A Feasibility Trial of Neoadjuvant Cisplatin-Pemetrexed With Atezolizumab in Combination and in Maintenance for Resectable Malignant Pleural Mesothelioma
Phase: PHASE1
Conditions: Biphasic Mesothelioma, Epithelioid Mesothelioma, Stage I Pleural Malignant Mesothelioma AJCC v7, Stage IA Pleural Malignant Mesothelioma AJCC v7, Stage IB Pleural Malignant Mesothelioma AJCC v7, Stage II Pleural Malignant Mesothelioma AJCC v7, Stage III Pleural Malignant Mesothelioma AJCC v7
Sponsor: National Cancer Institute (NCI)

 
 
Version Date: September 2, 2022 
 
 
TO:  
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office (E-mail protocols@swog.org)  
 
RE: 
S1619, “A Feasibility Trial of Neoadjuvant Cisplatin-Pemetrexed with Atezolizumab 
in Combination and in Maintenance for Resectable Malignant Pleural Mesothelioma.” 
Primary Study Chair: Anne Tsao, M.D. 
  
REVISION #6 
 
Study Chair: Anne Tsao, M.D. 
Phone number: 713/792-6363 
E-mail: atsao@mdanderson.org 
 
Status Change 
( √ )  
IRB Review only 
 
Action Codes 
( √ ) 
Expedited review allowed 
 
Key Updates    
(√)  
Editorial / Administrative changes to the Protocol 
(√)  
Other: Planned Enrollment Table was updated 
 
Sites using the CIRB as their IRB of record:  The protocol and/or informed consent form changes 
have been approved by the CIRB and must be activated within 30 days of distribution of this notice 
through the CTSU Bi-Monthly Broadcast email.  
 
Sites not using the NCI CIRB:  Per CTMB Guidelines, the protocol updates and/or informed consent 
changes must be approved by local IRBs within 90 days of distribution of this notice through the CTSU 
Bi-Monthly Broadcast email. 
 
REVISION #6 
 
This revision has been prepared in response to CTEP’s request to remove the international accrual table 
in S1619 to align with the NIH Human Subject System (HSS).  
 
Protocol Changes 
 
1. 
The version date has been updated. 
 
2. 
Throughout the protocol, formatting, typographical errors, pagination, and cross-references have 
been corrected as needed. 
 
3. 
Section 2.0: The international planned enrollment table has been removed to meet the HSS 
requirements. 
 
Model Consent Form Changes 
 
1. 
The version date has been updated. 
 
The updated protocol and model informed consent form can be accessed from the CTSU website 
(www.ctsu.org).  Please discard any previous versions of the documents and replace with the updated 
versions. Please contact lungquestion@crab.org or 206/652-2267 with any questions. 
 

This study has been reviewed and approved by the NCI’s Central Institutional Review Board (CIRB).  
 
This memorandum serves to notify the NCI and SWOG Statistics and Data Management Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 

 
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PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG 
 TITLE 
 
A FEASIBILITY TRIAL OF NEOADJUVANT CISPLATIN-PEMETREXED WITH ATEZOLIZUMAB IN 
COMBINATION AND IN MAINTENANCE FOR RESECTABLE MALIGNANT PLEURAL 
MESOTHELIOMA  
 
NCT#03228537 
 
STUDY CHAIR: 
AGENTS: 
 
Anne Tsao, M.D. (Primary Chair, Medical Oncology) 
IND-Exempt Agents:  
University of Texas  
Cisplatin (NSC 119875) 
MD Anderson Cancer Center 
Pemetrexed (Alimta®) (NSC-698037) 
1515 Holcombe Blvd. Unit 432 
Houston, TX 77030 
NCI-Supplied Investigational Agent: 
Phone: 713-792-6363 
Atezolizumab (NSC-783608) 
FAX: 713-792-1220 
(DCTD-sponsored IND-131853) 
E-mail: astsao@mdanderson.org   
  
Jeremy Cetnar, M.D. M.S. (Co-Chair, Medical Oncology) 
Oregon Health & Science University 
3181 SW Sam Jackson Park Rd 
Mail Code L586 
Portland, OR  97239 
Phone: 503- 494-8534 
FAX: 503- 494-3257 
E-mail: cetnarj@ohsu.edu  
BIOSTATISTICIANS: 
 
 
 
Boris Sepesi, M.D. (Co-Chair, Surgical Oncology) 
Katherine Minichiello, M.S. 
MD Anderson Cancer Center 
Mary Redman, Ph.D. 
1515 Holcombe Blvd. Unit 1489 
SWOG Statistics and Data Management Center 
Houston, TX 77030 
1100 Fairview Ave N, M3-C102 
Phone: 713-792-7664 
PO Box 190204 
FAX: 713-794-4091 
Seattle, WA 98109-1024 
E-mail: bsepesi@mdanderson.org  
Phone: 206-667-4623 
 
FAX: 206-667-4408 
 
E-mail: kmini@fredhutch.org 
Daniel R. Gomez, M.D. (Co-Chair, Radiation Oncology) 
E-mail: mredman@fredhutch.org  
MD Anderson Cancer Center 
 
1515 Holcombe Blvd., FCT6.5012 
 
Houston, TX 77030 
Phone:  832/857-6585 
FAX:  713-563-2331 
E-mail:  dgomez@mdanderson.org  
PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 
 
 

 
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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 1 
TABLE OF CONTENTS ............................................................................................................................... 2 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 4 
SCHEMA ....................................................................................................................................................... 5 
1.0 
OBJECTIVES .................................................................................................................................. 6 
1.1 
Primary Objective(s) ......................................................................................................................... 6 
1.2 
Secondary Objective(s) .................................................................................................................... 6 
1.3 
Translational Medicine Objective(s) ................................................................................................. 6 
2.0  
BACKGROUND ............................................................................................................................... 6 
3.0  
DRUG INFORMATION .................................................................................................................... 9 
3.1 
Atezolizumab (NSC # 783608) (IND #131853) ................................................................................ 9 
3.2 
Cisplatin (CDDP, Platinol®, Platinol-AQ) (NSC-119875) ............................................................... 19 
3.3 
Pemetrexed for injection (Alimta®) (NSC-698037) ........................................................................ 20 
4.0 
STAGING CRITERIA ..................................................................................................................... 22 
4.1 
Staging Criteria (AJCC Cancer Staging Manual, 7th edition) ........................................................ 23 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 25 
5.1 
STEP 1: NEOADJUVANT .............................................................................................................. 25 
5.2 
STEP 2: SURGERY ....................................................................................................................... 28 
5.3 
STEP 3: MAINTENANCE............................................................................................................... 29 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 29 
7.0 
TREATMENT PLAN ...................................................................................................................... 29 
7.1 
Treatment Overview ....................................................................................................................... 30 
7.2 
Neoadjuvant therapy (Registration Step 1) .................................................................................... 31 
7.3 
Surgery (Registration Step 2) ........................................................................................................ 33 
7.4 
Radiation Therapy .......................................................................................................................... 34 
7.5 
MAINTENANCE (Registration Step 3) ........................................................................................... 38 
7.6 
Full CDUS Reporting Requirement ................................................................................................ 38 
7.7 
Criteria for Removal from Protocol Treatment ............................................................................... 38 
7.8 
Discontinuation of Treatment ......................................................................................................... 39 
7.9 
Follow-Up Period ............................................................................................................................ 39 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 39 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 39 
8.2 
Neoadjuvant Treatment (Atezolizumab, Pemetrexed, and Cisplatin) ............................................ 39 
8.3 
Maintenance (Atezolizumab) ......................................................................................................... 60 
8.4 
Dose Modification Contacts ........................................................................................................... 60 
8.5 
Adverse Event Reporting ............................................................................................................... 60 
9.0 
STUDY CALENDAR ...................................................................................................................... 61 
9.1 
Neoadjuvant (Registration Step 1) ................................................................................................. 61 
9.2 
Surgery +/- Radiation (Registration Step 2) ................................................................................... 64 
9.3 
Maintenance (Registration Step 3) ................................................................................................ 66 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 68 
10.1 
Measurability of lesions .................................................................................................................. 68 
10.2 
Objective status at each disease evaluation .................................................................................. 69 
10.3 
Best Response ............................................................................................................................... 70 
10.4 
Performance Status ....................................................................................................................... 71 
10.5 
Modified RECIST ........................................................................................................................... 71 
10.6 
Progression-free survival by RECIST 1.1 ...................................................................................... 72 
10.7 
Progression-free survival by Modified RECIST 1.1 ....................................................................... 72 
10.8 
Relapse-Free Survival .................................................................................................................... 72 
10.9 
Time to Death ................................................................................................................................. 72 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 72 

 
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11.1 
This study will evaluate the safety/tolerability and feasibility of neoadjuvant cisplatin-pemetrexed-
atezolizumab, followed by surgery +/- radiation, followed by adjuvant maintenance atezolizumab
 ....................................................................................................................................................... 72 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 73 
12.1 
Surgery Review .............................................................................................................................. 73 
12.2 
Radiation Therapy Review ............................................................................................................. 74 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 76 
13.1 
Registration Timing ........................................................................................................................ 76 
13.2 
Investigator/Site Registration ......................................................................................................... 76 
13.3 
OPEN Registration Requirements ................................................................................................. 79 
13.4 
Registration Procedures................................................................................................................. 80 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 81 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 81 
14.1 
Data Submission Requirement ...................................................................................................... 81 
14.2 
Master Forms ................................................................................................................................. 81 
14.3 
Data Submission Procedures ........................................................................................................ 81 
14.4 
Data Submission Overview and Timepoints .................................................................................. 82 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 85 
15.1 
Specimens for Translational Medicine and Banking ...................................................................... 85 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 87 
16.1  
Adverse Event Reporting Requirements ........................................................................................ 89 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 95 
18.0 
APPENDIX ..................................................................................................................................... 98 
18.1 
New York Heart Association Functional Classifications ................................................................ 99 
18.2 
Translational Medicine Studies and Instructions for SWOG Biospecimen Bank ......................... 100 
18.3 
Surgical Guidelines ...................................................................................................................... 106 
18.4 
Autoimmune Serious Adverse Events and URLs ........................................................................ 108 
 
 
 

 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal.   
 
Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.   
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
at 1-866-651-2878 to receive 
further instruction and support.   
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench via the SWOG 
website (www.swog.org). 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center by phone or email: 
206/652-2267 
lungquestion@crab.org  
 
For treatment or toxicity related questions contact the Study Chairs by phone or email: Anne Tsao, 
M.D., Phone: 713-792-6363 or E-mail: astsao@mdanderson.org or Jeremy Cetnar, M.D., Phone: 503- 
494-8534 or Email: cetnarj@ohsu.edu 
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 

 
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SCHEMA 
 
Chemotherapy naive patients diagnosed with resectable malignant pleural mesothelioma 
 
 
 
 
Step 1: Neoadjuvant 
Treatment with cisplatin + pemetrexed + atezolizumab x 4 cycles 
Stratification factor: EPP vs. P/D 
     
 
 
 
Step 2: Surgery 
Extrapleural pneumonectomy (EPP) and radiation therapy  
OR 
Pleurectomy/decortication (P/D) 
 
 
 
Step 3: Maintenance 
Maintenance atezolizumab for up to 1 year 
 
 
 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective(s)  
 
a. 
To 
evaluate if the regimen of neoadjuvant cisplatin-pemetrexed-atezolizumab, 
surgery +/- radiation, then maintenance atezolizumab is 
feasible and safe (as 
defined in Section 11.1) for patients with resectable malignant pleural 
mesothelioma. 
 
1.2 
Secondary Objective(s) 
 
a. 
To evaluate progression free survival (both by RECIST 1.1 and also using a 
Modified RECIST for Pleural Tumors) in patients with resectable malignant pleural 
mesothelioma treated with a regimen of neoadjuvant cisplatin-pemetrexed-
atezolizumab, surgery +/- radiation, followed by one year of maintenance 
atezolizumab. 
 
b. 
To evaluate overall survival in patients with resectable malignant pleural 
mesothelioma treated with a regimen of neoadjuvant cisplatin-pemetrexed-
atezolizumab, surgery +/- radiation, followed by one year of maintenance 
atezolizumab. 
 
c. 
To evaluate response rate (confirmed and unconfirmed, complete and partial, both 
by RECIST 1.1 and also using a Modified RECIST for Pleural Tumors) in the subset 
of this patient population with measurable disease. 
 
1.3 
Translational Medicine Objective(s) 
 
a. 
To evaluate the association between immunohistochemical (IHC) expression of 
PD-L1 in tumors and clinical outcomes in mesothelioma patients treated with 
trimodality/bimodality therapy including atezolizumab (anti-PD-L1). 
 
b. 
To evaluate the association between expression of immune-related genes identified 
by Immune Nanostring (depending on RNA availability) and clinical outcomes in 
mesothelioma patients treated with trimodality/bimodality therapy including 
atezolizumab. 
 
c. 
To evaluate the association between multiplex immunofluorescence (IF) of up to 10 
immune markers in two panels and clinical outcomes in mesothelioma patients 
treated with trimodality/bimodality therapy including atezolizumab. 
 
 
2.0  
BACKGROUND 
 
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with a poor prognosis.
 (1) 
MPM is a challenging therapeutic and diagnostic cancer; consequently, there has been very little 
progress toward improved survival outcomes. In the United States, it is 
standard practice to 
administer 4 cycles of cisplatin-pemetrexed to multimodality therapy for resectable mesothelioma 
(NCCN 
guidelines). Ultimately, the decision to administer neoadjuvant or adjuvant systemic 
therapy should be made in a multidisciplinary setting.  Neoadjuvant therapy has the inherent risk 
to adversely delay surgery or cause complications, with the extratrapleural pneumonectomy (EPP) 
completion 
rates ranging between 42-84%. (2,3,4,5,6,7,8,9) On the other hand, neoadjuvant 
therapy yields response rates between 29-44%
 and can give 
prognostic information with 
responders having better survival outcomes.
  ( 10 , 11 , 12 ) Adjuvant chemotherapy does not 
compromise surgical resection, but poor patient tolerance after surgery and radiation often preclude 
delivery of chemotherapy. 

 
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To date, there are no randomized trials comparing neoadjuvant or adjuvant therapy, and both 
approaches are accepted as standard practice. Although trimodality therapy is standard practice, 
both neoadjuvant and adjuvant studies still only yield median overall survival rates between 16.6 
to 25.5 months. (13,14,15,16,17,18,19,20) There is a clear need for the addition of novel agents or 
immunotherapies to 
trimodality treatment to improve survival outcomes. These agents must 
improve response rates, have reasonably low toxicity profiles with no compromise of trimodality 
treatment, and must be able to be administered in a maintenance setting. 
 
The standard choice of cisplatin-pemetrexed chemotherapy for neoadjuvant therapy is based on 
Phase III data in the unresectable setting which demonstrated an improvement in OS from 9.3 
months to 12.1 months (HR 0.74, p=0.003) compared to cisplatin alone.. (21) Since there are no 
actionable driver mutations, the use of targeted agents has been disappointing in MPM with the 
exception of bevacizumab, which recently demonstrated a two month median OS benefit in the 
unresectable frontline setting in the IIFCT-GFPC-0701 MAPS trial. (22) Unfortunately, cisplatin-
pemetrexed-bevacizumab is not an acceptable neoadjuvant regimen due 
to the high risk of 
bleeding complications that would be associated with the subsequent resection.  However, one 
promising avenue of discovery in MPM has been immunotherapy since MPM is considered to be 
an immunogenic tumor. 
 
Programmed death 1 (PD-1) protein, a T-cell co-inhibitory receptor, and one of its ligands, PD-L1, 
are potential targets for 
immunotherapy.  PD-1 receptor binds with PD-L1 and inhibits T-cell 
inhibition and downregulates T-cell responses.  Inhibition of their interaction has been shown to 
lead to restoration of T-cell activity and a subsequent anti-tumor effect in several tumor 
types.  
Mansfield et al. reported a 40% positive PD-L1 IHC expression in pleural mesotheliomas (n=224) 
using a mouse monoclonal anti-human B7-H1 (clone 5H1-A3). (23) An IHC score of less than 5% 
expression was considered to be a negative result. Patients with positive PD-L1 IHC expression 
were associated with having more disease burden and being less likely to be a surgical candidate.  
Also, PD-L1 IHC expression was associated with a worse survival (6 months vs. 14 months, 
p<0.0001). (24) 
 
There are several PD-1 and PD-L1 inhibitors under development including pembrolizumab (Merck), 
nivolumab (Bristol-Myers Squibb), BMS0936559 (Bristol-Myers Squibb), MEDI-4736 (Medimmune), 
avelumab (EMD Soreno, Merck) and atezolizumab (Genentech). Although limited and preliminary, 
there are a few reports of the use of these agents in mesothelioma, primarily as part of large solid 
tumor basket trials. At AACR 2015, KEYNOTE-028, a clinical trial administering pembrolizumab 
monotherapy (PD-1 inhibitor, 10 mg/kg every 2 weeks) to PD-L1 IHC positive solid tumor patients, 
reported results from 25 patients 
in the mesothelioma cohort. (25) Six patients had a response 
(24% ORR) and 12 patients had disease stabilization as the best response.  This translated into a 
76% disease control rate. This study is ongoing and accruing unresectable mesothelioma patients. 
(26) In a larger mesothelioma cohort study (n=53) from JAVELIN presented recently at ASCO 2016, 
avelumab (PD-L1 inhibitor) reported 5 partial responses (9% ORR) and 25 patients with stable 
disease (47% SD). (27) In the JAVELIN trial, patients with ≥ 5% PD-L1 IHC staining had a higher 
response rate compared to those with PD-L1 negative tumors (14.3% vs 8.1% ORR). (28) 
 
There is a growing body of literature that supports the premise that mesothelioma is a highly 
immunogenic disease and there are 
multiple ongoing studies in the unresectable setting 
investigating anti-PD1/PD-L1 therapies. (29) One example of a biomarker-based 
study is the 
NivoMeso Trial in Amsterdam, which is a single arm Phase II study that administers nivolumab to 
recurrent metastatic mesothelioma patients and biopsies them at baseline and week 6 to assess 
the impact of nivolumab on T cells and PD-L1 tumor IHC expression. 
 
Atezolizumab, a PD-L1 inhibitor, has been evaluated in preclinical models in combination with 
chemotherapy. Luoh et al. at AACR 2016 evaluated the effects of different classes of 
chemotherapeutic agents on the tumor immune microenvironment in syngeneic murine tumor 
models. (30) Most chemotherapies had a mild to moderate increase in CD8+ T cells in the tumor, 

 
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and some altered the activation states.  Some of the chemotherapies altered the number of CD4+ 
cells, including regulatory T cells and affected the myeloid subpopulations.  In addition to single 
agent studies, the combination of anti-PD-L1 therapy with chemotherapy led to pharmacodynamics 
marker changes.  The results indicate that chemotherapy can stimulate the tumor immune 
microenvironment through multiple mechanisms and suggest that combined anti-PD-L1 inhibition 
with chemotherapy may be beneficial with an anti-tumor effect. Early ongoing clinical trials with 
cisplatin-pemetrexed-atezolizumab are being conducted presently.  The large international ongoing 
clinical trials are in NSCLC.  IMpower110, “A Study of Atezolizumab (MPDL3280A) Compared With 
a Platinum Agent (Cisplatin or Carboplatin) + (Pemetrexed or Gemcitabine) in Participants With 
Stage IV Non-Squamous or Squamous Non-Small Cell Lung Cancer (NSCLC)” is open for 
enrollment (NCT02409342) and IMpower 132, “A Study of Atezolizumab in Combination With 
Carboplatin or Cisplatin + Pemetrexed Compared With Carboplatin or Cisplatin + Pemetrexed in 
Participants Who Are Chemotherapy-Naive and Have Stage IV Non-Squamous Non-Small Cell 
Lung Cancer (NSCLC)” (NCT02657434). 
 
Given the emerging literature on immunotherapies in MPM, we believe that the addition of 
atezolizumab to standard of care 
neoadjuvant chemotherapy prior to surgery with or without 
radiation will enhance T-cell activation against microscopic disease and will 
improve clinical 
outcomes for MPM. However, there is a knowledge gap on whether the immunotherapy agent, 
atezolizumab, will add toxicity to standard of care. It is also unclear how long to administer an 
immune checkpoint inhibitor but current trials in advanced cancers administer the agent for 1-2 
years and adjuvant trials are administering immune checkpoint inhibitors for one year. Therefore, 
this trial will also evaluate the feasibility of one-year of maintenance immunotherapy. 
 
If the regimen is shown to be feasible and safe a randomized Phase II trial comparing the 
atezolizumab containing regimen to the standard of care is planned.  We have prespecified that 
this regimen will be considered feasible and safe to move forward to a Phase II setting if 18/24 (75%) 
of patients are able to receive at least one dose of adjuvant maintenance atezolizumab therapy and 
no Grade 4 or 5 autoimmune toxicity is seen. 
 
Though mesothelioma is considered a highly immunogenic disease, little is known about 
mesothelioma PD-L1 IHC expression after treatment with immunotherapy.  To further investigate 
and quantify changes in the tumor immune microenvironment in response to cisplatin-pemetrexed-
atezolizumab treatment several correlative studies will be performed. We hypothesize that higher 
levels of PD-L1 IHC in tumor cells or immune infiltrate cells will be associated with improved clinical 
outcomes.  
 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex categories 
is shown in the table below.    
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
1 
2 
0 
0 
3 
White 
13 
11 
0 
1 
25 
More Than One Race 
0 
0 
0 
0 
0 
Total 
14 
13 
0 
1 
28 
 
 

 
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3.0  
DRUG INFORMATION 
 
Investigator Brochures  
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, cisplatin and pemetrexed are commercially available; therefore, Investigator 
Brochures are not applicable to these drugs.  Information about commercial drugs is publicly 
available in the prescribing information and other resources. 
 
For this study, atezolizumab is investigational and is being provided under an IND held by the 
National Cancer Institute.  The Investigator Brochure may be obtained by accessing PMB’s Online 
Agent Ordering Processing (OAOP) application 
(http://ctep.cancer.gov/branches/pmb/agent_order_processing.htm). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  Questions about IB access may be directed 
to the PMB IB coordinator via e-mail (IBCoordinator@mail.nih.gov). 
 
3.1 
Atezolizumab (NSC # 783608) (IND #131853) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Atezolizumab is a humanized immunoglobulin (IgG1) 
monoclonal antibody that is produced in Chinese hamster ovary (CHO) cells. 
Atezolizumab targets programmed death-ligand 1 (PD-L1) on 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 PD-L1: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. 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 function. By eliminating Fc-effector function and antibody dependent 
cell-mediated cytotoxicity (ADCC), antibody-mediated clearance of activated 
effector T cells is also eliminated. Atezolizumab shows anti-tumor activity in both 
nonclinical models and cancer patients, and is being investigated as a potential 
therapy in a wide variety of malignancies. 
 
