A Phase 2 Study of Anti-PD-L1 Antibody (Atezolizumab) in Chondrosarcoma and Clear Cell Sarcoma
Phase: PHASE2
Conditions: Central Chondrosarcoma, Grade 2, Central Chondrosarcoma, Grade 3, Dedifferentiated Chondrosarcoma, Metastatic Clear Cell Sarcoma of Soft Tissue, Metastatic Primary Central Chondrosarcoma, Unresectable Primary Central Chondrosarcoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 
10398 
 
Local Protocol #: 
000081 
 
ClinicalTrials.gov Identifier:  NCT04458922 
 
TITLE:  A Phase 2 Study of Anti-PD-L1 Antibody (Atezolizumab) in Chondrosarcoma and 
Clear Cell Sarcoma 
 
Corresponding Organization: LAO-NCI / National Cancer Institute LAO  
National Cancer Institute 
10 Center Drive, 12N226 
Bethesda, MD 20892 
 
Principal Investigator: 
Alice P. Chen, MD, DCTD/NCI 
31 Center Drive Suite 3A44 
Bethesda, MD 20892 
Phone: (240) 781-3320, Fax: (301) 402-0172 
chenali@mail.nih.gov 
 
Translational PI: 
Ralph Parchment, PhD 
 
 
Statistician: 
 
Jared Foster, PhD, BRB/DCTD/NCI 
9609 Medical Center Drive 
Rockville, MD 20850 
Phone: (240) 276-7385 
jared.foster@nih.gov 
 
Responsible Research Nurse: 
 
Nancy Moore, RN, DCTD/NCI 
Bldg 10/RM 8D53 
Bethesda, MD 20892 
Phone: (240) 760-6045, Fax: (301) 451-5625  
nancy.moore@nih.gov 
 
Responsible Research Nurse 
Jo Hurtt, MSN, RN, OCN, POB/CCR/NCI 
Pediatric patients:   
Bldg 10/1C244 
Bethesda, MD 20892 
Phone: (240) 858-7012; Fax: (301) 451-5746 
 
 
 
jo.hurtt@nih.gov 
 
NCI-Supplied Agent:  Atezolizumab (NSC 783608) 
 
IND #:  
 
IND Sponsor:  DCTD, NCI 
Protocol Type / Version # / Version Date: 
Amendment / Version A05 / November 10, 2022 

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Participating Organizations 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
 

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PRÉCIS 
Background: 
• Clear cell sarcoma (CCS) is a rare, aggressive, deep-seated tumor that accounts for <1% of 
all sarcomas.  CCS presents predominantly in young adults, with an overall poor prognosis 
due to widespread dissemination. 
• Chondrosarcoma (CS) is one of the most common malignant bone tumors in adults.  
Conventional CS tumors have a low metastatic potential but are typically refractory to 
chemotherapy and radiation therapy.  High-grade or dedifferentiated CS tumors have a high 
metastatic potential and a poor prognosis following resection alone. 
• Atezolizumab is a human monoclonal antibody directed against programmed death-ligand 1 
(PD-L1) with potential immune checkpoint inhibitory and antineoplastic activities.  Though 
studies in patients with CCS and CS are limited, there is clinical evidence that immune 
checkpoint pathways may play a role in CCS and CS progression. 
Objectives: 
• Determine the objective response rates (ORR) using RECIST v 1.1 of atezolizumab in adult 
(≥18 years) patients with CCS and CS 
• Determine duration of response (DOR) using RECIST v 1.1 and/or change in clinical 
symptoms (time frame: baseline until disease progression, death, loss to follow-up, initiation 
of another anti-cancer treatment, withdrawal of consent, or study termination) 
• Measure progression-free survival (PFS) time (time frame: baseline until disease progression, 
death, loss to follow-up, initiation of another anti-cancer treatment, withdrawal of consent, or 
study termination) 
• Assess the number of activated CD8+ T cells infiltrating the tumor before and after 
atezolizumab treatment, and correlate treatment-induced changes with clinical response 
• Compare RECIST v 1.1 vs immune RECIST (iRECIST) in patients with CCS and CS on 
atezolizumab 
• Examine changes in PD-1/PD-L1 expression in the tumor microenvironment before and after 
atezolizumab treatment, and correlate treatment-induced changes with clinical response 
• Evaluate potential associations between atezolizumab activity and tumor genomic alterations 
Eligibility: 
• Patients with documented EWSR1/ATF1 or EWSR1/CREB1 translocation or histologically 
confirmed CCS, documented grade 2 or 3 conventional CS, or documented dedifferentiated 
CS; disease must be measurable and must not be curable by surgery 
• ≥2 years of age at the NCI Clinical Center (≥12 years at other participating sites) 
Study Design: 
• Patients will receive atezolizumab at a fixed dose of 1200 mg IV for adults and 15 mg/kg for 
pediatric patients once every 21 days, in 21-day cycles 
• Tumor biopsies (mandatory at all sites) will be collected from adult patients (≥18 years of 
age) at baseline and prior to cycle 3 day 1 (±3 days; or sooner if there is clinical evidence that 
the patient is responding to drug) for pharmacodynamic assessment 
• A cohort will be halted unless there is at least one response in the initial 9 patients accrued 

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• Within each histology, the trial will remain open to pediatric patients (up to a maximum of 8 
patients across the three study histologies) for as long as the study is accruing adults of that 
histology 
 

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TABLE OF CONTENTS 
PRÉCIS 
3 
SCHEMA 
5 
1. 
OBJECTIVES 9 
1.1 
Primary Objectives ...................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
1.3 
Exploratory Objectives ............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Clear Cell Sarcoma ..................................................................................................9 
2.2 
Chondrosarcoma ....................................................................................................10 
2.3 
Atezolizumab .........................................................................................................11 
2.4 
Rationale ................................................................................................................17 
2.5 
Correlative Studies Background ............................................................................18 
3. 
PATIENT SELECTION ....................................................................................................23 
3.1 
Eligibility Criteria ..................................................................................................23 
3.2 
Exclusion Criteria ..................................................................................................25 
3.3 
Screening Evaluation .............................................................................................28 
4. 
REGISTRATION PROCEDURES ...................................................................................29 
4.1 
Investigator and Research Associate Registration with CTEP ..............................29 
4.2 
Site Registration .....................................................................................................31 
4.3 
Patient Registration ................................................................................................33 
4.4 
General Guidelines .................................................................................................34 
5. 
TREATMENT PLAN ........................................................................................................35 
5.1 
Agent Administration .............................................................................................35 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................37 
5.3 
Duration of Therapy ...............................................................................................38 
5.4 
Duration of Follow-Up ..........................................................................................39 
5.5 
Criteria for Removal from Treatment and/or Study ..............................................39 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................39 
6.1 
General AE Management and Dose Modification Guidelines ..............................39 
6.2 
Management of Specific AEs ................................................................................40 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................58 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................58 
7.2 
Adverse Event Characteristics ...............................................................................62 
7.3 
Expedited Adverse Event Reporting ......................................................................63 
7.4 
Routine Adverse Event Reporting .........................................................................67 
7.5 
Pregnancy ...............................................................................................................67 
7.6 
Secondary Malignancy ...........................................................................................67 

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7.7 
Second Malignancy ................................................................................................68 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................68 
8.1 
Atezolizumab (NSC #783608) ...............................................................................68 
8.2 
Availability ............................................................................................................69 
8.3 
Useful Links and Contacts .....................................................................................70 
9. 
CORRELATIVE STUDIES ..............................................................................................71 
9.1 
Biomarker Plan ......................................................................................................72 
9.2 
Correlative Assays in Tumor Tissue ......................................................................77 
9.3 
Correlative Assays in Blood ..................................................................................83 
9.4 
Sample Collection and Processing .........................................................................86 
9.5 
Privacy Considerations ..........................................................................................87 
9.6 
Management of Genomic Results ..........................................................................88 
10. 
STUDY CALENDAR .......................................................................................................88 
11. 
MEASUREMENT OF EFFECT........................................................................................90 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................90 
11.2 
RECIST Response Assessment..............................................................................91 
11.3 
iRECIST Response Assessment ............................................................................97 
11.4 
Treatment Beyond RECIST Progression .............................................................100 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................101 
12.1 
Study Oversight ...................................................................................................101 
12.2 
Data Reporting .....................................................................................................101 
12.3 
Data Quality Portal ..............................................................................................104 
12.4 
Human Data Sharing Plan ....................................................................................104 
12.5 
Collaborative Agreements Language ...................................................................105 
12.6 
Genomic Data Sharing Plan .................................................................................106 
13. 
STATISTICAL CONSIDERATIONS.............................................................................106 
13.1 
Study Design/Endpoints.......................................................................................106 
13.2 
Sample Size/Accrual Rate ....................................................................................107 
13.3 
Analysis of Secondary Endpoints ........................................................................108 
13.4 
For phase 2 protocols only: Reporting and Exclusions .......................................108 
14. 
HUMAN SUBJECTS PROTECTION ............................................................................109 
14.1 
Rationale for Subject Selection ............................................................................109 
14.2 
Justification for Exclusions ..................................................................................110 
14.3 
Evaluation of Benefits and Risks/Discomforts ....................................................110 
14.4 
Consent and Assent Process and Documentation ................................................110 
14.5 
Patient Advocate ..................................................................................................113 
15. 
REFERENCES ................................................................................................................114 

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APPENDIX A: 
PERFORMANCE STATUS CRITERIA ................................................118 
APPENDIX B: 
PATIENT DRUG INFORATION AND WALLET CARD ....................119 
APPENDIX C: 
CS PEDIATRIC INFORMATION SHEET (FOR 
PATIENTS 7-17 YEARS) ...............................................................................................121 
APPENDIX D: 
CCS PEDIATRIC INFORMATION SHEET (FOR 
PATIENTS 7-17 YEARS) ...............................................................................................123 
APPENDIX E: 
BLOOD AND TISSUE COLLECTION 
WORKSHEETS/ADULT AND PEDIATRIC OVER 12................................................125 
APPENDIX F: 
SHIPPING MANIFEST FOR BLOOD SAMPLES FOR 
GENETIC ANALYSIS ....................................................................................................130 
 
 
 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Determine the objective response rates (ORR) using RECIST v 1.1 of atezolizumab in 
adult (≥18 years) patients with CCS and CS 
 
1.2 
Secondary Objectives 
 
1.2.1 Determine duration of response (DOR) using RECIST v 1.1 and/or change in clinical 
symptoms (time frame: baseline until disease progression, death, loss to follow-up, 
initiation of another anti-cancer treatment, withdrawal of consent, or study termination) 
 
1.2.2 Measure progression-free survival (PFS) time (time frame: baseline until disease 
progression, death, loss to follow-up, initiation of another anti-cancer treatment, 
withdrawal of consent, or study termination) 
 
1.2.3 Assess the number of activated CD8+ T cells infiltrating the tumor before and after 
atezolizumab treatment, and correlate treatment-induced changes with clinical response 
 
 
1.3 
Exploratory Objectives 
 
1.3.1 Compare RECIST v1.1 vs immune RECIST (iRECIST) in patients with CCS and CS on 
atezolizumab 
 
1.3.2 Examine changes in PD-1/PD-L1 expression in the tumor microenvironment before and 
after atezolizumab treatment, and correlate treatment-induced changes with clinical 
response  
 
1.3.3 Evaluate potential associations between atezolizumab activity and tumor genomic 
alterations 
 
2. 
BACKGROUND 
 
2.1 
Clear Cell Sarcoma 
 
Clear cell sarcoma (CCS) is a rare, aggressive, deep-seated tumor that accounts for <1% of all 
sarcomas.  The disease presents predominantly in young adults in the third decade of life as a 
slowly enlarging tender or painful mass in the extremities [1, 2].  The most common site of CCS 
is the deep soft tissues, juxtaposed to tendons, aponeuroses, or fascia of the lower extremities, 
particularly the area of the foot and ankle [1].  CCS is associated with local recurrence, regional 
lymph node metastases, and distant metastases [3].  It is usually a progressive disease with an 
overall poor prognosis due to widespread dissemination, with 5- and 10-year overall survival 
(OS) rates of 59% and 41%, respectively [4].  Molecularly, CCS is associated with a recurrent 
chromosomal translocation t (12;22), resulting in a fusion of the EWSR1 gene on 22q with the 

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ATF1 gene on 12q and producing the chimeric protein EWS/ATF1; this translocation is present 
in 70-90% of cases of CCS [4].  EWSR1-CREB1 fusions have also been consistently described 
in CCS [5]. 
 
One of the largest CCS data sets comes from a retrospective review of 52 patients with CCS in 
France [4].  In this study, the majority of patients presented with localized disease; 44 patients 
had a local resection (5 patients received neoadjuvant chemotherapy), of which 25 had residual 
microscopic disease and underwent radiation treatment.  Surgical treatments varied between 
local excision, wide local excision, radical compartment resection, and amputation.  Two patients 
presented with metastatic disease to regional lymph nodes.  Twenty-nine of the 52 patients 
developed a local recurrence; the time interval between initial treatment and local relapse ranged 
from 1 month to 20 years (median 38 months).  Local recurrence was seen in 55% of the patients 
at 5 years and in 63% at 10 years (4).  Nineteen patients developed regional lymph node 
metastasis (34% of them at 5 years and 41% of them at 10 years).  Thirty patients developed 
distant metastasis (43% of them at 5 years and 62% at 10 years).  The most common sites of 
distant metastasis were pulmonary (27 cases), bone (2 cases), and distant lymph nodes (1 case).  
 
There are no current national guidelines for the treatment of CCS, as there is no effective 
treatment for this disease when metastatic.  Complete surgical excision of the primary tumors, 
when possible, is generally accepted as the best treatment option in the non-metastatic setting.  
Overall, review of the literature regarding clinical experience with CCS demonstrates a lack of 
objective responses to standard chemotherapies and an overall poor prognosis with propensity 
for recurrences, early metastases, and poor overall survival. 
 
While CCS typically presents in the 3rd-4th decade of life, cases occur in the pediatric age range 
and make up a significant percentage of patients with this disease.  Gonzaga and colleagues 
reported patients as young as 9 years of age at diagnoses with 12% of cases presenting in patients 
less than 20 years of age [6].  The Italian and German Soft Tissue Sarcoma Cooperative Group 
reported a series of 28 pediatric patients with CCS ranging in age from 2 to 21 years [7].  In a 
recent analysis of the SEER database 172 cases of CCS were identified ranging in age at 
diagnosis from 9 to 91 years with 43 of 172 patients less than 25 years of age [8].  These reports 
demonstrate that CCS occurs in the pediatric age range and represents approximately 10% of 
cases of the disease.  The prognosis for pediatric patients with CCS is not different from that 
adult patients and children would benefit from improved therapies for CCS thus justifying the 
inclusion of pediatric patients in this study. 
 
2.2 
Chondrosarcoma 
 
Chondrosarcoma (CS) is one of the most common malignant bone tumors in adults [9]. 
Histologic grade, on a scale from 1-3, is considered the most important indicator of clinical 
behavior and prognosis [10].  Conventional CS, of which the majority of cases are low- to 
intermediate-grade, represents around 85% of CS overall [9, 11].  These tumors are slow 
growing with a low metastatic potential but are typically refractory to chemotherapy and 
radiation therapy.  In contrast, high-grade or dedifferentiated CS (5-10% of CS overall) tumors 
have a high metastatic potential and a poor prognosis following resection alone [11].  In one of 
the largest studies of dedifferentiated CS, the 5-year survival rate was 13% [12].  Current 

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guidelines suggest that patients with dedifferentiated chondrosarcoma should be treated with 
osteosarcoma regimens (NCCN Guidelines for Bone Cancer V.1.2018).   
 
Efforts to define the molecular characteristics of chondrosarcomas in general have noted 
recurrent activating mutations in isocitrate dehydrogenase (IDH) 1 and 2; the presence of these 
mutations was associated with shorter survival in some studies [13, 14].  More recently, multi-
omics classification based on proliferation status, 14q32 locus microRNA expression, and IDH-
related genome hypermethylation was found to be closely associated with prognosis, and pointed 
to a multi-step disease progression process [15].  However, a study of 89 central 
chondrosarcomas stratified by tumor grade found no association between IDH mutations and 
overall survival but, rather, a significant association between IDH1/2 mutations and both relapse-
free survival and metastasis-free survival in grade II and grade III chondrosarcomas[16].  
Frequent point mutations in H3F3B have also been reported [17].   
 
While significantly more common in older adults, CS is the third most common primary tumor 
of bone after osteosarcoma and Ewing sarcoma in pediatric patients representing approximately 
5% of primary bone tumors in children.  Evaluation of the SEER database of cases between 1973 
and 2014 identified 247 cases of chondroma in patients ≤18 years of age, including several CS 
cases among patients 0-14 years of age [18].  Cases series from Finland and Norway showed an 
incidence of chondrosarcoma of 0.3-0.5 per million per year among pediatric patients [19, 20].  
As in adult disease, there are no effective treatment options beyond a complete surgical resection 
for pediatric patients.  In the setting of metastatic or recurrent disease, prognosis is dismal with 
minimal therapeutic options.  Because of the occurrence of CS in pediatric patients along with 
the lack of effective therapeutic options for metastatic, progressive, or nonresectable disease we 
will include pediatric patients in this study. 
 
2.3 
Atezolizumab 
Atezolizumab is a human monoclonal antibody directed against programmed death-ligand 1 
(PD-L1) with potential immune checkpoint inhibitory and antineoplastic activities.  
Atezolizumab targets immune cells or tumor cells and prevents interaction with either 
programmed death-1 (PD-1) receptor or B7.1 (CD80), both of which function as inhibitory 
receptors expressed on T cells.  Interference of the PD-L1:PD-1 and PDL1: B7.1 interactions 
may enhance the magnitude and quality of the tumor-specific T-cell response through increased 
T-cell priming, expansion, and/or effector function [21, 22].  In May 2016, atezolizumab 
(Tecentriq™) was approved for the treatment of patients with locally advanced or metastatic 
urothelial carcinoma whose disease had worsened during or following platinum-containing 
chemotherapy, or within 12 months of receiving platinum-containing chemotherapy.  Subsequent 
approvals have been granted for atezolizumab (some as a monotherapy and some in combination 
with other agents) in non-small cell lung cancer, triple-negative breast cancer, and small cell lung 
cancer. 
Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid 
substitution at position 298 on the heavy chain, which results in a non-glycosylated antibody that 
has minimal binding to Fc receptors and, consequently, eliminates detectable Fc‑effector 

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function.  By eliminating Fc-effector function and antibody dependent cell-mediated cytotoxicity 
(ADCC), antibody-mediated clearance of activated effector T cells is also eliminated. 
 
