoint immunotherapy and cytotoxic chemotherapy: 
Pembrolizumab (Pembro) plus either docetaxel or gemcitabine in patients with advanced 
or metastatic urothelial cancer., ASCO Genitourinary Cancers Symposium, 2017 
37. Kelderman S, Schumacher TN, Haanen JB: Acquired and intrinsic resistance in cancer 
immunotherapy. Mol Oncol 8:1132-9, 2014 
38. Herbst RS, Baas P, Kim DW, et al: Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a 
randomised controlled trial. Lancet 387:1540-50, 2016 
39. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-
PD-1 antibody in cancer. N Engl J Med 366:2443-54, 2012 
40. Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-
L1 antibody MPDL3280A in cancer patients. Nature 515:563-7, 2014 
41. Carles J, Nogue M, Domenech M, et al: Carboplatin-gemcitabine treatment of patients 
with transitional cell carcinoma of the bladder and impaired renal function. Oncology 
59:24-27, 2000 
42. von der Maase H: Gemcitabine in locally advanced and/or metastatic bladder cancer. 
Critical reviews in oncology/hematology 34:175-183, 2000 
43. Soga N, Onishi T, Arima K, et al: Paclitaxel Carboplatin chemotherapy as a second‐line 
chemotherapy for advanced platinum resistant urothelial cancer in Japanese cases. 
International journal of urology 14:828-832, 2007 


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44. Vaishampayan UN, Faulkner JR, Small EJ, et al: Phase II trial of carboplatin and 
paclitaxel in cisplatin‐pretreated advanced transitional cell carcinoma. Cancer 104:1627-
1632, 2005 
45. Furubayashi N, Negishi T, Yamashita T, et al: The combination of paclitaxel and 
carboplatin as second-line chemotherapy can be a preferred regimen for patients with 
urothelial carcinoma after the failure of gemcitabine and cisplatin chemotherapy. 
Molecular and clinical oncology 7:1112-1118, 2017 
46. Kouno T, Ando M, Yonemori K, et al: Weekly paclitaxel and carboplatin against 
advanced transitional cell cancer after failure of a platinum-based regimen. European 
urology 52:1115-1122, 2007 
47. McCaffrey JA, Hilton S, Mazumdar M, et al: Phase II trial of docetaxel in patients with 
advanced or metastatic transitional-cell carcinoma. J Clin Oncol 15:1853-7, 1997 
 
 
 


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APPENDIX 1: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE EVENTS 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology. 
 
PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will also have computed tomography (CT) scans of the chest 
performed at every tumor assessment.   
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension.   
 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary event, 
Grade 1  
 Continue atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For recurrent pneumonitis, treat as a Grade 3 or 4 event
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 12 mg/kg/day oral prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
 For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c 
 Bronchoscopy or BAL is recommended. 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BAL = bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or 
equivalent.   
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by the investigator.
 
 
 


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HEPATIC EVENTS 
Immune-related hepatitis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment.   
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of 
the next dose of study drug. 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 Continue atezolizumab. 
 Monitor LFTs until values resolve to within normal limits.  
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c 
 Consider patient referral to gastrointestinal specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury.  
 Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
LFT = liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by the investigator (or an appropriate delegate). 
 
 
 


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GASTROINTESTINAL EVENTS 
Immune-related colitis has been associated with the administration of atezolizumab.  All events 
of diarrhea or colitis should be thoroughly evaluated for other more common etiologies.  For 
events of significant duration or magnitude or associated with signs of systemic inflammation or 
acute-phase reactants (e.g., increased C-reactive protein, platelet count, or bandemia):  Perform 
sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with three to five specimens 
for standard paraffin block to check for inflammation and lymphocytic infiltrates to confirm 
colitis diagnosis.  
 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
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 12 
mg/kg/day oral prednisone or equivalent.  
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
Diarrhea or 
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 12 mg/kg/day IV methylprednisolone or equivalent and 
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to GI specialist for evaluation and confirmation biopsy. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and 
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time will be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate).  


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ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab.   
 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) and free triiodothyronine and 
thyroxine levels should be measured to determine whether thyroid abnormalities are present.  
Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, 
follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] 
levels, and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with 
detailed pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency. 
 
Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 
 Continue atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly.
Symptomatic 
hypothyroidism 
 Withhold atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid 
function is improving.
Asymptomatic 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab. 
 Monitor TSH every 4 weeks. 
TSH  0.1 mU/L: 
 Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism 
 Withhold atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
 Permanently discontinue atezolizumab. c
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 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better or patient is not stable 


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Event 
Management 
on replacement therapy while withholding atezolizumab, permanently 
discontinue atezolizumab. c
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab. 
 Initiate treatment with insulin if needed. 
 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 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 
 Permanently discontinue atezolizumab c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated.
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  10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate).  
 
 
 
 


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


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IMMUNE-RELATED MYOCARDITIS 
Immune-related myocarditis has been associated with the administration of atezolizumab.  
Immune-related myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Immune-related myocarditis 
needs to be distinguished from myocarditis resulting from infection (commonly viral, e.g., in a 
patient who reports a recent history of GI illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy.  All patients with 
possible myocarditis should be urgently evaluated by performing cardiac enzyme assessment, an 
ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per institutional 
guidelines.  A cardiologist should be consulted.  An endomyocardial biopsy may be considered 
to enable a definitive diagnosis and appropriate treatment, if clinically indicated. Patients with 
signs and symptoms of myocarditis, in the absence of an identified alternate etiology, should be 
treated according to the guidelines below. 
 
Management Guidelines for Immune-Related Myocarditis 
Event 
Management 
Immune-related 
myocarditis, Grade  
2-4 
 Permanently discontinue atezolizumab and contact sponsor-investigator. a 
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement.  
 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 Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event.  The decision to re-challenge patients should be based on the investigator’s 
assessment of benefit-risk and documented by the investigator (or an appropriate delegate). Sponsor-
investigator is available to advise as needed.
 
 
 


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INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release cyndrome (CRS) 
with atezolizumab may receive premedication with antihistamines, antipyretics and/or analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab. These reactions, which are thought to be due to release of cytokines 
and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells. Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction [29]. 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 
[30, 31], 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 Table 7.   
 
Table 7 
Management Guidelines for Infusion-Related Reactions 
Event
Management
Grade 1a  
Feverb with or 
without 
constitutional 
symptoms 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait 30 minutes and then restart infusion at half the 
rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate 
may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment,c including maintenance of IV fluids for 
hydration. 
 In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per Grade 2. 
 For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs 
and/or CRS.
Grade 2a 
Feverb with 
hypotension not 
requiring 
vasopressors 
and/or 
 Immediately interrupt atezolizumab infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at half 
the rate being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate). Administer IV fluids as clinically indicated, and manage 


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Hypoxia 
requiring low-
flow oxygend 
by nasal cannula 
or blow-by 
constitutional symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
 Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e 
 Consider hospitalization until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose 
of atezolizumab may be administered. For subsequent infusions, consider 
administration of oral premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive days, contact 
Medical Monitor.
Grade 3a 
Feverb with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)  
and/or 
Hypoxia 
requiring high-
flow oxygend 
by nasal cannula, 
face mask, non-
rebreather mask, 
or venturi mask 
 Permanently discontinue atezolizumab.f 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus and vasopressor as needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring in the 
ICU is recommended. Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
 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.
Grade 4a 
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.f 
 Administer symptomatic treatment.c 
 Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed. Monitor other organ 
function closely. Manage constitutional symptoms and organ toxicities as per 
institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e For patients who are refractory to anti-cytokine 
therapy, experimental treatmentsg may be considered at the discretion of the 
investigator. 
  Hospitalize patient until complete resolution of symptoms. 


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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; HLH= hemophagocytic lymphohistiocytosis; IRR = infusion-related 
reaction; MAS= macrophage activation syndrome.
Note: The management guidelines have been adapted from NCCN guidelines for management of 
CAR T-cell-related toxicities (Version 2.2019). 
a. Grading system for management guidelines is based on ASTCT consensus grading for CRS. NCI 
CTCAE (version as specified in the protocol) should be used when reporting severity of IRRs, 
CRS, or organ toxicities associated with CRS on the Adverse Event eCRF. Organ toxicities 
associated with CRS should not influence overall CRS grading.  
b. Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop 
CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer 
required when subsequently determining event severity (grade). In this case, the grade is driven by 
the presence of hypotension and/or hypoxia. 
c. Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may 
be administered as per institutional practice. 
d. Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen 
delivered at > 6 L/min. 
e. There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are limited, 
and the role of such treatment in the setting of antibody-associated CRS has not been established. 
f. Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). 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 considering the benefit-risk ratio. 
g. Refer to Riegler et al. [32] for information on experimental treatments for CRS.
 