 

 
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b. 
PHARMACOKINETICS  
 
On the basis of available preliminary PK data (0.03-20 mg/kg), atezolizumab 
appeared to show linear pharmacokinetics at doses ≥ 1 mg/kg. For the 1 mg/kg 
and 20 mg/kg dose groups, the mean apparent CL and the mean Vss had a range 
of 3.20 to 4.44 mL/day/kg and 48.1 to 65.7 mL/kg, respectively, which is consistent 
with the expected profile of an IgG1 antibody in humans. 
 
Serum atezolizumab concentrations exhibited a biphasic disposition with an initial 
rapid distribution phase followed by a slow elimination phase. Atezolizumab 
exhibited nonlinear pharmacokinetics at doses <1 mg/kg (i.e., 0.03-0.3 mg/kg), 
likely due to target-mediated CL at lower concentrations. Atezolizumab exhibited 
linear pharmacokinetics at doses ≥ 1 mg/kg. At doses ≥ 1 mg/kg, the mean Cmax 
increased in a dose-proportional manner and was 26.0 mcg/mL for the 1-mg/kg 
dose group and 472 mcg/mL for the 20 mg/kg dose group. Similarly, at doses ≥ 1 
mg/kg, the group mean AUC0-∞ had a range of 340-6050 Day x mcg/mL for 1 
mg/kg and 20 mg/kg dose group and was approximately dose proportional, by 
similar CL across the dose range. The observed CL and Vss for atezolizumab at 
doses ≥ 1 mg/kg are consistent with these of a typical IgG1 antibody in humans.  
Currently available PK and ATA data from Study PCD4989g suggest that the 15-
mg/kg atezolizumab q3w regimen (or fixed-dose equivalent) for Phase II and 
Phase III studies would be sufficient to both maintain trough concentration 
(Ctrough) ³ 6 mg/mL and further safeguard against both interpatient variability and 
the potential effect of ATAs that could lead to subtherapeutic levels of 
atezolizumab relative to the 10-mg/kg atezolizumab q3w regimen (or fixed-dose 
equivalent). From inspection of available observed Ctrough data, moving further 
to the 20-mg/kg atezolizumab q3w regimen does not appear to be warranted to 
maintain targeted Ctrough levels relative to the proposed 15-mg/kg atezolizumab 
q3w level.  
 
Refer to the atezolizumab Investigator’s Brochure for details regarding nonclinical 
and clinical pharmacology of atezolizumab. 
 
c. 
ADVERSE EFFECTS  
 
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/aeguide
lines.pdf for further clarification. Frequency is provided based on 3,097 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 

 
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SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
 
Version 2.3, March 11, 20211 
 
 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
CARDIAC DISORDERS 
 
 
 
Heart failure2 
 
 
 
Myocarditis2 
 
 
 
Pericardial 
effusion2 
 
 
 
Pericardial 
tamponade2 
 
 
 
Pericarditis2 
 
ENDOCRINE DISORDERS 
 
 
 
Adrenal 
insufficiency2 
 
 
 
Endocrine 
disorders - 
Other 
(diabetes)2 
 
 
Hyperthyroidism2 
 
 
 
 
Hypophysitis2 
 
 
Hypothyroidism2 
 
 
EYE DISORDERS 
 
 
 
Eye disorders - 
Other (ocular 
inflammatory 
toxicity)2 
 
 
 
Uveitis2 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
Abdominal pain 
(Gr 2) 
 
 
Colitis2 
 
 
Diarrhea 
 
Diarrhea (Gr 2) 
 
Dysphagia 
 
 
 
Nausea 
 
Nausea (Gr 2) 
 
 
Pancreatitis2 
 
 
Vomiting 
 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 

 
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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
Fatigue 
 
 
Fatigue (Gr 2) 
 
Fever3 
 
 
 
Flu like symptoms3  
 
HEPATOBILIARY DISORDERS 
 
 
 
Hepatic failure2  
 
 
Hepatobiliary 
disorders - 
Other 
(hepatitis)2 
 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction3 
 
 
 
 
Anaphylaxis3 
 
 
 
Cytokine 
release 
syndrome3 
 
 
 
Immune system 
disorders - 
Other (systemic 
immune 
activation)2 
 
INFECTIONS AND INFESTATIONS 
 
Infection4 
 
 
 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
 
 
Infusion related 
reaction3 
 
 
INVESTIGATIONS 
 
 
Alanine 
aminotransferase 
increased2 
 
 
 
Alkaline 
phosphatase 
increased2 
 
 
 
Aspartate 
aminotransferase 
increased2 
 
 
 
Blood bilirubin 
increased2 
 
 
 
 
Creatinine 
increased 
 
 
GGT increased2 
 
 
 
Lipase increased* 
 
 

 
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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
 
Platelet count 
decreased 
 
 
Serum amylase 
increased* 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 2) 
 
 
Hyperglycemia2  
 
Hypokalemia 
 
 
 
Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia2 
 
 
 
Back pain 
 
 
 
 
Generalized 
muscle 
weakness 
 
 
Myalgia 
 
 
 
 
Myositis2 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
Ataxia2 
 
 
 
Encephalopath
y2 
 
 
 
Nervous 
system 
disorders - 
Other 
(encephalitis 
non-infective)2 
 
 
 
Guillain-Barre 
syndrome2 
 
 
 
Nervous 
system 
disorders - 
Other 
(meningitis 
non-infective)2 
 
 
 
Myasthenia 
gravis2 
 
 
 
Paresthesia2 
 
 
 
Peripheral 
motor 
neuropathy2 
 

 
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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
 
Peripheral 
sensory 
neuropathy2 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney 
injury 
 
 
 
Renal and 
urinary 
disorders - 
Other 
(nephritis)2 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Cough 
 
Cough (Gr 2) 
 
Dyspnea 
 
 
 
Hypoxia 
 
 
 
Nasal congestion 
 
Nasal congestion 
(Gr 2) 
 
 
Pleural 
effusion2 
 
 
 
Pneumonitis2 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
 
Bullous 
dermatitis2 
 
 
 
Erythema 
multiforme2 
 
 
Pruritus 
 
 
 
Rash acneiform 
 
 
 
Rash maculo-
papular 
 
 
 
 
Skin and 
subcutaneous 
tissue disorders 
- Other (drug 
reaction with 
eosinophilia 
and systemic 
symptoms 
[DRESS])2 
 

 
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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
Skin and 
subcutaneous 
tissue disorders - 
Other (lichen 
planus)2 
 
 
 
 
Skin and 
subcutaneous 
tissue disorders 
- Other 
(exanthematou
s pustulosis)2 
 
 
 
Stevens-
Johnson 
syndrome2 
 
 
 
Toxic epidermal 
necrolysis2 
 
* Denotes adverse events that are <3%. 
1 This table will be updated as the toxicity profile of the agent is revised. Updates 
will be distributed to all Principal Investigators at the time of revision. The current 
version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, 
the name of the investigator, the protocol and the agent should be included in 
the e-mail. 
2 Atezolizumab, being a member of a class of agents involved in the inhibition of 
“immune checkpoints,” may result in severe and possibly fatal immune-mediated 
adverse events probably due to T-cell activation and proliferation. Immune-
mediated adverse reactions have been reported in patients receiving 
atezolizumab. Adverse events potentially related to atezolizumab may be 
manifestations of immune-mediated adverse events. In clinical trials, most 
immune-mediated adverse reactions were reversible and managed with 
interruptions of atezolizumab, administration of corticosteroids and supportive 
care. 
3 Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, 
and cytokine release syndrome, which have been observed following 
administration of atezolizumab, may manifest as fever, chills, shakes, itching, 
rash, hypertension or hypotension, or difficulty breathing during and immediately 
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 

 
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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. 
 
1. 
Pregnancy and Lactation:  No developmental or reproductive toxicity 
studies have been conducted with atezolizumab as several nonclinical 
studies have already demonstrated that the PD-L1/PD-1 signaling 
pathway is essential in establishing maternal/fetal tolerance, which is 
necessary for embryo-fetal survival during gestation.  Based on the critical 
role that PD-L1/PD1 pathway plays in the maintenance of maternal-fetal 
tolerance, atezolizumab should not be administered to pregnant women.  
The effects of atezolizumab on human reproduction or on the fetus or the 
developing infant are unknown but expected to have an adverse effect. 
 
It is not known whether atezolizumab is excreted in human milk. However, 
antibodies are known to cross the placenta and are excreted in breast milk 
during lactation.  Atezolizumab should not be administered to nursing 
mothers. 
 
Male patients and female patients of childbearing potential should utilize 
contraception and take active measures to avoid pregnancy while 
undergoing atezolizumab treatment and for at least 5 months (150 days) 
after the last dose of atezolizumab. 
 
2. 
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. 
 
 

 
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d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan. 
 
e. 
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. Atezolizumab 
is formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 120 mM 
sucrose, 0.04% polysorbate 20, at 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. 
 
f. 
STORAGE, PREPARATION & STABILITY  
 
Atezolizumab must be refrigerated at 2°C-8°C (36°F- 46°F) upon receipt until use. 
No preservative is used in atezolizumab and therefore, the vial is intended for 
single use only. Discard any unused portion of drug remaining in a vial. Vial 
contents should not be frozen or shaken and should be protected from direct 
sunlight. 
 
Atezolizumab (1200 mg per vial) will be administered in 250 mL 0.9% NaCl IV 
infusion bags and infusion lines equipped with 0.2 micron in-line filters. The IV bag 
may be constructed of polyvinyl chloride (PVC) or polyolefin (PO); the IV infusion 
line may be constructed of polyvinyl chloride (PVC) or polyethylene (PE); and the 
0.2 micron in-line filter may be constructed of polyehersulfone (PES). 
Atezolizumab must be prepared/diluted under appropriate aseptic conditions as it 
does not contain antimicrobial preservatives. The solution for infusion should be 
used immediately to limit microbial growth in case of potential accidental 
contamination. If not used immediately, in-use storage time and conditions prior to 
use are the responsibility of the user.  
 
The dose solution prepared for IV bag delivery may be stored at 2°C to 8°C (36°F 
to 46°F) and/or at room temperature for up to a total in-use storage time of 8 hours. 
 
g. 
DRUG ORDERING & ACCOUNTABILITY  
 
1. 
Drug ordering: Atezolizumab is an investigational agent supplied to 
Investigators by the Division of Cancer Treatment and Diagnosis (DCTD), 
NCI. NCI-supplied agents may be requested by the Principal Investigator 
(or their authorized designees) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that the agent 
be shipped directly to the institution where the patient is to be treated. PMB 
does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained). The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The 
responsible investigator at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA form 1572 and a 
CV. 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 investigator at that institution. Active CTEP-registered 

 
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investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online 
Agent 
Order 
Processing 
(OAOP) 
application 
https://eapps- 
ctep.nci.nih.gov/OAOP/. Access to OAOP requires the establishment of a 
CTEP Identity and Access Management (IAM) account https://eapps-
ctep.nci.nih.gov/iam/ and the maintenance of an “active” account status 
and a “current” password. For questions about drug orders, transfers 
returns or accountability, call 240/276-6575 Monday through Friday 
between 
8:30 
am 
and 
4:30 
pm 
(ET) 
or 
e-mail 
PMBAfterHours@mail.nih.gov any time.  
 
2. 
Drug Handling and Accountability  
 
 
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, dispensing, and return of all drugs received from the 
PMB using the Drug Accountability Record Form available on 
the NCI home page (http://ctep.cancer.gov).  
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 
 
3. 
Drug Return and/or Disposition Instruction  
 
 
Drug Returns: All unused drug supplies should be returned to the 
PMB. When it is necessary to return study drug (e.g., sealed vials 
remaining when expired vials are recalled by the PMB), 
investigators should return the study drug to the PMB using the 
NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov).  
 
 
Drug expiration: If packaging has expiration date, indicate drug 
expiration date on the DARF under Manufacturer and Lot # and 
use the drug lots with shorter expiration date first. 
 
4. 
Contact Information 
 
Useful Links and Contacts 
• 
CTEP 
Forms, 
Templates, 
Documents:  
http://ctep.cancer.gov/forms/  
• 
RCR Help Desk:  RCRHelpDesk@nih.gov  
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:   
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx  
• 
CTEP Identity and Access Management (IAM) account:   
https://ctepcore.nci.nih.gov/iam/index.jsp  
• 
CTEP Associate Registration and IAM account help:   
ctepreghelp@ctep.nci.nih.gov  
• 
PMB IB Coordinator:  IBCoordinator@mail.nih.gov  
• 
PMB e-mail:  PMBAfterHours@mail.nih.gov  
 
PMB phone and hours of service:  210/276-6675 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 

 
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3.2 
Cisplatin (CDDP, Platinol®, Platinol-AQ) (NSC-119875) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action:  
 
Cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex containing a 
central platinum atom surrounded by two chloride atoms and two ammonia 
molecules in the cis position. It is water soluble and acts as a bifunctional alkylating 
agent with cell cycle nonspecific characteristics.  The intra-strand cross-links, in 
particular with guanine and cytosine, change DNA conformation and inhibit DNA 
synthesis leading to the cytotoxic and anti-tumor effects of cisplatin. Although 
cisplatin seems to act as an alkylating agent, there are data to indicate that its 
mode and sites of action are different from those of nitrogen mustard and the 
standard alkylating agents and that cisplatin does not exhibit cross-resistance with 
other alkylating agents or nitrosoureas.   
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Following rapid IV injection of cisplatin over up to one hour, 
peak plasma drug and platinum concentrations occur immediately.  When 
cisplatin is administered by IV infusion over 6 or 24 hours, plasma 
concentrations of total platinum increase gradually during the infusion and 
peak immediately following the end of the infusion.  
 
2. 
Distribution: Following intravenous dosing, cisplatin distributes rapidly into 
tissues, with highest concentrations in the liver, prostate and kidney.  
Plasma levels of cisplatin decay in a biphasic mode with an initial half-life 
of 25 to 49 minutes, and a secondary phase ranging from 58 to 73 hours.  
This prolonged phase is due to protein binding, which exceeds 90%.  
Cisplatin penetrates poorly into the CNS. 
 
3. 
Metabolism: Cisplatin is non-enzymatically transformed to one or more 
metabolites that are extensively protein bound and have minimal cytotoxic 
activity.  The non-protein bound (unchanged) fraction is cytotoxic. 
 
4. 
Elimination: Urinary excretion is incomplete.  Following bolus injection or 
infusion over a dose range of 40-140 mg/m2 varying in length from 1-24 
hours, from 10 to about 40% of the administered platinum is excreted in 
the urine in 24 hours.  Renal clearance of free platinum exceeds the 
glomerular filtration rate, indicating that cisplatin or other platinum-
containing molecules are actively secreted by the kidneys.  Renal 
clearance of free platinum is nonlinear and variable, and is dependent on 
dose, urine flow rate, and individual variability in the extent of active 
secretion and possible tubular reabsorption. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of cisplatin: Adverse effects reported in 10% or more 
of patients receiving cisplatin include peripheral neuropathy, nausea, 
vomiting, 
diarrhea, 
myelosuppression, 
liver 
enzymes 
elevation, 
nephrotoxicity (acute renal failure and chronic renal insufficiency), 
alopecia, tissue irritation, and ototoxicity. 
 
Human toxicity includes anorexia, nausea, vomiting, renal toxicity (with an 
elevation of BUN, creatinine, serum uric acid and impairment of 

 
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endogenous creatinine clearance, as well as renal tubular damage), 
ototoxicity (with hearing loss which initially is in the high-frequency range, 
as well as tinnitus), peripheral neuropathy and hyperuricemia.  Much more 
severe and prolonged toxicity has been observed in patients with 
abnormal or obstructed urinary excretory tracts. Raynaud’s phenomena 
and digital ischemia has been described.  Anaphylactic-like reactions 
including facial edema, bronchoconstriction, tachycardia and hypotension 
may occur within minutes of administration.  Myelosuppression, often with 
delayed erythrosuppression, is expected.  In the high-dose treatment 
regimen with osmotic diuresis, the nadir of white cells and platelets 
occurred regularly at about two weeks with recovery generally at about 
three weeks after the initiation of therapy.  Alopecia, malaise and asthenia 
have been reported. Rare complications are alopecia, seizures, loss of 
taste and allergic reactions.  Tetany may occur due to hypomagnesemia 
and/or hypocalcemia.  Other electrolyte disturbances may occur. At high 
doses patients have experienced optic neuritis, papilledema, cerebral 
blindness, blurred vision, and altered color perception.  Patients have also 
experienced cardiac abnormalities, elevated aspartate aminotransferase 
and rash. Subsequent courses should not be given until serum creatinine 
returns to normal if elevated.  Audiometric analyses should be monitored 
and courses withheld until auditory acuity is within normal limits. The 
occurrence of acute leukemia has been reported rarely in patients treated 
with anthracycline/alkylator combination chemotherapy. 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
2. 
Pregnancy and Lactation: Category D. Cisplatin can cause fetal harm 
when administered to a pregnant woman. In mice, cisplatin is teratogenic 
and embryotoxic.  This drug has been found to be excreted in human milk 
and because of the potential for serious adverse reactions in nursing 
infants, patients receiving cisplatin should not breast feed. 
 
3. 
Drug 
Interactions: 
During 
cisplatin 
therapy, 
plasma 
levels 
of 
anticonvulsant agents may become sub-therapeutic and should be 
monitored.  For complete information refer to the current FDA-approved 
package insert. 
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Section 7.0 Treatment Plan  
 
2. 
Refer to the current FDA-approved package insert for drug administration.  
 
e. 
PREPARATION, STORAGE & STABILITY 
 
Refer to the current FDA-approved package insert for storage, stability and special 
handling information. 
 
f. 
HOW SUPPLIED  
 
Cisplatin is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert. 
 
3.3 
Pemetrexed for injection (Alimta®) (NSC-698037) 
 

 
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a. 
PHARMACOLOGY 
 
Mechanism of Action: Pemetrexed for injection, is a folate analog metabolic 
inhibitor that exerts its action by disrupting folate dependent metabolic processes 
essential for cell replication. In vitro studies have shown that pemetrexed inhibits 
thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide 
ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes 
involved in the de novo biosynthesis of thymidine and purine nucleotides. 
Pemetrexed is taken into cells by membrane carriers such as the reduced folate 
carrier and membrane folate binding protein transport systems. Once in the cell, 
pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate 
synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS 
and GARFT. Polyglutamation is a time- and concentration-dependent process that 
occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. 
Polyglutamated metabolites are thought to have an increased intracellular half-life 
resulting in prolonged drug action in malignant cells. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: The pharmacokinetics of pemetrexed administered as a 
single-agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-
minute period have been evaluated in 426 cancer patients with a variety 
of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum 
plasma concentration (Cmax) increase proportionally with dose. The 
pharmacokinetics of pemetrexed do not change over multiple treatment 
cycles. 
 
2. 
Distribution: Pemetrexed has a steady-state volume of distribution of 16.1 
liters. In vitro studies indicate that pemetrexed is approximately 81% 
bound to plasma proteins. Binding is not affected by degree of renal 
impairment. 
 
3. 
Metabolism: Pemetrexed is not metabolized to an appreciable extent and 
is primarily eliminated in the urine, with 70% to 90% of the dose recovered 
unchanged within the first 24 hours following administration. 
 
4. 
Elimination:  The clearance of pemetrexed decreases, and exposure 
(AUC) increases, as renal function decreases. The total systemic 
clearance of pemetrexed is 91.8 mL/min and the elimination half-life of 
pemetrexed is 3.5 hours in patients with normal renal function (creatinine 
clearance of 90 mL/min). 
 
c. 
ADVERSE EFFECTS  
 
1. Possible Side Effects of Pemetrexed: Refer to the current FDA-approved 
package insert for the most comprehensive and up to date information on 
adverse reactions. 
 
Adverse effects reported in > 20% of subjects treated with pemetrexed 
include: 
anemia, 
fatigue, 
constipation, 
nausea, 
vomiting, 
mucositis/stomatitis, thrombocytopenia, bleeding, infection, neutropenia, 
and desquamation. 
 
Adverse effects reported in 4% to 20% of subjects include: diarrhea, 
edema, increased serum creatinine, increased serum ALT, increased 

 
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serum AST, interstitial pneumonitis, pulmonary fibrosis, pruritus, rash, and 
erythema multiforme.  
 
Serious adverse effects reported in ≤ 3% of subjects include: bowel 
obstruction, neuropathy, alopecia, and thrombosis/embolism. 
 
2. 
Pregnancy and Lactation:  Pregnancy Category D. Pemetrexed can cause 
fetal harm when administered to a pregnant woman. Pemetrexed 
administered intraperitoneally to mice during organogenesis was 
embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the 
recommended human dose. If pemetrexed is used during pregnancy, or if 
the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to the fetus. Women of childbearing 
potential should be advised to avoid becoming pregnant. Women should 
be advised to use effective contraceptive measures to prevent pregnancy 
during treatment with pemetrexed. Due to the potential for serious adverse 
reactions in the nursing infant, a decision should be made to discontinue 
pemetrexed or to discontinue breast-feeding during therapy, taking into 
account the benefits of treatment to the mother.  
 
3. 
Drug Interactions: Although ibuprofen (400 mg four times a day) can 
decrease the clearance of pemetrexed, it can be administered with 
pemetrexed in patients with normal renal function (creatinine clearance 
≥80 mL/min). No dose adjustment of pemetrexed is needed with 
concomitant non-steroidal anti-inflammatory drugs (NSAIDs) in patients 
with normal renal function. Caution should be used when administering 
NSAIDs concurrently with pemetrexed to patients with mild to moderate 
renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs 
with short elimination half-lives (e.g., diclofenac, indomethacin) should be 
avoided for a period of 2 days before, the day of, and 2 days following 
administration of pemetrexed. In the absence of data regarding potential 
interaction between pemetrexed and NSAIDs with longer half-lives (e.g., 
meloxicam, nabumetone), patients taking these NSAIDs should interrupt 
dosing for at least 5 days before, the day of, and 2 days following 
pemetrexed administration. If concomitant administration of NSAIDs is 
necessary, patients should be monitored closely for toxicity, especially 
myelosuppression, renal, and gastrointestinal toxicity. 
 