2.3.1 Mechanism of Action 
 
PD-L1 expression is prevalent in many human tumors (e.g., lung, bladder, ovarian, melanoma, 
colon carcinoma), and its overexpression has been associated with poor prognosis in patients 
with several cancers [23-26].  PD-L1 binds to two known receptors, PD-1 and B7.1 (CD80).  
PD-l is expressed on activated T cells, and receptor expression is sustained in states of chronic 
stimulation such as chronic infection or cancer [27, 28].  Ligation of PD-L1 with PD-1 inhibits 
T-cell proliferation, cytokine production, and cytolytic activity, leading to the functional 
inactivation or inhibition of T cells (Figure 1).  Similarly, while the receptor B7.1 has been best 
defined as a costimulatory molecule expressed by B lymphocytes and other antigen-presenting 
cells (APCs), B7.1 expressed on the surface of T cells may provide an additional signaling 
mechanism through which PD-L1 can negatively regulate T cell responses [21].  As a result, 
aberrant expression of PD-L1 on tumor cells and tumor-infiltrating immune cells, such as 
macrophages and dendritic cells, has been reported to impede anti-tumor immunity and 
contribute to immune evasion [29, 30].   
 
 
 
Figure 1: PD-1 and PD-L1 interaction and T cell responses.  A) Binding of T-cell PD-
1 by tumor PD-L1 results in the downregulation of T-cell proliferation and effector 
functions that destroy tumor tissue.  B) Blockade of this pathway by an anti-PD-1 
antibody prevents this downregulation, and allows T cells to maintain their antitumor 
response and ability to mediate tumor cell death (adapted from Sznol et al., 2013[31]).   
 
Given the inhibitory effects of PD-L1 signaling on T cell proliferation and activity, targeted 
interruption of the PD-L1/PD-1 and PD-L1/B7.1 pathways represent an attractive strategy to 
reinvigorate tumor-specific T-cell immunity.  The other known ligand of PD-1, programmed 

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death-ligand 2 (PD-L2), is primarily expressed in normal tissues such as the lung.  As a result, 
targeting tumor-overexpressed PD-L1 is a more promising strategy than targeting PD-1, as it 
preserves the immune homeostatic PD-L2:PD-1 interaction in normal tissues while dually 
inhibiting the PD-L1:PD-1 and PD-L1:B7.1 pathways to enhance anti-tumor T cell immunity. 
 
Blockade of PD-L1 or PD-1 with monoclonal antibodies has been reported to result in strong and 
often rapid antitumor effects in several mouse tumor models [32, 33].  These data suggest that 
tumor-specific T cells may be present in the tumor microenvironment in an inactive or inhibited 
state, and blockade of the PD-L1/PD-1 pathway can reinvigorate tumor-specific T-cell 
responses. 
 
Collectively, these data establish the PD-L1/PD-1 pathway as a promising new therapeutic target 
in patients with advanced tumors.  Immune-related adverse events reported from the two recent 
studies were consistent with the role of the PD-L1/PD-1 pathway in regulating peripheral 
tolerance. 
 
2.3.2 Summary of Nonclinical Experience 
 
The safety, pharmacokinetics (PK), and toxicokinetics of atezolizumab were investigated in mice 
and cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting the 
appropriate starting dose in humans.  Given the similar binding of atezolizumab for cynomolgus 
monkey and human PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, PK, and toxicokinetics of atezolizumab.  
 
Overall, the nonclinical PK and toxicokinetics observed for atezolizumab supported entry into 
clinical studies, including providing adequate safety factors for the proposed phase 1 starting 
doses.  The results of the toxicology program were consistent with the anticipated pharmacologic 
activity of down-modulating the PD-L1/PD-1 pathway and supported entry into clinical trials in 
patients.  Please refer to the Investigator’s Brochure for details on the nonclinical studies. 
 
2.3.3 Summary of Clinical Experience 
 
Current clinical studies of atezolizumab include 101 company-sponsored studies with 
atezolizumab as a single agent or in combination with other therapies.  Details of all ongoing 
studies can be found in the Atezolizumab Investigator’s Brochure. 
 
2.3.4 Clinical PK and Immunogenicity 
 
2.3.4.1 
Adult Patients 
 
Atezolizumab pharmacokinetics and other data have been analyzed from a number of company-
sponsored monotherapy studies (Investigator’s Brochure, 2019).  Exposure to atezolizumab 
increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg, including the fixed 
dose of 1200 mg administered every 3 weeks.  On the basis of a population pharmacokinetic 
analysis that included 472 patients (Studies PCD4989g and JO28944) in the dose range of 1 
mg/kg to 20 mg/kg, the typical population clearance (CL) was 0.20 L/day, the volume of 

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distribution at steady state (Vss) was 6.9 L, and the terminal half-life (t1/2) was 27 days.  The 
population PK analysis suggested that steady state was obtained after 6 to 9 weeks (2 to 3 cycles) 
of repeated dosing.  The systemic accumulation in area under the concentration-time curve 
(AUC), maximum concentration (Cmax), and trough concentration (Cmin) was 1.91, 1.46, and 
2.75-fold, respectively, following intravenous administration of 1200 mg atezolizumab every 3 
weeks.  Atezolizumab pharmacokinetics after combination administrations with other anti-cancer 
agents were comparable to those following atezolizumab monotherapy administrations. 
 
ADAs to atezolizumab have been observed at ≤ 1 mg/kg to 20 mg/kg and at 1200 mg 
(Investigator’s Brochure, 2019).  ADA status appears to have no clinically relevant impact on 
pharmacokinetics, safety, or efficacy. 
 
2.3.4.2 
Pediatric Patients 
 
Clinically meaningful differences in monoclonal antibody distribution between adult and 
pediatric patients are not expected after taking into account differences in body size.  Because 
infants and children are able to maintain homeostasis of immunoglobulins, it is presumed that 
there are no age-related developmental differences in disposition for therapeutic proteins when 
nonspecific elimination is the major pathway.  For atezolizumab, the nonspecific antibody 
elimination pathway appears to be primary on the basis of the observation of linear 
pharmacokinetics.  Furthermore, a review of the PK characteristics of 12 approved therapeutic 
proteins showed comparable steady-state peak and trough concentrations and terminal half-lives 
between pediatric and adult patients after adjustment for body size.  Weight-based dosing of 
atezolizumab in children should therefore result in exposure similar to that in adults. 
 
Preliminary pediatric PK data (n=48) are available from the GO29664 trial, an early-phase, 
multicenter, open-label, single-arm study in pediatric (<2 to 17 years of age) and young adult 
patients with relapsed or refractory solid tumors with known or expected PD-L1 pathway 
involvement.  Exposure was compared between different pediatric age groups and shown to be 
similar to adults.  Median Cmin values were 53.6 µg/mL (2 to <6 years), 54.1 µg/mL (6 to <12 
years), and 62.0 µg/mL (12 to <18 years) compared with 68.0 µg/mL in adults.  Cmin values in 
all age groups are above the concentration expected to produce maximum receptor occupancy (6 
µg/mL). 
 
15 mg/kg is the weight-based dose equivalent to the standard adult dose of 1200 mg, assuming 
an adult body weight of 80 kg.  This dosing regimen is expected to produce exposure in children 
that is in a similar range to adult exposure.  In the GO29664 trial, the infusion was tolerated by 
pediatric patients. 
 
As of the clinical cutoff date for the 2019 Atezolizumab Investigator’s Brochure, there were 87 
safety-evaluable patients enrolled in Study GO29664 in 12 cohorts of patients with various 
tumor types including Ewing sarcoma, other soft tissue sarcomas, and osteosarcoma.  Overall, 
atezolizumab was well-tolerated and its safety profile in pediatric patients was consistent with its 
known safety profile in adults.  There were no new safety signals identified.  The incidence of 
adverse events was similar across age groups and cohorts. 
 

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2.3.4.3 
Clinical Safety Summary 
 
As of May 17, 2019, atezolizumab has been administered (alone or in combination with other 
agents) to > 21,000 patients with solid tumors and hematologic malignancies (Investigator’s 
Brochure, 2019).  Safety findings of single-agent atezolizumab across multiple tumor types in 
the clinical development program are consistent with the known mechanism of action of 
atezolizumab and the underlying disease.  Overall, treatment with atezolizumab is well tolerated 
with a manageable adverse event profile.  Currently, no maximum tolerated dose (MTD), no 
dose-limiting toxicities (DLTs), and no clear dose-related trends in the incidence of adverse 
events (AEs) have been determined. 
 
Among 3178 patients treated with single-agent atezolizumab for whom pooled safety data are 
available, the most commonly reported AEs (≥ 10%) include fatigue, decreased appetite, nausea, 
cough, dyspnea, constipation, pyrexia, diarrhea, anemia, back pain, vomiting, asthenia, 
arthralgia, pruritus, rash, headache, urinary tract infection, and peripheral edema (Investigator’s 
Brochure, 2019).  The safety profile was generally consistent between the two highly enrolled 
populations (urotherlial carcinoma and non-small cell lung cancer). 
 
As of the data extraction date of December 15, 2015, there were 629 safety-evaluable patients 
from the first-in-human phase 1a study PCD4989g (Investigator’s Brochure, 2017).  The median 
age was 61 years.  The median duration of treatment for this cohort is currently 12.14 weeks 
(range: 0.0 − 71.4), and the median number of atezolizumab cycles administered is 5.0 (range: 1 
− 19 cycles).  Of the 629 patients, 619 patients (98.4%) reported at least one AE of any grade or 
attribution to atezolizumab, and 316 patients (50.2%) experienced at least one grade 3 or 4 AE of 
any attribution.  A total of 444 patients (70.6%) reported at least one treatment-related AE, and 
86 patients (13.7%) experienced at least one treatment-related grade 3 or 4 AE.  The most 
frequently observed AEs of any grade and attribution (occurring in 10% of treated patients) 
include fatigue, decreased appetite, nausea, pyrexia, constipation, cough, dyspnea, diarrhea, 
anemia, vomiting, asthenia, back pain, headache, arthralgia, pruritus, rash, abdominal pain, 
insomnia, peripheral edema, and dizziness. 
 
Serious AEs (SAEs) have been reported in 261 patients (41.5%) in study PCD4989g 
(Investigator’s Brochure, 2017).  Reported SAEs were consistent with the underlying disease.  
Treatment-related SAEs (57 patients [9.1%]) included pyrexia, dyspnea, pneumonitis, malaise, 
fatigue, hypoxia, colitis, and bone pain.  
 
2.3.4.4 
Immune-Related Adverse Events 
 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated AEs have been closely monitored during the atezolizumab clinical program 
(Investigator’s Brochure, 2019).  These include potential dermatologic, hepatic, endocrine, 
gastrointestinal, and respiratory events as well as events of hepatitis/elevated liver function tests 
(LFTs) and influenza-like illness.  To date, immune-related adverse events associated with 
atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, myasthenic 
syndrome/myasthenia gravis, meningoencephalitis, myocarditis, nephritis, and myositis.   

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Pericardial and pleural involvement with associated effusions is common in patients with cancer 
and has the theoretical potential to be exacerbated by inflammation associated with antitumor 
immunity following PD-L1 blockade.  Dyspnea, cough, fatigue, hypoxia, pneumonitis, and 
pulmonary infiltrates have been associated with the administration of atezolizumab and have 
primarily been observed in patients with underlying NSCLC. 
 
For further details, see the most recent Atezolizumab Investigator’s Brochure. 
 
2.3.4.5 
Clinical Efficacy Summary 
 
Patients with multiple tumor types were included in study PCD4989g, with the largest cohorts 
consisting of patients with NSCLC, RCC, and UC (Investigator’s Brochure, 2017).  Objective 
responses with atezolizumab monotherapy were observed in a broad range of malignancies, 
including NSCLC, RCC, melanoma, UC, colorectal cancer, head and neck cancer, gastric cancer, 
breast cancer, and sarcoma.  Objective responses were recorded for 20 of 88 (22.7%) response-
evaluable patients with NSCLC, including responses in squamous and non-squamous patients.  
The median duration of survival follow-up at the time of the data cut-off (December 2, 2014) 
was 22.5 months.  At that timepoint, the median duration of all responders was 17.3 months, 
with 40% (8 of 20) of responders having an ongoing response.  
 
Analyses of tumor cells and tumor-infiltrating immune cells for PD-L1 expression on baseline 
tumor tissue have been performed for study PCD4989g, including expansion cohorts of patients 
with NSCLC (88 efficacy-evaluable patients), UC (87 efficacy-evaluable patients), and RCC (62 
efficacy-evaluable patients) [22, 34] (Investigator’s Brochure, 2017).  Preliminary results suggest 
that PD-L1 expression in tumor-infiltrating immune cells is likely to be associated with response 
to atezolizumab.  An objective response rate (ORR) of 43% (13 of 30 patients, including 2 
complete responses) was observed in UC patients with tumor-infiltrating immune cells with PD-
L1 immunohistochemistry (IHC) scores of 2 or 3, whereas the ORR among IHC 0/1 UC patients 
was 11% (4 of 35) [34].  While the median had not been reached as of January 1, 2014, the 
duration of response ranged from 0.1+ to 30.3+ weeks for patients with IHC 2/3 tumor-
infiltrating immune populations and from 0.1+ to 6.0+ weeks for patients with IHC 0/1.  
Response to atezolizumab in the UC cohort was associated with the tumor-infiltrating immune 
cell IHC scores (P=0.026) but not with tumor cell IHC scores (P=0.93).  Similarly, a preliminary 
analysis of the NSCLC cohort (53 evaluable patients) and the total patient population (175 
evaluable patients) of PCD4989g found that response was significantly associated with PD-L1 
IHC score in tumor-infiltrating immune cells (P=0.015 in NSCLC, P=0.007 in all tumors) but not 
with IHC score in tumor cells (P=0.920 in NSCLC, P=0.079 in all tumors) [22].  Eighty-three 
percent of NSCLC patients with an IHC score of 3 (tumor-infiltrating immune cell) responded to 
treatment, whereas 43% of NSCLC patients with IHC 2 were limited to disease stabilization. 
 
Extensive efficacy data are now available for patients with non-small cell lung cancer (1636 
atezolizumab-treated patients) and patients with metastatic urothelial carcinoma (983 
atezolizumab-treated efficacy-evaluable patients; Investigator’s Brochure, 2019).  The results 
from studies evaluating atezolizumab as monotherapy in patients with locally advanced or 
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2L/3L NSCLC intent to treat population, in comparison with standard of care, in both non-
squamous and squamous histologies, and across all PD-L1 expression subgroups.  Other 
available efficacy data suggested that treatment with atezolizumab as a single agent or in 
combination with other therapeutic agents resulted in anti-tumor activity across a range of other 
tumor types and hematologic malignancies (including pediatric-type tumors), across lines of 
therapy, and across PD-L1 expression subgroups. 
 
2.4 
Rationale 
 
Wide surgical resection remains the only curative treatment for localized CCS, leaving a paucity 
of therapeutic options for the treatment of this often recurrent and metastatic aggressive disease 
[35].  Scheinberg and colleagues reported a retrospective study of young adult patients with 
advanced sarcomas, including CCS, with data suggesting patients with CCS may benefit from 
treatment with anti-PD-1 antibody pembrolizumab [36].  Complete clinical response has been 
reported in a case of mediastinal CCS with pembrolizumab when the agent was combined with 
standard fractionation radiotherapy [37].  A phase 1 study of the checkpoint inhibitor ipilimumab 
(anti-CTLA-4) in pediatric patients reported stable disease in one patient with CCS (n=2) [38].  
Finally, one patient with advanced CCS experienced a partial response with pembrolizumab 
(personal communication).  These results suggest that similar checkpoint inhibitor agents such as 
the anti-PD-L1 antibody atezolizumab may be effective in CCS, providing a possible therapeutic 
option for a rare disease with limited treatment possibilities.  To our knowledge, treatment of 
patients with CCS with atezolizumab has not been reported in the literature. 
 
Likewise, there remains an urgent need for novel CS treatments, given the recurrence rates and 
the chemo- and radio-resistance of the disease [39].  With the growing success and FDA 
approvals of immune checkpoint inhibitors in other cancer types, several studies have examined 
the expression of PD-1 and its ligands in bone sarcomas, including CS [40].  Dedifferentiated CS 
may be the subtype of CS most amenable to checkpoint inhibitor treatment, as these tumors were 
shown to uniquely express PD-L1 and to have tumor-infiltrating immune cells [15, 41].  More 
recently, however, PD-L1 expression and TILs were also reported in conventional CS specimens 
and were associated with tumor aggressiveness [42, 43].  Clinical reports of immune checkpoint 
inhibitors in CS remain scarce, since most investigations have been conducted in osteosarcoma 
or across wide arrays of sarcoma subtypes.  Wagner and colleagues have reported a case of a 
near complete response to the PD-1 inhibitor nivolumab in conventional CS, following a well-
documented pseudoprogression response after 4 cycles of therapy [44].  Additionally, objective 
responses have been reported in two patients with dedifferentiated CS with immune checkpoint 
inhibitors [45, 46]. 
 
This trial is designed to provide eligible patients with a promising treatment approach while also 
providing insight into immunotherapy mechanisms of action and potential strategies for patient 
selection, because despite the success that has been achieved with checkpoint inhibitor therapy in 
a subset of patients with melanoma, NSCLC, and some other cancers, there is no cellular marker 
that consistently predicts which patients will respond.  Our objective endpoint will be to 
determine the ORRs of atezolizumab in adult and pediatric/adolescent patients with CCS and CS.   
 
Biopsies will be used to determine immune status of the tumor microenvironment (presence and 

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activation of tumor-infiltrating T cells) and genomic makeup of the tumor pre- and post-
treatment; these will be correlated with the response to checkpoint inhibitor therapy.  We will 
atezolizumab investigate whether TMB correlates with response to atezolizumab; while 
sarcomas driven by chromosomal translocations are often low-TMB, it is thought that mutational 
burden increases over time as the disease progresses [47, 48].  Blood samples will be used for the 
analysis of immune cell subsets and measurement of T-cell activation in the periphery, allowing 
us to follow changes in the T-cell population longitudinally and potentially correlate increases in 
T-cell activation with reduction in tumor burden. 
 
2.5 
Correlative Studies Background 
 
Although checkpoint inhibitory agents have been shown to have clinical activity, there is as yet 
no predictive biomarker for this class of agent.  Blocking PD-L1:PD-1 and PD-L1: B7.1 
interactions with atezolizumab may release the immune checkpoint blockade, affecting the 
activity of tumor infiltrating lymphocytes (TILs), CD4+CD25+FOXP3+ regulatory T cells 
(Tregs), myeloid-derived suppressor cells (MDSCs), T-helper 2 (Th2) CD4+T cells, M2 
macrophages, and N2 neutrophils, and allowing TILs to mount an immune response [49, 50].  
From the pharmacodynamic perspective, a relationship between extent of mutational load and 
molecular response of the T-cell receptor in CD8+ TILs could be observed following PD-L1 
therapy in cases that are baseline PD-L1+ tumor/PD-1+ TILs (i.e., in cases with a high likelihood 
that the PD-1 pathway is the immune checkpoint).  The “negative control” is that this should not 
occur in tumors that utilize some other immune checkpoint, as evidenced by PD-L1- tumor or 
PD-1- TIL phenotyping.   
 