 
 


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PANCREATIC EVENTS 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.   
 
Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or 
lipase elevation, 
Grade 1
 Continue atezolizumab 
 Monitor amylase and lipase prior to dosing 
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 x ULN: 
 
Treat as a Grade 3 event. 
Amylase and/or 
lipase elevation, 
Grade 3 or 4 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Monitor amylase and lipase every other day. 
 If no improvement, consider treatment with 12 mg/kg/day oral prednisone 
or equivalent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent events, permanently discontinue atezolizumab. c
Immune-related 
pancreatitis, Grade 2 
or 3 
 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to GI specialist. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
 For recurrent events, permanently discontinue atezolizumab. c
Immune-related 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab. c 
 Refer patient to GI specialist. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  The acceptable length 


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Event 
Management 
of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event.  Patients can be re-challenged with atezolizumab only after approval has been 
documented by the investigator (or an appropriate delegate). 
 
 
 


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


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NEUROLOGIC DISORDERS 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies.   
 
Management Guidelines for Neurologic Disorders 
Event
Management
Immune-related neuropathy, 
Grade 1 
 Continue atezolizumab. 
 Investigate etiology.
Immune-related neuropathy, 
Grade 2  
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Investigate etiology. 
 Initiate treatment as per institutional guidelines. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c
Immune-related neuropathy, 
Grade 3 or 4 
 Permanently discontinue atezolizumab. c  
 Initiate treatment as per institutional guidelines.
Myasthenia gravis and 
Guillain-Barré syndrome 
(any grade) 
 Permanently discontinue atezolizumab. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate). 
 
 
 


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IMMUNE-RELATED MENINGOENCEPHALITIS 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process.   
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. 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-Related Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, all 
grades 
 Permanently discontinue atezolizumab. a 
 Refer patient to neurologist. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate).
 
 
 


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IMMUNE-RELATED NEPHRITIS 
Immune-related nephritis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate renal function, and renal function, including serum creatinine, 
should be monitored throughout study treatment. Patients with abnormal renal function should be 
evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as nonsteroidal anti-inflammatory drugs). Refer the 
patient to a renal specialist if clinically indicated. A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. If no alternative cause of acute kidney injury is 
identified, patients with signs and symptoms of acute kidney injury, in the absence of an 
identified alternate etiology, should be treated according to the management guidelines for 
immune-related renal events in the table below. 
 
Management Guidelines for Renal Events 
 
Event 
Management 
Renal event, 
Grade 1 
 
Continue atezolizumab. 
 
Monitor kidney function, including 
creatinine, closely until values resolve to 
within normal limits or to baseline values. 
Renal event, 
Grade 2 
 
Withhold atezolizumab for up to 12 weeks 
after event onset. a 
 
Refer patient to renal specialist. 
 
Initiate treatment with corticosteroids 
equivalent to 1-2 mg/kg/day oral 
prednisone. 
 
If event resolves to Grade 1 or better, 
resume atezolizumab. b 
 
If event does not resolve to Grade 1 or 
better while withholding atezolizumab, 
permanently discontinue atezolizumab. c
Renal event, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab. 
 
Refer patient to renal specialist and 
consider renal biopsy. 
 
Initiate treatment with corticosteroids 
equivalent to 1-2 mg/kg/day oral 
prednisone. 
 
If event does not improve within 48 hours 
after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, 
taper corticosteroids over ≥ 1 month.
 
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.  


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a. Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 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 sponsor-investigator. 
b. If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent 
of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c. Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the sponsor-investigator. 
 
 
 
 
 


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IMMUNE-RELATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are amongst the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatinine-kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle-biopsy. One etiology of 
myositis is immune-mediated, which is the current concern with atezolizumab. 
  