Due to potential drug interactions, a complete patient medication list, 
including pemetrexed, should be screened prior to initiation of and during 
treatment with pemetrexed. See Section 8.0 Toxicities to be Monitored and 
Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
e. 
HOW SUPPLIED 
 
Pemetrexed is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
 
4.0 
STAGING CRITERIA  

 
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CRITERIA (AJCC 7TH EDITION, 2010) 
 
4.1 
Staging Criteria (AJCC Cancer Staging Manual, 7th edition) 
 
Primary Tumor (T)  
 
TX 
Primary tumor cannot be assessed 
  
T0 
No evidence of primary tumor  
 
T1 
Tumor limited to the ipsilateral parietal pleura with or without mediastinal pleura 
and with or without diaphragmatic pleural involvement  
 
T1a 
No involvement of the visceral pleura  
 
T1b 
Tumor also involving the visceral pleura  
 
T2 
Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, 
diaphragmatic, and visceral pleura) with at least one of the following:  
 
 
 
Involvement of diaphragmatic muscle  
 
Extension of tumor from visceral pleura into the underlying pulmonary 
parenchyma  
 
T3 
Locally advanced but potentially resectable tumor.  Tumor involving all of the 
ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral 
pleura) with at least one of the following: 
  
 
 
Involvement of the endothoracic fascia 
 
 
 
Extension into the mediastinal fat  
 
Solitary, completely resectable focus of tumor extending into the soft 
tissues of the chest wall  
 
 
 
Nontransmural involvement of the pericardium  
 
T4 
Locally advanced technically unresectable tumor.  Tumor involving all of the 
ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral 
pleura) with at least one of the following:  
 
Diffuse extension on multifocal masses of tumor in the chest wall, with or 
without associated rib destruction  
 
Direct transdiaphragmatic extension of tumor to the peritoneum  
 
 
 
Direct extension of tumor to the contralateral pleura  
 
 
 
Direct extension of tumor to mediastinal organs  
 
 
 
Direct extension of tumor into the spine  
 

 
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Tumor extending through to the internal surface of the pericardium with or 
without a pericardial effusion or tumor involving the myocardium  
 
Regional Lymph Nodes (N)  
 
NX 
Regional lymph nodes cannot be assessed  
 
N0 
No regional lymph node metastases  
 
N1 
Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes  
 
N2 
Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes including 
the ipsilateral internal mammary and peridiaphragmatic nodes  
 
N3 
Metastases in the contralateral mediastinal, contralateral internal mammary, 
ipsilateral or contralateral supraclavicular lymph nodes  
 
Distant Metastasis (M) 
 
M0 
No distant metastasis 
  
M1 
Distant metastasis present  
 
ANATOMIC STAGE/PROGNOSTIC GROUPS  
 
Stage I  
T1 
 
N0 
 
M0 
 
Stage IA 
T1a 
 
N0 
 
M0 
 
 
Stage IB 
T1b 
 
N0 
 
M0 
 
 
 
 
 
Stage II  
T2 
 
N0 
 
M0 
 
Stage III 
T1, T2  
N1 
 
M0 
 
 
T1, T2  
N2 
 
M0 
 
 
T3 
 
N0, N1, N2 
M0 
 
Stage IV 
T4 
 
Any N  
M0 
 
 
Any T  
N3 
 
M0 
 
 
Any T  
Any N  
M1 
 
HISTOLOGICAL GRADE (G)  
 
Grade is reported in registry systems by the grade value.  A two-grade, three-grade, or 
four-grade system may be used.  If a grading system is not specified, generally the 
following system is used:  
 
 
 
GX 
Grade cannot be assessed  
 
 
 
G1 
Well differentiated  
 
 
 
G2 
Moderately differentiated  
 
 
 
G3 
Poorly differentiated  
 

 
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G4 
Undifferentiated  
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for registration.  For each criterion requiring test results and dates, please record this 
information on the Onstudy Form and submit via Medidata Rave® (see Section 14.0).  Any potential 
eligibility issues should be addressed to the SWOG Statistics and Data Management Center in 
Seattle at 206/652-2267 or Lungquestion@crab.org prior to registration. NCI policy does not allow 
for waiver of any eligibility criterion  
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be 
considered Day 28.  This allows for efficient patient scheduling without exceeding the guidelines.  
If Day 28 or 90 falls on a weekend or holiday, the limit may be extended to the next working 
day. 
 
5.1 
STEP 1: NEOADJUVANT 
 
a. 
Disease Related Criteria  
 
1. 
Patient must have Stage I-III malignant pleural mesothelioma that is 
deemed resectable and must be planning to undergo pleurectomy 
decortication (P/D) or extrapleural pneumonectomy (EPP).  
 
2. 
Patient must have epithelioid or biphasic histology (sarcomatoid histology 
is excluded). Histologic diagnosis and typing of mesothelioma requires at 
least a core needle biopsy or surgical biopsy of the pleura via thoracoscopy 
and small thoracotomy. Cytology only will not be regarded as sufficient for 
the diagnosis. 
 
3. 
Patient must have CT of the chest/abdomen with contrast or FDG-PET/CT 
scan performed within 28 days prior to Step 1 registration. 
 
4. 
Patient must have non-measurable or measurable disease (see Section 
10.1) documented by CT or MRI. The CT from a combined PET/CT may 
be used to document only non-measurable disease unless it is of 
diagnostic quality as defined in Section 10.1c. Measurable disease must 
be assessed within 28 days prior to Step 1 registration. Non-measurable 
disease must be assessed within 42 days prior to Step 1 registration. All 
disease must be assessed and documented on the RECIST 1.1 and 
Modified RECIST Baseline Tumor Assessment Form. 
 
5. 
Patient must have undergone extended surgical staging including 
mediastinoscopy or endobronchial ultrasound. At minimum, samples must 
be obtained from the mediastinal stations 4R, 7 (subcarinal), and 4L. This 
surgical staging must be performed within 42 days prior to Step 1 
registration. Patient must be T1-3 and N0-N2 (single station). 
 
6. 
Patient must undergo video-assisted thoracoscopic surgery and 
diagnostic laparoscopy within 28 days prior to Step 1 registration to rule 
out peritoneal disease spread. 
 

 
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7. 
Patient must have consultation with a surgeon within 21 days prior to Step 
1 registration. The surgeon must confirm that the patient’s disease is 
resectable 
by 
pleurectomy 
decortication 
(P/D) 
or 
extrapleural 
pneumonectomy (EPP) and that the patient is an appropriate candidate for 
the surgical procedures described in Section 7.3 and Appendix 18.3). 
 
b. 
Prior/Concurrent Therapy Criteria 
 
1. 
Patient must not have had prior immunotherapy or chemotherapy for 
malignant pleural mesothelioma. 
 
c. 
Clinical/Laboratory Criteria 
 
1. 
Patient must be ≥18 years of age. 
 
2. 
Patient must have Zubrod performance status 0 or 1 documented within 
28 days prior to Step 1 registration. 
 
3. 
Patients requiring hearing aids or reporting hearing loss must have 
audiogram performed within 28 days prior to Step 1 registration.  
 
4. 
Patient must have not had any major surgery or radiation within 28 days 
prior to Step 1 registration. Diagnostic thoracotomies and laparoscopies 
are not considered major surgeries. 
 
5. 
Patient must not have any anticancer therapy or investigational agent 
within 28 days prior to Step 1 registration. 
 
6. 
Patient must have adequate hematologic function defined as ANC ≥ 
1,500/mcl, Hemoglobin ≥ 9 g/dl, and platelets ≥ 100,000/mcl documented 
within 28 days prior to Step 1 registration. 
 
7. 
Patient must have adequate kidney function defined as creatinine ≤ 1.5 x 
ULN and creatinine clearance ≥ 45ml/min documented within 28 days prior 
to Step 1 registration. 
 
8. 
Patient must have adequate liver function defined as total bilirubin ≤ 1.5 x 
upper limit of normal (ULN), and aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT) ≤ 3 x ULN within 28 days prior to Step 1 
registration. 
 
9. 
No other prior malignancy is allowed except for the following: adequately 
treated basal cell or squamous cell skin cancer, in situ cervical cancer, 
adequately treated Stage I or II cancer from which the patient is currently 
in complete remission, or any other cancer from which the patient has 
been disease free for three years. 
 
10. 
Patients must not be pregnant or nursing due to the potential teratogenic 
side effects of the protocol treatment.  Women of reproductive potential 
and men must have agreed to use an effective contraceptive method for 
the duration of study treatment and for 5 months (150 days) after the last 
dose of atezolizumab.  A woman is considered to be of "reproductive 
potential" if she has had menses at any time in the preceding 12 
consecutive months.  In addition to routine contraceptive methods, 
"effective contraception" also includes heterosexual celibacy and surgery 
intended to prevent pregnancy (or with a side effect of pregnancy 

 
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prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral 
tubal ligation.  However, if at any point a previously celibate patient 
chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for 
beginning contraceptive measures. 
 
11. 
Patient must NOT have a history of severe allergic, anaphylactic, or other 
hypersensitivity reactions to chimeric or humanized antibodies or fusion 
proteins. 
 
12. 
Patient must NOT have a known hypersensitivity or allergy to 
biopharmaceuticals produced in Chinese hamster ovary cells or any 
component of the atezolizumab formulation. 
 
13. 
Patient must not have severe infections within 28 days prior to Step 1 
registration, including but not limited to hospitalization for complications of 
infection, bacteremia, or severe pneumonia. 
 
14. 
Patient must not have active autoimmune disease that has required 
systemic treatment in past two years (i.e., with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. Autoimmune diseases include, but are 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. This protocol includes an immunotherapy 
agent which can precipitate known autoimmune diseases. 
 
15. 
Patient must not have undergone prior allogeneic bone marrow 
transplantation or prior solid organ transplantation. 
 
16. 
Patient must not have active tuberculosis. 
 
17. 
Patient must not have history of idiopathic pulmonary fibrosis, pneumonitis 
(including drug induced), organizing pneumonia (i.e., bronchiolitis 
obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active 
pneumonitis. This protocol includes an immunotherapy agent which can 
precipitate known pneumonitis. 
 
18. 
Patient must not have active (chronic or acute) hepatitis B virus (HBV) 
infection as evidenced by testing performed within 28 days prior to 
registration.  Patients with past or resolved HBV infection are eligible.   
 
Active HBV is defined as having a positive hepatitis B surface antigen 
(HBsAg) test. 
 
Past or resolved HBV is defined as having a negative HBsAG test and a 
positive total hepatitis B core antibody (HBcAb) test. 
 
Patient must not have active hepatitis C virus (HCV) infection as 
evidenced by testing performed within 28 days prior to registration.   
 

 
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Active HCV is defined as having a positive HCV antibody test followed by 
a positive HCV RNA test. 
 
19. 
Patient must NOT have a known positive test for HIV.  Patients do not 
need to be screened for HIV.  Patients with HIV are excluded due to a 
potential incompetent immune system and need for medications that could 
interfere with the treatment and immunotherapy.   
 
20. 
Patient must not have significant cardiovascular disease, such as New 
York Heart Association cardiac disease (Class II or greater), myocardial 
infarction within 3 months prior to initiation of treatment, unstable 
arrhythmias, or unstable angina given the higher risks associated with 
surgical resection.  
 
21. 
Patient must not receive live, attenuated influenza vaccine within 4 weeks 
prior to registration or at any time during the study and until 5 months after 
the last dose of atezolizumab. 
 
d. 
Specimen Submission Criteria 
 
1. 
Patient must be willing to have tissue specimens submitted for 
translational medicine studies as described in Section 15.1. 
 
2. 
Patient must be offered the opportunity to participate in tissue and blood 
banking for future studies. 
 
e. 
Regulatory Criteria 
 
1. 
Patient must be informed of the investigational nature of this study and 
must sign and give written informed consent in accordance with 
institutional and federal guidelines. 
 
2. 
As a part of the OPEN registration process, (see Section 13.4 for OPEN 
access instructions) the treating institution's identity is provided in order to 
ensure that the current (within 365 days) date of institutional review board 
approval for this study has been entered in the system. 
 
5.2 
STEP 2: SURGERY 
 
a. 
Disease Related Criteria 
 
1. 
Patient must have a CT of chest/abdomen with contrast or FDG-PET/CT 
scan within 28 days prior to Step 2 registration. Patients must not have 
evidence of progression per RECIST 1.1 or Modified RECIST for Pleural 
Tumors. 
 
2. 
Patients planning to receive EPP must also be evaluated for 
appropriateness of RT by a Radiation Oncologist within 14 days prior to 
Step 2 registration. 
 
b. 
Clinical/Laboratory Criteria 
 
1. 
Patient must have a Zubrod performance status of 0-1 documented within 
28 days prior to Step 2 registration. 
 

 
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2. 
Patient must have postoperative predicted FEV1 > 35% and postoperative 
predicted DLCO > 35%.  Pulmonary function tests to ascertain these 
values must be obtained within 28 days prior to Step 2 registration. 
 
3. 
Patient must have received at least two cycles of triplet neoadjuvant 
therapy (all three drugs) during Step 1. 
 
4. 
Patient must be registered to Step 2 no less than 21 days and no more 
than 90 days after the end of their final cycle of neoadjuvant therapy. 
 
5.3 
STEP 3: MAINTENANCE 
 
a. 
Patient must have received either P/D or EPP and must have recovered from all 
effects of surgery with adequate wound healing.  Patients who received radiation 
therapy (RT) must be registered to Step 3 within 90 days after discontinuing RT.  
Patients who did not receive RT must be registered to Step 3 within 90 days after 
surgery. 
 
b. 
Patient must have a CT of chest/abdomen/pelvis with contrast or FDG-PET/CT 
scan within 28 days prior to Step 3 registration. Patient must not have evidence of 
progression per RECIST 1.1 or modified RECIST for pleural tumors. 
 
c. 
Patient may have discontinued RT early due to toxicity or other reasons.  
 
d. 
Patient must have a Zubrod performance status of 0-1 documented within 28 days 
prior to Step 3 registration. 
 
e. 
Patient must have adequate hematologic function defined as ANC > 1,500/mcl, 
hemoglobin > 9 g/dl, and platelets > 100,000/mcl documented within 28 days prior 
to Step 3 registration.  
 
f. 
Patient must have adequate kidney function defined as creatinine < 1.5 x ULN 
documented within 28 days prior to Step 3 registration. 
 
g. 
Patient must have adequate liver function defined as total bilirubin ≤ 1.5 x upper 
limit of normal (ULN), and aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 3 x ULN within 28 days prior to Step 3 registration. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be stratified prior to registration for Step 1 by the planned type of surgery: extrapleural 
pneumonectomy (EPP) versus pleurectomy/decortication (P/D). The decision regarding the type of 
surgery should be based on patient’s physiologic status (ability to tolerate EPP), and on invasive 
pre-treatment staging. 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Anne Tsao, M.D., Phone: 713-792-
6363 or E-mail: astsao@mdanderson.org or Jeremy Cetnar, M.D., Phone: 503- 494-8534 or Email: 
cetnarj@ohsu.edu. For surgical questions, please contact Boris Sepesi, M.D., Phone: 713-792-
7664, or Email: bsepesi@mdanderson.org. 
 
For dosing principles or questions, please consult the SWOG Policy #38 "Dosing Principles for 
Patients on Clinical Trials" at https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf. 

 
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7.1 
Treatment Overview 
 
Protocol treatment consists of the following: 
 
a. 
Neoadjuvant therapy (see Section 7.2) 
 
b. 
Surgery – extrapleural pneumonectomy or pleurectomy/decortication (see Section 
7.3) 
 
c. 
Radiation Therapy – ONLY for patients who received extrapleural pneumonectomy 
(see Section 7.4) 
 
d. 
Maintenance therapy (see Section 7.5) 
 
 

 
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7.2 
Neoadjuvant therapy (Registration Step 1) 
 
a. 
Supportive care 
 
The following supportive care for pemetrexed is required. 
 
Agent 
Dose 
Route 
Schedule 
Folic Acid 
400 mcg 
PO 
Daily; beginning 7 days before 
first dose of pemetrexed and 
continuing until 3 weeks after the 
last dose of pemetrexed 
Vitamin B12 
1,000 mcg 
IM 
q 9 weeks; beginning 7 days 
before first dose of pemetrexed 
and continuing until 3 weeks after 
the last dose of pemetrexed a 
a  
i.e., if a scheduled vitamin B12 dose falls within 3 weeks following 
pemetrexed, it should be given. 
 
In addition, the following supportive care for pemetrexed and cisplatin is 
recommended. 
 
Agent 
Dose 
Route 
Schedule 
Dexamethasone 
4 mg a 
PO twice 
per day  
q 12 hours on the day before 
Day 1 of each cycle unless 
clinically contraindicated 
Dexamethasone 
12 mg 
IV 
Day 1 of each cycle 
Dexamethasone 
8 mg 
PO twice 
per day 
q 12 hours for three days 
starting 12 hours after 
chemotherapy completion 
Fosaprepitant  b 
150 mg 
IV 
Day 1 of each cycle 
Ondansetron b 
8 mg 
IV 
Day 1 of each cycle 
Ondansetron  b 
8 mg 
PO three 
times per 
day prn 
q 8 hours as needed for 
nausea/vomiting 
Prochlorperazine 
10 mg 
PO four 
times per 
day prn 
Q 6 hours as needed for 
nausea/vomiting; use in 
addition to ondansetron if 
continued nausea 
a 
Higher or additional doses are permitted for reasons other than routine rash 
prophylaxis (e.g., antiemetic prophylaxis) 
b   Or acceptable alternative 
 
Premedication is not permitted for the first dose of atezolizumab.  Premedication 
with antihistamines or antipyretics/analgesics (e.g., acetaminophen) may be 
administered for subsequent infusions at the discretion of the treating physician.   
 

 
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b. 
Neoadjuvant therapy treatment details 
 
Agent 
Dose 
Route 
Day 
Schedule 
 
 
Atezolizumab 
1200 mg 
IV 
D1 of 21 day cycle 
X 4 cycles 
 
Pemetrexed 
500 mg/m2 IV 
D1 of 21 day cycle 
X 4 cycles 
 
Cisplatin 
75 mg/m2 
IV 
D1 of 21 day cycle  
X 4 cycles 
 
 
 
 
 
 
 
 
* Note:  One cycle = 21 days 
 
Deliver the initial dose of atezolizumab over 60 (±15) minutes.  If the first infusion 
is tolerated without infusion-associated AEs, the second infusion may be delivered 
over 30 (±10) minutes.  If the 30-minute infusion is well tolerated, all subsequent 
infusions may be delivered over 30 (±10) minutes.  
 
After completion of atezolizumab, administer pemetrexed over 10 minutes. 
 
Thirty minutes after completion of pemetrexed infusion, administer cisplatin over 2 
hours (±15) minutes. 
 
c. 
Infusion Related Reactions (atezolizumab) 
 
Administration of atezolizumab must be performed in a setting with emergency 
medical facilities and staff who are trained to monitor for and respond to medical 
emergencies. 
 
For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood 
pressure, and temperature) should be determined within 60 minutes before, during 
(every 15 [±5] minutes), and 30 (±10) minutes after the infusion.  For subsequent 
infusions, vital signs will be collected within 60 minutes before and within 
30 minutes after the infusion.  Vital signs should be collected during the infusion 
only if clinically indicated.  Patients will be informed about the possibility of delayed 
post-infusion symptoms and instructed to contact their study physician if they 
develop such symptoms. 
 
The management of Infusion Related Reactions will be according to severity as 
follows: 
 
• 
In the event that a patient experiences a Grade 1 Infusion Related 
Reaction during Cycle 1, the infusion rate should be reduced to half the 
rate being given at the time of event onset.  Once the event has resolved, 
the investigator should wait for 30 minutes while delivering the infusion at 
the reduced rate.  If tolerated, the infusion rate may then be increased to 
the original rate. 
 
• 
In the event that a patient experiences a Grade 2 Infusion Related 
Reaction, or flushing, fever, or throat pain, the infusion should be 
immediately interrupted and the patient should receive aggressive 
symptomatic treatment.  The infusion should be restarted only after the 
symptoms have adequately resolved to baseline grade.  The infusion rate 
at restart should be half of the infusion rate that was in progress at the time 
of the onset of the Infusion Related Reaction.  For subsequent infusions, 
administer oral premedication with antihistamine and anti-pyretic and 

 
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monitor closely for Infusion Related Reactions. 
 
• 
For Grade 3 or 4 Infusion Related Reactions, the infusion should be 
stopped immediately, and aggressive resuscitation and supportive 
measures should be initiated (e.g., oral or IV antihistamine, anti-pyretic, 
glucocorticoids, epinephrine, bronchodilators, oxygen).  Atezolizumab 
should be permanently discontinued.  Resumption of atezolizumab may 
be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event; retreatment requires 
consultation with, and consent of, the trial Principal Investigator (PI). 
 
For anaphylaxis precautions, use the following procedure: 
 
Equipment Needed 
 
• 
Tourniquet 
• 
Oxygen 
• 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in 
accordance with standard practice  
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
Procedures 
 
In the event of a suspected anaphylactic reaction during atezolizumab infusion, the 
following procedures should be performed: 
 
1. 
Stop the study drug infusion. 
2. 
Apply a tourniquet proximal to the injection site to slow systemic 
absorption of study drug.  Do not obstruct arterial flow in the limb. 
3. 
Maintain an adequate airway. 
4. 
Administer antihistamines, epinephrine, or other medications as required 
by patient status and directed by the physician in charge. 
5. 
Continue to observe the patient and document observation. 
 
7.3 
Surgery (Registration Step 2) 
 
Prior to protocol surgery, patients must meet all of the eligibility criteria listed in Section 5.2 
and be registered to Step 2 via CTSU OPEN. 
 
Surgery must occur between 21 and 90 days following the end of patient’s final cycle of 
neoadjuvant therapy. 
 
All patients will undergo surgical resection with the intent to provide macroscopic disease 
eradication, unless: (1) there is objective evidence of progression of disease; or (2) 
deterioration of functional status occurs following induction therapy, which is felt to 
significantly increase operative mortality/morbidity.  
 
Extrapleural pneumonectomy (EPP) and pleurectomy/decortication (PD) will be treated as 
equal surgical techniques in terms of their ability to achieve macroscopic cytoreduction and 
shall be performed in all cases.  
 

 
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Recognizing that there are individual variations required in surgical technique from patient 
to patient and surgeon to surgeon, Appendix 18.3 describes a standardized recommended 
approach to the operation and intraoperative decision-making regarding choosing one 
approach over the other.  
 
Decision to proceed with surgical therapy for mesothelioma will be based on 
comprehensive physiologic work up, and invasive disease staging performed prior to 
initiation of therapy and patient enrollment on this clinical trial. 
 
7.4 
Radiation Therapy 
 
Patients who have extrapleural pneumonectomy (EPP) must receive radiation therapy as 
described in this section.  Patients who have pleurectomy/decortication (PD) will not 
receive radiation therapy. 
 
See Section 12.2 for information regarding radiation therapy review requirements, 
TRIAD, and credentialing. 
 
There is substantial literature supporting the safety of radiation therapy after EPP.  While 
historically this treatment has been delivered using conventional techniques, over the past 
decade experience has been building in numerous centers with intensity modulated 
radiation therapy (IMRT).  Indeed, IMRT is now considered the standard technique in this 
context. 
 
a. 
Radiation Simulation 
 
All patients will be treated with IMRT.  Patients will undergo a 4D simulation to 
assess for treatment motion.  Simulation will occur with a customized cradle, with 
the arms above the head if tolerated.  Bolus can be placed over drainage and 
incision sites, though placement of bolus is optional.   
 
b. 
Radiation Treatment Volumes 
 
The treatment volume will consist of the ipsilateral hemithorax.  Mediastinal lymph 
nodes will only be included if involved with disease. Target volumes will be 
contoured as follows:  
  
• 
Gross tumor volume (GTV)=gross disease with respiratory motion (if 
applicable). 
• 
Circumferential margin around GTV = GTVmargin 
• 
internal target volume (ITV) = ipsilateral hemithorax (CTV) plus motion, with 
the external boundary of the chest wall/ribs.   Longitudinally, this volume 
typically covers from the thoracic inlet/T1 to approximately L1/L2, or the chest 
wall as defined by the 12th (final) rib.  The volume will exclude the external skin 
surface.  The ITV should also encompass the GTVmargin. 
• 
planning target volume (PTV)=ITV plus 5 mm for setup variation if daily kV 
orthogonal imaging is utilized and 3 mm if daily CT is utilized. 
 