One of the challenges of developing assays to measure the effects of immunotherapeutic agents 
is that the target is an immune cell rather than a tumor.  It is therefore necessary to measure 
primary effects on immune cells and secondary effects on the cancer cells, as well as the 
interactions between these two populations (Figure 2).  Experimental models with an intact 
immune system are required for this, thereby excluding immunodeficient xenograft models and 
tumor cell lines.   
 
 

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Figure 2. Immune checkpoint blockade.  Assays to measure the PD effects of checkpoint 
blockade agents must encompass effects on the immune cell-tumor cell interface, the T cell, and 
adjoining tumor cells (adapted from Parchment et al. [51]).   
Adult patients will undergo tumor biopsies for pharmacodynamic studies at baseline and prior to 
Cycle 3 Day 1 (±3 days; or sooner if there is clinical evidence that the patient is responding to 
drug) such as at confirmation of PR.  Blood specimens will also be collected at these and other 
timepoints.  We plan to use these research samples to evaluate the pharmacological effect of 
atezolizumab on immune cell components of the tumor, the tumor microenvironment, and 
peripheral T cell populations which will help to elucidate the mechanism of action of this agent 
in sarcoma and demonstrate the impact of a PD-L1 inhibitor on signaling pathways mediating the 
immune response.  As there are differences in biological characteristics among sarcoma 
subtypes, pharmacodynamic comparisons will only be made within the CS and CCS sarcoma 
cohorts, rather than CCS and CS samples being pooled for analysis.  Efforts will be made to 
correlate any observed treatment-induced changes with clinical response or resistance to therapy. 
2.5.1 Pharmacodynamic Assessment of Drug Response 
 
Using the multiplex quantitative immunofluorescence assay (immunoPD IFA) platform 
developed by PADIS (Figure 3 and Figure 4), we plan to quantify the number of activated CD8+ 
T cells infiltrating the tumor and characterize the activation status of the T cells around and 
within the tumor region.  The tumor and T cell markers analyzed in the immunoPD IFA will 
include:  
 
• PD-1 and PD-L1 expression 
• T cell phenotypic markers CD8 and CD4 
• Phosphorylation of the T-cell receptor complex (TCR-CD3 ζ) to demonstrate antigen 
recognition by T cells [52]   
• Phosphorylated tyrosine phosphatases SHP1 (Y536) and SHP2 (Y542 and Y580) in T 
cells as markers of the status of PD1/PDL1 checkpoint signaling (primary PD) [53] 
• Phosphorylated Zap70 kinase (Y493), an indication of further transduction of the T cell-
activating TCR signal (secondary PD), that serves as a convergence point for TCR and 
PD1/PDL1 signaling [54] 
• Tumor marker(s), such as β-catenin, to identify tumor region 
 

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Figure 3.  PADIS is developing and validating these IF assays to report T cell activation, PD-
1 and PD-1 levels, and relationship of TILs to invasive tumor margins.  Test panels (such as 
the example shown here) include IFA multiplexes and an H&E slide for pathologist 
annotation and registration of adjacent slides.  Additional biomarkers can be incorporated into 
panels as they come available.  Adjacent slides may also be evaluated by HalioDx (France) 
using its Immunoscore® and Immunoseek® assays for independent CD8+ T-cell counts. 
 
PADIS has demonstrated the use of this IFA in identifying and enumerating CD8+ T cells within 
tumor tissue that has been segmented using the tumor marker β-catenin.  The number of 
activated CD8+ T cells present inside and outside of the tumor marker-positive area will be 
reported for biopsies collected at baseline and on Cycle 3 Day 1, as modulation of the tumor 
immune microenvironment is expected to require an extended response time frame.  T-cell 
activation status will be determined through detection of pZAP70 and pCD3ζ phosphorylation.  
This endpoint will be correlated with patient response to immunotherapy.  Figure 4 shows the 
clinical feasibility of the immunoassay demonstrated in a tissue microarray core specimen. 
 

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Figure 4. Performance of the immunoPD IFA on T cells captured in a colorectal cancer 
tumor microarray (collected with an ischemia time of 5 minutes or less), demonstrating our 
ability to identify activated T cells in tissue specimens collected from patients under 
Developmental Therapeutics Clinic SOPs. 
 
While there is evidence to suggest that PD-L1 expression is associated with response to anti-PD-
1/PD-L1 checkpoint inhibitors, there are not enough data available to definitively establish PD-
L1 as a predictive biomarker for atezolizumab response in sarcoma.  PADIS immunoPD IFA 
panels will be used in an exploratory fashion to measure baseline expression of PD-L1 in 
responders and non-responders, as well as the effects of atezolizumab on PD-L1 expression in 
tumor cells and PD-1 expression in T cells.  Multiplex IFA panels measuring these markers in 
conjunction with CD3, CD8, and β-catenin are in development. 
 
Intracellular staining and flow cytometry assays evaluating the immune signaling and activation 
in peripheral T cells will also be performed on blood samples collected at select sites.  Peripheral 
T-cell subsets will be identified using phenotypic surface markers CD3, CD4, and CD8.  
Activation status will be determined based on expression of intracellular phosphomarkers 
(pZAP70, pSHP1/SHP2, and pCD3ζ).  PADIS has demonstrated clinical validation of this flow 
cytometry assay using blood specimens collected at DTC clinic (a manuscript is in progress).  
These studies will allow us to follow changes in the T-cell population longitudinally and 
potentially correlate increases in T-cell activation with reduction in tumor burden.  The data 
obtained from this continuous analysis may also inform the adjustment of biopsy timepoints to 
capture drug-induced immune changes in tumor tissue. 
 
2.5.2 Immunopharmacodynamic Assay Validation Summary 
 
As suitable immunocompetent animal models were not available for methods development and 
biomarker validation, an in vitro system was established to activate T cells from healthy donors 
recruited through the Research Donor Program at FNLCR.  A manuscript describing this process 
is in preparation.  Testing for activation biomarkers and immune signaling was performed using 
multicolor flow cytometry.  After identifying biomarker/antibody pairs, control FFPE blocks 
were prepared using activated donor T cells and control tissue (liver); these provide an ongoing 
and consistent control set of known reactivity that can be used over the time course of months to 
years until exhausted.  Each of the monoclonal antibody lots that will be used in this clinical trial 
were validated by time course of marker activation and dilution of the reporter antibody 
conjugate. 
 
The multicolor flow cytometry data obtained by PADIS demonstrate the ability to evaluate T- 
cell activation in blood specimens; activation of known internal signaling pathways in CD4+ and 
CD8+ T cells is a multiday event in vitro, and there is a variable time to activation for each of the 
identified biomarkers of interest. 
 
Antibodies to PD-1 and PD-L1 were also screened and analytically validated (Figure 5).  PD-1 
could be identified in control human thymus and PD-L1 was identified in human xenograft 
tissues and in tissue microarray.  Both colorimetric IHC and immunofluorescence were used in 
evaluation of the FFPE slides. 
 

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sequenced to distinguish germline from tumor-specific alterations and thus to call somatic 
mutations in the whole exome sequencing results from the tumor tissue specimens and, possibly, 
from the cell-free DNA.   
 
Blood for circulating tumor DNA (ctDNA) analysis will be collected before treatment, 
throughout the trial, and at the time of disease progression.  Once a patient has come off study, 
ctDNA from blood samples correlating to clinically informative time points will be analyzed by 
MoCha with the TSO500 targeted sequencing assay to quantitatively assess longitudinal changes 
in ctDNA levels (as a percentage of total circulating, cell-free DNA) and to identify any 
mutations that may be associated with atezolizumab sensitivity or resistance.   
 
If possible, we will explore changes to mutational load over the therapy duration as there is some 
support for the hypothesis that mutations accumulate over time [55, 56].  These findings may be 
relevant for whether “better” responses are observed in later versus earlier line patients.  In 
addition to evaluating changes in tumor mutations over time (post-treatment), extensive 
molecular characterization of pre-treatment tumor biopsy tissue from each patient enrolled on 
this trial will enable identification of valuable potential biomarkers to predict which patients are 
more or less likely to respond to treatment. 
 
For patients who choose to undergo optional “restaging follow-up” or progression biopsies, the 
first 2 flash-frozen biopsy cores will be reserved for analysis by the CLIA-certified Oncomine 
version 3 (OCAv3) targeted sequencing assay to identify mutations in patient tumor tissue.  
Results from the OCAv3 assay will be returned to patients, in the form of an Oncomine report, 
for use in selecting future treatment options. 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have documented EWSR1/ATF1 or EWSR1/CREB1 translocation or 
histologically confirmed clear cell sarcoma, documented grade 2 or 3 conventional 
chondrosarcoma, or documented dedifferentiated chondrosarcoma.  The disease must 
not be curable by surgery. 
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  See Section 11 
(Measurement of Effect) for the evaluation of measurable disease. 
 
3.1.3 Patients with newly diagnosed, unresectable, metastatic and measurable  clear cell 
sarcoma, EWSR1/ATF1 or EWSR1/CREB1 translocation, grade 2 or 3 conventional 
chondrosarcoma, or dedifferentiated chondrosarcoma will also be eligible if they show 
clinical evidence of disease progression (including history and increasing physical 
symptoms).  On-study documentation will include a physician’s rationale that supports 

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evidence of clinical disease progression (i.e., increasing tumor pain). 
 
3.1.4 Age ≥2 years at the NCI Clinical Center (≥12 years at other participating sites) 
 
3.1.5 ECOG performance status ≤2 (Karnofsky or Lansky ≥70%, see Appendix A). 
 
3.1.6 Life expectancy of greater than 3 months. 
 
3.1.7 Patients must have adequate organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
 
≥1,000/mcL 
− 
platelets  
 
≥100,000/mcL 
− 
hemoglobin 
 
≥8 g/dL 
− 
total bilirubin 
 
≤ institutional upper limit of normal (ULN)  
(however, patients with known Gilbert disease who 
have serum bilirubin level 3  ULN may be 
enrolled) 
− 
AST(SGOT)/ALT(SGPT) 
 
≤3 × institutional ULN  
(AST and/or ALT 5  ULN for patients with liver 
involvement) 
− 
alkaline phosphatase 
 
≤2.5 × ULN 
(5  ULN for patients with documented liver 
involvement or bone metastases) 
− 
creatinine  
 
 
 
For adult patients (≥18 years of age):   
≥30 mL/min/1.73 m2 by Cockroft-Gault 
 
(140 − age)  (weight in kg)            ( 0.85 if female) 
72  (serum creatinine in mg/dL) 
 
 
 
 
 
For pediatric patients (<18 years of age), a serum 
creatinine based on age and gender as follows:  
Serum Creatinine for Age/Gender 
Age 
Maximum Serum Creatinine (mg/dL) 
 
Male 
Female 
2 to <6 years 
0.8 
0.8 
6 to <10 years 
1 
1 
10 to <13 years 
1.2 
1.2 
13 to <16 years 
1.5 
1.4 
16 to <18 years 
1.7 
1.4 
The threshold creatinine values in this table were derived from the Schwartz formula for 
estimating GFR [57], utilizing child length and stature data published by the CDC. 
 
3.1.8 Patients with treated brain metastases are eligible if follow-up brain imaging after 
central nervous system (CNS)-directed therapy shows no evidence of progression for ≥1 

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month after treatment of the brain metastases. 
 
3.1.9 Patients with new or progressive brain metastases (active brain metastases) or 
leptomeningeal disease are eligible if the treating physician determines that immediate 
CNS-specific treatment is not required and is unlikely to be required during the first 2 
cycles of therapy. 
 
3.1.10 Patients with a prior malignancy whose natural history or treatment does not have the 
potential to interfere with the safety or efficacy assessment of the investigational regimen 
are eligible for this trial. 
 
3.1.11 Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification.  To be eligible 
for this trial, patients should be class 2B or better. 
 
3.1.12 Willingness to provide biopsy samples for research purposes (patients ≥18 years of age 
only). 
 
3.1.13 Administration of atezolizumab may have an adverse effect on pregnancy and poses a 
risk to the human fetus, including embryo-lethality.  Female patients of child-bearing 
potential and male patients must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for 5 months (150 days) after the last dose of study agent.  Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately. 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent document or 
a parent/guardian able to do the same. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Any prior therapy must have been completed ≥4 weeks or, if known, ≥5 half-lives of the 
prior agent (whichever is shorter) prior to enrollment on protocol (minimum of 1 week 
between prior therapy and study enrollment), and the participant must have recovered to 
eligibility levels from prior toxicity.  Patients should be at least 6 weeks out from 
nitrosoureas and mitomycin C.  Prior definitive radiation should have been completed 
≥4 weeks or palliative radiation should have been completed >2 weeks prior to study 
enrollment and all associated toxicities resolved to eligibility levels (patients on study 
may be eligible for palliative radiotherapy to non-targeted lesions after 2 cycles of 
therapy at the PI’s discretion).  Patients who have had prior monoclonal antibody 
therapy must have completed that therapy ≥6 weeks (or 3 half-lives of the antibody, 
whichever is shorter) prior to enrollment on protocol (minimum of 1 week between prior 
therapy and study enrollment).  A patient who has received a cumulative dose of >350 
mg/m2 of anthracycline (regardless of cardioprotectant) may only be enrolled if their 

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ejection fraction measured by an echocardiogram is within normal institutional limits. 
 
3.2.2 Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting 
agents. 
• Patients who have received prior treatment with anti-CTLA-4 may be enrolled, 
provided the following requirements are met: 
o Minimum of 12 weeks from the first dose of anti-CTLA-4 and 6 weeks 
from the last dose 
o No history of severe immune-related adverse effects from anti-CTLA-4 (NCI 
CTCAE Grade 3 and 4) 
 
3.2.3 Treatment with any other investigational agent within 4 weeks (or within five half-lives 
of the investigational product, whichever is shorter) prior to Cycle 1, Day 1 (minimum 
of 1 week between prior therapy and study enrollment).  Patients must be ≥ 2 weeks 
since any investigational agent administered as part of a Phase 0 study (also referred to 
as an “early Phase I study” or “pre-Phase I study” where a sub-therapeutic dose of drug 
is administered) at the Coordinating Center PI’s discretion, and should have recovered to 
eligibility levels from any toxicities. 
 
3.2.4 Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon- or interleukin-2 [aldesleukin]) within 6 weeks prior to Cycle 1, Day 1. 
 
3.2.5 Treatment with systemic immunosuppressive medications (including, but not limited to, 
prednisone [>10 mg/day], cyclophosphamide, azathioprine, methotrexate, thalidomide, 
and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, 
Day 1. 
• Patients who have received acute, low dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea) may be 
enrolled. 
• The use of inhaled corticosteroids and systemic mineralocorticoids (e.g., 
fludrocortisone) for patients with orthostatic hypotension or adrenocortical 
insufficiency is allowed. 
 
3.2.6 Patients taking bisphosphonate therapy for symptomatic hypercalcemia.  Use of 
bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is 
allowed. 
 
3.2.7 Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies. 
 
3.2.8 History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric 
or humanized antibodies (i.e., antibodies with generic names ending in "ximab" or 
"zumab", respectively) or fusion proteins 
 
3.2.9 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 

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arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.10 Pregnant women are excluded from this study because atezolizumab is an 
investigational agent with the unknown potential for teratogenic or abortifacient effects.  
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with atezolizumab, breastfeeding should be 
discontinued if the mother is treated with atezolizumab. 
 
3.2.11 Patients with a history of HIV-positive on antiretroviral therapy are eligible with an 
undetectable viral load.  For these patients, an HIV viral load test must be completed 
within 28 days prior to enrollment. 
 
3.2.12 Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis; cirrhosis; fatty liver; and inherited liver disease. 
• Patients with past or resolved hepatitis B infection (defined as having a negative 
hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to 
hepatitis B core antigen] antibody test) are eligible.  For these patients, HBsAg 
and anti-HBc tests must be done within 28 days prior to enrollment. 
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA.  For these patients, 
an HCV RNA test must be done within 28 days prior to enrollment. 
 
3.2.13 History or risk of autoimmune disease, including, but not limited to, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune 
thyroid disease, vasculitis, or glomerulonephritis. 
• Patients with a history of autoimmune hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible. 
• Patients with autoimmune hyperthyroid disease not requiring 
immunosuppressive treatment may be eligible. 
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may 
be eligible. 
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
o Patients with psoriasis must have a baseline ophthalmologic exam to rule 
out ocular manifestations 
o Rash must cover less than 10% of body surface area (BSA) 
o Disease is well controlled at baseline and only requiring low potency 
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) 
o No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral 

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steroids) 
 
3.2.14 History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) 
scan.  History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
3.2.15 Patients with active tuberculosis (TB) are excluded. 
 
3.2.16 Severe infections within 4 weeks prior to Cycle 1, Day 1, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
 
3.2.17 Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1. 
 
3.2.18 Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1, Day 1.  
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible. 
 
3.2.19 Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need 
for a major surgical procedure during the course of the study. 
 
3.2.20 Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live, attenuated vaccine will be required during the study and up 
to 5 months after the last dose of atezolizumab. 
• Influenza vaccination should be given during influenza season only 
(approximately October to March).  Patients must not receive live, attenuated 
influenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at any time during 
the study. 
 
3.3 
Screening Evaluation 
 
Patient eligibility screening tests will be performed as described below.  Eligibility history, 
physical examination, laboratory evaluations, urinalysis, and EKG are to be conducted within 
8 days prior to enrollment.  As noted in Section 5, if protocol therapy is started within 8 days 
of these eligibility screening evaluations, values from the screening evaluations may be used 
as baseline measurements; if >8 days have passed since the screening evaluations, the medical 
history, physical examination, laboratory evaluations, urinalysis, and EKG must be repeated 
prior to starting protocol therapy.  ECHO must be done within 28 days prior to enrollment.  
ECHO and baseline imaging scans must be done within 28 days prior to the start of protocol 
therapy; eligibility screening results (ECHO and radiographs) can be used if done ≤28 days 
prior to start of protocol therapy and the site investigator determines that they are of 
acceptable quality. 
 