It is recommended that atezolizumab should be withheld for moderate or severe (Grade 2 or 3) 
immune-related myositis and permanently discontinued for recurrent severe or life-threatening 
myositis (recurrent Grade 3 and Grade 4). Please refer the patient to rheumatologist and/or 
neurologist and consider muscle biopsy and supportive measures as clinically indicated. 
Corticosteroids treatment with 1-2 mg/kg/day IV methylprednisolone or higher-dose bolus if 
severely compromised (weakness severely limiting mobility, cardiac function, respiratory 
function, dysphagia) and/or additional immunosuppressive agents should be administered for ≥ 
Grade 2 events or if the event does not improve after initial corticosteroids. Please refer to the 
table below for detailed management guidelines for immune-mediated myositis. 
  
Management Guidelines for Immune-Related Myositis  
Event 
Management 
Immune-related myositis, Grade 1 
 
Continue atezolizumab 
 
Refer subject to rheumatologist or neurologist 
 
Initiate treatment as per institutional 
guidelines 
Immune-related myositis, Grade 2 
 
Withhold atezolizumab for up to 12 weeks 
after event onseta and contact site investigator. 
 
Refer subject to rheumatologist or neurologist 
 
Initiate treatment as per institutional 
guidelines 
 
Consider treatment with corticosteroid 
equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 
mg/kg/day oral prednisone or equivalent upon 
improvement. 
 
If corticosteroids are initiated and event does 
not improve within 48 hours after initiating 
corticosteroids, consider adding an 
immunosuppressive agent 
 
If event resolves to Grade 1 or better, resume 
atezolizumab.b 
 
If event does not resolve to Grade 1 or better 
while withholding atezolizumab, permanently 
discontinue atezolizumab and contact the 
sponsor-investigator. c
Immune-related myositis, Grade 3 
 
Withhold atezolizumab for up to 12 weeks 
after event onseta and contact site 
investigator.


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 
Refer subject to rheumatologist or 
neurologist 
 
Initiate treatment as per institutional 
guidelines 
 
Respiratory support may be required in more 
severe cases 
 
Initiate treatment with corticosteroid 
equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher dose bolus if 
subject is severely compromised (eg, cardiac 
or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); 
convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event does not improve within 48 hours 
after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, resume 
atezolizumab.b 
 
If event does not resolve to Grade 1 or better 
while withholding atezolizumab, 
permanently discontinue atezolizumab and 
contact HCRN. c 
 
For recurrent events, treat as a Grade 4 event
Immune-related myositis, Grade 4 
 
Permanently discontinue atezolizumab and 
contact site investigator.c 
 
Refer subject to rheumatologist or 
neurologist 
 
Initiate treatment as per institutional 
guidelines. Respiratory support may be 
required in more severe cases 
 
Initiate treatment with corticosteroid 
equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher dose bolus if 
subject is severely compromised (eg, cardiac 
or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); 
convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event does not improve within 48 hours 
after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper 
corticosteroids over ≥ 1 month.
IV, intravenous 
a Atezolizumab may be withheld for a period of time (ie, > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be agreed upon by the investigator and the sponsor-
investigator. 


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b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully 
recovered from the immune-related event. Subjects can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the sponsor-
investigator. 
 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).   
 
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014).  A patient should be classified as having HLH if five of the following eight 
criteria are met: 
 Fever  38.5°C 
 Splenomegaly 
 Peripheral blood cytopenia consisting of at least two of the following: 
– Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
– Platelet count  100  109/L (100,000/L) 
– ANC  1.0  109/L (1000/L) 
 Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 Low or absent natural killer cell activity 
 Ferritin  500 mg/L (500 ng/mL) 
 Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as 
having MAS if the following criteria are met: 
 Ferritin  684 mg/L (684 ng/mL) 
 At least two of the following: 
– Platelet count  181  109/L (181,000/L) 
– AST  48 U/L 
– Triglycerides  1.761 mmol/L (156 mg/dL) 
– Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 1. 


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Table 1 
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue atezolizumab and contact Medical Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
 
References 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resouce on the Internet]. 2014 [updated 29 October 2018; 
cited: 17 May 2019]. Available from: https://www.uptodate.com/contents/clinical-features-
and-diagnosis-of-hemophagocytic-lymphohistiocytosis. 
 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:4819.