Therefore, the following steps should be used to contour patients for this protocol. 
 
1. 
Identify gross disease with respiratory motion, if applicable, and contour 
as GTV. 
2. 
Define a margin of 0-5 mm around the GTV, label GTVmargin. 
3. 
Delineate CTV=the ipsilateral hemithoracic pleura to encompass the 
external margin of the first to twelfth ribs as noted in the figure below (blue 
region).  The volume should be shaved off of the spinal canal when 
necessary. The heart and mediastinum are not included, other than the 

 
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region of the pleura/pericardium that is on the ipsilateral hemithorax of the 
heart (see images below). 
When bolus is placed, the ITV can be expanded to the region of the bolus.  
When delineating the CTV, ensure that it also encompasses the GTV 
margin.  Below the diaphragm, the volume will be a crescent-shaped 
contour which will be manually expanded to cover the pleura to the 
sternum, the diaphragm, and the diaphragmatic crura to midline anteriorly 
and the paravertebral space superiorly. 
4. 
ITV=CTV plus target volume motion.   
5. 
Expand the ITV by 0-5 mm for the PTV.  While a PTV margin of 3-5 mm is 
standard, in regions such as the pericardium, to minimize the dose to the 
heart, the investigator may elect to reduce or eliminate the PTV margin.   
 
Daily IGRT with kV imaging or cone-beam CT is recommended.  As with the ITV, 
the PTV will exclude the external skin surface. 
 
All volumes should be verified through each cycle of the respiratory phase.  Note 
that it is important to not solely use the maximum projection image (MIP) for 
delineation, particularly in the region near the diaphragm where the MIP images 
can obscure target volumes.   
 
Figure 1:  Example of ITV volume (blue) in a patient after EPP. 
 
 
 

 
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Figure 2:  Cross-sectional examples of a patient with subcarinal involvement.  The 
aqua volume depicts the PTV, which was expanded externally to the bolus.  
 
c. 
Radiation Treatment Planning 
 
 
Both static field IMRT and VMAT/arc therapy are acceptable techniques.  For static 
field IMRT, 7-8 beams are typically used, equally distributed with a gantry angle 
separation of approximately 30 degrees. For VMAT/Arc therapy, 4 half arcs are 
commonly used, covering the ipsilateral side over approximately 200 degrees. 
 
The required prescription dose to the PTV is 1.8 Gy x 28 = 50.4 Gy.  However, 
dose de-escalation is allowed to 45 Gy to meet normal tissue constraints. In this 
case, RT would be given for 25 days. Note that while a simultaneous integrated 
boost (SIB) regimen has been explored in limited studies, for the purposes of this 
trial an SIB is not allowed.  All patients should undergo daily orthogonal kV image 
guided radiation therapy (IGRT).  Daily CT scanning is optional (cone beam CT) 
and if this IGRT technique is used, a PTV margin of 3 mm can be applied (vs. 5 
mm for daily kV imaging). 
 
The collapsed cone convolution algorithm for heterogeneity corrections will be 
used. 
 
 

 
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Target volume criteria and normal tissue dose constraints are below.  All of these 
structures should be defined by the treating physician, to facilitate plan 
acceptability: 
 
Target/Normal 
Structure 
Standard 
Name 
Criteria Value 
Variation 
Acceptable 
Deviation 
Unacceptable 
Rx Dose 
 
45-50.4 Gy in 
1.8 Gy/fraction 
None 
<45 Gy in 1.8 
Gy/fraction 
GTV  
GTV 
D95 ≥95% 
D95 90%≤D95<95% 
D95<90% 
ITV 
ITV 
D95 ≥95% 
D95 85%≤D95<95% 
D95<85% 
PTV 
PTV 
D95 ≥95% 
D95 85%≤D95<95% 
D95<85% 
Contralateral 
lung 
 
V20≤8%    
 
Mean dose ≤8 
Gy 
None 
Contralateral (e.g. 
total) lung 
V20>8%    
 
Contralateral lung 
mean dose >8 Gy 
Esophagus 
Esophagus 
Mean dose 
≤34 Gy 
Mean dose >34 Gy 
 
Spinal cord 
(defined as 
spinal canal) 
SpinalCord 
Dmax≤50 Gy 
None 
Dmax>50 Gy 
Heart 
Heart 
Right sided:  
V40≤25% 
Left sided:  
V40≤35% 
Right sided meso: 
25% < V40 ≤ 35% 
with mean dose ≤ 30 
Gy  
Left sided meso: 
35% < V40 ≤ 37% 
with mean dose ≤ 30 
Gy  
V30Gy ≥ 50%  
Dmean ≥30 Gy  
 
Left and Right 
Kidney 
Kidneys 
V18≤33%  
V18>33% 
V18>50% 
Liver (not 
including the 
PTV) 
Liver-PTV 
Mean dose 
≤30 Gy 
V30≤50% 
 
Mean dose >30 
Gy 
V30>50% 
Stomach (not 
including PTV) 
Stomach-
PTV 
Mean 
dose≤30 Gy 
Max dose≤50 
Gy 
Mean dose >30 Gy 
and ≤40 Gy 
Mean dose >40 
Gy 
Max dose >50 Gy 
Bowel (upper 
abdomen, to 
include large 
and small bowel 
and inferiorly to 
3 slices below 
the PTV) 
Bowel 
Dmax≤55 Gy  
D5cc≤50 Gy 
D5cc>50 Gy and 
≤55 Gy 
D5cc >55 Gy 
 
 
 

 
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7.5 
MAINTENANCE (Registration Step 3) 
 
Prior to beginning maintenance therapy, patients must meet all of the eligibility criteria 
listed in Section 5.3 and be registered to Step 3 via CTSU OPEN. 
 
Agent 
Dose 
Route 
Day 
Schedule 
 
 
Atezolizumab 
1200 mg 
IV   
D1 of 21 
X 1 year  
 
 
 
 
 
day cycle  
 
* Note:  One cycle = 21 days 
 
For patients who had pleurectomy/decortication (PD), atezolizumab maintenance therapy 
will begin within 90 days after completion of surgery. 
 
For patients who had extrapleural pneumonectomy (EPP) with or without radiation, 
atezolizumab maintenance therapy will begin within 90 days after completion of surgery or 
radiation therapy, whichever is last. 
 
Maintenance atezolizumab is delivered as a flat dose 1200 mg IV over 60 minutes (+/- 15 
minutes) every 3 weeks. 
 
7.6 
Full CDUS Reporting Requirement 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4, the S1619 Treatment Form, and 
the S1619 Adverse Event Form).  During neoadjuvant therapy and maintenance therapy, 
a cycle is defined as 21 days. Surgery +/- radiation therapy is considered one cycle. 
 
7.7 
Criteria for Removal from Protocol Treatment 
 
a. 
Step 1: Neoadjuvant 
 
1. 
Progression of disease by either RECIST 1.1 or by Modified RECIST for 
Pleural Tumors or symptomatic deterioration (as defined in Section 10.2). 
 
2. 
Unacceptable toxicity. 
 
3. 
Treatment delay for any reason > 2 weeks. 
 
4. 
The patient may withdraw from the study at any time for any reason. 
 
5. 
The patient receives less than two cycles of triplet neoadjuvant therapy (all 
three drugs). 
 
6. 
Completion of neoadjuvant therapy. 
 
b. 
Step 2: Surgery 
 
7. 
Progression of disease by either RECIST 1.1 or by Modified RECIST for 
Pleural Tumors or symptomatic deterioration (as defined in Section 10.2). 
 
8. 
Patient does not receive surgery for any reason (patient refusal, patient 
deemed inappropriate by attending surgeon, etc.). 
 

 
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9. 
Completion of surgery (+/- radiation). 
 
c. 
Step 3: Maintenance 
 
1. 
Progression of disease by either RECIST 1.1 or by Modified RECIST for 
Pleural Tumors or symptomatic deterioration (as defined in Section 10.2). 
 
2. 
Unacceptable toxicity.  
 
3. 
Treatment delay for any reason > 90 days. 
 
4. 
The patient may withdraw from the study at any time for any reason. 
 
5. 
Completion of maintenance therapy. 
 
7.8 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.9 
Follow-Up Period 
 
All patients will be followed until death or 3 years after registration to Step 1, whichever 
occurs first.  
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
5.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
8.2 
Neoadjuvant Treatment (Atezolizumab, Pemetrexed, and Cisplatin) 
 
a. 
General 
 
For any concomitant conditions already apparent at baseline, the dose 
modifications will apply according to the corresponding shift in toxicity grade, if the 
investigator feels it is appropriate.  For example, if a patient has Grade 1 asthenia 
at baseline that increases to Grade 2 during treatment, this will be considered a 
shift of one grade and treated as Grade 1 toxicity for dose-modification purposes. 
When several toxicities with different grades of severity occur at the same time, 
the dose modifications should be according to the highest grade observed. 
 
If, in the opinion of the investigator, a toxicity is considered to be due solely to one 
component of the study treatment (i.e., atezolizumab, or cisplatin and/or 
pemetrexed if applicable) and the dose of that component is delayed or modified 
in accordance with the guidelines below, other components may be administered 
if there is no contraindication. 
 
When treatment is temporarily interrupted because of toxicity caused by 
atezolizumab, cisplatin and/or pemetrexed (if applicable), the treatment cycles will 

 
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be restarted such that the atezolizumab (if applicable) infusions remain 
synchronized and aligned with the chemotherapy schedule. 
 
If, in the opinion of the investigator, a toxicity is considered to be due solely to 
one chemotherapy drug, the dose of the other chemotherapy drug does not 
require modification. 
 
The investigator may use discretion in modifying or accelerating the 
dose modification guidelines described below depending on the severity of toxicity 
and an assessment of the risk versus benefit for the patient, with the goal of 
maximizing patient compliance and access to supportive care. 
 
b. 
Atezolizumab  
 
1. 
General 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 Chair in consultation with CTEP. 
 
Atezolizumab must be permanently discontinued if the patient 
experiences any of the following events, regardless of benefit: 
 
• 
Grade 4 pneumonitis 
• 
AST or ALT >5×ULN or total bilirubin >3×ULN  
• 
Grade 4 diarrhea or colitis 
• 
Grade 4 hypophysitis 
• 
Any grade myasthenic syndrome/myasthenia gravis, Guillain-
Barré or meningoencephalitis 
• 
Grade 4 ocular inflammatory toxicity 
• 
Grade 4 pancreatitis or any grade of recurrent pancreatitis 
• 
Grade 4 rash 
• 
Any grade myocarditis 
 
Treatment may, under limited and compelling circumstances, be resumed 
in patients who have recovered from the following events, but only after 
consultation with the trial Study Chair: 
 
• 
Grade 3 pneumonitis 
• 
Grade 3 ocular inflammatory toxicity 
• 
Grade 3 or 4 infusion-related reactions 
 

 
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Any toxicities associated or possibly associated with atezolizumab 
treatment should be managed according to standard medical practice.  
Additional tests, such as autoimmune serology or biopsies, may be used 
to determine a possible immunogenic etiology.  Although most immune-
related adverse events (irAEs) observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early 
and treated promptly to avoid potential major complications (Di Giacomo 
et al., 2010).  Discontinuation of atezolizumab may not have an immediate 
therapeutic effect, and there is no available antidote for atezolizumab.  
In severe cases, immune-related toxicities may be acutely managed with 
topical 
corticosteroids, 
systemic 
corticosteroids, 
or 
other 
immunosuppressive agents.  The investigator should consider the benefit-
risk balance prior to further administration of atezolizumab.   
 
For detailed information regarding management of adverse events 
associated with atezolizumab, please refer to the most current version of 
the Atezolizumab Investigator’s Brochure and the FDA product label. 
 
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. 
 
Patients should be assessed clinically (including review of laboratory 
values) for toxicity prior to, during, and after each infusion.  If 
unmanageable toxicity due to atezolizumab occurs at any time during the 
study, treatment with atezolizumab should be discontinued. 
 
2. 
Systemic Immune Activation 
 
Systemic immune activation is a rare condition characterized by an 
excessive immune response. Given the mechanism of action of 
atezolizumab, systemic immune activation is considered a potential 
risk when given in combination with other immunomodulating agents.  
Systemic immune activation should be included in the differential 
diagnosis for patients who, in the absence of an alternative etiology, 
develop a sepsis-like syndrome after administration of atezolizumab, and 
the initial evaluation should include the following: 
 
• 
CBC with peripheral smear 
• 
PT, PTT, fibrinogen, and D-dimer 
• 
Ferritin 
• 
Triglycerides 
• 
AST, ALT, and total bilirubin 
• 
LDH 
• 
Complete neurologic and abdominal examination (assess for 
hepatosplenomegaly) 
 
If systemic immune activation is still suspected after the initial evaluation, 
contact the Principal Investigator for additional recommendations. 

 
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3. 
Management of Specific Adverse Events (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 Section 7.2c 
for guidelines for the management of Infusion Related Reactions and 
Anaphylaxis. 
 
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. 
 
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. 
 
Endocrine disorders 
 
Patients experiencing one or more unexplained AEs possibly indicative of 
endocrine dysfunction (including 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-stimulating hormone (TSH) and free T3 and T4 levels should be 
obtained to determine whether thyroid abnormalities are present.  TSH, 
prolactin, and a morning cortisol level will help to differentiate primary 
adrenal insufficiency from primary pituitary insufficiency.  The table below 
describes 
dose 
management 
guidelines 
for 
hyperthyroidism, 
hypothyroidism, symptomatic adrenal insufficiency, and hyperglycemia. 
 
Meningoencephalitis 
 
Immune-related meningoencephalitis is an identified risk associated with 
the administration of atezolizumab.  Immune-related meningoencephalitis 
should be suspected in any patient presenting with signs or symptoms 
suggestive of meningitis or encephalitis, including, but not limited to, 
headache, neck pain, confusion, seizure, motor or sensory dysfunction, 
and altered or depressed level of consciousness.  Encephalopathy from 
metabolic or electrolyte imbalances needs to be distinguished from 

 
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potential meningoencephalitis resulting from infection (bacterial, viral, or 
fungal) or progression of malignancy, or secondary to a paraneoplastic 
process. 
 
All patients being considered for meningoencephalitis should be urgently 
evaluated with a CT scan and/or MRI scan of the brain to evaluate for 
metastasis, inflammation, or edema.  If deemed safe by the treating 
physician, a lumbar puncture should be performed and a neurologist 
should be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence 
of an identified alternate etiology, should be treated according to the 
guidelines. 
 
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. 
 
The table below presents management and dose modification guidelines 
for specific AEs.  For recommendations to hold atezolizumab and begin 
corticosteroid treatment, use the following guidance for tapering the 
corticosteroid and resuming atezolizumab therapy after resolution of the 
event: 
 
• 
Corticosteroids must be tapered over ≥1 month to ≤ 10 mg/day 
oral prednisone or equivalent before atezolizumab can be 
resumed. 
• 
Atezolizumab may be held for a period of time beyond 12 weeks 
(up to four weeks) to allow for corticosteroids to be reduced to ≤10 
mg/day oral prednisone or equivalent. 
 
AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
Abdominal pain 
Acute abdominal 
pain 
Symptoms of abdominal pain 
associated with elevations of 
amylase and lipase, suggestive 
of pancreatitis, have been 
associated with administration 
of other immunomodulatory 
agents.  The differential 
diagnosis of acute abdominal 
pain should include 
pancreatitis.  Appropriate 
workup should include an 
evaluation for obstruction, as 
well as serum amylase and 
lipase tests.  See the guidelines 
for “Amylase and/or lipase 
increase” and “Immune-related 

 
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Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
pancreatitis” elsewhere in this 
table, as needed. 
 
Right upper-quadrant 
abdominal pain and/or 
unexplained nausea or 
vomiting should be evaluated 
for potential hepatotoxicity (see 
the “Hepatotoxicity” guideline 
elsewhere in this table). 
 
Adrenal 
insufficiency 
Grade 2+ 
(symptomatic) 
Hold atezolizumab. 
 
Refer patient to 
endocrinologist. 
 
Perform appropriate imaging. 
 
Initiate treatment with 1−2 
mg/kg/day intravenous 
methylprednisolone or 
equivalent and convert to 
1−2 mg/kg/day oral prednisone 
or equivalent upon 
improvement. 
 
If event resolves to grade 1 or 
better and patient is stable on 
replacement therapy (if 
required) within 12 weeks, 
taper corticosteroids and 
resume atezolizumab 
according to the guidelines 
above. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to grade 1 or better or 
patient is not stable on 
replacement therapy within 12 
weeks. 
Amylase and/or 
lipase 
increased 
Grade 1 
Continue atezolizumab. 
 
Monitor amylase and lipase 
prior to dosing. 
Grade 2 
Continue atezolizumab. 
 
Monitor amylase and lipase 
weekly. 
 

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
For prolonged elevation (e.g., 
>3 weeks), consider treatment 
with 10 mg/day oral prednisone 
or equivalent. 
Grade 3 or 4 
Hold atezolizumab. 
 
Refer patient to gastrointestinal 
(GI) specialist. 
 
Monitor amylase and lipase 
every other day. 
 
If no improvement, consider 
treatment with 1−2 mg/kg/day 
oral prednisone or equivalent. 
 
If event resolves to grade 1 or 
better within 12 weeks, taper 
corticosteroids and resume 
atezolizumab according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to grade 1 or better 
within 12 weeks. 
 
For recurrent events, 
permanently discontinue 
atezolizumab.  
 
Dermatologic 
toxicity/rash 
(e.g., 
maculopapular 
or purpura) 
Grade 1 
Continue atezolizumab. 
 
Consider topical steroids and/or 
other symptomatic therapy 
(e.g., antihistamines). 
Grade 2 
Continue atezolizumab.  
Consider dermatologist referral. 
 
Administer topical 
corticosteroids. 
 
Consider higher potency topical 
corticosteroids if event does not 
improve. 
Grade 3 
Hold atezolizumab.   
 
Refer patient to dermatologist.  
Administer oral prednisone 
10 mg or equivalent.  If the 
event does not improve within 
48−72 hours, increase dose 

 
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Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
to1–2 mg/kg/day or equivalent. 
Restart atezolizumab if event 
resolves to grade 1 or better 
within 12 weeks. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to grade 1 or better 
within 12 weeks. 
Grade 4 
Permanently discontinue 
atezolizumab.  Patient may not 
resume treatment, regardless 
of benefit.  Otherwise, manage 
as above. 
Persistent and/or 
severe rash or 
pruritus, any grade 
A dermatologist should 
evaluate the event.  A biopsy 
should be performed unless 
contraindicated. 
Diarrhea or 
colitis 
Any grade 
Patients should be advised to 
inform the investigator if any 
diarrhea occurs, even if it is 
mild. 
 
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 CRP, 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. 
Grade 1 
Continue atezolizumab. 
 
Initiate symptomatic treatment. 
 
Endoscopy is recommended if 
symptoms persist for >7 days. 
 
Monitor closely. 
Grade 2 
Hold atezolizumab. 
 
Initiate symptomatic treatment. 

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
 
Patient referral to GI specialist 
is recommended. 
 
For recurrent events or events 
that persist >5 days, initiate 
treatment with 1−2 mg/kg/day 
oral prednisone or equivalent.  
 
If event resolves to grade 1 or 
better within 12 weeks, taper 
corticosteroids and resume 
atezolizumab according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to grade 1 or better 
within 12 weeks.  Resumption 
of atezolizumab may be 
considered, after consultation 
with the trial PI, in patients who 
are deriving benefit and have 
fully recovered from the 
immune-related event. 
Grade 3 
Hold atezolizumab. 
 
Refer patient to GI specialist for 
evaluation and confirmatory 
biopsy. 
 
Initiate treatment with 1−2 
mg/kg/day intravenous 
methylprednisolone or 
equivalent and convert to 
1−2 mg/kg/day oral prednisone 
or equivalent upon 
improvement. 
 
If event resolves to grade 1 or 
better within 12 weeks, taper 
corticosteroids and resume 
atezolizumab according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to Grade 1 or better 
within 12 weeks.  Resumption 
of atezolizumab may be 
considered, after consultation 
with the trial PI, in patients who 
are deriving benefit and have 

 
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Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
fully recovered from the 
immune-related event. 
Grade 4  
Permanently discontinue 
atezolizumab. Patient may not 
resume treatment, regardless 
of benefit. 
 
Refer patient to GI specialist for 
evaluation and confirmation 
biopsy. 
 
Initiate treatment with 1−2 
mg/kg/day intravenous 
methylprednisolone or 
equivalent and convert to 1−2 
mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event does not improve within 
48 hours after initiating 
corticosteroids, consider adding 
an immunosuppressive agent. 
 
If event resolves to grade 1 or 
better, taper corticosteroids 
over ≥1 month. 
Hepatotoxicity  
Right upper-
quadrant 
abdominal pain 
and/or unexplained 
nausea or vomiting 
Risk of immune-mediated 
hepatitis.  LFTs should be 
performed immediately, and 
LFTs should be 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. 
 
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 
also include pancreatitis, as 
described below. 
Grade 1 hepatic 
event 
Continue atezolizumab. 
 
Monitor LFTs until values 
resolve to within normal limits. 

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
Grade 2 hepatic 
event, ≤5 days 
Continue atezolizumab. 
 
Monitor LFTs more frequently 
until values resolve to baseline 
values. 
Grade 2 hepatic 
event, >5 days 
Hold atezolizumab. 
 
Initiate treatment with 1−2 
mg/kg/day oral prednisone or 
equivalent. 
 
If event resolves to grade 1 or 
better within 12 weeks, taper 
corticosteroids and resume 
atezolizumab according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to Grade 1 or better 
within 12 weeks. 
Grade 3 or 4 
hepatic event 
Permanently discontinue 
atezolizumab. 
 
Consider patient referral to GI 
specialist for evaluation and 
liver biopsy to establish etiology 
of hepatic injury.  
 
Initiate treatment with 1−2 
mg/kg/day oral prednisone or 
equivalent. 
 
If event does not improve within 
48 hours after initiating 
corticosteroids, consider adding 
an immunosuppressive agent. 
 
If event resolves to grade 1 or 
better, taper corticosteroids 
over ≥1 month. 
Hyperglycemia 
Grade 1 or 2 
Continue atezolizumab. 
 
Initiate treatment with insulin if 
needed. 
 
Monitor for glucose control. 
Grade 3 or 4 
Hold atezolizumab. 
 
Initiate treatment with insulin. 
 

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
Monitor for glucose control. 
 
Resume atezolizumab when 
symptoms resolve and glucose 
levels are stable. 
Hyperthyroidism Grade 1 
(asymptomatic) 
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. 
Grade 2+ 
(symptomatic) 
Hold 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 for 
life-threatening immune-related 
hyperthyroidism. 
Hypothyroidism 
Grade 1 
(asymptomatic) 
Continue atezolizumab.   
 
Start thyroid-replacement 
hormone.   
 