3.3.1 Histologic confirmation:  For patients enrolling on the basis of CCS diagnosis, in the 
absence of documented EWSR1 translocation, histological confirmation of CCS will be 
required at the enrollment site prior to enrollment.  Reports from outside institutions will 

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be accepted for documentation of EWSR1/ATF1 or EWSR1/CREB1 translocation, grade 2 
or 3 conventional chondrosarcoma, or dedifferentiated chondrosarcoma. 
3.3.2 History and Physical Examination - complete history and physical examination 
(including height, weight, vital signs, and performance score [ECOG, Karnofsky, or 
Lansky, see Appendix A]) will be conducted within 8 days prior to both enrollment and 
the start of protocol therapy. 
3.3.3 Imaging Studies - every participant should have an evaluation of known sites of disease, 
conducted via a CT scan of the chest/abdomen/pelvis.  This scan may be done at the 
enrolling institution; alternatively, images or reports from scans conducted at an outside 
institution may be used.  Either way, the scan, image, or report used to determine 
eligibility must be at least as recent as the time of disease progression determination on 
the patient’s last treatment.  Scans for baseline tumor measurements must be done within 
28 days prior to the start of protocol therapy; radiographs used to determine eligibility 
can be used for baseline measurements if the scans were conducted ≤28 days prior to start 
of protocol therapy and the site investigator determines that they are of acceptable 
quality.  At the discretion of the PI and as clinically indicated, the following imaging 
studies may also be performed: MRI or CT scan with contrast of the brain, MRI liver, or 
MRI for other disease sites. 
3.3.4 Laboratory Evaluation - laboratory data are to be obtained within 8 days prior to both 
enrollment and start of protocol therapy: 
• Hematological Profile: CBC with differential, hemoglobin, platelets 
• Biochemical Profile: ACTH, albumin, alkaline phosphatase (ALP), AM cortisol, 
bicarbonate, total bilirubin, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, TSH, free 
T4, amylase, lipase 
• Urinalysis  
• Serum or urine pregnancy test for female participants of childbearing potential 
• PT and PTT only for patients undergoing research biopsies 
3.3.5 Cardiac Evaluation  
• EKG - to be performed within 8 days prior to both enrollment and start of protocol 
therapy 
• ECHO - to be performed within 28 days prior to both enrollment and start of protocol 
therapy 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 

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https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website.  
Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation, 
• IRB-signed CTSU IRB Certification Form, and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• Compliance with all protocol-specific requirements (PSRs). 
 

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4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment.  To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Participating 
Organization on the protocol.  
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-NCI, and 
protocol number 10398, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided.  (Note:  For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU as described above.)  
 
4.2.2 Protocol Specific Requirements For P10398 Site Registration 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments.  The enrolling site will select their credentialed provider treating the subject in the 
OPEN credentialing screen, and may need to answer additional questions related to treatment in 
the eligibility checklist.   
• A teleconference training led by the Coordinating Center is required for each 
participating site prior to the site’s initial activation in RSS. 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log on to the CTSU members’ website → 
Regulatory → Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website.  The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an Approved site registration status 

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and enrolling patients to the study.  To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off.  Any individual at the enrolling site on a 
participating roster may initiate the site DTL.  Once the DTL is submitted for CI approval, only 
the designated DTL Administrators or the CI may update the DTL.  Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and include a Master 
Task List, which describes DTL task assignments, CI signature, and CTEP registration 
requirements. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site’s registration status on the members’ side of the CTSU website.  
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note:  The status shown only reflects institutional compliance with site registration requirements 
as outlined above.  It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment.  OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
 
Requirements for OPEN access:   
 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations:  Be on an LPO roster, ETCTN 
Corresponding roster, or Participating Organization roster with the role of Registrar.  
Registrars must hold a minimum of an AP registration type. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar task on 
the DTL for the site. 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 

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OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the IWRS Slot Reservation System to ensure that a slot on the 
protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  Slots can be reserved for a maximum of 14 
calendar days.  
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Following registration, patients should begin protocol treatment within 8 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator. 
 
4.3.2 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN link of the CTSU website 
at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11.  This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 

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Following registration, patients should begin protocol treatment within 8 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5. 
TREATMENT PLAN 
 
This is a multicenter open-label phase 2 trial evaluating atezolizumab in adult subjects ≥18 years 
of age and in pediatric/adolescent subjects ≥2 years of age with advanced CCS or CS.  Patients 
will be divided into cohorts based on histology upon enrollment.  There will be three cohorts: 
histologically confirmed CCS (or EWSR1 translocation), conventional CS (grade 2 or 3), and 
dedifferentiated CS. 
 
Patient evaluations will be performed throughout the study as described below.  Baseline history, 
physical examination, laboratory evaluations, urinalysis, and EKG are to be conducted within 8 
days prior to the start of protocol therapy.  If protocol therapy is started within 8 days of these 
eligibility screening evaluations (see Section 3.3), values from the screening evaluations may be 
used as baseline measurements; if >8 days have passed since the screening evaluations, the 
medical history, physical examination, laboratory evaluations, urinalysis, and EKG must be 
repeated prior to starting protocol therapy.  Baseline imaging scans and ECHO must be done 
within 28 days prior to the start of protocol therapy.   
 
History and physical examination will be done within 8 days of Day 1 of all cycles.  Labs (serum 
chemistries and CBC with differential) will be performed at baseline as described above, on 
Cycle 1 Day 15 [± 1 day], and then up to 3 days before the start of each subsequent cycle (LDH 
and protein do not need to be checked again after baseline).  TSH will be checked at baseline 
(within 8 days of Cycle 1 Day 1) and then up to 3 days before the start of each subsequent cycle.  
EKG will be repeated as clinically indicated after the baseline measurement described above. 
 
Patients will have a CT scan at baseline (within 28 days prior to start of protocol therapy).  
Patients will undergo a CT scan and be re-evaluated for response at the end of Cycle 3 and every 
two cycles thereafter (every 3 cycles for patients on study for >1 year; every 4 cycles for patients 
on study for >2 years).  Given the concern of pseudoprogression (“tumor flare”), patients that are 
clinically well may continue on therapy following RECIST progression if they meet the criteria 
outlined in Section 11.4. 
 
Research biopsies (mandatory for adult patients at all sites) and blood samples for PD studies 
(mandatory for patients ≥12 years of age) will be collected as described in Section 9.2 and Section 
9.3. 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis according to the regimen table below.  
Reported adverse events and potential risks are described in Section 7.  Administration of 
atezolizumab will be performed in a setting with emergency management capabilities and staff 

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who are trained to monitor for and respond to medical emergencies. 
 
There will be no dose reduction for atezolizumab in this study.  Appropriate dose delays are 
described in Section 6.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy. 
 
Regimen Description 
Atezolizumab 
Dose 
Route 
Schedule 
Cycle Length 
Adults ≥18 yrs 
1200 mg 
IV  
Day 1, week 1 21 days  
Pediatrics ≥2 yrs 
15 mg/kg (1200 mg max) IV  
Day 1, week 1 21 days 
 
For anaphylaxis precautions, see the management guidelines.  Atezolizumab infusions will be 
administered per the instructions outlined in the table below:  
 
Administration of First and Subsequent Atezolizumab Infusions 
 
First Infusion 
Subsequent Infusions 
• No premedication is permitted prior to the 
atezolizumab infusion. 
• Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should be 
measured within 60 minutes prior to the 
infusion. 
• Atezolizumab should be infused over 
60 ( 15) minutes. 
• If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
• Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
• If the patient experienced an infusion-related 
reaction with any previous infusion, 
premedication with antihistamines, antipyretics, 
and/or analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
• Vital signs should be measured within 
60 minutes prior to the infusion. 
• Atezolizumab should be infused over 30 ( 10) 
minutes if the previous infusion was tolerated 
without an infusion-related reaction, or 60 
( 15) minutes if the patient experienced an 
infusion-related reaction with the previous 
infusion. 
• If the patient experienced an infusion-related 
reaction with the previous infusion or if 
clinically indicated, vital signs should be 
measured during the infusion and at 
30 ( 10) minutes after the infusion. 
 
 
For anaphylaxis precautions, use the following procedure: 
 
Equipment Needed 
 
● Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
● Oxygen 

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● Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice  
● Antihistamines 
● Corticosteroids 
● IV infusion solutions, tubing, catheters, and tape 
 
Procedures 
 
In the event of a suspected anaphylactic reaction during atezolizumab infusion, the 
following procedures should be performed: 
 
1. Stop the study drug infusion. 
2. Call for additional medical assistance. 
3. Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible. 
4. Administer antihistamines, epinephrine, or other medications as required by 
patient status and directed by the physician in charge. 
5. Continue to observe the patient and document observation. 
6. Draw serum/plasma samples for immunogenicity testing. 
7. Ask participant to return for washout immunogenicity sample if appropriate. 
 
 
Atezolizumab Dose Preparation 
The prescribed dose of atezolizumab should be diluted in 0.9% NaCl to a concentration between 
3.2 mg/mL and 16.8 mg/mL and infused through a 0.2 or 0.22 micrometer in-line filter.  The IV 
bag may be constructed of polyvinyl chloride (PVC), polyolefin (PO), polyethylene (PE), or 
polypropylene (PP); the IV infusion line may be constructed of PVC, PE, or polybutadiene (PB); 
and the 0.2 or 0.22 micrometer in-line filter may be constructed of polyethersulfone (PES) or 
polysulfone (PSU).  The prepared solution may be stored at 2°C–8°C for up to 24 hours or at 
ambient < 25°C (77°F) for 8 hours.  If the dose solution is stored at 2°C–8°C (36°F–46°F), it 
should be removed from refrigeration and allowed to reach room temperature prior to 
administration.  This time includes storage and time for administration for infusion.  Do not 
shake or freeze infusion bags containing the dose solution. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of atezolizumab with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies.  The Principal Investigator should be alerted if 
the patient is taking any agent known to affect or with the potential for drug interactions.  The 
study team should check a frequently-updated medical reference for a list of drugs to avoid or 
minimize use of.  Appendix B (Patient Drug Information Handout and Wallet Card) is available.  
 
Palliative radiotherapy to non-targeted lesions may be permitted for patients receiving 
atezolizumab after completing 2 cycles of therapy and achieving stable or responding disease, at 
the Principal Investigator’s discretion.  

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Drugs to be avoided: 
 
• Traditional herbal or homeopathic or natural medicines should be limited and used at the 
discretion of the investigator 
• Ingredients for such medicines have not been fully studied, and their use may result in 
unanticipated drug-drug interactions that may cause or confound assessment of toxicity. 
• Immunostimulatory agents, including but not limited to interferon (IFN)-, IFN-, 
anti-TNF-, or IL-2 (aldesleukin) (prohibited prior to and during the study and for 
10 weeks after the last dose of atezolizumab; see Section 3.2.4).  These agents, in 
combination with atezolizumab, could potentially increase the risk for autoimmune 
conditions. 
• Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide.  These agents could potentially alter the 
activity and the safety of atezolizumab. 
• Live vaccines and live, attenuated vaccines (prohibited during the study and for 100 days 
after the last dose of study drug).  
• Initiation of granulocyte colony-stimulating factors (e.g., filgrastim and biosimilar products, 
sargramostim, and/or pegfilgrastim) should be discussed with the Medical Monitor. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression 
• 
With the caveat that patients who show evidence of clinical benefit may be 
permitted to continue atezolizumab treatment after disease progression, if they 
meet the criteria outlined in Section 11.4. 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of childbearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 

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5.4 
Duration of Follow-Up 
 
Patients will be followed for 90 days after the last dose of atezolizumab is administered or until 
the patient enrolls on another protocol or death, whichever comes first.  Follow-up will consist of 
three  telephone calls from the Study Team: one call between Day 27 and Day 30 after the last 
dose of atezolizumab, one call between Day 57 and Day 60 after the last dose, and one call 
between Day 87 and Day 90 after the last dose.  Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.5 
Criteria for Removal from Treatment and/or Study 
 
Patients will be removed from study for one of the following reasons: completed 30-day follow-
up period, toxicities are unresolved but stabilized, patient enrolls on another protocol, patient 
receives other type of treatment-intent therapy, pregnancy, or death.  The reason for study 
removal and the date the patient was removed must be recorded on the case report form. 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
General AE Management and Dose Modification Guidelines 
 
There will be no dose reduction for atezolizumab in this study.   
 
Patients may temporarily suspend study treatment for up to 84 days (12 weeks) beyond the 
scheduled date of delayed infusion if study drug-related toxicity requiring dose suspension is 
experienced.  If atezolizumab is held because of AEs for 84 days beyond the scheduled date of 
infusion, the patient will be discontinued from atezolizumab and will be followed for safety and 
efficacy as specified in this protocol.  If the AE resolves within 84 days and the patient is 
receiving corticosteroid therapy for the event, atezolizumab may be held for longer than 84 days 
(up to 4 weeks) in order to allow tapering of the steroid dose to ≤10 mg oral prednisone or 
equivalent. 
 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be allowed.  
The acceptable length of interruption will be at the discretion of the study PI in consultation with 
CTEP. 
 
The primary approach to grade 1 to 2 irAEs is supportive and symptomatic care with continued 
treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be withheld and oral 
and/or parenteral steroids administered.  Recurrent grade 2 irAEs may also mandate withholding 
atezolizumab or the use of steroids.  Assessment of the benefit risk balance should be made by 
the investigator, with consideration of the totality of information as it pertains to the nature of the 
toxicity and the degree of clinical benefit a given patient may be experiencing prior to further 
administration of atezolizumab.  Atezolizumab should be permanently discontinued in patients 
with life threatening irAEs. 
 

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6.2 
Management of Specific AEs 
 
Management of certain AEs of concern, including immune-related pneumonitis, hepatitis, colitis, 
endocrinopathies, pancreatitis, neuropathies, meningoencephalitis, and potential ocular toxicities 
are presented in the Atezolizumab Investigator’s Brochure.  See the Agent Administration 
Guidelines in this document, including the “Administration of First and Subsequent 
Atezolizumab Infusions” table for guidelines for the management of Infusion Related Reactions 
and Anaphylaxis. 
 
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. 
 
[Use the following paragraph in studies enrolling patients with lung cancer.  Studies not 
enrolling lung cancer patients may delete.]  Pleural and pericardial effusion 
 
Patients experiencing dyspnea, chest pain, or unexplained tachycardia should be evaluated for 
the presence of a pericardial effusion.  Patients with pre-existing pericardial effusion should be 
followed closely for pericardial fluid volume measurements and impact on cardiac function.  
When intervention is required for pericardial or pleural effusions, atezolizumab should be held, 
and appropriate workup includes cytology, lactate dehydrogenase (LDH), glucose, cholesterol, 
protein concentrations (with pleural effusions), and cell count. 
 
Pulmonary events 
 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will have computed tomography (CT) scans of the chest 
performed at every tumor assessment. 
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension.  Management 
guidelines for pulmonary events are provided in the table below. 
 
Event 
Management 
Pulmonary event, 
Grade 1  
● Continue atezolizumab and monitor closely. 
● Re-evaluate on serial imaging. 
● Consider patient referral to pulmonary specialist. 
Pulmonary event, 
Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset. a 

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Event 
Management 
● Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL. 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
● For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
● Permanently discontinue atezolizumab.  
● Bronchoscopy or BAL is recommended. 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
BAL  =  bronchoscopic alveolar lavage 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of ≤10 mg/day oral prednisone before atezolizumab can be resumed. 
 
Hepatic events 
 
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of total 
bilirubin and hepatic transaminases, and liver function will be monitored throughout study 
treatment.  Management guidelines for hepatic events are provided in the table below. 
 
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. 
 
Event 
Management 
Hepatic event, 
Grade 1 
• Continue atezolizumab. 

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Event 
Management 
• Monitor LFTs until values resolve to within normal limits or to 
baseline values.  
Hepatic event, 
Grade 2 
All events: 
• Monitor LFTs more frequently until return to baseline values.  
Events of 5 days’ duration: 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Hepatic event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. 
• Consider patient referral to gastrointestinal specialist for evaluation 
and liver biopsy to establish etiology of hepatic injury.  
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 1 
month. 
LFT  =  liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Gastrointestinal events 
 
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in the table below.   
 
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. 
 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for 7 days. 

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Event 
Management 
• Monitor closely. 
Diarrhea or 
colitis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist  5 days, initiate treatment 
with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone.  
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Diarrhea or 
colitis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Diarrhea or 
colitis, Grade 4 
• Permanently discontinue atezolizumab. 
• Refer patient to GI specialist for evaluation and confirmation biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Endocrine disorders 
 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab.  Management guidelines for endocrine 
events are provided in the table below. 
 
Patients experiencing one or more unexplained AEs possibly indicative of endocrine dysfunction 
(including headache, fatigue, myalgias, impotence, mental status changes, and constipation) 
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 

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stimulating hormone (TSH) and free T3 and T4 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 MRI of the brain 
(with detailed pituitary sections) may help to differentiate primary pituitary insufficiency from 
primary adrenal insufficiency.  The table below describes dose management guidelines for 
hyperthyroidism, hypothyroidism, symptomatic adrenal insufficiency, and hyperglycemia. 
 
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.  
Symptomatic adrenal 
insufficiency, Grade 2−4  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab.  
Hyperglycemia, Grade 1 
or 2  
• Continue atezolizumab. 

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Event 
Management 
• Investigate for diabetes.  If patient has Type 1 diabetes, treat as a 
Grade 3 event.  If patient does not have Type 1 diabetes, treat as 
per institutional guidelines. 
• Monitor for glucose control. 
Hyperglycemia, Grade 3 
or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Consider referral to endocrinologist, particularly if patient is 
deemed to have atezolizumab-induced diabetes; if so, obtain C-
peptide level paired with glucose, autoantibody levels (e.g. 
GAD65, islet cell autoantibodies), and hemoglobin A1C level. 
• If patient is found to have diabetic ketoacidosis or 
hyperglycemic hyperosmolar syndrome, treat as per institutional 
guidelines with appropriate management and laboratory values 
(e.g. anion gap, ketones, blood pH, etc.) reported.   
• Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
Hypophysitis (pan-
hypopituitarism), Grade 
2 or 3  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab.  
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan-
hypopituitarism), Grade 
4  
• Permanently discontinue atezolizumab.  
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.  
 

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Ocular events 
 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in the table below. 
 
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. 
Ocular event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. 
• Refer patient to ophthalmologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone.   
• If event resolves to Grade 1 or better, taper corticosteroids over 
1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Immune-mediated Myocarditis 
 
Immune-mediated myocarditis has been associated with the administration of atezolizumab.  
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-NP [B-
Natriuretic Peptide]) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope.  
 
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of gastrointestinal 
illness), ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.  All patients with possible myocarditis should be urgently 
evaluated by performing cardiac enzyme assessment, an electrocardiogram (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 

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diagnosis and appropriate treatment, if clinically indicated. 
 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in the table below. 
 
Event 
Management 
Immune-related 
myocarditis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
• Consider treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• If symptoms resolve to below Grade 2 (i.e. patient is completely 
asymptomatic), resume atezolizumab. b 
• If symptoms do not resolve to below Grade 2 while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Immune-related 
myocarditis, Grade 3-
4 
• Permanently discontinue atezolizumab. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 1−2 mg/kg/day 
oral prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If symptoms resolve to below Grade 2, taper corticosteroids 
over 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed. 
 
Infusion-Related Reactions and Cytokine-Release Syndrome 
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) 
with atezolizumab may receive premedication with antihistamines, antipyretics, and/or 
analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited 
in treating atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
IRRs are known to occur with the administration of monoclonal antibodies and have been 

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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 (Lee et al., 2019).  CRS has 
been well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell 
engager antibody therapies but has also been reported with immunotherapies that target PD-1 or 
PD-L1 (Rotz et al., 2017; Adashek and Feldman 2019) including atezolizumab. 
 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in the table below. 
 
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome 
 
Event 
Management 
Grade 1a  
Feverb with or 
without 
constitutional 
symptoms 
● Immediately interrupt infusion. 
● Upon symptom resolution, wait 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
● If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment,c including maintenance of IV fluids 
for hydration. 
● In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
● For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics, and monitor closely 
for IRRs and/or CRS. 
Grade 2a 
Feverb with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia 
requiring low-
flow oxygend 
by nasal cannula 
or blow-by 
● Immediately interrupt atezolizumab infusion. 
● Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment.c 
● For hypotension, administer IV fluid bolus as needed. 
● Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS. 

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● Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy.e 
● Consider hospitalization until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab. 
● If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, anti-
pyretics, and/or analgesics and monitor closely for IRRs and/or CRS. 
● If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Principal Investigator. 
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. 
● 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 
Feverb with 
hypotension 
requiring 
multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia 
requiring 
oxygen by 
positive pressure 
(e.g., CPAP, 
● Permanently discontinue atezolizumab. 
● 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 treatmentsf may be considered at the 
discretion of the investigator. 

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BiPAP, 
intubation and 
mechanical 
ventilation) 
●  Hospitalize patient until complete resolution of symptoms. 
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. Refer to Riegler et al. for information on experimental treatments for CRS. 
 
Pancreatic events 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  
Management guidelines for pancreatic events, including pancreatitis, are provided in the table 
below. 
 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase 1.5−2.0  ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase 2.0−5.0  ULN: 

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Event 
Management 
• Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with corticosteroids 
equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
• For recurrent events, permanently discontinue atezolizumab. 
Immune-related 
pancreatitis, Grade 2 or 3 
 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab.  
• For recurrent events, permanently discontinue atezolizumab. 
Immune-related 
pancreatitis, Grade 4 
• Permanently discontinue atezolizumab. 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.  
 
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.  A dermatologist should evaluate 

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persistent and/or severe rash or pruritus.  Although uncommon, cases of severe cutaneous 
adverse reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been 
reported with atezolizumab.  A biopsy should be considered unless contraindicated.  
Management guidelines for dermatologic events are provided in the table below. 
 
 
Event 
Management 
Dermatologic 
event, Grade 1  
● Continue atezolizumab. 
● Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
● Continue atezolizumab. 
● Consider patient referral to dermatologist for evaluation and if 
indicated, biopsy. 
● Initiate treatment with topical corticosteroids. 
● Consider treatment with higher-potency topical corticosteroids if event 
does not improve. 
Dermatologic 
event, Grade 3  
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to dermatologist for evaluation and if indicated, biopsy. 
● Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 1-2 mg/kg/day if event does not 
improve within 48-72 hours. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab.  
Dermatologic 
event, Grade 4 
● Permanently discontinue atezolizumab.  
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. 
Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed. 
 

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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 are provided in 
the table below. 
 
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 symptoms resolve to below Grade 2, resume atezolizumab. b 
• If symptoms do not resolve to below Grade 2 while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Immune-related 
neuropathy, Grade 
3 or 4 
• Permanently discontinue atezolizumab.  
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
• Permanently discontinue atezolizumab. 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day oral 
or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Immune-Mediated Meningoencephalitis 
 
Immune-mediated meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-mediated meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  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 

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be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in the table below. 
 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
• Permanently discontinue atezolizumab. 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
1 month. 
 
Renal events 
 
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum creatinine, 
should be monitored throughout study treatment.  Patients with abnormal renal function should 
be evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as non-steroidal anti-inflammatory drugs).  Refer the 
patient to a renal specialist if clinically indicated.  A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. 
 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in the table below. 
 

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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. 
Renal event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 1 
month. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed. 
 
Immune-Mediated Myositis 
 
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are among the most common 
disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatine kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle biopsy. 
 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in table below. 
 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
• Continue atezolizumab. 
• Refer patient to rheumatologist or neurologist.  
• Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 

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

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Event 
Management 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.  
• 
 
• 
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 (2017).  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/mcL) 
– 
ANC  1.0 × 109/L (1000/mcL) 
● 
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/mcL) 
– 
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 below. 
 

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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. 
 
 
 
 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Sections 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Atezolizumab (MPDL3280A, NSC 783608) 
 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system.  In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text.  This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification.  Frequency is provided based on 3097 patients.  Below is the CAEPR for 
Atezolizumab (MPDL3280A). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE 
in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and 
has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
Version 2.3, March 11, 2021 (1)  

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after administration of atezolizumab. 
 
 4 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on atezolizumab (MPDL3280A) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that atezolizumab (MPDL3280A) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Cardiac arrest; Ventricular tachycardia 
GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Multi-organ failure 
HEPATOBILIARY DISORDERS - Portal vein thrombosis 
INVESTIGATIONS - Lymphocyte count decreased; Neutrophil count decreased; Weight loss; White blood 
cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypophosphatemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle cramp: Pain in 
extremity 
NERVOUS SYSTEM DISORDERS - Headache 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Pulmonary hypertension; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin2; Hyperhidrosis 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
Note: Atezolizumab (MPDL3280A) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
Section 7.3.4. 
 

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• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 CTEP-AERS 
 
The Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting, and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting. 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to 
collect AEs that start during the period or persist from the previous reporting period.  The 
Clinical Research Associate (CRA) will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS integration.  
AEs that occur prior to enrollment must begin and end on the baseline Adverse Event 
form and should not be included on the standard Adverse Events form that is available at 
treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free 
(fields added to the form during study build do not need to be query-free for the 
integration call with CTEP-AERS to be a success). 
The CRA reports AEs in Rave at the time the Investigator learns of the event.  If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form.  Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting.  A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements.  The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the deep link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 

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website: 
• Study specific documents:  Protocols > Documents > Education and Promotion, 
and   
• Expedited Safety Reporting Rules Evaluation user guide:  Resources > CTSU 
Operations Information > User Guides. 
NCI requirements for SAE reporting are available on the CTEP website:  
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguid
elines.pdf. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred within 30 days after the last administration of the 
investigational agent.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
 
 

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CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
Investigations 
Lymphocyte count decreased 
Any 
Regardless 
Skin and subcutaneous tissue 
disorders 
Alopecia 
Any 
Regardless 
Blood and lymphatic system 
disorders 
Anemia 
2 
Regardless 
Metabolism and nutrient disorders Hypoalbuminemia; hyperglycemia; 
hyperuricemia; hypernatremia; 
hyponatremia; hypokalemia; 
hypophosphatemia; 
hypomagnesemia 
2 
Regardless 
Investigations 
INR increased; activated partial 
thromboplastin time prolonged 
2 
Regardless 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. 
 
7.3.5 Adverse Events of Special Interest in Atezolizumab Studies 
 
The following AEs are considered of special interest (AESIs) in patients receiving atezolizumab 
and must be reported expeditiously through CTEP-AERS, irrespective of regulatory seriousness 
criteria:  
 
Drug-Specific AESIs 
• Systemic lupus erythematosus 
• Nephritis  
• Ocular toxicities (e.g., uveitis, retinitis) 
• Grade ≥2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, macrophage activating syndrome and hemophagocytic lymphohistiocytosis. 
• Vasculitis  
• Autoimmune hemolytic anemia  
• Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
Non Drug-Specific AESIs 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law 
and based on the following observations: 
o Treatment-emergent ALT or AST > 3 x ULN (or > 3 x baseline value in disease 
states where LFTs may be elevated at baseline) in combination with total bilirubin > 2 
x ULN (of which ≥ 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 x ULN (or > 3 x baseline value in disease 
states where LFTs may be elevated at baseline) in combination with clinical jaundice 

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• Suspected transmission of an infectious agent by the study treatment, as defined below: 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product.  This term applies only when a contamination 
of study treatment is suspected. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 150 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
7.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 

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Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
 
8.1 
Atezolizumab (NSC #783608) 
 
Other Names: Tecentriq™, MPDL3280A 
 
Classification: monoclonal antibody 
 
M.W.: 150 KD 
 
Mode of Action: anti-PD-L1 
 
Description: 
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two heavy chains 
(448 amino acids) and two light chains (214 amino acids). Atezolizumab targets human 
PD-L1 and inhibits its interaction with its receptor PD-1. Atezolizumab also blocks the 
binding of PD-L1 to B7.1, an interaction that is reported to provide additional inhibitory 
signals to T cells (Butte et al. 2007).  
 
How Supplied:  
Atezolizumab is provided by Genentech/F.Hoffmann-La Roche LTD and distributed by 
the Pharmaceutical Management Branch, CTEP, NCI.  The agent is supplied in a single-
use, 20-mL glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear 
liquid solution intended for IV administration. Each 20 mL vial contains 1200 mg of 
atezolizumab and is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), 
polysorbate 20 (8 mg), and sucrose (821.6 mg), with a pH of 5.8.  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.  
 
Preparation:   
The prescribed dose of atezolizumab should be diluted in 0.9% NaCl to a concentration 
between 3.2 mg/mL and 16.8 mg/mL and infused with or without a low-protein binding 0.2 

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or 0.22 micrometer in-line filter. The IV bag may be constructed of polyvinyl chloride 
(PVC), polyolefin (PO), or polyethylene (PE).  The prepared solution may be stored at 2°C-
8°C for up to 24 hours or at ambient < 25°C (77°F) for 6 hours from the time of preparation.  
If the dose solution is stored at 2 C–8 C (36 F–46°F), it should be removed from refrigeration 
and allowed to reach room temperature prior to administration.  These times include the storage 
and administration times for the infusion. Do not shake or freeze infusion bags containing 
the dose solution. 
 
Storage: 
2°C-8°C (36°F-46°F) Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
 
If a storage temperature excursion is identified, promptly return atezolizumab to 2°C-8°C 
(36°F-46°F) and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Stability studies are ongoing. 
 
CAUTION:  No preservative is used in atezolizumab; therefore, the vial is intended for 
single use only. Discard any unused portion of drug remaining in a vial.  
 
Route of Administration: IV infusion 
 
Method of Administration:  
Atezolizumab is administered as an intravenous infusion over 60 minutes. If the first 
infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Do not 
administer atezolizumab as an intravenous push or bolus. No premedication is indicated 
for administration of Cycle 1 of atezolizumab. Patients who experience an infusion 
related reaction with Cycle 1 of atezolizumab may receive premedications with 
subsequent infusions. 
 
Potential Drug Interactions:  
Cytochrome P450 enzymes as well as conjugation/glucuronidation reactions are not 
involved in the metabolism of atezolizumab. No drug interaction studies for atezolizumab 
have been conducted or are planned. There are no known interactions with other 
medicinal products or other form of interactions. 
 
Patient Care Implications: 
Female patients of childbearing potential should utilize contraception and take active 
measures to avoid pregnancy while undergoing atezolizumab treatment and for at least 
150 days after the last dose of atezolizumab. 
 
09/22 MJB 
 
8.2 
Availability 
 

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Atezolizumab is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Atezolizumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.5). 
 
8.2.1 Agent Ordering and Agent Accountability 
 
8.2.1.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 
Atezolizumab may be ordered once a patient has been registered to the trial. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
8.2.1.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.2.2 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.3 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 

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• NCI CTEP Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
9. 
CORRELATIVE STUDIES 
 
We plan to evaluate the effect of the study drug on immune cell components of the tumor, tumor 
microenvironment, and peripheral blood.  The correlative studies that will be carried out on the 
paired (pre- and post-treatment) biopsies and blood samples will help elucidate the mechanism of 
action of atezolizumab on signaling pathways mediating the immune response, focusing on 
subsets of effector cells.  Additionally, the paired biopsy samples will be used to evaluate the 
tumor microenvironment to see if any changes or lack thereof are associated with either response 
or resistance to therapy.  Blood samples will be collected and the nucleic acid from the 
mononuclear cells will be sequenced to serve as a germline control for calling somatic alterations 
in the whole exome sequencing results from the tumor specimens and, possibly, cell-free DNA. 
 
 

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distinguish germline from tumor-specific alterations and thus enable the calling of somatic 
mutations in whole exome sequencing results.  The nucleic acid extracted from plasma will be 
used to evaluate DNA alterations found in cell-free, circulating tumor DNA and their potential 
correlation with response to atezolizumab. 
 
At NCI only, mandatory peripheral blood collections from patients ≥12 years of age will also be 
used for assessment of pharmacodynamic endpoints.  See Section 9.3.2. 
 
Specimen collection time points and assay priorities are specified in the table below. 
 
 

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9.2 
Correlative Assays in Tumor Tissue 
 
Tumor biopsies (mandatory when deemed safe and feasible) will be collected for research from 
adult patients (≥18 years of age).   
 
Pharmacodynamic Analysis (ImmunoPD) 
 
Pharmacodynamic assays will be performed on these tumor specimens to evaluate the effect of 
atezolizumab on immune cell components of the tumor and microenvironment.  The results of 
these assays will help to elucidate the mechanism of action of atezolizumab in sarcoma and 
demonstrate the impact of a PD-L1 inhibitor on signaling pathways mediating the immune 
response.  Efforts will be made to correlate any observed treatment-induced changes with clinical 
response or resistance to therapy. 
 
Activated CD8+ T cells will be defined by the expression of TCR activation (Zeta chain 
phosphorylation) or phosphorylated Zap70 (pY493); CD8+ cells present within the tumor section 
that are positive for these markers will be quantified.  Other targets of PD assays will include 
PD-L1 and PD-1 levels in cells present in the biopsy, suppressive immune checkpoint signaling 
(SHP1/SHP2 phosphorylation), CD4, and a tumor marker (e.g., β-catenin) to identify tumor 
region.   
 
These biomarkers will be measured through multiplex immunofluorescence assays designed and 
validated by PADIS (See Section 2.5).  Measurements on the Nikon A1/Definiens platform will 
include cell enumeration and proximity of tumor cells (by pathology analysis and tumor marker 
IFA) to T-cells.  Monoclonal antibodies to all markers have been validated by the standard 
PADIS approach, and PADIS has previously validated and reported on the tumor cell marker set. 
 
Genetic Analysis 
 
We will also perform exploratory genomic sequencing (WES and RNA-Seq) on biopsy tissue, 
with the goal of identifying potential correlations between atezolizumab activity and tumor 
genomic alterations (such as those involved in relevant immune pathways, neoantigen 
presentation, etc.).  MSI status and mutational signatures may also be assessed.  We will assess 
whether changes in the genomic makeup of the tumor is associated with treatment response 
and/or progression, and whether TMB correlates with patient outcome.  Germline DNA obtained 
from PBMCs will be used as a point of comparison to identify somatic mutations.  In addition to 
evaluating changes in tumor mutations over time (post-treatment), extensive molecular 
characterization of pre-treatment tumor biopsy tissue from each patient enrolled on this trial will 
enable identification of valuable potential biomarkers to predict which patients are more or less 
likely to respond to treatment. 
 
At progression (or pre-progression, following any restaging at which a 10-19% increase in tumor 
volume is observed), tumor tissue from the optional biopsy will also be analyzed by the CLIA-
certified OCAv3 assay, and an Oncomine report will be returned to patients to inform future 
treatment. 
 

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9.2.1 Timing of Tumor Biopsies 
 
Biopsies will be collected from adult patients at: 
• Baseline 
• Prior to Cycle 3 Day 1 (±3 days).  If, at any point before Cycle 3 Day 1, there is clinical 
evidence that the patient is responding to drug, the biopsy will be conducted then instead 
of at the Cycle 3 Day 1 (±3 days) timepoint. 
• Optional:  Day 1 (±2 days) of the cycle following any restaging at which a 10-19% 
increase in tumor volume is observed (according to RECIST v1.1 criteria) if the patient 
has been on study for at least 4 cycles (the “restaging follow-up biopsy”), or at time of 
disease progression 
 
9.2.2 Tumor Biopsy Procedure 
 
Serial tumor biopsies will be obtained by the Interventional Radiology team by a cutaneous 
approach, a dermatologist for skin lesions, or an ENT for lesions that are easily biopsiable 
through ENT exam.  The investigators will meet regularly with the Interventional Radiology 
team to review patient scans and discuss patients’ medical history.  If a site is deemed 
appropriate for biopsy with minimal risk to the participant by agreement between the 
investigators and the biopsy team, an attempt for biopsy will be made.  Because approximately 
20% of tumor biopsies collected on research trials are not usable due to the presence of stroma or 
normal and/or necrotic tissue and paired biopsies are necessary for analysis, up to 5 core biopsies 
≥18-gauge in diameter and ≥1 cm in length, or equivalent, will be obtained during each 
procedure to try and ensure adequate tumor content and quality.  If possible, the lesion from 
which each biopsy is taken, and whether the specimen came from the center or periphery of the 
lesion, will be documented. 
 
Acceptable biopsy procedures are: 
• Percutaneous biopsy with local anesthetic. 
• Excisional cutaneous biopsy with local anesthetic 
• Other biopsy with local anesthetic and/or sedation that has been shown to have a risk of 
severe complications < 2%.  Note:  This risk determination is made by the interventional 
radiologist after determining the complication rate for the patient through discussion of 
the patient’s scans and medical history with the investigators.  
 
The use of imaging to facilitate biopsies will be decided by members of the biopsy team and may 
include ultrasound, CT scan, or MRI.  Should a CT scan be needed for biopsy, the number of 
scans for each procedure will be limited to the minimum number needed to safely obtain a 
biopsy.  Tumor biopsies and local anesthesia will be administered only if they are considered to 
be of low risk to the participant, as determined by the investigators and the biopsy team.  Cores 
from different areas of the tumor are preferred when feasible.  The clinical, radiologic, and 
pharmacodynamic members of the research team will meet monthly to review the adequacy of 
the biopsy specimens for analysis. 
 
Baseline biopsies will be performed following patient enrolling on study.  If an initial attempt at 
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attempt.  A separate consent form must be signed for each biopsy procedure, so patients may 
choose not to undergo subsequent biopsies.  If the baseline biopsy is unsuccessful or the patient 
refuses to undergo subsequent biopsies, no further biopsies will be performed but the patient will 
remain on study, receive study medication, and other correlative studies will be performed. 
 
9.2.3 Tumor Specimen Processing 
 
Biopsy cores will be processed as described in NCI DCTD SOP340507.  All external sites are 
required to follow NCI DCTD SOP340507 for biopsy collection, processing, and shipment; the 
SOP can be found by following the link below. 
http://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507 Biopsy Frozen.pdf 
A webinar training session with PADIS staff will be held with each participating site prior 
to their first biopsy collection to review proper procedure.  The sites should contact 
NCI_PD_Support@mail.nih.gov to initiate training and clarify shipping procedures.   
 
Dermatologic and ENT biopsies should be collected per guidance from FNLCR PD Central 
Receiving (NCI_PD_Support@mail.nih.gov, 301-846-1951, or 301-846-6747). 
 
Briefly, the biopsy cores (up to 5 per time point) or equivalent tissue, will be individually 
transferred into 1.5-mL pre-chilled cryovials and then flash frozen in liquid nitrogen.  In 
accordance with SOP340507, biopsy specimens are collected into pre-chilled 1.5-mL Sarstedt, 
O-ring screw cap tubes (VWR, Cat#: 83009-010) and then flash-frozen in liquid nitrogen or a 
dry ice/ethanol bath.  It is imperative that biopsies are flash frozen within 2 minutes of 
collection in order to preserve key pharmacodynamic biomarkers. 
 