Monitor TSH weekly. 
Grades 2+ 
(symptomatic) 
Hold atezolizumab.   
 
Start thyroid-replacement 
hormone.  Consider referral to 
an endocrinologist.  
 
Monitor TSH weekly. 
 
Restart atezolizumab when 
symptoms are controlled and 
thyroid function is improving.  

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
Meningo-
encepahlitis, 
immune-related 
 
(signs and 
symptoms in 
absence of an 
identified 
alternate 
etiology) 
 
All grades 
Permanently discontinue 
atezolizumab. Patient may not 
resume treatment, regardless 
of benefit. 
 
Refer patient to neurologist. 
 
Initiate treatment with 1−2 
mg/kg/day IV 
methylprednisolone or 
equivalent and convert to 
1−2 mg/kg/day oral prednisone 
or equivalent upon 
improvement. 
 
If event resolves to grade 1 or 
better, taper corticosteroids 
over ≥1 month. 
 
If event does not improve within 
48 hours after initiating 
corticosteroids, consider adding 
an immunosuppressive agent. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome 
All grades 
Permanently discontinue 
atezolizumab. Patient may not 
resume treatment, regardless 
of benefit. 
 
Refer patient to neurologist. 
 
Initiate treatment as per 
institutional guidelines. 
 
Consider initiation of 1−2 
mg/kg/day oral or IV 
prednisone or equivalent. 
Myocarditis 
All grades 
Permanently discontinue 
atezolizumab. Patient may not 
resume treatment, regardless 
of benefit. 
Neuropathy, 
immune-related 
 
(sensory and/or 
motor) 
Grade 1 
Continue atezolizumab. 
 
Evaluate for alternative 
etiologies. 
Grade 2 
Hold atezolizumab. 
 
Evaluate for alternative 
etiologies. 
 
Initiate treatment as per 
institutional guidelines. 
 

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
Resume atezolizumab if event 
resolves to grade 1 or better 
within 12 weeks. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to grade 1 or better 
within 12 weeks. 
Grade 3 or 4 
Permanently discontinue 
atezolizumab. 
 
Initiate treatment as per 
institutional guidelines. 
Ocular event 
(e.g., uveitis, 
retinal events) 
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. 
Grade 2 
Withhold atezolizumab. 
 
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 within 12 weeks, taper 
corticosteroids and resume 
atezolizumab according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to grade 1 or better 
within 12 weeks. 

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
Grade 3 or 4 
Permanently discontinue 
atezolizumab.   
 
Refer patient to 
ophthalmologist. 
 
Initiate treatment with 1−2 
mg/kg/day oral prednisone or 
equivalent. 
 
If event resolves to grade 1 or 
better, taper corticosteroids 
over ≥1 month. For grade 3 
AEs, patient may only resume 
treatment after consultation 
with the trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 
Pancreatitis, 
immune related 
Grade 2 or 3 
Hold atezolizumab. 
 
Refer patient to GI specialist. 
 
Initiate treatment with 1−2 
mg/kg/day intravenous 
methylprednisolone or 
equivalent and convert to 
1−2 mg/kg/day oral prednisone 
or equivalent upon 
improvement. 
 
If event resolves to grade 1 or 
better within 12 weeks, taper 
corticosteroids and resume 
atezolizumab according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to grade 1 or better 
within 12 weeks.  Patient may 
only resume treatment after 
consultation with the trial PI. 
 
For recurrent events, 
permanently discontinue 
atezolizumab.  Patient may not 
resume treatment, regardless 
of benefit. 

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
Grade 4 
Permanently discontinue 
atezolizumab. Patient may not 
resume treatment, regardless 
of benefit. 
 
Refer patient to GI specialist. 
 
Initiate treatment with 1−2 
mg/kg/day intravenous 
methylprednisolone or 
equivalent and convert to 
1−2 mg/kg/day oral prednisone 
or equivalent upon 
improvement. 
 
If event does not improve within 
48 hours after initiating 
corticosteroids, consider adding 
an immunosuppressive agent. 
 
If event resolves to grade 1 or 
better, taper corticosteroids 
over ≥1 month. 
Pulmonary 
toxicity 
All pulmonary 
events 
Evaluate thoroughly for other 
commonly reported etiologies 
such as pneumonia/infection, 
lymphangitic carcinomatosis, 
pulmonary embolism, heart 
failure, chronic obstructive 
pulmonary disease (COPD), or 
pulmonary hypertension. 
Grade 1 
Continue atezolizumab and 
monitor closely.   
 
Re-evaluate on serial imaging. 
 
Consider patient referral to a 
pulmonary specialist. 
 
For recurrent pneumonitis, treat 
as a grade 3 or 4 event. 
Grade 2 
Hold atezolizumab.   
 
Refer patient to pulmonary and 
infectious disease specialists 
and consider bronchoscopy or 
bronchoscopic alveolar lavage 
(BAL). 
 
Initiate treatment with 1−2 
mg/kg/day oral prednisone or 
equivalent. 
 

 
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AE Management and Dose Interruption  
Guidelines for Specific Toxicities 
Toxicity 
Severity/Duration 
Management 
If event resolves to grade 1 or 
better within 12 weeks, taper 
corticosteroids and resume 
atezolizumab according to the 
guidelines above. 
 
Permanently discontinue 
atezolizumab if event does not 
resolve to grade 1 or better 
within 12 weeks. 
 
For recurrent events, treat as a 
Grade 3 or 4 event. 
Grade 3 or 4 
Permanently discontinue 
atezolizumab. 
 
Bronchoscopy or BAL is 
recommended. 
 
Initiate treatment with 1−2 
mg/kg/day oral prednisone or 
equivalent. 
 
If event does not improve within 
48 hours after initiating 
corticosteroids, consider adding 
an immunosuppressive agent. 
 
If event resolves to grade 1 or 
better, taper corticosteroids 
over ≥1 month.  For grade 3 
AEs, patient may only resume 
treatment after consultation 
with the trial PI; for grade 4, 
patient cannot resume 
treatment, regardless of 
benefit. 
 
c. 
Pemetrexed 
 
The dose modification guidelines are applicable for pemetrexed used as a single 
agent or in combination with cisplatin or carboplatin. 
 
Treatment with pemetrexed should be discontinued if a patient experiences any 
hematologic or non-hematologic Grade 3 or 4 toxicity after two dose reductions or 
if treatment is delayed for more than 14 days due to toxicities (see table below). 
 
1. 
Hematologic Toxicity 
 
At the start of each cycle, the ANC must be ≥ 1500/mcl and the platelet 
count must be ≥ 100,000/mcL.  Neoadjuvant treatment should be delayed 
for up to 14 days to allow sufficient time for recovery.  Growth factors may 
be used in accordance with American Society of Clinical Oncology (ASCO) 

 
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and National Comprehensive Cancer Network (NCCN) guidelines. Upon 
recovery, dose adjustments at the start of a subsequent cycle will be made 
on the basis of the lowest (nadir) platelet and neutrophil values from the 
previous cycle (see table below). 
 
In the event that dose adjustments are needed for both ANC and platelets, 
patients are to receive the lower dose. 
 
Table 1: Pemetrexed Dose Modification for Hematologic Toxicities 
 
 
Investigators should be vigilant and alert to early and overt signs of 
myelosuppression, infection, or febrile neutropenia so that these 
complications can be promptly and appropriately managed.  Patients 
should be made aware of these signs and encouraged to seek medical 
attention at the earliest opportunity. 
 
If neoadjuvant chemotherapy must be withheld because of hematologic 
toxicity, full blood counts (including differential WBC) should be obtained 
weekly until the counts reach the lower limits for treatment as outlined.  
The treatment then can be resumed. 
 
No dose reductions are recommended for anemia.  Patients should be 
supported per the treating physician’s institution’s guidelines. 
 
2. 
Non-Hematologic Toxicity 
 
At the start of each cycle, the CRCL must be ≥ 45 mL/min. For enrollment 
and dosing decisions, CRCL will be estimated using the original, weight-
based Cockcroft and Gault formula or measured using the appropriate 
radiolabeled method (51-CrEDTA or Tc99m-DTPA) to determine the GFR.  
The method of CRCL assessment used at baseline should be used 
throughout the study. 
 
If a patient develops a non-hematologic toxicity (Table 2), pemetrexed 
should be withheld for up to 14 days until resolution to equal or less than 
the patient’s baseline (or Grade ≤ 1 if patient did not have that toxicity at 
baseline).  Treatment should be resumed according to the guidelines in 
Table 2. 
 
 
Toxicity a 
Pemetrexed Dose  
ANC 
< 500 
cells/mcL 
and 
platelets 
≥ 50,000/mcL 
75% of previous dose 
Platelets < 50,000/mcL, regardless of ANC 
75% of previous dose 
Platelets 
< 50,000/mcL 
with 
Grade 
≥ 2 
bleeding, regardless of ANC 
50% of previous dose 
aNadir of prior cycle. 

 
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Table 2: Pemetrexed Dose Modification for Non-Hematologic 
Toxicities 
Toxicity 
Pemetrexed Dose 
Any diarrhea requiring hospitalization 
(irrespective of grade) or Grade 3 or 4 
diarrhea that occurs on adequate 
anti-diarrhea medication 
 
75% of previous dose 
Neurotoxicity 
 
    Grade 2 
75% of previous dose 
    Grade 3 or 4 
50% of previous dose or 
permanent discontinuation 
      Any other Grade 3 or 4 toxicities 
75% of previous dose 
 
For more details regarding pemetrexed dose modification, see the 
prescribing information for pemetrexed. 
 
d. 
Cisplatin 
 
Treatment with cisplatin should be discontinued if a patient experiences any 
hematologic or non-hematologic Grade 3 or 4 toxicity after two dose reductions or 
if treatment is delayed for more than 14 days due to toxicities. 
 
1. 
Hematologic Toxicity 
 
At the start of each cycle, the ANC must be ≥ 1500/mcL and the platelet 
count must be ≥ 100,000/mcL.  Neoadjuvant chemo treatment should be 
delayed for up to 14 days to allow sufficient time for recovery.  Growth 
factors may be used in accordance with ASCO and NCCN guidelines. 
Upon recovery, dose adjustments at the start of a subsequent cycle will 
be made on the basis of the lowest platelet and neutrophil values from the 
previous cycle (see Table 3). 
 
In the event that dose adjustments are needed for both ANC and platelets, 
patients are to receive the lower dose. 
 
Investigators should be vigilant and alert to early and overt signs of 
myelosuppression, infection, or febrile neutropenia so that these 
complications can be promptly and appropriately managed.  Patients 
should be made aware of these signs and encouraged to seek medical 
attention at the earliest opportunity. 
 
If chemotherapy must be withheld because of hematologic toxicity, full 
blood counts (including differential WBC) should be obtained weekly until 
the counts reach the lower limits for treatment as outlined.  The treatment 
then can be resumed. 
 
No dose reductions are recommended for anemia.  Patients should be 
supported per the treating physician’s institution’s guidelines. 
 
 

 
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Table 3: Cisplatin Dose Modification for Hematologic Toxicities 
Toxicity a 
Cisplatin Dose 
ANC < 500 cells/mcL and platelets ≥ 50,000/mcL 
75% of previous dose 
Platelets < 50,000/mcL, regardless of ANC 
75% of previous dose 
Platelets < 50,000/mcL with Grade ≥ 2 bleeding, 
regardless of ANC 
50% of previous dose 
ANC < 1000/mcL plus fever of ≥ 38.5°C 
75% of previous dose 
a Nadir of prior cycle. 
 
2. 
Non-Hematologic Toxicity 
 
If a patient develops a non-hematologic toxicity (see Table 4) cisplatin 
should be withheld for up to 14 days until resolution to equal or less than 
the patient’s baseline (or Grade ≤ 1 if patient did not have that toxicity at 
baseline).  Treatment should be resumed according to the guidelines in 
Table 4.  
 
Diarrhea should be controlled with adequate anti-diarrhea medication. 
Nausea and/or vomiting should be controlled with adequate anti-emetics. 
 
 
Table 4: Cisplatin Dose Modification for Non-Hematologic Toxicities 
(Excluding Neurotoxicity) 
Toxicity 
Cisplatin Dose 
Any 
diarrhea 
requiring 
hospitalization 
(irrespective of grade) or Grade 3 or 4 diarrhea 
that 
occurs 
on 
adequate 
anti-diarrhea 
medication 
75% of previous dose 
Grade 3 or 4 nausea/vomiting a 
75% of previous dose 
Any other Grade 3 or 4 toxicity 
75% of previous dose 
a Despite the use of anti-emetics. 
 
3. 
Nephrotoxicity 
 
CRCL must be 45 mL/min prior to the start of any cycle.  If there is a 
decrease in CRCL between cycles, but the CRCL is still above 45 mL/min 
at time of next cycle, the treating physician should use his or her clinical 
judgment regarding continuing cisplatin, dose reduction, or delaying the 
cycle.  If a patient’s CRCL value has not returned to 45 mL/min within 
21 days following last cisplatin administration, the patient must be 
discontinued from cisplatin. 
 
4. 
Neurotoxicity 
 
In the event of neurotoxicity, the recommended dose adjustment for 
cisplatin is documented in Table 5.  For a Grade 3 or 4 neurotoxicity, 
cisplatin should be resumed at 50% of the previous dose upon 
improvement or discontinued immediately (based on investigator’s clinical 
judgment). 
 
 

 
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Table 5: Cisplatin Dose Modification for Associated Neurotoxicity 
 
Toxicity 
Cisplatin Dose 
Grade 0–1 neurotoxicity 
100% of previous dose 
Grade 2 neurotoxicity 
75% of previous dose 
Grade 3 or 4 neurotoxicity 
50% of previous dose or permanent 
discontinuation 
 
5. 
Ototoxicity  
 
Audiogram should be obtained any time the patient experiences 
subjectively worsening hearing loss.  If hearing impairment is ≥ CTCAE 
Grade 3, permanently discontinue cisplatin. 
 
6. 
Non-Hematologic Toxicity 
 
For a non-hematologic toxicity (see Table 4), treatment should be delayed 
for up to 14 days until resolution to less than or equal to the patient’s 
baseline value (or Grade ≤ 1 if patient did not have that toxicity at baseline).  
Dose reductions at the start of the subsequent cycle will be made on the 
basis of non-hematologic toxicities from the dose administered in the 
preceding cycle.  Table 4 provides the relevant dose adjustments for non-
hematologic toxicities. 
 
7. 
Potential Overlapping Toxicities 
 
To date, the risk of overlapping toxicities between atezolizumab, cisplatin, 
and pemetrexed is thought to be minimal.  Nevertheless, the attribution 
and management of certain adverse events that have been associated 
with 
each 
agent 
separately 
(e.g., hepatotoxicity, 
skin, 
and 
gastrointestinal toxicity) may not be unambiguous when the agents are 
administered together.  It is theoretically possible that allergic or 
inflammatory adverse events associated with these chemotherapeutic 
agents 
(e.g., hepatotoxicity) 
could 
be 
exacerbated 
by 
the 
immunostimulatory activity of atezolizumab. 
 
Toxicities should initially be managed according to the recommendations 
in Section 8.2b with dose holds and modifications (if applicable) applied to 
the component of the study drug judged to be the primary cause.  For 
severe (Grade 3) or persistent Grade 1 or 2 diarrhea, an endoscopic 
evaluation should be considered.  Additional tests, such as autoimmune 
serology or biopsies, may be used to determine a possible immunogenic 
etiology for adverse events listed above.   
 
If, in the opinion of the investigator, atezolizumab is a potential inciting 
factor, the dose of atezolizumab may be withheld for a maximum of 7 days 
beyond when the next dose should have been given (see Section 8.2 b).  
Prompt symptomatic management is appropriate for mild immune-related 
adverse events.  In severe cases, immune-mediated toxicities may be 
acutely managed with systemic corticosteroids or TNF-α inhibitors.  These 
cases should be discussed with the Study Chair. 
 
 

 
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8.3 
Maintenance (Atezolizumab) 
 
There will be no dose reductions for atezolizumab in this study. In the maintenance setting, 
patients may temporarily suspend study treatment for up to 90 days beyond the last dose 
if they experience an adverse event that requires a dose to be withheld.  If atezolizumab is 
withheld because of adverse events for more than 90 days beyond the last dose, then the 
patient will be discontinued from atezolizumab treatment and will be followed up for safety 
and efficacy. 
 
If, in the judgment of the treating investigator, the patient is likely to derive clinical benefit 
from maintenance atezolizumab after a hold beyond 90 days, study drug may be restarted 
with the approval of the Study Chair. 
 
If a patient must be tapered off steroids used to treat adverse events, maintenance 
atezolizumab may be withheld for additional time beyond 90 days from the last dose until 
steroids are discontinued or reduced to prednisone dose (or dose equivalent) ≤ 10 mg/day.  
The acceptable length of interruption will depend on agreement between the investigator 
and the Study Chair. 
 
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, 
may be allowed with Study Chair approval.  The acceptable length of interruption will 
depend on agreement between the investigator and the Study Chair. 
 
For additional information, see Section 8.2b. 
 
8.4 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Anne Tsao, M.D., Phone: 
713-792-6363 or E-mail: astsao@mdanderson.org or Jeremy Cetnar, M.D., Phone: 503- 
494-8534 or Email: cetnarj@ohsu.edu. 
 
8.5 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, the Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 

 
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9.0 
STUDY CALENDAR 
 
9.1 
Neoadjuvant (Registration Step 1) 
 
  
PRE-REG 
A 
AFTER 
REG, 
PRIOR TO 
CYCLE 1 
Cycle 
1 
Cycle 2 
Cycle 3 
Cycle 4 
At Step 1 
Off Tx  
For patients not continuing on to 
registration Step 2 
(Each cycle = 21 days) 
Follow-Up Prior 
to ProgressionJ 
Follow-Up After 
ProgressionK  
Day 1 
Day 1 
Day 1 
Day 1 
PHYSICAL 
  
  
  
  
  
  
  
  
  
History & Physical Exam 
X 
  
X 
X 
X 
X 
X 
X 
  
Weight & Zubrod 
Performance Status 
X 
  
X 
X 
X 
X 
X 
X 
  
Height 
X 
  
  
  
  
  
  
  
  
Disease AssessmentB 
X 
  
  
  
X 
  
X 
X 
  
Toxicity Notation 
X 
  
X 
X 
X 
X 
X 
XL 
XL 
Baseline Abnormalities 
X 
  
  
  
  
  
  
  
  
Vital signsC 
X 
  
X 
X 
X 
X 
X 
  
  
LABORATORY  
  
  
  
  
  
  
  
  
  
CBC/Diff/Platelets/Hgb 
X 
  
XH 
X 
X 
X 
X 
  
  
Creatinine and creatinine 
clearance 
X 
  
XH 
X 
X 
X 
  
  
  
Total bilirubin, AST, and 
ALT 
X 
  
XH 
X 
X 
X 
  
  
  
Hepatitis serologyD 
X 
 
 
 
 
 
 
 
 
TSH w/ Reflex Free T4 
 
 
XP 
XP 
 
XP 
 
 
 
 
Calendar 9.1 continued on next page.  Click here for footnotes. 
 
 

 
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PRE-REG 
A 
AFTER 
REG, 
PRIOR TO 
CYCLE 1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
At Step 1 
Off Tx  
For patients not continuing on to 
registration Step 2 
(Each cycle = 21 days) 
Follow-Up Prior to 
ProgressionJ 
Follow-Up After 
ProgressionK 
Day 1 
Day 1 
Day 1 
Day 1 
SCANS 
  
  
  
  
  
  
  
  
  
AudiogramF 
X 
  
  
  
  
  
  
  
  
CT chest/abdomen with 
contrast, FDG-PET/CT 
ScanB, or MRI for Disease 
Assessment 
XN 
  
  
  
X 
 
X 
X 
 
STAGING 
  
  
  
  
  
  
  
  
  
Mediastinoscopy or 
endobronchial ultrasound 
(EBUS) 
XG 
  
  
  
  
  
  
  
  
Diagnostic laparoscopy 
X 
  
  
  
  
  
  
  
  
Video-assisted 
thoracoscopic surgery 
X 
  
  
  
  
  
  
  
  
SPECIMEN 
SUBMISSION 
  
  
  
  
  
  
  
  
  
Tumor Tissue for 
translational research 
X 
  
  
  
  
  
  
  
Plasma and buffy coat for 
banking (if patient 
consents) 
  
X 
  
  
  
  
X 
  
XM 
TREATMENT 
  
  
  
  
  
  
  
  
  
Folic Acid 
  
X 
See Section 7.2a for schedule 
  
  
  
Vitamin B12 
  
X 
  
  
  
Atezolizumab  
  
  
X 
X 
X 
X 
  
  
  
Pemetrexed 
  
  
X 
X 
X 
X 
  
  
  
Cisplatin 
  
  
X 
X 
X 
X 
  
  
  
Click here for footnotes. 

 
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Calendar 9.1 Footnotes: 
 
NOTE: Forms are found on the protocol abstract page on the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0. 
 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as 
outlined in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 
A  To be performed within 28 days prior to registration, except as otherwise indicated. 
B  Scanning method must meet diagnostic quality criteria in protocol Section 10.1.c. Disease assessments must be repeated every 6 weeks (+- 7 day window until  
 
registration to Step 2. 
C  Vital signs include the following: blood pressure, heart rate, oxygen saturation, respiratory rate. 
D  Hepatitis serology includes the following: HBsAg, HBcAb, and anti-HCV. 
F  Audiogram to be performed at baseline if patient requires hearing aids or reports hearing loss.  Audiogram to be repeated while on cisplatin as clinically indicated  
     (see Section 8.2.d.5). 
G  Mediastinoscopy / endobronchial ultrasound (EBUS)must be performed within 42 days prior to registration to Step 1. 
H  Does not need to be completed if pre-registration labs were performed within 14 days prior to Cycle 1 Day 1. 
J  After off treatment prior to progression, patients should be followed by repeating indicated tests every three months for the first year, then every six months for the  
    second year, then at the end of year three from the date of Step 1 registration. 
K  After off treatment after progression, follow-up will occur every six months for two years, then at the end of year three from the date of Step 1 registration. 
L  Assessments should continue until resolution of all acute adverse events. 
M  Plasma and buffy coat submission optional at time of progression. 
N For patients receiving adjuvant radiation therapy on Step 2, this baseline scan is part of the RT planning materials that must be submitted to IROC as detailed 
in Section 12.2. 
P TSH with reflex free T4 to be performed prior to treatment on Cycle 1, at the end of Cycle 2, and at the end of Cycle 4. 
 
 

 
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9.2 
Surgery +/- Radiation (Registration Step 2) 
 
  
PRE-REG (to 
STEP 2) 
P/D or 
EPP 
Adjuvant 
radiation 
treatment D 
Post-
Surgery/Radiation 
(At Step 2 Off Tx)E 
For patients not continuing on to registration Step 3 
Follow-up Prior to 
Progression / RelapseF 
Follow-up After 
Progression / RelapseG 
PHYSICAL 
  
  
  
  
  
  
History & Physical Exam 
X 
  
X 
X 
X 
  
Weight & Zubrod Performance 
Status 
X (within 28 
days prior to 
reg) 
  
X 
X 
X 
  
Disease AssessmentA 
X (within 28 
days prior to 
reg) 
  
  
  
X 
  
Toxicity Notation 
X 
  
  
X 
XH 
XH 
Vital signsB 
  
  
X 
X 
  
  
Consultation with surgeon 
X 
  
  
  
  
  
Consultation with radiation 
oncologist C 
X (within 14 
days prior to 
reg) 
  
  
  
  
  
LABORATORY STUDIES 
  
  
  
  
  
  
CBC/Diff/ Platelets/Hgb 
X 
  
  
X 
  
  
CARDIOPULMONARY 
CLEARANCE TESTING 
  
  
  
  
  
  
Pulmonary function testing 
X (within 28 
days prior to 
reg) 
  
  
  
  
  
 
Calendar 9.2 continued on next page.  Click here for footnotes. 
 
 

 
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PRE-REG (to 
STEP 2) 
P/D or 
EPP 
Adjuvant 
radiation 
treatment D 
Post-
Surgery/Radiation 
(At Step 2 Off Tx)E 
For patients not continuing on to registration Step 3 
Follow-up Prior to 
Progression / RelapseF 
Follow-up After 
Progression / RelapseG 
SPECIMEN SUBMISSION 
  
  
  
  
  
  
Tumor Tissue for translational 
research 
  
X 
  
  
  
  
Plasma and buffy coat for banking 
(if patient consents) 
  
  
  
  
  
XJ 
SCANS 
  
  
  
  
  
  
CT chest/abdomen with contrast, 
FDG-PET/CT ScanA, or MRI for 
Disease Assessment 
X (within 28 
days prior to 
reg) 
  
  
X 
X 
  
 
Calendar 9.2 Footnotes: 
 
NOTE: 
Forms are found on the protocol abstract page on the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 
 
A  Scanning method must meet diagnostic quality criteria in protocol Section 10.1.c.  
B  Vital signs includes the following: blood pressure, heart rate, oxygen saturation, respiratory rate. 
C  For patients planning to receive EPP.  Submit materials via TRIAD to IROC as detailed in Section 12.2. 
D  For patients receiving EPP.  Should be started no later than 45 days following surgery.  See Section 7.4.  Submit materials via TRIAD to IROC as detailed  
in Section 12.2. 
E  To be completed within 28 days following surgery (if no radiation) or radiation. 
F  After off treatment prior to progression/relapse, patients should be followed by repeating indicated tests every three months for the first year, then every  
six months for the second year, then at the end of year three from the date of Step 1 registration. 
G  After off treatment after progression/relapse, follow-up will occur every six months for two years, then at the end of year three from the date of Step 1 registration. 
H  Assessments should continue until resolution of all acute adverse events. 
J  Plasma and buffy coat submission optional at time of progression. 

 
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9.3 
Maintenance (Registration Step 3)  
  
PRE-
REGISTRATION  
(to STEP 3) A 
Maintenance 
(every 21 days for 
up to 1 year) 
Every 2 cycles for 
Up to 1 Year 
At Step 3 Off Tx  
Follow-up Prior to 
Progression / 
RelapseE 
Follow-up After 
Progression / 
RelapseF 
PHYSICAL 
  
  
  
  
  
  
History & Physical Exam 
X 
  
X 
X 
X 
  
Weight & Zubrod Performance 
Status 
X 
  
X 
X 
X 
  
Disease Assessment B 
X 
  
X 
X 
X 
  
Toxicity Notation 
X 
X 
 
X 
XG 
XG 
Vital signs C 
X 
  
X 
X 
  
  
LABORATORY STUDIES 
  
 
  
  
  
  
CBC/ Diff/ Platelets/Hgb 
X 
X 
 
X 
  
  
Creatinine and creatinine 
clearance 
X 
X 
 
X 
  
  
Total bilirubin, AST, and ALT 
X 
X 
  
  
  
  
TSH w/ Reflex Free T4 
 
XP 
 
 
 
 
SCANS 
  
 
  
  
  
  
CT chest/abdomen with 
contrast, FDG-PET/CT Scan B, 
or MRI for Disease 
Assessment 
X 
  
X 
X 
X 
  
TREATMENT 
  
  
  
  
  
  
Atezolizumab 
  
X D 
  
  
  
  
SPECIMEN SUBMISSION 
  
  
  
  
  
  
Plasma and buffy coat for 
banking (if patient consents) 
  
  
  
  
  
XH 
Click here for footnotes. 

 
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Calendar 9.3 Footnotes: 
 
NOTE: Forms are found on the protocol abstract page on the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0. 
 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in 
https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. 
 
 
A To be completed within 28 days of step 3 registration. 
B Scanning method must meet diagnostic quality criteria in protocol Section 10.1c. Disease assessments must be repeated every 6 weeks (+- 7 day window)  
     while on treatment. 
C  Vital signs include the following: blood pressure, heart rate, oxygen saturation, respiratory rate. 
D Must start within 90 days following completion of definitive surgery (P/D or EPP) or radiation. 
E After off treatment prior to progression/relapse, patients should be followed by repeating indicated tests every three months for the first year, then every  
    six months for the second year, then at the end of year three from the date of step 1 registration. 
F After off treatment after progression/relapse, follow-up will occur every six months for two years, then at the end of year three from the date of step 1 registration. 
G Assessments should continue until resolution of all acute adverse events. 
H Plasma and buffy coat submission optional at time of progression. 
P TSH with reflex free T4 to be performed prior to treatment on Cycle 1, at the end of Cycle 2, then after every two cycles while on maintenance. 
 
 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
In this study, disease is to be assessed using both RECIST 1.1 and the Modified RECIST for Pleural 
Tumors. This means that pleural tumors must be assessed using BOTH methods. RECIST 1.1 
criteria are outlined in Sections 10.1-10.2. In addition, modified RECIST measurements as 
determined by six pleural thickness measurements perpendicular to the chest wall are to be 
obtained and incorporated into determination of objective status as outlined in Section 10.5.  For a 
practical guide to modified RECIST and RECIST measurements, please see Tsao et al. (31) 
 
10.1 
Measurability of lesions 
 
a. 
Measurable disease  
 
Measurable disease is defined differently for lymph nodes compared with other 
disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 cm  
with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters (or 
millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm 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 non-measurable as are previously radiated 
lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, 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 by performed with breath-hold scanning 
techniques, if possible.  
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a 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, then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT. 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
4. 
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. 
5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 

 
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measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 
 
10.2 
Objective status at each disease evaluation   
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. 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.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease.   
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas. Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans. For study-specific imaging requirements, see the Study 
Calendar in Section 9.0.   
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.   Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed using 
the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
 
 
d. 
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm.  Unequivocal 
progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).  Appearance of any new lesion/site.  Death due to 
disease without prior documentation of progression and without symptomatic 
deterioration (see Section 10.2f). 
 
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using 
the date of the initial scan. 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans in 
identifying new lesions according to the following algorithm.  
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of progression based on a new lesion. 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a confirmation 
by anatomical assessment (e.g. CT, MRI, x-ray) as new site of disease to 

 
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be considered progressive disease.  In such a case, the date of 
progressive disease will be the date of the initial abnormal FDG-PET.   
  
e. 
Relapse/Progression, Following Surgery: Unequivocal progression of non-
measurable disease in the opinion of the treating physician (an explanation must 
be provided).  Appearance of any new lesion/site.  Death due to disease without 
prior documentation of progression and without symptomatic deterioration. 
 
f. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
g. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
 
h. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).  
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.   
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
5. 
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression. However, increase in the soft 
tissue component of a lesion as measured by CT or MRI would constitute 
progression. 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute unequivocal 
progression, since the fluid status of the patient could alter the size of the 
effusion.  
7. 
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy or fine needle aspirate.   
 
10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 

 
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b. 
PR: Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as 
CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.   
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 12 
weeks of registration, not qualifying as anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
10.4 
Performance Status  
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
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.   
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair.   
 
 
10.5 
Modified RECIST  
 
Modified RECIST for Pleural Tumors:  Response is to be assessed both via RECIST and 
also modified RECIST for pleural tumors.  (32)  
 
For RECIST 1.1, the definitions outlined in Section 10.1 must be followed. The longest 
diameter of the pleural lesion, as defined in Section 10.1a.1, must be recorded in the target 
lesion section of the RECIST and Modified RECIST Baseline Tumor Assessment Form 
(Form #35990) and the Follow Up Tumor Assessment Form-RECIST and Modified 
RECIST (Form #23757). If a longest diameter that fulfills the criteria outlined in Section 

 
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10.1a.1 cannot be obtained, then it should be recorded in the non-target lesion section of 
the respective forms. 
 
In addition, for modified RECIST, measurements based on the sum of 6 CT cuts in the 
pleura perpendicular to the chest wall are to be obtained via the description below and 
applied (along with unidimensional measurements from other non-pleural lesions) to 
standard RECIST criteria (sum of 6 = one univariate diameter).  The six pleural thickness 
measurements are to be documented on the Mesothelioma Baseline Tumor Assessment 
Form and the Mesothelioma Follow-Up Tumor Assessment Form.  
 
Tumor thickness perpendicular to the chest wall or mediastinum should be measured in 
two positions at three separate levels on transverse cuts of the CT scan. The sum of the 
six measurements defines a pleural unidimensional measure. Transverse cuts at least 1 
cm apart and related to anatomical landmarks in the thorax should be chosen to allow for 
reproducible assessment at later time points. If measurable tumor is present, transverse 
cuts in the upper thorax, above the level of the division of the main bronchi are preferred. 
At reassessment, pleural thickness should be measured at the same position at the same 
level and by the same observer. This is not necessarily the greatest tumor thickness at that 
level. Nodal, subcutaneous and other measurable lesions should be measured 
unidimensionally as per the RECIST criteria. Unidimensional measurements are added to 
obtain the total tumor measurement. 
 
10.6 
Progression-free survival by RECIST 1.1 
 
From date of registration to Step 1 to date of first documentation of progression by RECIST 
1.1 (defined in Section 10.2d), symptomatic deterioration (as defined in Section 10.2f), or 
death due to any cause.  Patients last known to be alive and progression free are censored 
at date of last disease assessment. 
 
10.7 
Progression-free survival by Modified RECIST 1.1 
 
From date of registration to Step 1 to date of first documentation of progression by modified 
RECIST 1.1 (defined in Section 10.5), symptomatic deterioration (as defined in Section 
10.2f), or death due to any cause.  Patients last known to be alive and progression free are 
censored at date of last disease assessment. 
 
10.8 
Relapse-Free Survival   
 
From date of Step 2 registration to date of first documentation of relapse/progression (as 
defined in Section 10.2e), symptomatic deterioration (as defined in Section 10.2f), or death 
due to any cause.  Patients last known to be alive and free of disease are censored at date 
of last disease assessment. 
 
10.9 
Time to Death 
 
From date of initial registration to date of death due to any cause.  Patients last known to 
be alive are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
This study will evaluate the safety/tolerability and feasibility of neoadjuvant cisplatin-
pemetrexed-atezolizumab, followed by surgery +/- radiation, followed by adjuvant 
maintenance atezolizumab 
 
The accrual goal to this study is 24 eligible and evaluable patients, with a goal of 12 
patients undergoing EPP and 12 P/D. A patient will be deemed evaluable if they receive 

 
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at least two cycles of the triplet neoadjuvant therapy (all three drugs). Patients who are not 
evaluable will be replaced. Both cohorts will be open in parallel.  The regimen will be 
pursued in a future study if it satisfies both the safety and feasibility criteria.  
 
The regimen will be considered safe and tolerable if no patients experience a Grade 4-5 
immune-related adverse event. The following table describes the probability of observing 
Grade 4-5 non-hematologic toxicity or Grade 4-5 immune-related event if the true 
prevalence is 1%, 5%, or 10%. 
 
Table 1: Probability of observing Grade 4-5 immune-related event 
 
True Prevalence 
1% 
5% 
10% 
Probability at least one patient observed with an event: 
21% 
71% 
92% 
 
The regimen will be considered feasible if 18/24 (75%) patients receive at least one dose 
of maintenance therapy. Given data from other studies, the anticipated rate of patients 
receiving maintenance therapy is 70-80%. We would consider the observation of at least 
18/24 to be evidence that maintenance therapy is feasible in this setting. With at least 18 
patients receiving maintenance therapy following neoadjuvant cisplatin-pemetrexed-
atezolizumab, estimates of the safety/tolerability of maintenance therapy have precision of 
23.5% (95% CI width) and any toxicity with at least 10% prevalence has at least an 85% 
chance of being observed.    
 
Analyses will separately evaluate patients who receive P/D and those who receive an EPP 
for their surgical procedure.  
 
Survival outcomes (PFS, OS, mR-PFS) will be evaluated using the method of Kaplan-Meier.  
Confidence intervals around the median will be calculated using the Brookmeyer-Crowley 
method, confidence intervals around landmark time points will use the Greenwood formula 
for standard errors. With 24 evaluable patients, proportions (toxicity, response rate, 
landmark survival percentage) can be estimated within 20% with 95% confidence. 
 
It is anticipated that a total of 28 patients will need to be registered in order to accrue 24 
eligible and evaluable patients. 
 
There is no formal Data and Safety Monitoring Committee for this study.  Accrual reports 
are generated weekly and study-specific accrual monitoring is done by the Study Chair, 
Study Statistician and the Disease Committee Chair.  Reports summarizing adverse events, 
serious adverse events (SAEs) and treatment administration are provided monthly to the 
Study Chair and Study Statistician for monitoring.  In addition, all SAEs, which by definition 
require expeditious reporting, are reviewed and processed by the Adverse Event 
Coordinator at the SWOG Operations Office and a physician reviewer based on data 
provided via the NCI CTEP-AERS system.  Cumulative study-specific SAE reports are 
provided to the Study Chair and Study Statistician upon occurrence of an event. Formal 
reports summarizing the study are prepared for all SWOG members every 6 months. 
 
 
12.0 
DISCIPLINE REVIEW 
 
12.1 
Surgery Review 
 
Operative reports and a pathology report are to be submitted within 14 days after protocol 
surgery.  The primary operative report and the SWOG Surgical Form will be reviewed by 
the Surgical Study Chair. 
 

 
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12.2 
Radiation Therapy Review 
 
a. 
Submission of Digital Radiation Therapy Data 
 
Submission of treatment plans in digital format as DICOM RT is required. Digital data 
must include CT scans, structures, plan, and dose files. This study uses TRIAD for 
RT data submission. Use of TRIAD requires several preliminary steps (see Section 
12.2b).  Additional information is available at:  
http://triadhelp.acr.org/ClinicalTrials/NCISponsoredTrials.aspx  
 
Use of SFTP will also be accepted as an alternate method of data submission on 
this study.  See the instructions for submission of data via SFTP on the IROC 
Rhode Island website under Digital Data. 
 
Any items on the list below that are not part of the digital submission may be included 
with the transmission of the digital RT data. 
 
One week prior to the start of radiotherapy, the following data must be 
submitted for pre-treatment review for all cases: 
 
1. 
Treatment Planning System Output 
• 
RT treatment plans including CT from baseline in Step 1, structures, 
dose and plan files. These items are included in the digital plan. 
• 
Dose volume histograms (DVH) for the composite treatment plan for 
all target volumes and required organs at risk. For all RT plans, a DVH 
shall be submitted for a category of tissue called “unspecified tissue.” 
This is defined as tissue contained within the skin, but which is not 
otherwise identified by containment within any other structure. DVHs 
are included in the digital plan. 
• 
Treatment planning system summary report that includes the monitor 
unit calculations, beam parameters, calculation algorithm, and volume 
of interest dose statistics. 
2. 
Supportive Data 
• 
Copies and reports of all imaging studies used to define the target 
volume. 
• 
Prescription sheet for entire treatment. 
3. 
Forms 
• 
RT-1 Dosimetry Summary Form 
• 
Motion Management Reporting Form  
 
Within 21 days after the completion of radiotherapy (Step 2), the following 
data must be submitted for all patients: 
 
• 
The RT-2 Radiotherapy Total Dose Record Form 
• 
A copy of the patient's radiotherapy record including the prescription, and the 
daily and cumulative doses to all required areas. 
• 
Documentation listed above showing any modifications from the original 
submission. 
 
Supportive data and forms may be included with the transmission of the digital RT 
data or submitted separately via e-mail to DataSubmission@qarc.org. 
 
Questions regarding the dose calculations or documentation should be directed to: 
Protocol Dosimetrist 
IROC Rhode Island QA Center 
Phone: (401) 753-7600 

 
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Email: physics@qarc.org 
 
b. 
Digital RT Data Submission Using TRIAD  
 
TRIAD is the American College of Radiology’s (ACR) image exchange application.  
TRIAD provides sites participating in clinical trials a secure method to transmit 
DICOM RT and other objects. TRIAD anonymizes and validates the images as 
they are transferred. 
 
TRIAD Access Requirements: 
 
Site staff who will submit images through TRIAD will need to be registered with the 
Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP 
Identity and Access Management (IAM) account.  Please refer to CTEP 
Registration Procedures of the protocol for instructions on how to request a CTEP-
IAM account. 
 
To submit digital RT data and images (DICOM and DICOM RT), the site user must 
be on the site’s roster and be assigned the 'TRIAD site user' role. Users should 
contact the site’s roster Administrator to request assignment of the TRIAD site user 
role.   
 
TRIAD Installations: 
 
When a user applies for a CTEP-IAM account with the proper user role, he/she will 
need to have the TRIAD application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be found by following this 
link https://triadinstall.acr.org/triadclient/   
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
c. 
Credentialing 
 
RT   
Credentialing 
Requirements 
Web 
Link 
for 
Credentialing 
Procedures 
and 
Instructions 
http://irochouston.mdanderson.org 
Treatment Modality 
 
Photon 
Key Information 
Facility 
Questionnaire 
x 
The IROC Houston electronic facility questionnaire (FQ) 
should be completed or updated with the most recent 
information about your institution.  To access this FQ, 
email irochouston@mdanderson.org to receive your 
FQ link. 
Phantom 
Irradiation 
x 
An IMRT phantom study provided by the IROC Houston 
QA Center must be successfully completed. Instructions 
for requesting and irradiating the phantom are found on 
the 
IROC 
Houston 
web 
site 
(http://irochouston.mdanderson.org). 
IGRT 
x 
Only institutions interested in using reduced margins 
will be required to complete this credentialing step. 
Instructions for IGRT credentialing may be found on the 

 
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RT   
Credentialing 
Requirements 
Web 
Link 
for 
Credentialing 
Procedures 
and 
Instructions 
http://irochouston.mdanderson.org 
Treatment Modality 
 
Photon 
Key Information 
IROC 
Houston 
website 
(http://irochouston.mdanderson.org).   
Credentialing 
Status Inquiry 
Form 
x 
To determine if your institution has completed the 
requirements above, please complete a “Credentialing 
Status Inquiry Form” found under Credentialing on the 
IROC 
Houston 
QA 
Center 
website 
(http://irochouston.mdanderson.org). 
Credentialing Notification Issued to: 
Institution 
Institution will be credentialed for the treatment modality 
that they intend to use on all patients. IROC Houston QA 
Center 
will 
notify 
the 
institution 
and 
SWOG 
Headquarters 
that 
all 
desired 
credentialing 
requirements have been met. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
a. 
Step 1: Neoadjuvant 
 
Patients must be registered prior to initiation of neoadjuvant therapy (no more than 
seven calendar days prior to planned start of treatment). 
 
b. 
Step 2: Surgery 
 
Patients must be registered prior to receiving surgery (no more than seven 
calendar days prior to surgery date).  
 
c. 
Step 3: Maintenance 
 
Patients must be registered prior to initiation of maintenance therapy (no more than 
seven calendar days prior to planned start of treatment).  
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored clinical 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 (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to 

 
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OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements 
per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) 
tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, 
please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
b. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria including 
but not limited to: the following: 
 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the 
following criteria: 
 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 
1572 

 
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• 
An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the 
CIRB for this study are not required to submit IRB approval documentation 
to the CTSU Regulatory Office. For sites using the CIRB, IRB approval 
information is received from the CIRB and applied to the RSS in an 
automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRB Manager to 
indicate their intent to open the study locally.  The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office. In order for 
the SSW approval to be processed, the Signatory Institution must inform 
the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
2. 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the S1619 protocol page 
located on the CTSU members’ website.  
• 
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol 
tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the SWOG link to expand, then select trial protocol S1619 
• 
Click on LPO Documents, select the Site Registration documents link, 
and download and complete the forms provided.  
 
3. 
Requirements for S1619 Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol 
of 
Human 
Subjects 
Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted) 
• 
CTSU RT Facilities Inventory Form  
NOTE:  Per NCI policy all institutions that participate on protocols with 
a radiation therapy component must participate in the Image and 
Radiation Oncology Core (IROC) monitoring program.  If this form has 
been previously submitted to CTSU it does not need to be resubmitted 
unless updates have occurred at the RT facility. 
 
4. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via 
the Regulatory Submission Portal, where they will be entered and tracked 
in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org (members’ area)  
Regulatory Tab  Regulatory Submission 
 
When applicable, original documents should be mailed to: 
 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 

 
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Institutions with patients waiting that are unable to use the Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order 
to receive further instruction and support. 
 
5. 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the 
CTSU website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements as 
outlined by the Lead Network. 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. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < 
https://ctepcore.nci.nih.gov/iam >) and a ‘Registrar’ role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type.  If a DTL 
is required for the study, the registrar(s) must also be assigned the OPEN Registrar task 
on the DTL.  
 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database.  OPEN can be accessed at https://open.ctsu.org or from the 
OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.  To assign 
an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 
1572 in RCR the IRB number used on the site’s IRB approval.  If a DTL is required for the 
study, the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 

 
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e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 

 
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the registering investigator or another investigator designate. Site staff should 
refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see below for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS). To access Rave via iMedidata, you must have 
an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA Lab Admin, SLA, or Site 
Investigator) on either the LPO or participating organization roster at the enrolling 
site. To hold the Rave CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type.  To hold the Rave Site Investigator role, the 
individual must be registered as an NPIVR or IVR.  Associates can hold read-only 
roles in Rave.  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 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 users must log into the Select Login 

 
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(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users 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. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial 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, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 
888/823-5923 or by e-mail at ctsucontact@westat.com. 
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.swog.org).  
 
For 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
14.4 
Data Submission Overview and Timepoints    
 
a. 
STEP 1: NEOADJUVANT 
 
1. 
WITHIN 7 DAYS OF REGISTRATION TO STEP 1: NEOADJUVANT, 
SUBMIT:   
  
S1619 Onstudy Form 
 
Baseline Abnormalities Form 
 
Mesothelioma Baseline Tumor Assessment Form 
 
Pathology Report* 
 
All reports from surgical staging* 
 
Radiology reports from all scans performed to assess disease at baseline* 
 
*NOTE: Upload these reports via the Source Documentation: Baseline 
form in Rave® 
 
2. 
SUBMIT SPECIMENS: 
 
Specimens as outlined in Section 15.0. 
 