9.2.4 Baseline and C3D1 Biopsy Specimens 
 
The frozen baseline and C3D1 biopsy specimens are transferred to PADIS in pairs on dry ice, 
where they are stored at -80°C or colder, and subsequently processed within 7-10 days for 
analysis or as directed by the Principal Investigator.  Biopsy samples will be analyzed as 
described above; any additional samples will be kept for future analysis in the Frederick 
National Laboratories CR Biorepository in liquid nitrogen freezers.  Additional studies, if 
performed, will be conducted following an amendment to the current protocol. 
Biopsy specimens should be labeled with: 
• Sample type (e.g., Biopsy) 
• Time point (e.g., C01D01 pre dose) 
• Collection date and time 
• Sample ID, containing: 
o CTEP protocol number 
o Unique patient ID (Do NOT include patient name, medical record 
number, or initials) 
o 500-series sample collection number (e.g., 500, 501, 502, etc.) 
o Pass/Core identifier (e.g., A, B, C, etc.) 
For example, the sample ID for the first core of a baseline sample collected for NCI DTC 

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patient #004 should be:  10398_NCIDTC_004_500A. 
 
9.2.4.1 
Shipping Baseline and C3D1 Biopsy Specimens from Non-NIH Sites 
 
Shipping Address: 
Biopsies for PD analysis should be shipped on dry ice via FedEx (using PADIS 
account number) to: 
Attn: Dan Danner 
NCI-F/FNLCR 
1073 Beasley Street, Building 1073 
Fort Detrick 
Frederick, MD 21701 
Phone: 301-846-5748 
Shipping Method: 
Baseline and post-treatment biopsy samples should be held at -80ºC or colder and 
shipped to PADIS together upon completion of the second biopsy.  Participating 
sites are required to create a FedEx shipping label to accommodate the variable 
dry ice weight of the shipment package.  Use only FedEx Priority Overnight 
Shipping.  NCI-F PD Support will provide a FedEx account number to cover the 
cost of the shipment.  By linking the NCI-F FedEx account number provided to 
the biopsy shipment, NCI-F PD Support can closely monitor the shipment and 
cover all shipping costs.   
PADIS Contact(s): 
Please contact Amy Pantella (office: 301-846-6747, cell: 301-401-8070) or 
Rachel Andrews (office: 301-846-1951, cell: 240-344-5697) (email: 
NCI PD Support@mail.nih.gov) to obtain the PADIS FedEx account number 
or to ask any questions regarding storage or shipment of the baseline and C3D1 
biopsy specimens. 
Special Shipping Instructions: 
Email the NCI-F PADIS group at NCI PD Support@mail.nih.gov prior to 
shipping with expected arrival date, protocol number, specimen IDs, histologic 
classification of the primary tumor, tracking information, and site information.  
PADIS needs to be notified as soon as possible of all protocol deviations or 
issues, prior to shipment of specimens(s), and these must be noted on the sample 
shipping manifest and batch record, both of which are included in SOP340507.  
One batch record is completed per patient’s biopsy specimens, with all required 
information noted.  If shipping multiple patient biopsies, one shipping manifest 
can be completed, including all patient specimens within the shipment. 
Specimens should be shipped on dry ice.  Do not ship frozen biopsy specimens 
on Fridays or one day prior to any Federal holiday as FNLCR receiving is 
closed and unable to receive samples on weekends and on all Federal holidays.  
This prevents the risk of dry ice sublimation and loss of sample integrity. 

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9.2.4.2 
Shipping Baseline and C3D1 Biopsy Specimens from the NIH Clinical Center 
 
For NIH Clinical Center specimens only: Baseline and post-treatment biopsy 
samples should be held at -80ºC or colder and shipped to PADIS together upon 
completion of the second biopsy.  Shipment should be by CSP Courier and may be 
arranged by contacting Mike Johnston, FNLCR, Tel.: 301-846-5893.  Non-NIH sites 
should not contact this number; please contact NCI PD Support as described in 
Section 9.2.4.1. 
 
9.2.5 Optional Restaging Follow-Up or Progression Biopsy Specimens 
 
Biopsies will be collected and flash frozen as above (Section 9.2.3).   
The sample shipping manifest and batch record, both of which are included in NCI 
DCTD SOP340507, should be completed and included with the shipment.  NCI DCTD 
SOP340507 for biopsy collection, processing, and shipment; the SOP can be found by 
following the link below. 
http://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507 Biopsy Fro
zen.pdf 
 
Biopsy specimens should be labeled with: 
• Sample type (e.g., Biopsy) 
• Time point (e.g., Restaging) 
• Collection date and time 
• Sample ID, containing: 
o CTEP protocol number 
o Unique patient ID (Do NOT include patient name, medical record 
number, or initials) 
o 500-series sample collection number (e.g., 500, 501, 502, etc.) 
o Pass identifier (e.g., A, B, C, etc.) 
For example, the sample ID for the first core of a restaging follow-up sample collected 
for NCI DTC patient #004 should be:  10398-NCIDTC-004-502A (if C1D1 and C3D1 
were already collected as 500 and 501, respectively). 
 
9.2.5.1 
Shipping Optional Restaging Follow-Up or Progression Biopsy Specimens from Non-
NIH Sites 
 
The first 2 cores 
Shipping Address: 
The first 2 cores should be shipped on dry ice via FedEx (using MoCha 
account number) to: 
Attn: Gloryvee Rivera 

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MoCha Histology Lab 
Frederick National Laboratory for Cancer Research 
Leidos Biomedical Research, Inc. 
1050 Boyles Street 
Building 321 Room 107 
Frederick, MD 21702 
Shipping Method: 
The first 2 cores should be shipped on dry ice on the day of biopsy collection 
to the MoCha Laboratory at FNLCR for genomic analysis using the OCAv3 
assay.  Participating sites are required to create a FedEx shipping label to 
accommodate the variable dry ice weight of the shipment package.  Use only 
FedEx Priority Overnight Shipping.  The MoCha Lab will provide a FedEx 
account number to cover the cost of the shipment. 
MoCha Contact(s): 
Please contact Maria Saeed at 301.846.7035 (email: 
MoChaSampleReceiving@nih.gov) to obtain the MoCha FedEx account 
number or to ask any questions regarding storage or shipment of the restaging 
or progression biopsy specimens. 
Special Shipping Instructions: 
Email the MoCha Histology group at MoChaSampleReceiving@nih.gov 
prior to shipping with expected arrival date, protocol number, specimen IDs, 
histologic classification of the primary tumor, tracking information, and site 
information.  MoCha should be notified as soon as possible of all protocol 
deviations or issues, prior to shipment of specimens(s). 
Specimens should be shipped on dry ice.  Do not ship frozen biopsy 
specimens on Fridays or one day prior to any Federal holiday as FNLCR 
receiving is closed and unable to receive samples on weekends and on all 
Federal holidays.  This prevents the risk of dry ice sublimation and loss of 
sample integrity. 
 
Any remaining cores 
Any remaining cores (beyond the first 2 cores) should be shipped to PADIS as 
described in Section 9.2.4.1. 
 
9.2.5.2 
Shipping Optional Restaging Follow-Up or Progression Biopsy Specimens from the 
NIH Clinical Center 
 
For NIH Clinical Center specimens only: Shipment should be by CSP Courier 
and may be arranged by contacting Mike Johnston, FNLCR, Tel.: 301-846-5893.  
Non-NIH sites should not contact this number; please contact the MoCha Lab as 
described in Section 9.2.5.1. 
 
The first 2 cores should be shipped to MoCha.  Any remaining cores should be 

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shipped to PADIS. 
 
9.3 
Correlative Assays in Blood 
 
9.3.1 Genetic Analysis – All Sites 
 
Blood collection for genetic analysis is mandatory at all sites for patients ≥12 years of age. 
 
9.3.1.1 
Blood Collection for Genetic Analysis (Performed at All Sites) 
 
Two whole blood samples (at least 7.5 mL each in 10-mL Streck tubes) will be 
collected at each of the following time points from patients ≥12 years of age and 
shipped at ambient temperature to MoCha within 2 days for ctDNA analysis: 
• Baseline 
• C2D1 
• C3D1 (±3 days, or sooner if there is clinical evidence that the patient is 
responding to drug); 
• at the first two restaging visits (end of C3 and end of C5); 
• every two restaging visits after that (e.g., C9, C13, etc.); and 
• at progression. 
 
Blood specimens should be labeled with: 
• Sample type (e.g., Whole blood) 
• Time point (e.g., C1D1 pre dose) 
• Collection date and time 
• Sample ID, containing: 
o CTEP protocol number 
o Unique patient ID (Do NOT include patient name, medical record 
number, or initials) 
o 800-series sample collection number (e.g., 800, 801, 802, etc.) 
For example, the sample ID for the baseline sample collected for NCI DTC patient 
#004 should be:  10398_NCIDTC_004_800. 
 
Mononuclear cells will be isolated from whole blood by the MoCha Laboratory for 
nucleic acid extraction and exploratory WES to allow for germline and somatic 
variants to be accurately identified, and to enable the accurate assessment of 
mutational signatures in the tumor specimen and, possibly, cell-free DNA.  The 
results of these studies will not be returned to patients. 
 
Circulating tumor DNA (ctDNA) monitoring will be performed with the TSO500 
assay and, potentially, WES.  Patient plasma will be analyzed for ctDNA by the 
TSO500 panel and, if a sufficient proportion of the circulating, cell free DNA 
(cfDNA) is ctDNA, then WES of cfDNA will also be considered to uncover 
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be returned to patients.  Once a patient has come off study, ctDNA from blood 
samples correlating to clinically informative time points (minimally, before treatment 
and at restaging scans suggesting tumor growth) will be analyzed.   
 
9.3.1.2 
Shipping Blood for Genetic Analysis from Non-NIH Sites 
 
Shipping Address: 
Ship blood specimens at ambient temperature via FedEx (using MoCha 
account number) to: 
Attn: Gloryvee Rivera 
MoCha Histology Lab 
Frederick National Laboratory for Cancer Research 
Leidos Biomedical Research, Inc. 
1050 Boyles Street 
Building 321 Room 107 
Frederick, MD 21702 
Shipping Method: 
Blood samples should be shipped at ambient temperature to the MoCha 
Laboratory at FNLCR via FedEx First Overnight or FedEx Priority Overnight.  
The MoCha Lab will provide a FedEx account number to cover the cost of the 
shipment.  The sample shipping manifest, which can be found in Appendix F, 
should be completed and included with the shipment. 
MoCha Contact(s): 
Please contact Alyssa Chapman at 301-846-1718 (email: 
MoChaSampleReceiving@nih.gov) to obtain the MoCha FedEx account 
number or to ask any questions regarding storage or shipment of these 
specimens. 
Special Shipping Instructions: 
Email the MoCha Histology group at MoChaSampleReceiving@nih.gov 
prior to shipping with expected arrival date, protocol number, specimen IDs, 
histologic classification of the primary tumor, tracking information, and site 
information.  MoCha should be notified as soon as possible of all protocol 
deviations or issues, prior to shipment of specimens(s). 
Samples should arrive at MoCha within 2 days of collection when 
possible; arrival within 3 days of collection is permissible when necessary.  
Note that FNLCR receiving is closed and unable to receive samples on 
weekends and on all Federal holidays.  Therefore, these blood samples 
should not be collected on a Friday, or the day before a Federal holiday. 
 
9.3.1.3 
Shipping Blood for Genetic Analysis from the NIH Clinical Center 
 
For NIH Clinical Center specimens only: Shipment to MoCha should be by CSP 
Courier and may be arranged by contacting Mike Johnston, FNLCR, Tel.: 301-846-

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5893.  Non-NIH sites should not contact this number; please contact the MoCha Lab 
as described in Section 9.3.1.2. 
 
9.3.2 Pharmacodynamic Analysis – NCI Only 
 
At NCI only, collection of blood samples for ImmunoPD studies will be mandatory for patients 
≥12 years of age.   
 
These samples will be used for the analysis of immune cell subsets and measurement of T-cell 
activation in the periphery.  The activation status of peripheral T cell subsets will be determined 
based phosphomarker expression (pZAP70, pCD3ζ, pSHP1/SHP2) assessed through intracellular 
staining and flow cytometry).  These studies will allow us to follow changes in the T-cell 
population longitudinally and potentially correlate increases in T-cell activation with reduction in 
tumor burden. 
 
9.3.2.1 
Blood Sample Collection for ImmunoPD (NCI Only) 
 
Blood samples (4 mL) will be obtained from patients ≥12 years of age at the 
following times:  
• at baseline (on Cycle 1 Day 1 prior to drug administration) 
• on Cycle 1 Day 15 (optional) 
• on the first day of every subsequent cycle prior to drug administration 
• at re-staging follow-up or disease progression 
 
Per NIH Clinical Center CC Policy for pediatric patients, no more than 5 mL/kg may 
be drawn for research purposes in a single day, and no more than 9.5 mL/kg may be 
drawn over any eight-week period. 
 
Samples will be collected into NaHep tubes (4 mL of blood into one 6 mL tube at 
each timepoint) and then added to 1x Lyse/Fix buffer per DCTD SOP 
LHTP003.08.15.  Blood must be mixed with Lyse/Fix buffer within 5 minutes of 
collection.  Once samples are processed, they should be stored in 60% methanol at -
20˚C for at least one hour (no longer than 6 hours) and then transferred to -80˚C.  
Please see DCTD SOP LHTP003.08.15 for detailed guidance. 
 
Materials for sample collection and processing will be provided to the clinic’s sample 
collection team.  
 
For NIH Clinical Center specimens only: At least 24 hours prior to blood sample 
collection, the research nurse will contact the NCI Phase I/II PK/PD Support 
Group in NIH Building 10: E-mail NCIPK-PDsupportgroup@mail.nih.gov, Pager: 
102-12798 Phone: 301-451-1169 Fax: 301-480-5871. 
 
9.3.2.2 
Blood Sample Shipping for ImmunoPD (NCI Only) 
 
All samples should be sent on dry ice via courier to PADIS at FNLCR: 

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Attn: Rachel Andrews/Amy Pantella 
Frederick National Laboratory for Cancer Research 
Leidos Biomedical Research, Inc. 
1050 Boyles Street 
Building 425, Room 105 
Frederick, MD 21702 
Phone: 301-846-1951 or 301-846-6747 
 
For NIH Clinical Center specimens only: Shipment should be by CSP Courier 
and may be arranged by contacting Mike Johnston, FNLCR, Tel.: 301-846-5893.  
Non-NIH sites should not contact this number. 
 
 
9.4 
Sample Collection and Processing 
 
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality (analyte preservation) and patient confidentiality pursuant to informed consent 
provisions.  Information about each specimen (e.g., blood, tumor biopsy, per specific protocol) 
will be recorded on a PK/PD collection worksheet included in Appendix E. 
 
Using a computerized inventory system and a backup hardcopy process, all specimen collection 
and processing steps will be documented and the specific location of each specimen will be 
tracked.  Each new specimen collected will be assigned a unique barcode identifier that can be 
linked to the original specimen collected and other relevant information within the inventory 
system.  To ensure patient confidentiality, only containers used for the initial specimen 
collections will be labeled with patient identifiers.   
 
Only the barcode identifier will be applied to all subsequent specimen containers.  When 
specimens are processed and aliquoted, no patient information will be included on the new 
containers.  Original specimen containers will be discarded.  Only barcode-labeled specimens 
without patient identifiers will be shipped for analysis and/or storage.  Specimen labels will 
indicate: CTEP protocol number, unique patient accession number, 3-digit sample number (see 
list below), collection time, and total volume collected, as appropriate.  Samples from sets of at 
least three patients will be grouped for scientific analysis. 
 
Standardized 3-digit sample collection numbers: 
200 series: blood for PK 
300 series: blood for PD 
500 series: tumor biopsies 
800 series: blood for genetic/genomic analyses 
900 series: blood for ImmunoPD (NCI only) 
 
The inventory process contains other security provisions sufficient to safeguard patient privacy 
and confidentiality.  Access to the inventory system and associated documents will be restricted 
to appropriate individuals.  Requests to use specimens stored in the repository must be approved.  
The only patient information available in the inventory system will be the patient sex, diagnosis, 

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and level of informed consent given.  SOPs ensure that any changes in informed consent made 
by a patient and relayed to the PI will be reflected in the inventory system to ensure that 
specimens are destroyed as appropriate.  All laboratory personnel will be trained to adhere to 
SOPs and will be monitored for high-quality performance. 
 
Any new use of these samples will require prospective IRB review and approval.  Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. 
 
NCI patients participating in treatment protocols are often also enrolled on the NCI DTC 
longitudinal protocol, 17-C-0156, which enables transfer of a patient’s research data and 
specimens longitudinally across multiple trials in which the patient has been enrolled.  For NCI 
patients on the atezolizumab in CS and CCS study who are also enrolled on this longitudinal 
protocol, any frozen biopsy samples collected on this trial that are not needed to be used as the 
“baseline” tissue sample to determine the eligibility of the patient for a subsequent treatment-
intent protocol (i.e., for which there is the possibility of direct benefit), can at the discretion of 
the PI be used for additional pharmacodynamic analysis to address questions about tumor 
responses to treatment.  This affords us the opportunity to measure dynamic drug-specific target 
effects (e.g., changes in epithelial-mesenchymal transition, DNA damage response, or immune 
cell infiltration) in patients on consecutive clinical trials at the Developmental Therapeutics 
Clinic; there is tremendous value in being able to evaluate molecular changes before and during 
disease progression to understand why the tumors initially responded but then became resistant 
to treatment.    
 
Patients on this study will not be consented to new use of their research tissue samples or 
informed of the results of these studies because (i) broad consent was obtained under the 
longitudinal protocol and (ii) there will be no direct benefit or added risk to the patient.  No new 
samples will be collected on this study beyond those specified in the current protocol to meet the 
primary and secondary objectives.  No information beyond that associated with the patient’s 
longitudinal protocol registration ID will be shared with investigators performing the 
pharmacodynamic studies.  
 
If at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request.  Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB.  Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e., broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
 
9.5 
Privacy Considerations 
 
As patient clinical response data (both for this study and, potentially, after a patient is off study) 
will be required for comparison to sequencing results, delinking the samples from identifying 
information is not feasible.  A Certificate of Confidentiality has been obtained to help protect the 
privacy of all study participants.  The informed consent document for this protocol contains 
language informing patients about the performance of genetic studies. 

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9.6 
Management of Genomic Results 
 
The results of the OCAv3 targeted sequencing assay performed by MoCha (under CLIA 
certification #21D2097127) on restaging follow-up or progression tumor biopsy tissue will be 
returned to patients in the Oncomine report. 
 
Information regarding the Genomic Data Sharing Plan can be found in Section 12.6.   
 