3. 
WITHIN 7 DAYS AFTER EACH CYCLE (1 CYCLE = 21 DAYS) OF 
NEOADJUVANT THERAPY, SUBMIT: 
 
S1619 Neoadjuvant Treatment Form 
 
S1619 Adverse Event Form 

 
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4. 
WITHIN 7 DAYS AFTER EACH DISEASE ASSESSMENT (INCLUDING 
BOTH ON TREATMENT AND OFF TREATMENT PRIOR TO DISEASE 
PROGRESSION), SUBMIT:  
 
Mesothelioma Follow Up Tumor Assessment Form 
 
Radiology reports from all scans performed to assess disease at follow 
up* 
 
*NOTE: Upload these reports via the Source Documentation: Follow Up 
form in Rave® 
 
5. 
WITHIN 21 DAYS OF DISCONTINUATION OF NEOADJUVANT 
THERAPY SUBMIT: 
 
Off Treatment Notice  
 
S1619 Neoadjuvant Treatment Form 
 
S1619 Adverse Event Form 
 
6. 
WITHIN 14 DAYS OF PROGRESSION ON NEOADJUVANT THERAPY, 
SUBMIT:  
 
Mesothelioma Follow Up Tumor Assessment Form 
 
Lung Carcinoma First Site(s) of Progression or Relapse Form 
 
Radiology reports from all scans performed to document progression* 
 
If the patient was off treatment, also submit S1619 Follow Up Form 
 
*NOTE: Upload these reports via the Source Documentation: Follow Up 
form in Rave® 
 
b. 
STEP 2: SURGERY 
 
1. 
WITHIN 7 DAYS OF REGISTRATION TO STEP 2: SURGERY, SUBMIT: 
 
S1619 Surgery Eligibility Form, confirming patient’s eligibility for surgery 
 
Mesothelioma Follow Up Tumor Assessment Form 
 
Radiology reports from all scans performed to assess disease at follow 
up* 
 
All reports from pulmonary function tests* 
 
*NOTE: Upload these reports via the Source Documentation: Follow Up 
form in Rave® 
 
2. 
SUBMIT RADIATION THERAPY REVIEW MATERIALS: 
 
Submit radiation therapy materials via TRIAD as described in Section 12.2 
 

 
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3. 
WITHIN 30 DAYS OF COMPLETION OF SURGERY, SUBMIT: 
 
S1619 Adverse Event Form** 
 
Lung Carcinoma Surgeon’s Post-Operative Assessment Form  
 
Operative Report from Surgery* 
 
Pathology Report from Surgery* 
 
*NOTE: Upload these reports via the Source Documentation: Follow Up 
form in Rave® 
 
**Only for patients who received P/D. 
 
4. 
WITHIN 30 DAYS OF COMPLETION OF RADIATION THERAPY, IF 
APPLICABLE, SUBMIT: 
 
Lung Carcinoma Radiation Therapy Form 
 
S1619 Adverse Event Form** 
 
Radiation Summary Note* 
 
*NOTE: Upload these reports via the Source Documentation: Follow Up 
form in Rave® 
 
**Only for patients who received EPP + RT 
 
c. 
STEP 3: MAINTENANCE 
 
1. 
WITHIN 7 DAYS OF REGISTRATION TO STEP 3: MAINTENANCE, 
SUBMIT: 
 
S1619 Maintenance Therapy Eligibility Form 
 
S1619 Disease Assessment Form 
 
Radiology reports from all scans performed to assess disease at follow 
up* 
 
*NOTE: Upload these reports via the Source Documentation: Follow Up 
form in Rave® 
 
2. 
WITHIN 7 DAYS AFTER EACH CYCLE OF MAINTENANCE THERAPY 
(1 CYCLE = 21 DAYS) UP TO 1 YEAR, SUBMIT: 
 
S1619 Maintenance Treatment Form 
 
S1619 Adverse Event Form 
 
3. 
WITHIN 7 DAYS AFTER EACH DISEASE ASSESSMENT (INCLUDING 
BOTH ON TREATMENT AND OFF TREATMENT PRIOR TO DISEASE 
PROGRESSION/RELAPSE), SUBMIT: 
 
S1619 Disease Assessment Form 
 

 
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Radiology reports from all scans performed to assess disease at follow 
up* 
 
*NOTE: Upload these reports via the Source Documentation: Follow Up 
form in Rave® 
 
4. 
WITHIN 21 DAYS OF DISCONTINUATION OF MAINTENANCE 
THERAPY, SUBMIT: 
 
Off Treatment Notice 
 
S1619 Maintenance Treatment Form 
 
S1619 Adverse Event Form 
 
5. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE ON MAINTENANCE 
THERAPY, SUBMIT: 
 
S1619 Disease Assessment Form 
 
Lung Carcinoma First Site(s) of Progression or Relapse Form 
 
Radiology 
reports 
from 
all 
scans 
performed 
to 
document 
progression/relapse*  
 
*NOTE: Upload these reports via the Source Documentation: Follow Up 
form in Rave® 
 
d. 
APPLY TO ALL REGISTRATION STEPS 
 
1. 
ONCE OFF STUDY, EVERY 3 MONTHS FOR FIRST YEAR, THEN 
EVERY 6 MONTHS FOR THE SECOND YEAR, THEN AT THE END OF 
YEAR 3, SUBMIT: 
 
Lung Carcinoma Follow Up Form 
 
Late Effects Form (if prior to treatment for recurrence or relapse or a 
second primary, and prior to non-protocol treatment, the patient 
experiences any severe [Grade ≥ 3] long term toxicity that has not been 
previously reported) 
 
2. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH, SUBMIT: 
 
Notice of Death.  
 
If the patient was still on protocol treatment, also submit the forms listed in 
Section 14.4a.5 (if on neoadjuvant therapy) or Section 14.4c.5 (if on 
maintenance therapy). 
 
If the patient was off treatment, also submit the Lung Carcinoma Follow-
Up Form. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Specimens for Translational Medicine and Banking 
 

 
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a. 
Tumor Tissue (MANDATORY for patient) 
 
Tissue must be collected at two time points:  (1) pre-registration; and (2) protocol 
surgery. 
 
Within 14 days after registration and again within 14 days after surgery, submit 
a paraffin-embedded tissue block containing 10% normal buffered formalin fixed 
tumor.  Please note that only 10% normal buffered formalin fixation is acceptable 
for tissue submission. Cytology (e.g. fine-needle aspirations, pleural effusion 
specimens) can be accepted only if they are paraffin embedded as cell blocks, 
positive for malignant cells, and provide sufficient number of required blocks or 
slides.  Submission of blocks is strongly encouraged.  However, if blocks are 
unavailable, submit ALL of the following: 
 
• 
Two H&E slides 
• 
14-20 FFPE slides (5-7 microns) per timepoint 
 
Refer to the general labeling, packaging, and shipping instructions at 
https://www.swog.org/member-resources/biospecimen-resources and ship to Lab 
#201 (SWOG Biospecimen Bank - Solid Tissue, Myeloma, and Lymphoma 
Division - see the Specimen Tracking System). 
 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
These specimens will be used for the translational medicine studies described in 
Section 18.2.  Any tissue remaining after testing will be banked and, with additional 
patient consent, may be used for future unspecified research. 
 
b. 
Plasma and Buffy Coat (OPTIONAL for patient) 
 
With patient consent, blood must be collected at three time points:  (1) before 
beginning neoadjuvant treatment; (2) after completing neoadjuvant treatment; and 
(3) at progression. 
 
Follow the procedures below for processing plasma and buffy coat.  DO NOT use 
the processing instructions from the SWOG website. 
 
At each time point, draw approximately 10 mL blood in 1-2 lavender (EDTA) tubes.  
Place blood on wet ice immediately after collection and process as soon as 
possible (preferably within 2 hours). Centrifuge vacutainer tubes at approximately 
800 x g for 10 minutes (preferably in a refrigerated centrifuge, if available).  
Immediately after centrifugation, carefully transfer plasma to a new 15 mL conical 
tube using a pipette and being careful not to aspirate the interface between the 
plasma and the platelets (buffy coat layer).  Set aside original purple top tubes for 
later processing.  Then centrifuge plasma a second time at 1200 x g for 10 minutes.  
After the second centrifugation, aliquot plasma in 500 mcl aliquots into 6-10 labeled 
1.8-2.0 ml cryovials, being careful not to disturb the pellet in the bottom of the tube.  
The buffy coat, a whitish layer of cells between the plasma and red blood cell 
layers, should be collected from the original purple top tube(s) and transferred into 
2 labeled 1.8-2.0 ml cryovials (contamination with RBC not a concern).  Freeze 
cryovials immediately and store at or below -70° until shipped to the SWOG 
Biospecimen Bank on dry ice.   
 
Refer to the general labeling, packaging, and shipping instructions at 
http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp and ship to 
Lab #201 (SWOG Biospecimen Bank - Solid Tissue, Myeloma, and Lymphoma 
Division - see the Specimen Tracking System). 

 
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Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
Plasma and buffy coat will be banked and used for future unspecified research. 
 
15.2 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using the SWOG 
online Specimen Tracking system. SWOG members may log on the online system via the 
CRA Workbench. To access the CRA Workbench, go to the SWOG Web site 
(http://swog.org). Non-SWOG users may log into SpecTrack using their CTSU UserID and 
password on the SpecTrack login page located at  
https://spectrack.crab.org (select the option “SWOG – SWOG – CTSU”).  SpecTrack start-
up instructions (both written and demo) are available after signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen Tracking system 
should be printed and placed in the pocket of the specimen bag if it has one, or in a 
separate resealable bag. The Specimen Submission Form is NOT required when the online 
system is used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org. For procedural 
help with logging and shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page (https://spectrack.crab.org/Instructions); or contact the Data 
Operations Center at 206/652-2267 to be routed to the Data Coordinator for further 
assistance. 
 
Lab #201:  
SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma 
Division, Lab #201 
Phone: 614/722-2865 
Contact:  SWOG Repository Coordinator 
Email: bcpbal@nationwidechildrens.org 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice:  
 
Informed Consent  
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). They must 
be followed to comply with FDA regulations for the conduct and monitoring of clinical investigations. 
 
Institutional Review  
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46).  
 

 
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Drug Accountability  
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact  
 
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 in this study:  
 
1.  
Agent(s) may not be used 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 investigational 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 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 which 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 
investigational 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 exclusively 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 Identifiable Health 
Information set forth in 45 C.F.R. Part 164.  
 

 
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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 the Collaborator(s) for Phase III 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 the 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:  
 
E-mail: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information.  
 
Monitoring  
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, 
July 31, and October 31.  
 
Confidentiality  
 
Please note that the information contained in this protocol is considered confidential and 
should not be used or shared beyond the purposes of completing protocol requirements 
until or unless additional permission is obtained.  
 
16.1  
Adverse Event Reporting Requirements  
 
a. 
Purpose  
 
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. Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 
patient safety and care. The following guidelines describe expedited adverse event 
reporting for this protocol.  
 
b. 
Reporting Method  

 
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This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm 
  
c. 
When to report an event in an expedited manner  
 
Some adverse events require 24-hour notification (refer to Table 16.1).  
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event, as specified in Table 16.1. 
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301/897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection. 
 
Any supporting documentation should be submitted to CTEP per NCI guidelines 
for AE reporting located at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf. 
 
d. 
Other recipients of adverse event reports  
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures.  
 
e. 
Expedited reporting for investigational agents  
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agent(s) used in this study are atezolizumab, 
cisplatin, and pemetrexed. If there is any question about the reportability of an 
adverse event or if on-line CTEP-AERS cannot be used, please telephone or email 
the SAE Specialist at the Operations Office, 210/614-8808 or adr@swog.org, 
before preparing the report. 
 
 
 

 
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Table 16.1: 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1 atezolizumab, cisplatin, and pemetrexed 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or [Section 
16.1f].  
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
May 5, 2011 
 
 
 

 
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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 1 and Early Phase 2 Studies Utilizing an Agent 
under a CTEP-IND:  
 
1. 
Group-specific instructions  
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements. In addition, 
you may be asked to submit supporting clinical data to the SWOG 
Operations Offices in order to complete the evaluation of the event.  If 
requested, the supporting data should be sent within 5 calendar days by 
fax to 210-614-0006.  Supporting clinical data submitted should include: 
 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical sourced documentation of the event. 
• 
If applicable, and they have not yet been submitted to the SWOG 
Statistics and Data Management Center, copies of Off Treatment 
Notice and/or Notice of Death.  
 
2. 
Adverse Events of Special Interest in Atezolizumab Studies 
 
The following AEs are considered of special interest in patients receiving 
atezolizumab and must be reported expeditiously through CTEP-AERS, 
irrespective of regulatory seriousness criteria:  
 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies: 
 
diabetes 
mellitus, 
pancreatitis, 
hyperthyroidism, hypophysitis, and adrenal insufficiency 
• 
Hepatitis, including AST or ALT > 10 × ULN  
• 
Systemic lupus erythematosus 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic 
syndrome or myasthenia gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, cytokine release, influenza-
like illness, systemic inflammatory response syndrome, systemic 
immune activation, or infusion-related reactions  
• 
Nephritis  
• 
Ocular toxicities (e.g., uveitis, retinitis) 
• 
Myositis  
• 
Myopathies, including rhabdomyolysis  
• 
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, 
pericarditis) 
• 
Vasculitis 
 
g. 
Reporting Secondary Malignancies, including AML/ALL/MDS 
 
1. 
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 to be reported via CTEP-AERS.  Three 
options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 

 
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Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in 
each protocol. 
 
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 reporting via 
CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf  
 
2. 
Any supporting documentation should be submitted to CTEP per NCI 
guidelines for AE reporting located at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf. 
 
A copy of the report and the following supporting documentation must also 
be submitted to SWOG Operations Office within 30 days by fax to 210-
614-0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
h. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy loss  Pregnancy loss defined in CTCAE as “Death in 
utero.” should be reported expeditiously, as Grade 4 “Pregnancy 

 
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loss” under the Pregnancy, puerperium and perinatal conditions 
SOC. 
 
3. 
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4, “Death 
neonatal” under the General disorders and administration SOC. 
 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm   
 
 

 
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17.0 
BIBLIOGRAPHY 
 
1. 
Tsao AS, Wistuba I, Roth JA, Kindler HL. Malignant Pleural Mesothelioma. J Clin Oncol 
27(12):2081-90, 4/2009. e-Pub 3/2009. PMID: 19255316. 
 
2. 
Van Schil PE, Baas P, Gaafar R, et al: Trimodality therapy for malignant pleural mesothelioma: 
results from an EORTC phase II multicentre trial. Eur Respir J 36:1362-9, 2010. 
 
3  
Krug LM, Pass HI, Rusch VW, et al: Multicenter phase II trial of neoadjuvant pemetrexed plus 
cisplatin followed 
by extrapleural pneumonectomy and radiation for malignant pleural 
mesothelioma. J Clin Oncol 27:3007-13, 2009. 
 
4  
Federico R, Adolfo F, Giuseppe M, et al: Phase II trial of neoadjuvant pemetrexed plus cisplatin 
followed by surgery and radiation in the treatment of pleural mesothelioma. BMC Cancer 13:22, 
2013. 
 
5  
Weder W, Stahel R, Bernhard J, et al: Multicenter trial of neo-adjuvant chemotherapy followed by 
extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol, 2007. 
 
6  
Flores RM: Induction chemotherapy, extrapleural pneumonectomy, and radiotherapy in the 
treatment of malignant pleural mesothelioma: the Memorial Sloan-Kettering experience. Lung 
Cancer 49 Suppl 1:S71-4, 2005. 
 
7  
Weder W, Kestenholz P, Taverna C, et al: Neoadjuvant chemotherapy followed by extrapleural 
pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 22:3451-7, 2004. 
 
8  
Rea F, Marulli G, Bortolotti L, et al: Induction chemotherapy, extrapleural pneumonectomy (EPP) 
and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): Feasibility and 
results. Lung Cancer 57:89-95, 2007. 
 
9  
Opitz I, Kestenholz P, Lardinois D, et al: Incidence and management of complications after 
neoadjuvant 
chemotherapy followed by extrapleural pneumonectomy for malignant pleural 
mesothelioma. Eur J Cardiothorac Surg 29:579-84, 2006. 
 
10  
Van Schil PE, Baas P, Gaafar R, et al: Trimodality therapy for malignant pleural mesothelioma: 
results from an EORTC phase II multicentre trial. Eur Respir J 36:1362-9, 2010. 
 
11  
Krug LM, Pass HI, Rusch VW, et al: Multicenter phase II trial of neoadjuvant pemetrexed plus 
cisplatin followed 
by extrapleural pneumonectomy and radiation for malignant pleural 
mesothelioma. J Clin Oncol 27:3007-13, 2009. 
 
12  
Krug LM, Pass HI, Rusch VW, et al: Multicenter phase II trial of neoadjuvant pemetrexed plus 
cisplatin followed 
by extrapleural pneumonectomy and radiation for malignant pleural 
mesothelioma. J Clin Oncol 27:3007-13, 2009. 
 
13  
Van Schil PE, Baas P, Gaafar R, et al: Trimodality therapy for malignant pleural mesothelioma: 
results from an EORTC phase II multicentre trial. Eur Respir J 36:1362-9, 2010. 
 
14  
Krug LM, Pass HI, Rusch VW, et al: Multicenter phase II trial of neoadjuvant pemetrexed plus 
cisplatin followed 
by extrapleural pneumonectomy and radiation for malignant pleural 
mesothelioma. J Clin Oncol 27:3007-13, 2009. 
 
15  
Federico R, Adolfo F, Giuseppe M, et al: Phase II trial of neoadjuvant pemetrexed plus cisplatin 
followed by surgery and radiation in the treatment of pleural mesothelioma. BMC Cancer 13:22, 
2013. 

 
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16  
Weder W, Kestenholz P, Taverna C, et al: Neoadjuvant chemotherapy followed by extrapleural 
pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 22:3451-7, 2004. 
 
17  
Rea F, Marulli G, Bortolotti L, et al: Induction chemotherapy, extrapleural pneumonectomy (EPP) 
and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): Feasibility and 
results. Lung Cancer 57:89-95, 2007. 
 
18  
Weder W, Stahel RA, Bernhard J, et al: Multicenter trial of neo-adjuvant chemotherapy followed by 
extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 18:1196-202, 2007. 
 
19  
Flores RM, Krug LM, Rosenzweig KE, et al: Induction chemotherapy, extrapleural 
pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural 
mesothelioma: a phase II trial. J Thorac Oncol 1:289- 95, 2006. 
 
20  
Batirel HF, Metintas M, Caglar HB, et al: Trimodality treatment of malignant pleural mesothelioma. 
J Thorac Oncol 3:499-504, 2008. 
 
21  
Volgezang N, Rusthoven J, Symanowski J, et al.  Phase III study of pemetrexed in combination 
with cisplatin versus    cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 
21:2636-2644, 2003. 
 
22  
Zalcman G, Mazieres J, Scherpereel A, et al: IFCT-GFPC-0701 MAPS trial, a multicenter 
randomized phase III trial of pemetrexed-cisplatin with or without bevacizumab in patients with 
malignant pleural mesothelioma (MPM). Lancet 387:1405-14, 2016. 
 
23  
Mansfield A, Peikert T, Roden A, et al: Programmed cell death 1 ligand 1 expression and 
association with survival in mesothelioma. Journal of Thoracic Oncology 9 S7-S52, 2014. 
 
24  
Mansfield A, Peikert T, Roden A, et al: Programmed cell death 1 ligand 1 expression and 
association with survival in mesothelioma. Journal of Thoracic Oncology 9 S7-S52, 2014. 
 
25  
Alley E, Santoro A, Beckey K, et al: Clinical safety and efficacy of pembrolizumab (MK-3475) in 
patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028 Abstract 
CT103.  AACR  2015. Pennsylvania Convention Center, 2015. 
 
26  
Alley E, Santoro A, Beckey K, et al: Clinical safety and efficacy of pembrolizumab (MK-3475) in 
patients with malignant pleural  mesothelioma: Preliminary results from KEYNOTE-028 Abstract  
CT103.  AACR 2015. Pennsylvania Convention Center, 2015. 
 
27  
Hassan R, Thomas A, Patel M, et al: Avelumab (MSB0010718C; anti-PD-L1) in patients with 
advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical 
activity, and PD-L1 expression [Abstract 8503]. J Clin Oncol 34, 2016. 
 
28  
Hassan R, Thomas A, Patel M, et al: Avelumab (MSB0010718C; anti-PD-L1) in patients with 
advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical 
activity, and PD-L1 expression [Abstract 8503]. J Clin Oncol 34, 2016. 
 
29  
Thomas A, Hassan R. Immunotherapies for non-small-cell lung cancer and mesothelioma. The 
lancet oncology 13:e301-10, 2012. 
 
30  
Hassan R, Thomas A, Patel M, et al: Avelumab (MSB0010718C; anti-PD-L1) in patients with 
advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical 
activity, and PD-L1 expression [Abstract 8503]. J Clin Oncol 34, 2016. 
 

 
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31  
Tsao AS, Garland L, Redman M, Kernstine K, Gandara D, Marom EM. A practical guide of the 
Southwest Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and 
modified RECIST criteria. J Thorac Oncol 6(3):598-601, 3/2011. PMCID: PMC3643692. 
 
32  
Shiuh-Ming Luoh, Jeanne Cheung, Erin McNamara, et al. Effects of chemotherapeutic agents on 
the tumor immune microenvironment. AACR Abstract 4898, 2016. 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
New York Heart Association Functional Classifications  
 
18.2 
Translational Medicine Studies and Instructions for SWOG Biospecimen Bank 
 
18.3 
Surgical Guidelines 
 
18.4 
Autoimmune Serious Adverse Events and URLs 
 
 

 
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18.1 
New York Heart Association Functional Classifications 
 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
** At accustomed occupation or usual tasks. 
 
 
 

 
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18.2 
Translational Medicine Studies and Instructions for SWOG Biospecimen Bank 
 
Malignant pleural mesothelioma (MPM) is an orphan disease that is difficult to treat. (1)  In 
early stage disease, patients can be resectable.  However, it is clear that multi-modality 
therapy is essential to increase survival outcomes. (2,3,4)  Mesothelioma is considered an 
immunogenic disease and it is surmised that the addition of a PD-L1 inhibitor to cisplatin-
pemetrexed in the neoadjuvant setting would be clinically beneficial for our patients.  
However, little is known about the immunologic phenotype in mesothelioma and additional 
translational research is needed.  
  
Inhibition of programmed death 1 (PD-1) protein, a T-cell co-inhibitory receptor, and its 
ligand PD-L1 has been shown to restore T-cell activity and lead to a subsequent anti-tumor 
effect in several tumor types. (5,6,7,8)  In non-small cell lung cancer, response rates 
ranging between 10% to 26% have been reported using these PD-L1 inhibitors as 
monotherapy in Phase I and II trials. (9,10,11)  In general, although nivolumab was FDA 
approved without a prerequisite biomarker, it is widely surmised that patients with PD-L1 
immunohistochemical (IHC) expression are more likely to have improved response rates 
and survival. Preliminary data suggest that response to atezolizumab across multiple 
indications is associated with PD-L1 expression in the tumor microenvironment by IHC as 
well as with markers of Th1 cells in tumor tissue by gene expression. (12,13) There is little 
data on the IHC expression patterns in mesothelioma.  As discussed in the protocol, it is 
known that mesothelioma tumors have PD-L1 IHC expression in cell membranes, but less 
data is known about the microenvironment.   
 