10. STUDY CALENDAR 
 
Eligibility screening evaluations (see Section 3.3) are to be conducted within 8 days prior to 
patient enrollment, with the exception of informed consent, echocardiogram (ECHO), and 
imaging, which must be done within 28 days prior to patient enrollment.  Baseline history, 
physical examination, laboratory evaluations, and EKG are to be conducted within 8 days prior 
to the start of protocol therapy.  If protocol therapy is started within 8 days of the eligibility 
screening evaluations, values from the screening evaluations may be used as baseline 
measurements; if >8 days have passed since the screening evaluations, the medical history, 
physical examination, laboratory evaluations, and EKG must be repeated prior to starting 
protocol therapy.  Baseline imaging scans and ECHO must be done within 28 days prior to the 
start of protocol therapy.   
 
Each cycle is 21 days (± 3 days due to scheduling conflicts).  The start of a new cycle may be 
delayed up to 2 weeks to accommodate scheduling conflicts and other unexpected events.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy.  
 

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Pre- 
Study 
Screening 
Cycle 1 
Week 1 
Cycle 1 
Week 2 
Cycle 1 
Week 3 
Cycle 2 
Week 1 
Cycle 3 
Week 1 
Cycles 4+ 
Week 1 
Off 
Treatment 
Atezolizumaba 
 
A 
 
 
A 
A 
A 
 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
  Xj 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------X 
 
Physical examb 
X 
 Xj 
 
 
X 
X 
X 
X 
Vital signs 
X 
 Xj 
 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 Xj 
 
 
X 
X 
X 
X 
Performance status 
X 
 Xj 
 
 
X 
X 
X 
X 
CBC w/diff, pltsc 
X 
 Xj 
 
 
X 
X 
X 
X 
Serum chemistryc 
X 
 Xj 
 
 
X 
X 
X 
X 
TSHd 
X 
 Xj 
 
 
X 
X 
X 
X 
EKGe 
X 
Xj 
 
 
 
 
 
 
Echocardiograme 
X 
Xj 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X---------------------------------------------------------------X 
X 
Tumor 
measurementsf 
X 
Tumor measurements are repeated every 6 weeks.  Documentation 
(radiologic) must be provided for patients removed from study for 
progressive disease. 
X 
B-HCGg 
X 
Xj 
 
 
X 
X 
X 
 
Biopsyh 
 
X 
 
 
 
 Xh 
 
Xi 
Blood for PDk 
 
X 
 
Xk 
X 
X 
X 
X 
Blood for geneticsl 
 
X 
Blood for ctDNA analysis at C2D1, at the time of any 
biopsy, at the first two restagings (end of C3 and end of 
C5), and every two restaging visits after that (e.g., C9, 
C13, etc.) 
X 
a: Atezolizumab dose as assigned; adults ≥18 years at 1200 mg IV and in pediatric/adolescents ≥2 years at 15 
mg/kg (max single dose=1200 mg); drug will be administered once on Day 1 only of each cycle. Each cycle 
is 21 days (± 3 days). Start of new cycle may be delayed up to 2 weeks to accommodate scheduling conflicts. 
b: History and physical at baseline and up to 8 days before the start of each subsequent cycle.   
c:  CBC w/diff, plts, and serum chemistry (ACTH, albumin, alkaline phosphatase, AM cortisol, amylase, 
bicarbonate, total bilirubin, BUN, calcium, chloride, creatinine, glucose, LDH, lipase, phosphorus, 
potassium, pregnancy test per institutional standard at each participating sitetotal protein, SGOT [AST], 
SGPT [ALT], sodium, free T4) at baseline and then up to 3 days before the start of each subsequent cycle. 
After baseline, amylase, LDH, lipase, protein, and free T4 do not need to be checked. 
d:  TSH levels at baseline and then up to 3 days before the start of each subsequent cycle. 
e:  Baseline and as indicated. 
f:  CT scan or other imaging test at baseline, at the end of Cycle 3, and every two cycles thereafter (every 3 
cycles for patients on study for >1 year; every 4 cycles for patients on study for >2 years).   
g: Serum or urine pregnancy test (women of childbearing potential) within 8 days prior to enrollment.  If 

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clinically indicated, serum or urine pregnancy test is required for women of childbearing potential ≤8 days 
before the start of each treatment cycle[per institutional standard at each participating site]; outside lab results 
are acceptable. 
h:  Adult patients (≥18 years of age; mandatory at all sites), at baseline and prior to C3D1 (±3 days) or sooner if 
there is clinical evidence that the patient is responding to drug, as described in Section 9.2.1. 
i:  One optional tumor biopsy may be collected following progression or a 10-19% increase in tumor volume at 
restaging, as described in Section 9.2.1. 
j:  Eligibility screening results may be used for these baseline measurements if conducted within 8 days (for 
medical history, physical exam, CBC, serum chemistry, TSH, and EKG) or 28 days (for ECHO) prior to the 
start of protocol therapy.  See Sections 3.3 and 5. 
k:  At NCI only: blood for ImmunoPD (mandatory from patients ≥12 years of age) on C1D1, C1D15 (optional), 
day one of each cycle, and at restaging follow up or progression as described in Section 9.3. 
l:  At all sites, blood for genetic analysis is mandatory for patients ≥12 years of age.  Two tubes at each of the 
following time points: baseline, C2D1, C3D1 (±3 days, or sooner if there is clinical evidence that the patient 
is responding to drug); at the first two restagings (end of C3 and end of C5); every two restaging visits after 
that (e.g., C9, C13, etc.) as described in Section 9.3. 
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
Patients should be re-evaluated for response at the end of Cycle 3 (before Cycle 4), and at the 
end of every two cycles thereafter (before every even-numbered cycle).  Restaging scans may be 
performed less frequently for patients on study for more than 1 year (every three cycles for 
patients on study for more than 1 year; every four cycles for patients on study more than 2 
years).  Confirmatory scans should also be obtained ≥4 weeks following initial documentation of 
objective response.   
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[59].  Changes in the largest diameter (unidimensional measurement) of the tumor lesions and 
the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.   
 
Patients that are clinically well may continue on therapy following RECIST progression with 
new lesions or increase in target lesions, provided the criteria in Section 11.4 are met. 
 
Response will also be explored using iRECIST (see Section 11.3).  Increasing clinical experience 
indicates that traditional response criteria such as RECIST may not be sufficient to fully 
characterize activity in the new era of target therapies and/or biologics.  In studies with 
therapeutic antibodies, complete response, partial response, or stable disease has been shown to 
occur after an increase in tumor burden, characterized by progressive disease by traditional 
response criteria.  Therefore, conventional response criteria may not adequately assess the 
activity of immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure.  Long-term effect on the target 
disease must also be captured.  The iRECIST criteria, by incorporating specific response patterns 

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91 
that have been observed with immunotherapeutic agents, have been developed to address these 
issues and provide standardized response criteria for use with immmunotherapy [60]. 
 
11.2 
RECIST Response Assessment 
 
11.2.1 Definitions 
 
Evaluable for Toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with atezolizumab. 
 
Evaluable for Objective Response Rate.  Only those patients who have measurable disease 
present at baseline and have received at least one dose of therapy will be considered evaluable 
for the primary endpoint of objective response rate.  These patients will have their response 
classified according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of Cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
11.2.2 Disease Parameters 
 
Measurable Disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-Measurable Disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
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 

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present in the same patient, these are preferred for selection as target lesions. 
 
Target Lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-Target Lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
11.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest X-Ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 

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impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor Markers.  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [61-63].  In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer 
[64]. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 

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mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET.  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.2.4 Response Criteria 
 
11.2.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
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 (0.5 cm).  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Patients that are clinically well may continue on therapy following RECIST progression with 
new lesions or increase in target lesions provided the criteria in Section 11.4 are met. 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 

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qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.2.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.2.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 

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 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.2.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
11.2.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
11.2.7 Response Review 
 
For trials where the response rate is the primary endpoint, it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion.  
Simultaneous review of the patients’ files and radiological images is the best approach.  

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11.3 
iRECIST Response Assessment 
 
Overall response will also be assessed using iRECIST as an exploratory endpoint, for 
comparison to RECIST v1.1.   
 
Immunotherapeutics may result in infiltration of immune cells leading to transient increase in the 
size in malignant lesions, or undetectable lesions becoming detectable.  Investigators should 
continue treatment, as appropriate, in the absence of unacceptable toxicity, until unequivocal 
disease progression.  This is particularly important for patients in whom pseudoprogression may 
have occurred.  Follow up response assessments must be continued until unequivocal disease 
progression has occurred. 
 
The iRECIST criteria are identical to those of RECIST 1.1 in many respects but have been 
adapted to account for instances where an increase in tumor burden, or the appearance of new 
lesions, does not reflect true tumor progression. 
 
Key differences are described below.  All responses defined using iRECIST criteria are 
designated with a prefix.  iRECIST time-point and best overall responses will be recorded 
separately.  Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the 
terms iUPD (unconfirmed progression) and iCPD (confirmed progression).  Confirmatory scans 
should be performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
Confirming progression:  Unlike RECIST 1.1, iRECIST requires the confirmation of progression 
and uses the terms iUPD (unconfirmed progression) and iCPD (confirmed progression).  
Confirmatory scans should be performed at least 4 weeks, but no longer than 8 weeks, after 
iUPD. 
 
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is seen 
as evidenced by one or more of the following: 
• Continued increase in tumor burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease, or new lesions. 
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum. 
o Continued unequivocal progression in non-target disease with an increase in 
tumor burden. 
o Increase in size of previously identified new lesion(s) (an increase of at least 5 
mm in the absolute value of the sum of those considered to be target new lesions) 
or additional new lesions. 
• RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR, or iCR if those criteria are met 
compared to baseline).  The prior documentation of iUPD does not preclude assigning iCR, iPR, 

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or iSD in subsequent time-point assessments or as best overall response (BOR) providing that 
iCPD is not documented at the next assessment after iUPD (Lancet Oncol 18:e143-e152, 2017 - 
Table 2). 
 
New lesions:   
 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis [or 15 mm in short 
axis for nodal lesions]), and recorded as New Lesions - Target (NLT) and New Lesion - Non-
Target (NLNT) to allow clear differentiation from baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD).  However, 
the measurements of target lesions should NOT be included in the sum of measures of original 
target lesions identified at baseline.  Rather, these measurements will be collected on a separate 
table in the case record form. 
 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 
weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with 
either an increase of at least 5 mm in the absolute value of the sum of NLT OR an increase (but 
not necessarily unequivocal increase) in the size of NLNT lesions OR the appearance of 
additional new lesions. 
 
Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**, *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 
iUPD with 
no change 
OR decrease 
from last TP 
iUPD with no 
change OR 
decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs 
were previously identified and 
increase in size (≥5 mm in SOM 
for NLT or any increase for 
NLNT) or number. If no change 
in NLs (size or number) from 
last TP, remains iUPD. 

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Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**, *** 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based in further 
increase in size of NT disease 
(need not meet RECIST 1.1 
criteria for unequivocal PD). 
iUPD 
Non-iCR/Non-
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in SOM of at least 5 
mm, otherwise remains iUPD. 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in: 
• previously identified T 
lesion iUPD SOM ≥5 mm 
and/or 
• NT lesion iUPD (prior 
assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD 
confirmed based on further 
increase in: 
• previously identified T 
lesion iUPD ≥5 mm and/or 
• previously identified NT 
lesion iUPD (need not be 
unequivocal) and/or 
• size or number of new 
lesions previously identified 
Non-
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD 
confirmed based on increase in 
size or number of new lesions 
previously identified. 
* Using RECIST 1.1 principles.  If no PSPD occurs, RECIST 1.1 and iRECIST categories for 
CR, PR, and SD would be the same.  
** in any lesion category.  
*** previously identified in assessment immediately prior to this TP. 
 
All patients will have their iBOR from the start of study treatment until the end of treatment 

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classified as outlined below. 
 
iRECIST best overall response (iBOR) 
TPR 1 
TPR 2 
TPR 3 
TPR 4 
TPR 5 
iBOR 
iCR 
iCR, iPR, 
iUPD, NE 
iCR, iPR, 
iUPD, NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, 
NE 
iCR 
iCR, iPR, 
iSD, iUPD, 
NE 
iCR, iPR, 
iSD, iUPD, 
iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, 
iUPD, NE 
iPR, iSD, 
iUPD, NE, 
iCPD 
iPR, iSD, 
iUPD, NE, 
iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, 
iUPD, NE 
iPR, iSD, 
iUPD, 
iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, 
NE 
iSD, iUPD, 
iCPD, NE 
iSD, iUPD, 
ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
Table assumes a randomized study where confirmation of CR or PR is not required. 
• NE = not evaluable that cycle. 
• Designation "I" for BOR can be used to indicate prior iUPD to aid in data 
interpretation. 
• For patients with non-target disease only at baseline, only CR or non-CR/non-PD 
can be assigned at each TPR but is not shown in the table for ease of presentation. 
 
11.4 
Treatment Beyond RECIST Progression 
 
During treatment, patients who show evidence of clinical benefit will be permitted to continue 
atezolizumab treatment following progression (as defined by RECIST v1.1), as long as the 
increase in disease burden does not meet the definition of confirmed PD by immune response 
criteria and if they meet all of the following additional criteria: 
• 
Evidence of clinical benefit as assessed by the investigator and agreed upon by the Medical 
Monitor 
• 
Absence of symptoms or signs (including worsening laboratory values) indicating 
unequivocal progression of disease 
• 
No significant decline in performance status that can be attributed to disease progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
 
The investigator must discuss with the patient the risks and benefits of treatment continuation 
after possible worsening disease and must document the patient’s agreement to continue 

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receiving atezolizumab in the medical record. 
 
If the investigator and patient decide to continue treatment, confirmatory scans should be 
performed at least 4 weeks, but no longer than 8 weeks after the assessment in which the 
RECIST 1.1 definition of PD was met.  If this consecutive scan confirms PD, the patient 
should come off treatment. 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7. 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  To access Rave via iMedidata: 
 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site:  Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type, 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
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o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 

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every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
Study participants are responsible for submitting CDUS data and/or data forms to either the 
Coordinating Center or to the Lead Organization on the study quarterly.  The date for submission 
to the Coordinating Center or to the Lead Organization will be set by them.  CDUS does not 
accept data submissions from the participants on the study.  When setting the dates, allow time 
for Coordinating Center compilation, Principal Investigator review, and timely submission to 
CTEP by the quarterly deadlines (see Section 12.2.1).  For trials monitored by CTMS, a 
quarterly report of data will be provided by Theradex to the Coordinating Center. 
 
Either the Coordinating Center or the Lead Organization is responsible for compiling and 
submitting CDUS data to CTEP for all participants and for providing the data to the Principal 
Investigator for review.   
 

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12.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports.  Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note:  Some Rave protocols may not have delinquent form details or reports specified on 
the DQP.  A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP.  Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.  
12.4 
Human Data Sharing Plan 
 
What data will be shared?  
We will share human data generated in this research for future research as follows: 
x De-identified data in an NIH-funded or approved public repository  
x Identified data in BTRIS (automatic for activities in the NIH Clinical Center)  
x De-identified or identified data with approved outside collaborators under appropriate 
agreements  
 
How and where will the data be shared?  
Data will be shared through:  
x An NIH-funded or approved public repository: clinicaltrials.gov 
x BTRIS (automatic for activities in the NIH Clinical Center)  
x Approved outside collaborators under appropriate individual agreements  
x Publication and/or public presentations  
 
When will the data be shared?  
x At the time of publication or shortly thereafter 
 

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12.5 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
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4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.6 
Genomic Data Sharing Plan 
 
The NIH Genomic Data Sharing (GDS) Policy ensures broad and responsible sharing of genomic 
research data from all NIH-funded research (https://gds.nih.gov/index.html).  Providing that 
patient consent has been obtained, targeted sequencing, whole-exome sequencing, and RNA-seq 
data generated for research purposes will be submitted to the Database of Genotypes and 
Phenotypes (dbGaP) for controlled-access use within a time frame consistent with data 
publication.  The identities of research participants will not be disclosed to dbGaP or to 
secondary users of the data. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This study will enroll adult and pediatric patients, but only adults will be included in the primary 
and interim analyses.  For adult patients, a Simon two stage design will be employed within each 
of the three study cohorts, with a maximum of 17 evaluable patients per cohort.  For each cohort, 
accrual will be halted at 9 patients to evaluate for response before further enrollment.  If within 9 

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13.4.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
atezolizumab. 
 
13.4.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations.  Each patient will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) 
early death from malignant disease, 6) early death from toxicity, 7) early death because of other 
cause, or 9) unknown (not assessable, insufficient data).  [Note:  By arbitrary convention, 
category 9 usually designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.   
 
 
14. HUMAN SUBJECTS PROTECTION 
 
14.1 
Rationale for Subject Selection 
 
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met.  For safety reasons, pregnant women are 
excluded from this study.  Patients for this study will be recruited through internal referral, our 
physician referral base, and through various cancer information hotlines (i.e., Clinical Studies 
Support Center, 1-800-4Cancer).  Participants should realize that there is no guarantee of benefit 
to them from participation in this trial.  The results of this trial may benefit future cancer 
patients.  To date, there is no information that suggests that differences in drug metabolism or 
effect on tumor would be expected in one ethnic group compared to another.  Efforts will be 
made to extend accrual to each representative population, but a balance must be struck between 
participant safety considerations and limitations on the number of individuals exposed to 
potentially ineffective treatments on the one hand and the need to explore racial/ethnic aspects of 
clinical research on the other hand.  If differences in outcome that correlate to ethnic identity are 
noted, a follow-up study may be written to investigate those differences more fully. 

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Inclusion of Women and Minorities 
 
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met.  Accrual estimates can be found in the 
Planned Enrollment Report in Section 13.2. 
 
14.2 
Justification for Exclusions 
 
14.2.1 Pregnant Women 
 
Pregnant women are excluded from this study because atezolizumab has known abortifacient 
effects.  Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with these agents, breastfeeding should be discontinued.  
Participants with unstable or serious medical conditions or psychiatric illness/social situations 
that would limit compliance with study requirements are excluded due to the possibility that the 
underlying condition may obscure the attribution of effect and adverse events and may limit 
study compliance. 
 
14.2.2 Children <2 years of age 
 
This study includes patients ≥2 years of age at the NCI Clinical Center.  Because insufficient 
dosing or adverse event data are currently available on the use of atezolizumab in younger 
pediatric patients, children <2 years of age are excluded from this study, but may be eligible for 
future pediatric trials. 
 
14.3 
Evaluation of Benefits and Risks/Discomforts 
 
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence 
of any of a range of side effects that are listed in the consent document.  The procedure for 
protecting against or minimizing risks will be to medically evaluate patients as described in 
Section 5 and Section 6.  Although no compensation is available, any injury will be fully 
evaluated and treated in keeping with the benefits or care to which participants are entitled under 
applicable regulations.  A Certificate of Confidentiality has been obtained to help protect the 
privacy of all study participants.   
 
14.4 
Consent and Assent Process and Documentation 
 
14.4.1 Written Consent 
 
An associate or principal investigator on the trial will inform patients or the patient’s parents or 
guardian if he/she is a child, of the purpose, alternatives, drug administration plan, research 
objectives, and follow-up of this trial.  The patient will be provided a CIRB-approved consent for 
review and signature and his/her questions will be answered.  After a decision is made to enroll 
into the study, a signature will be obtained from the patient.  The original signed consent goes to 

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each participating site’s Medical Records; a copy will be placed in the research record. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
 
This protocol is open to pediatric patients ≥2 years of age at the NCI clinical center and ≥12 
years at other participating sites.  The investigators are requesting a waiver from the CIRB to 
allow only one parent to sign the informed consent to enter a child on the protocol.  Because 
many patients must travel to the NIH from long distances at substantial expense, requiring both 
parents to be present for the consent process could be a financial hardship for many families.  
Where deemed appropriate by the clinician and the child’s parents or guardian, the child will also 
be included in all discussions about the trial and verbal or written assent will be obtained 
depending on the age of the child. 
 
In situations where there is joint custody of a child, both parents must sign consent.  If only one 
parent can be present, the other parent’s consent can be obtained by telephone via the procedure 
described in Section 14.4.3.  When guardianship status of the child is uncertain, documentation 
of custody status must be obtained.   
 
14.4.2 Assent 
 
Where deemed appropriate by the clinician and the child’s parents or guardian, the child will also 
be included in all discussions about the trial and assent will be obtained.  Investigators may refer 
to or distribute the pediatric information sheets provided in Appendix C and Appendix D when 
explaining the study to patients ages 7-17.  As appropriate, verbal assent will be obtained from 
patients ages 7-13 and written assent will be obtained from patients ages 14-17.  Assent of 
children age 14 and older is a necessary condition for proceeding with the research; these 
patients (ages 14-17) should be informed about the study using the pediatric informed consent 
document.  Children under the age of 14 will not be required to provide assent because their 
capacity is so limited.  Regardless of the age of the child, the parent or guardian will sign the 
designated line on the pediatric informed consent granting permission for the child’s 
participation and, for patients 7 years of age and older, attesting to the fact that the child has 
given assent.   
 
All children will be contacted after they have reached the age of 18 to determine whether they 
wish to continue on the trial and informed consent will be obtained from them at that time.  The 
signature process for obtaining pediatric consent and assent may be adapted as necessary by 
participating institutions to adhere to local guidelines. 
 
14.4.3 Telephone Consent 
 
In situations where there is joint custody of a child, and only one parent can be present, the other 
parent’s consent can be obtained by telephone via the remote consent procedure outlined on the 
NCI CIRB’s website:  https://ncicirb.org/content/frequently-asked-questions-regarding-remote-
consent-procedures.   
 

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The parent must receive a copy of the informed consent document (e.g., via mail, fax or email) in 
advance of discussion regarding the study.  The investigator/designee must implement a method 
to ensure the identity of the parent.  The investigator/designee must have the same consent 
discussion via telephone/video conferencing that they would have during an in-person meeting 
and there must be a witness who can hear both sides of the conversation.  The witness’s signature 
(if required by the site) or name and the date of the original consenting phone call should be 
recorded in the research records to document the participation of the witness.   
 
Once the research team receives the signed informed consent document from the parent, the 
investigator/designee who conducted the consent process must sign and date the document using 
the current date.  Under the signature line, the investigator/designee must document whether 
consent was obtained over the telephone or video conferencing, the date of the telephone/video 
conference, the date the signed consent was received, and the reason the remote consent 
procedure was utilized.  The date the investigator/designee signs the informed consent document, 
not the date the consent discussion with the parent took place, is the official date of informed 
consent for the participant on the trial.   
 
The final informed consent document must be filed in the designated investigator/site regulatory 
file location.  A copy of the final informed consent document, signed by the parent, the 
investigator, and the witness (if applicable), must be sent back to the participant via email/scan, 
fax, or postal mail.  No research activities related to the study can begin until all steps of the 
informed consent process are complete. 
 
14.4.4 Participation of Subjects Unable to Give Consent 
 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary, and there is a possibility, though unlikely, that subjects could become 
decisionally impaired.  For this reason, and because there is a prospect of direct benefit from 
research participation, all subjects ≥ age 18 at the NCI only will be offered the opportunity to 
fill in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
 
14.4.5 Informed Consent of Non-English Speaking Subjects (at the NCI only) 
 
We do not anticipate consistent enrollment of any particular group of non-English speaking 
research participants into this study.  In the event there is consistent enrollment of one non-
English speaking group (i.e., more than 5 subjects from one non-English speaking group), the 
IRB approved full consent document will be translated into that language in accordance with the 
Clinical MAS Policy M77-2 at that time. 

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If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the PI and/or those authorized to obtain informed 
consent will use the Short Form Oral Consent Process as described in NCI Clinical SOP PM-2, 
MAS Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), 21 CFR 50.27 (b) (2)).  The 
summary that will be used is the English version of the extant IRB approved consent document.  
Signed copies of both the English version of the consent and the translated short form will be 
given to the subject or their legally authorized representative and the signed original will be filed 
in the medical record. 
 
Unless the authorized individual obtaining consent is fluent in the prospective subject’s 
language, an interpreter will be present to facilitate the conversation (using either the long 
translated form or the short form).  Preferably someone who is independent of the subject (i.e., 
not a family member) will assist in presenting information and obtaining consent.  Whenever 
possible, interpreters will be provided copies of the relevant consent documents well before the 
consent conversation with the subject (24 to 48 hours if possible).  
 
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of 
use of the Short Form.  The Short Form process will be used no more than 5 times per language, 
after which the full consent document will be translated into that language. 
 
14.5 
Patient Advocate 
 
At the NCI only, the patients’ rights representative is available to patients receiving treatment on 
this protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical 
Research Center, Room 1-3521, on the Bethesda NIH campus.  Patients will be informed that 
they can contact the study PI or RN at any time with questions about their medical care, and that 
the patients’ rights representative is also available to answer non-medical questions about the 
study. 
 
 

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APPENDIX A: 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance  
Status Scale 
Karnofsky Performance Scale 
Lansky Scale (age <16 years) 
Grade 
Description 
Percent 
Description 
Percent 
Description 
0 
Normal activity.  Fully 
active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, 
no evidence of disease. 
100 
Fully active. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
90 
Minor restriction in 
physically strenuous 
play. 
1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with 
effort; some signs or 
symptoms of disease. 
80 
Restricted in strenuous 
play, tires more easily, 
otherwise active. 
70 
Cares for self, unable to 
carry on normal activity 
or to do active work. 
70 
Both greater 
restrictions of, and less 
time spent, in active 
play 
2 
In bed <50% of the time.  
Ambulatory and capable of 
all self-care, but unable to 
carry out any work 
activities.  Up and about 
more than 50% of waking 
hours. 
60 
Requires occasional 
assistance, but is able to 
care for most of his/her 
needs. 
60 
Ambulatory up to 50% 
of time, limited active 
play with assistance/ 
supervision 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Considerable assistance 
required for any active 
play, fully able to 
engage in active play 
3 
In bed >50% of the time.  
Capable of only limited 
self-care, confined to bed 
or chair more than 50% of 
waking hours. 
40 
Disabled, requires 
special care and 
assistance. 
40 
Able to initiate quiet 
activities 
30 
Severely disabled, 
hospitalization 
indicated.  Death not 
imminent. 
30 
Needs considerable 
assistance for quiet 
activity 
4 
100% bedridden.  
Completely disabled.  
Cannot carry on any self-
care.  Totally confined to 
bed or chair. 
20 
Very sick, 
hospitalization 
indicated. Death not 
imminent. 
20 
Limited to very passive 
activity initiated by 
others (e.g., TV) 
10 
Moribund, fatal 
processes progressing 
rapidly. 
10 
Completely disabled, 
not even passive play 
5 
Dead. 
0 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B: 
PATIENT DRUG INFORATION AND WALLET CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug, atezolizumab.  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Cytochrome P450 enzymes as well as conjugation/glucuronidation reactions are not involved in the 
metabolism of atezolizumab.  No drug interaction studies for atezolizumab have been conducted.  There 
are no known interactions with other medicinal products or other forms of interactions.  However, 
ingredients for such medicines have not been fully studied, and their use may result in unanticipated 
drug-drug interactions that may cause or confound assessment of toxicity.  Immunostimulatory agents, 
including but not limited to interferon alfa, interferon gamma, tumor necrosis factor-alpha blockers, or 
interleukin-2 (aldesleukin), are prohibited during the study and for 10 weeks after the last dose of 
atezolizumab due to   potential for increased risk of autoimmune conditions.  Also to be avoided are 
immunosuppressive medications, including but not limited to cyclophosphamide, azathioprine, 
methotrexate, and thalidomide, which could potentially alter the activity and the safety of atezolizumab.  
Live vaccines and live, attenuated vaccines (prohibited during the study and for 100 days after the last dose 
of study drug) are prohibited.   
 
Initiation of granulocyte colony-stimulating factors (e.g., filgrastim and biosimilar products, sargramostim 
and/or pegfilgrastim) should be discussed with the study’s Principal Investigator.  Patients should also be 
advised to avoid traditional herbal or homeopathic or natural medicines  
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Atezolizumab may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this clinical 
trial.  It is also very important to tell your doctors if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study.  When you talk about your current medications 
with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or any 
herbal supplements such as St. John’s Wort.  It is helpful to bring your medication bottles or an updated 
medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that might interact with the study drug. 
 

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• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or call your 
study doctor before prescribing any new medicine or discontinuing any medicine.  Your study 
doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the 
experimental study drug Atezolizumab.  This clinical 
trial is sponsored by the NCI.  Atezolizumab may 
interact with other drugs that you are taking.  Because 
of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or 
if you start taking any new medicines. 
➢ Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplement. 
➢ Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care 
providers to review any medicines and herbal 
supplements that may interact with atezolizumab. 
➢ Before prescribing new medicines, your regular 
health care providers should go to a frequently-
updated medical reference for a list of drugs to 
avoid, or contact your study doctor.   
➢ Your study doctor’s name is:  
 
 and he/she can be contacted at:  

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APPENDIX C: 
CS PEDIATRIC INFORMATION SHEET (FOR PATIENTS 7-17 YEARS) 
 
 
 
INFORMATION SHEET FOR RESEARCH STUDY P10398 
 
A research study testing a new drug, atezolizumab, in your type of cancer called     
chondrosarcoma 
1. We have been talking with you about your illness, a type of cancer called chondrosarcoma.  This type of 
cancer grows in your bones.  It can grow in different parts of your body like your legs, arms, toes, fingers, 
pelvis, and shoulders.  It can cause pain and swelling.  
2. We want to help you and other young patients with chondrosarcoma by doing a research study.  A research 
study is a way to learn more about a new drug such as atezolizumab and its uses.  We are asking you to 
take part because we want to test the drug in chondrosarcoma.  We will test the drug by giving it to people 
with chondrosarcoma and watching to see if their cancer shrinks.  We do not yet know how well the new 
drug will work in children, teens, or adults.  
3. You do not have to be in this research study if you do not want to be.  You can say no and no one will be 
mad at you.  If you decide to stop after we begin, that's okay too.  If you do not want to be in this research 
study, we will tell you what other kinds of treatments there are for you (or other research studies). 
4. There are some things about this study that you should know.  There are things that take a long time, 
things that might make you uncomfortable, and things that share some of your private information with 
the researchers.  If you agree to take part in this research study, we will give you a newly invented, 
experimental drug called atezolizumab.  A newly invented, experimental drug is one that is not usually 
given to anyone with your type of cancer yet.  You will be given the drug through a vein in your arm 
(sometimes people call this way of getting a drug “IV”).  The drug will be given once every three weeks.  
Atezolizumab might have some side effects on your body.  It is not possible to know now if atezolizumab 
will shrink your cancer compared to the usual approach.   
5. Atezolizumab works by helping your immune system.  Your immune system is the part of your body that 
fights germs and prevents you from getting sick.  We hope that giving you atezolizumab will make your 
immune system fight your chondrosarcoma so that your tumors will stop growing. 
6. During the study, you will have imaging tests (like CT scans or X-ray scans) to help the doctors see inside 
of you.  This will help your doctors to figure out if the chondrosarcoma is getting worse, staying the same, 
or getting better.  You will also have your blood drawn every week for three weeks so that we can check 
if the drug is still safe for you.  Later, you will have your blood drawn once every three weeks to check if 
parts of your body, like your liver and kidneys, are still working right.  You have probably had these types 
of tests already.  
7. If you are 12 years of age or older, you will need to have extra blood samples collected for the study.  This 
blood will be used for research.  It will help the researchers understand how atezolizumab is working.  
Your doctor will tell you if your research blood collections will happen approximately every 3 weeks or 

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every 6 weeks.  Each time we collect research blood it will be about 1 or 2 teaspoons of blood.  Sometimes 
we will collect this research blood at the same time that we draw blood for safety tests.  There might be 
other times when we only collect research blood from you.  Each time we collect your blood, there is a 
chance that you will have mild pain, bleeding, bruising, or infection at the place where the needle poked 
your skin.  Fainting or light-headedness can sometimes happen, but they usually last only a few minutes. 
8. Not everyone who takes part in this study will benefit.  A benefit means that something good happens to 
you.  We hope that a benefit to you for being part of this study will be that your symptoms improve, and 
the chondrosarcoma tumor shrinks.  But we do not know for sure if there is any benefit of being part of 
this study. 
9. All drugs have some bad effects.  If you take part in this research study, you may have some of these effects 
or you may have very few.  Some things you might have are fever, throwing up, and feeling tired.  Your 
doctor will talk to you about other things that can happen, and it is okay to ask questions about bad effects.  
Tell your doctors and nurses about any bad effects you have.   
10. If you are 12 years old or older, we will do research tests called genetic sequencing to read the 
“instruction books” called genes that are in your normal blood cells and cancer cells.  We will not tell 
you or your parents anything about your genes. 
11. Please talk this over with your parents before you decide whether or not to take part. We will also ask 
your parents to give their permission for you to take part in this study.  But even if your parents say 
“yes” you can still decide not to do this.  You and your family can choose to be part of this study or 
not.  You and your family can also decide to stop being in this study at any time, even after you start.   
12. There may be other treatments or research studies for your chondrosarcoma that your doctors can tell 
you about.  Your doctors will continue to treat you whether or not you participate in this study.  Make 
sure to ask your doctors any questions that you have.  It is always okay to ask questions.  If you have a 
question later that you didn’t think of now, you can call me at _____________________ (insert telephone 
number) or ask me next time. 

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APPENDIX D: 
CCS PEDIATRIC INFORMATION SHEET (FOR PATIENTS 7-17 YEARS) 
 
 
 
INFORMATION SHEET FOR RESEARCH STUDY P10398 
 
A research study testing a new drug, atezolizumab, in your type of cancer called     
clear cell sarcoma  
1. We have been talking with you about your illness, a type of cancer called clear cell sarcoma (“CCS 
cancer”).  This type of cancer can grow in different places in your body.  It can grow on your legs, feet, 
arms, hands, and even around your tummy, head, or neck.  It can make bumps under your skin.  
2. We want to help you and other young patients with CCS cancer by doing a research study.  A research 
study is a way to learn more about a new drug such as atezolizumab and its uses.  We are asking you to 
take part because we want to test the drug in CCS cancer.  We will test the drug by giving it to people 
with CCS cancer and watching to see if their cancer shrinks.  We do not yet know how well the new drug 
will work in children, teens, or adults.  
3. You do not have to be in this research study if you do not want to be.  You can say no and no one will be 
mad at you.  If you decide to stop after we begin, that's okay too.  If you do not want to be in this research 
study, we will tell you what other kinds of treatments there are for you (or other research studies). 
4. There are some things about this study that you should know.  There are things that take a long time, 
things that might make you uncomfortable, and things that share some of your private information with 
the researchers.  If you agree to take part in this research study, we will give you a newly invented, 
experimental drug called atezolizumab.  A newly invented, experimental drug is one that is not usually 
given to anyone with your type of cancer yet.  You will be given the drug through a vein in your arm 
(sometimes people call this way of getting a drug “IV”).  The drug will be given once every three weeks.  
Atezolizumab might have some side effects on your body.  It is not possible to know now if atezolizumab 
will shrink your cancer compared to the usual approach.   
5. Atezolizumab works by helping your immune system.  Your immune system is the part of your body that 
fights germs and prevents you from getting sick.  We hope that giving you atezolizumab will make your 
immune system fight your CCS cancer so that your tumors will stop growing. 
6. During the study, you will have imaging tests (like CT scans or X-ray scans) to help the doctors see inside 
of you.  This will help your doctors to figure out if the CCS cancer is getting worse, staying the same, or 
getting better.  You will also have your blood drawn every week for three weeks so that we can check if 
the drug is still safe for you.  Later, you will have your blood drawn once every three weeks to check if 
parts of your body, like your liver and kidneys, are still working right.  You have probably had these types 
of tests already.  
7. If you are 12 years of age or older, you will need to have extra blood samples collected for the study.  This 
blood will be used for research.  It will help the researchers understand how atezolizumab is working.  
Your doctor will tell you if your research blood collections will happen approximately every 3 weeks or 

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124 
 
every 6 weeks.  Each time we collect research blood it will be about 1 or 2 teaspoons of blood.  Sometimes 
we will collect this research blood at the same time that we draw blood for safety tests.  There might be 
other times when we only collect research blood from you.  Each time we collect your blood, there is a 
chance that you will have mild pain, bleeding, bruising, or infection at the place where the needle poked 
your skin.  Fainting or light-headedness can sometimes happen, but they usually last only a few minutes. 
8. Not everyone who takes part in this study will benefit.  A benefit means that something good happens to 
you.  We hope that a benefit to you for being part of this study will be that your symptoms improve, and 
the CCS tumor shrinks.  But we do not know for sure if there is any benefit of being part of this study. 
9. All drugs have some bad effects.  If you take part in this research study, you may have some of these effects 
or you may have very few.  Some things you might have are fever, throwing up, and feeling tired.  Your 
doctor will talk to you about other things that can happen, and it is okay to ask questions about bad effects.  
Tell your doctors and nurses about any bad effects you have.   
10. If you are 12 years old or older, we will do research tests called genetic sequencing to read the 
“instruction books” called genes that are in your normal blood cells and cancer cells.  We will not tell 
you or your parents anything about your genes. 
11. Please talk this over with your parents before you decide whether or not to take part. We will also ask 
your parents to give their permission for you to take part in this study.  But even if your parents say 
“yes” you can still decide not to do this.  You and your family can choose to be part of this study or 
not.  You and your family can also decide to stop being in this study at any time, even after you start.   
12. There may be other treatments or research studies for your CCS cancer that your doctors can tell you 
about.  Your doctors will continue to treat you whether or not you participate in this study.  Make sure 
to ask your doctors any questions that you have.  It is always okay to ask questions.  If you have a 
question later that you didn’t think of now, you can call me at _____________________ (insert telephone 
number) or ask me next time.