Mansfield et al. reported a 40% PD-L1 IHC expression in pleural mesotheliomas (n=224) 
using a mouse monoclonal anti-human B7-H1 (clone 5H1-A3). (14,15) A score of <5% IHC 
expression was considered negative.  PD-L1 IHC expression was associated with more 
disease burden and less offers of surgery to the patient.  Also, PD-L1 IHC expression was 
associated with a worse survival 6 months vs 14 months, p<0.0001). (16)  However, little 
is known about the mesothelioma PD-L1 IHC expression after treatment with 
immunotherapy. 
 
Experimental approach, validated assays employed and expertise of PIs: 
 
PD-L1 
We will evaluate all of the enrolled patients at 2 time points for PD-L1 IHC expression – at 
the time of VATS and at the time of definitive resection (EPP/PD).  We hypothesize that 
patients with higher levels of PD-L1 IHC will have improved survival outcomes with the 
addition of atezolizumab to their trimodality or bimodality therapy.  
 
To investigate PD-L1 expression, Dr. Hirsch’s lab will utilize the Dako 22C3 PD-L1 
pharmDx assay. The Hirsch Biomarker Analysis Laboratory is CLIA certified. PD-L1 IHC 
will be evaluated in tumor cell cytoplasm and/or membrane staining of infiltrating 
lymphocytes.  Standard IHC parameters will be used. Tumor specimens will be batch 
stained.    
  
The Dako 22C3 PD-L1 pharmDx assay is a qualitative immunohistochemical assay using 
mouse monoclonal anti-PD-L1 clone 22C3 intended for use in the assessment of the PD-
L1 protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer 
(NSCLC) using the EnVision FLEX visualization system on the Link 48 autostainer. 
SK00621-5 50 tests PD-L1 protein expression is determined using the Tumor Proportion 
Score (TPS), which is the percentage of viable tumor cells showing partial or complete 
membrane staining at any intensity (≥ 1%). Patients will be considered high PD-L1 IHC 
expressers if the TPS is ≥ 50%. These will be the cutoffs used for the initial translational 

 
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correlate endpoint, given that most trials in mesothelioma have been utilizing this antibody 
and these cutoffs.  
 
The FDA approved PD-L1 Dako 22C3 pharmDx kit will be used for staining all specimens. 
Use of this kit requires operation with the manufacturer’s automated protocol and does not 
allow any changes to be made by the user. This ensures accurate and reproducible PD-L1 
staining as identified in the manufacturer’s FDA approval. PD-L1 expression in 
mesothelioma has been reported in several studies and therefore, preliminary staining is 
not required. (17,18,19)  Each staining run will include an in-run control slide provided by 
Dako containing the FFPE cell lines MCF-7 (PD-L1 negative) and NCD-H226 (PD-L1 
positive).  In addition, the Hirsch Lab has added a pre-qualified section of tonsil shown to 
express PD-L1.  This custom control slide is reviewed by both the histotechnologist and 
pathologist within the Hirsch lab and scored by both the primary and QC pathologist.  Data 
from multiple staining runs are compared to ensure staining consistency. 
 
Immune Nanostring panels 
 
Further tissue will be collected to analyze RNA expression of immune related genes. Only 
limited data on the expression of immune genes have been generated in mesothelioma to 
date, however thorough investigations are ongoing in NSCLC. The Nanostring immune 
panel has been utilized in solid tumor samples obtained from patients enrolled into clinical 
trials delivering atezolizumab. (20,21,22,23) For NSCLC, data generated with this assay 
have been presented at multiple conferences since 2013 and have led to the identification 
of a 8-gene T effector immune signature that is potentially predictive for response to 
atezolizumab in NSCLC; however detailed validation and confirmation of this hypothesis 
are currently ongoing in NSCLC. (24) The Nanostring immune panel will assess the RNA 
expression of immune-related genes.   
 
Extensive RNA expression profiling of immune-related genes will be assessed by 
Genentech's Immune Nanostring panel. The Nanostring panel is optimized to assess 
expression of ~800 genes, including PD-L1 and markers of Th1, Th2, myeloid, DC and NK 
cells, in RNA isolated from FFPE tumor specimens.  This approach has been validated on 
solid tumors obtained from clinical trials delivering Atezolizumab.  The GNE nanostring 
panel includes 784 targets related to multiple aspects of immunologic function and cancer 
biology.  In terms of immunologic function, the panel includes markers that can identify T-
cell subsets such as Th1, Th2, and Tregs; myeloid subsets such as MDSC, 
monocytes/macrophages, B-cells, and NK cells.   The panel also includes markers 
associated with activated signal transduction in solid tumors such as those in the MAPK 
and PI3K pathways, DNA damage response, and EMT. 
 
Multiplex Immunofluorescence (IF) Analysis 
Dr. Ignacio Wistuba’s laboratory will conduct multiplex immunofluorescence analysis of up 
to 10 immune markers, 2 panels, at MD Anderson Cancer Center. Currently, there are 2 
Vectra panels optimized: Panel#1, CD3, CD4, CD8, CD68, PD-L1, pan-cytokeratin and 
DAPI; Panel #2, PD-1, CD45RO, FOXP3, Granzyme B, CD57, pan-cytokeratin and DAPI.  
For the multiplex IF analysis, we will use the Opal chemistry and multispectral microscopy 
Vectra system (Perkin-Elmer) which includes the Nuance software; analysis will be 
performed using the InForm software. The appropriate cellular localization of the markers 
and the type of cells that express the markers will be taken into account when scoring 
them, e.g. PD-L1 is scored only on cells with membranous staining. For quantification of 
immune markers (immune cells infiltrates, immune checkpoints and other proteins) whole 
tissue sections or five randomly selected one-mm square areas within the tumor region will 
be selected for analysis. The expression of markers in malignant cells will be evaluated 
using image analysis to determine the percentage of positive cells (0 to 100) and intensity 

 
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(0 to 3+), with a total score ranging from 0 to 300 (H-score system). The intensity is 
classified as 0 (absent), 1 (weak apparently only on 100x magnification), 2 (moderate 
apparent on 50x magnification), and 3 (strong apparent on 16x magnification). This scoring 
system provides criteria that can be reproduced more consistently by pathologists.  The 
expression of protein markers and inflammatory cells will be examined using an infiltrate 
density score established by the number of cells expressing a determined marker by tissue 
area. The data and digital images will be available for sharing. 
 
Biomarker Evaluation 
Blood samples will be obtained for future biomarker evaluation (including but not limited to 
biomarkers that are related to mesothelioma or tumor immune biology) from all eligible 
patients pre and post-neoadjuvant therapy and at time of progression.  Samples will be 
processed to obtain plasma and buffy coat for the determination of changes in blood-based 
biomarkers (e.g., ctDNA). Whole blood samples may be processed to obtain their 
derivatives (e.g., RNA and DNA) and evaluated for immune-related, tumor type related, 
and other exploratory biomarkers (e.g., alterations in gene expression or single nucleotide 
polymorphisms). 
 
Translational Medicine Analyses 
 
The SWOG Biospecimen Bank will bank the tumor tissue from baseline and also the 
resected specimen. Peripheral blood will also be collected at these two time points and 
possibly at time of progression and banked with the SWOG Biospecimen Bank for future 
analysis. When the study is completed, tumor tissue will be distributed to Dr. Fred Hirsch’s 
laboratory (Denver, Colorado) for PD-L1 IHC, Dako 22C3, and Genentech for the 
Nanostring gene expression analysis, and Dr. Ignacio Wistuba’s laboratory (Houston, 
Texas) for immunofluorescence analysis. 
 
It is assumed that 20 of the 24 patients will have sufficient tissue for these analyses.  
 
Statistical analyses will be conducted to evaluate the association between clinical 
outcomes (progression free survival, modified RECIST progression free survival, overall 
survival, response rate) and PD-L1 expression levels, RNA expression levels, and 
Multiplex Immunofluorescence measurements. The focus will be on genes with a known 
role in the PD-1/PD-L1 pathway, the T effector signature as determined in NSCLC patients, 
as well as additional genes identifying T cell subsets such Th1, Th2, Tregs, myeloid 
subsets such as MDSC, monocytes / macrophages, B-cells, and NK cells.  
 
Data analysis performed by: 
 
SWOG Statistics and Data Management Center  
 
Testing Performed by: 
 
PD-L1 IHC on baseline and resected mesothelioma specimens   
Dr. Fred Hirsch  
Univ of Colorado Cancer Center 
PO Box 6511, MS 8117 
Aurora, CO  80045 
Phone: 303- 724-3858 
Email: fred.hirsch@ucdenver.edu 
 
Immune nanostring panel on baseline and resected tumor specimens 
Covance Genomics Laboratory 
9911 Willows Rd NE, suite 175 
Redmond, WA 98052 

 
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Phone:  425-979-5000 
 
Tumor Immunofluorescence Analysis on baseline and resected tumor specimens  
Dr. Ignacio Wistuba 
MD Anderson Cancer Center 
2130 W Holcombe Blvd 
Unit 2951, LSP9.4029 
Houston, TX  77030 
Phone: 713-563-9184 
Email: iiwistuba@mdanderson.org 
 
Instructions for SWOG Biospecimen Bank 
 
Tumor tissue blocks from baseline (archived specimens allowed) and resection will be 
obtained.  At baseline, it is anticipated that 1-2 tissue blocks will be available.  At time 
of resection, we anticipate 3-4 tissue blocks will be created.   
 
a. 
2-3 Tumor slides (5-7 microns) will be obtained from the tumor tissue blocks 
and stained for PD-L1 immunohistochemistry by Dr. Hirsch’s labs. 
 
b. 
Dr. Wistuba will require 8 slides each from baseline and also the resected 
specimen to support the analysis as follows: 
 
i. 
H&E: 1 slide 
ii. 
Immunofluorescent analysis: 7 slides (5-7 microns) sections  
 
c. 
Genentech will require 11 sections each from baseline and also the resected 
specimen, to support the analysis as follows: 
i. 
H&E: 1 slide 
ii. 
Gene expression (Nanostring) 10 sections (5-7 microns).  Genentech 
is looking to extract at least 500 ng of RNA (as assessed by Ribogreen) 
 
 
 
 

 
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References
 
1  
Tsao AS, Wistuba I, Roth JA, Kindler HL. Malignant Pleural Mesothelioma. J Clin 
Oncol 27(12):2081-90, 4/2009. e-Pub 3/2009. PMID: 19255316. 
 
2  
Krug LM, Pass HI, Rusch VW, et al: Multicenter phase II trial of neoadjuvant 
pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation 
for malignant pleural mesothelioma. J Clin Oncol 27:3007-13, 2009 
 
3  
Tsao AS, Wistuba I, Roth JA, Kindler HL. Malignant Pleural Mesothelioma. J Clin 
Oncol 27(12):2081-90, 4/2009. e-Pub 3/2009. PMID: 19255316. 
 
4  
Tsao AS, Mehran R, Roth JA. Neoadjuvant and intrapleural therapies for malignant 
pleural mesothelioma. Clin Lung Cancer 10(1):36-41, 1/2009. PMID: 19289370. 
 
5  
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody 
in patients with advanced cancer. The New England journal of medicine 
2012;366:2455-65. 
 
6  
Brahmer J, Rizvi N, Lutzky J, et al. Clinical activity and biomarkers of MEDI4736, 
an anti-PD-L1 antibody, in patients with NSCLC. Journal of Clinical Oncology 
2014;32:Abstract 8021. 
 
7  
Davies M. New modalities of cancer treatment for NSCLC: focus on 
immunotherapy. Cancer management and research 2014;6:63-75. 
 
8  
Brahmer JR. Harnessing the immune system for the treatment of non-small-cell 
lung cancer. J Clin Oncol 2013;31:1021-8. 
 
9  
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody 
in patients with advanced cancer. The New England journal of medicine 
2012;366:2455-65. 
 
10  
Brahmer J, Rizvi N, Lutzky J, et al. Clinical activity and biomarkers of MEDI4736, 
an anti-PD-L1 antibody, in patients with NSCLC. Journal of Clinical Oncology 
2014;32:Abstract 8021. 
 
11  
Brahmer JR. Harnessing the immune system for the treatment of non-small-cell 
lung cancer. J Clin Oncol 2013;31:1021-8. 
 
12  
Herbst R, Soria J, Kowanetz M, et al. Predictive correlates of response to the anti-
PD-L1 antibody MPDL3280A in cancer patients. Nature 515 (7528): 563-567, 
2014. 
 
13  
Thomas A, Hassan R. Immunotherapies for non-small-cell lung cancer and 
mesothelioma. The lancet oncology 2012;13:e301-10. 
 
14  
Thomas A, Hassan R. Immunotherapies for non-small-cell lung cancer and 
mesothelioma. The lancet oncology 2012;13:e301-10. 
 
15  
Mansfield A, Peikert T, Roden A, et al: Programmed cell death 1 ligand 1 
expression and association with survival in mesothelioma. Journal of Thoracic 
Oncology 9 S7-S52, 2014. 
 

 
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16  
Mansfield A, Peikert T, Roden A, et al: Programmed cell death 1 ligand 1 
expression and association with survival in mesothelioma. Journal of Thoracic 
Oncology 9 S7-S52, 2014. 
 
17  
Nguyen BH, Montgomery R, Fadia M, Wang J, Ali S. PD-L1 expression associated 
with worse survival outcome in malignant pleural mesothelioma. Asia Pac J Clin 
Oncol. 2018 Feb;14(1):69-73. 
 
18  
Cedres S, Ponce-Aix S, Zugazagoitia J. Analysis of expression of programmed cell 
death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM). PLoS One. 
2015;10:e0121071. 
 
19  
Mansﬁeld A, Roden A, Peikert T. B7-H1 expression in malignant pleural 
mesothelioma is associated with sarcomatoid histology and poor prognosis. 
JThoracOncol. 2014;9(7):1036–1040. 
 
20  
Wallin J, Bendell J, Funke R, et al. Atezolizumab in combination with bevacizumab 
enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. 
Nature Communications.  7 : 12624, 2016. 
 
21  
Powles T, Nickles D, Van Allen E, et al. Immune biomarkers associated with clinical 
benefit from atezolizumab (MPDL3280A; anti-PD-L1) in advanced urothelial 
bladder cancer (UBC). J Immunother Cancer 3 (Suppl 2): P83, 2015. 
 
22  
Ung C and Kockx M. Challenges & Perspectives of Immunotherapy Biomarkers & 
the HistoOncoImmune Methodology.  Expert Review of Precision Medicine and 
Drug Development.  1:1, 9-24, 2016. 
 
23  
Gettinger S, Kowanetz M, Koeppen H, et al. Molecular, immune and 
histopathological characterization of NSCLC based on PDL1 expression on tumor 
and immune cells and association with response to the anti-PDL1 antibody 
MPDL3280A. J Clin Oncol 33, 2015. (suppl; abstr 3015) 
 
24  
Gettinger S, Kowanetz M, Koeppen H, et al. Molecular, immune and 
histopathological characterization of NSCLC based on PDL1 expression on tumor 
and immune cells and association with response to the anti-PDL1 antibody 
MPDL3280A. J Clin Oncol 33, 2015 (suppl; abstr 3015) 
 
 
 

 
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18.3 
Surgical Guidelines 
 
Perioperative and post-operative pain control will be at the discretion of surgeons and 
anesthesia teams. Both epidural analgesia or rib infiltration with long acting local 
anesthetic, such as liposomal bupivacaine will be acceptable.    
 
After induction of general anesthesia patient will be intubated with a double lumen 
endotracheal tube. Intraoperative monitoring includes use of a central venous pressure 
line, arterial line and a pulse oximeter. The patient is then placed in the lateral decubitus 
position and operative side is prepped and draped in the usual sterile manner. The patient's 
hemithorax is approached via an extended posterolateral thoracotomy incision through the 
6th or 7th interspace, and the anterior part is taken down towards the costal margin to 
facilitate exposure to the hemidiaphragm. The 7th rib maybe removed to facilitate 
extrapleural dissection and later diaphragm reconstruction. An additional parallel incision 
at the 9th or 10th intercostal space posteriorly may be used, but is not recommended and 
generally not required for diaphragmatic resection. The parietal pleural tumor is mobilized 
away from the chest wall in the extrapleural plane, carrying the dissection to the apex of 
the hemithorax superiorly down to the diaphragm inferiorly, to the sternum anteriorly and 
to the spine posteriorly. Previous thoracoscopy and thoracotomy sites used previously for 
biopsy purposes may be excised but this is not necessary because of the postoperative 
radiation administered in this study. The chest retractor is inserted and dissection is 
continued circumferentially in the extrapleural plane, mobilizing the parietal and 
mediastinal pleural tumor back to the hilum in all directions. Once this has been 
accomplished, attention is turned to the diaphragmatic resection. The diaphragmatic tumor 
is mobilized along with the partial or full thickness of the diaphragm. Care is taken not to 
violate the underlying peritoneum. While not possible in all cases, preservation of the 
peritoneum is preferred, and therefore any tears in the peritoneum should be closed. 
Dissection of the diaphragmatic tumor and diaphragm is carried from the lateral toward the 
medial aspect back to the pericardium, and then up on the pericardium to the level of the 
inferior pulmonary vein. For right-sided resections, care should be taken to identify the 
small branches of the front vessels which drain from the diaphragm into the inferior vena 
cava and to ligate and divide those branches.  
 
Following complete mobilization of the tumor and lung in the extrapleural plane, resection 
of the diaphragm and portion of the pericardium, nodal sampling/dissection should be 
performed from the following nodal stations: on the right side: level 4R,7, 8R, 9R, 10R, 
internal mammary, and any visible intercostal lymph nodes if possible. On the left side: 
level 5, 6, 7, 8L, 9L, 10L, plus internal mammary lymph nodes, and any visible intercostal 
lymph nodes if possible. Frozen section should be sent from each nodal station for intra-
operative staging purposes.   
 
If all lymph nodes come back negative (N0 status), and patient’s physiologic status 
would tolerate pneumonectomy, it is acceptable to proceed with EPP. However, if 
any of the nodes come back positive, it is advisable to proceed with PD rather than 
EPP. However, this decision will be left up to the treating surgeon. 
 
Examination of the N1 lymph nodes (stations 10-14) within the resected specimen should 
be requested from the pathologist. To proceed with EPP, once the mainstem bronchus has 
been mobilized, it should be ligated with a stapling device and divided. Phrenic nerve is 
usually divided during the mobilization of diaphragm resection. The vagus nerve should be 
preserved. The hilar vessels can then be ligated and divided, again with vascular stapling 
devices. Resection of the pericardium is not required if the pleural tumor can be mobilized 
away from the pericardium completely. Pericardial resection for complete resection of all 
gross tumor should be performed as required. Pericardial resection is most safely 
accomplished at the time of division of the hilar vessels. Tacking sutures should be  placed 

 
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on the anterior border of pericardial resection to prevent retraction of the pericardium 
toward the contralateral hemithorax as the pericardial resection is performed. The 
pericardial defect can be reconstructed with either an absorbable (Dexon) or non-
absorbable (preferably Gortex) patch. Non-absorbable material is required for 
diagrammatic and pericardial replacement left sided resections. Either absorbable or non-
absorbable material can be used for the right sided diaphragmatic reconstruction. The 
selection of the reconstructive material will be at surgeon’s discretion. The prosthetic 
diaphragmatic patch is secured in place to the rim of remaining diaphragm along the 
pericardium medially. Care should be taken to secure this appropriately to and around the 
esophagus to prevent postoperative intrathoracic herniation of abdominal contents at that 
level. Posteriorly the prosthetic patch is secured to the endothoracic fascia. Laterally, it is 
secured with sutures placed around the ribs. The prosthetic patch should be placed as low 
as possible to mimic the normal position of the diaphragm. Therefore, the lateral sutures 
should be placed around the 8th, 9th and 10th ribs. This is particularly important to reduce 
the radiation exposure of the liver on the right and the stomach on the left during 
postoperative adjuvant radiotherapy. Hemostasis in the operated hemithorax is facilitated 
by use of cautery, argon beam coagulator, aquamentys device, or topical hemostatic 
agents.  
 
If PD is chosen as an operative approach, the steps of the procedure are identical to EPP, 
with the exception of leaving the lung in situ. After the tumor, lung, and diaphragm are 
completely mobilized, the visceral pleura is stripped from the lung parenchyma. 
Hemostasis is again achieved with available devices, and small bronchial injuries are over 
sewn or stapled to decrease the postoperative air leak. Reconstruction of the diaphragm 
and pericardium are performed on the same manner as for EPP. Chest cavity is then 
inspected to ensure there is no evidence of any visible tumor. Surgeon should document 
in the operative note, his or her impression of the completeness of surgical 
resection (R1 versus R2).  
 
It is preferable to completely remove all visible tumor. Any intra-operative thermal 
ablation techniques, photodynamic therapy, intra-operative heated chemotherapy 
are not permitted.  
 
At the end of the procedure a chest tube is inserted which is then placed to balanced 
drainage (such as a pneumonectomy Pleur-Evac). Reinforcement of the bronchial stump 
with a pericardial fat pad may be used but is not required. Use of an intercostal muscle flap 
for this purpose is not recommended. The thoracotomy incision is closed in the usual 
manner, but care should be taken to achieve a completely watertight seal during the 
closure. It is particularly important to achieve good approximation and watertight closure of 
the intercostal muscles to prevent pleural fluid from leaking out of the hemithorax in the 
immediate postoperative period. The chest tube is usually left in place for up to 72 hours 
following EPP and as needed following PD, until the pleural fluid draining through the chest 
tube has become serous or serosanguinous, rather than bloody, and the air leak has 
resolved.  
 
Perioperative antibiotic coverage should be provided according to institutional guidelines. 
This may include the entire length of time that the chest tube is in place. Perioperative anti-
arrhythmia prophylaxis may be considered according to institutional guidelines.  
 
In the instance where exploration reveals disease that cannot be completely resected, the 
operation should be aborted, and the reasons for abandoning the surgery documented 
(example: chest wall invasion, invasion of the esophagus, spine, heart or great vessels). 
Other common reasons for un-resectability include diffuse invasion of tumor through the 
endothoracic fascia, extrathoracic subcutaneous disease in discontinuous sites, direct 
extension of tumor though the diaphragm or metastatic disease involving the peritoneum 
which is not suspected preoperatively by imaging studies. Postoperative pathway and care 
will be at the discretion of individual surgeons. 

 
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18.4 
Autoimmune Serious Adverse Events and URLs 
 
The NCI CTCAE defines autoimmune at this URL: 
 
https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=CTCAE&ns=ctcae&cod
e=E11258  
 
The NCI CTCAE defines immune system disorders at this URL: 
 
https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=CTCAE&ns=ctcae&cod
e=E13871