Conditions: Pleural Biphasic Mesothelioma Pleural Epithelioid Mesothelioma Stage I Pleural Malignant Mesothelioma AJCC v8 Stage IA Pleural Malignant Mesothelioma AJCC v8 Stage IB Pleural Malignant Mesothelioma AJCC v8 Stage II Pleural Malignant Mesothelioma AJCC v8 Stage IIIA Pleural Malignant Mesothelioma AJCC v8
Keywords: Mesothelioma IMPRINT
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
This trial studies how well the addition of targeted radiation therapy to surgery and the usual chemotherapy treatment works for the treatment of stage I-IIIA malignant pleural mesothelioma. Targeted radiation therapy such as intensity-modulated radiation therapy or pencil beam scanning uses high energy rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as pemetrexed, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving targeted radiation therapy in addition to surgery and chemotherapy may work better than surgery and chemotherapy alone for the treatment of malignant pleural mesothelioma.

Detailed description:
PRIMARY OBJECTIVE:

I. To detect an improvement in overall survival with the addition of adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) to surgery and chemotherapy compared to surgery and chemotherapy alone.

SECONDARY OBJECTIVES:

I. To determine local failure-free survival, distant-metastases-free survival, and progression-free survival with the addition of adjuvant hemithoracic IMPRINT to surgery and chemotherapy compared to surgery and chemotherapy alone.

II. To evaluate the treatment-related toxicities in both arms per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

III. To detect a clinically meaningful 10-point change in global health status mean scores at 9 months after randomization with the addition of adjuvant IMPRINT as compared to surgery and chemotherapy alone.

EXPLORATORY OBJECTIVES:

I. To evaluate the degree of under-staging, concordant and upstaging between centrally reviewed clinical staging (based on positron emission tomography (PET), computed tomography (CT) and/or magnetic resonance imaging (MRI)) and pathologic staging.

II. To identify immunologic and pathologic biomarkers as predictors of response and potential targets for future combination trials.

III. To determine the magnitude of radiation dose escalation to gross residual disease based on combined modality imaging and associated local control rates with dose-painting intensity-modulated radiation therapy (IMRT).

IV. To determine the rate of R0/R1 and R2 resections, and type of procedures (extended pleurectomy/decortication \[P/D\], P/D and partial pleurectomy).

V. To evaluate the trajectory of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-Q30) and lung cancer specific module (LC13) symptoms in patients treated with IMPRINT by comparing the proportion of patients who respond with "quite a bit" or "very much" LC13 symptoms at 9-12 months post-randomization compared to at 3 months post-randomization.

VI. To evaluate changes in health-related quality of life, functional domains, and symptoms over time with the addition of adjuvant IMPRINT as compared to surgery and chemotherapy alone.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.

Arms:
arm 1: STEP 1: Patients who received allowed neoadjuvant systemic therapy before study entry undergo pleurectomy/decortication (P/D) within 4 to 8 weeks of systemic therapy. Otherwise, patients undergo P/D within 4 weeks of study entry followed within 4 to 8 weeks by four 21-day cycles of pemetrexed and cisplatin or carboplatin on day 1.

STEP 2: Patients receive no treatment. arm 2: STEP 1: Same as Arm 1.

STEP 2: Within 4-8 weeks from the end of Step 1 treatment, patients undergo 25-28 fractions of intensity modulated radiation therapy (IMRT) or pencil beam scanning (PBS) proton therapy 5 days/week over 6 weeks.

Interventions: intervention 1: Carboplatin intervention 2: Cisplatin intervention 3: Decortication intervention 4: Intensity-Modulated Radiation Therapy intervention 5: Pemetrexed intervention 6: Pemetrexed Disodium intervention 7: Pencil beam scanning proton therapy intervention 8: Pleurectomy
Intervention descriptions: intervention 1: Intravenously intervention 2: Intravenously intervention 3: Undergo decortication intervention 4: Daily fractions intervention 5: Intravenously intervention 6: Intravenously intervention 7: Daily fractions intervention 8: Undergo pleurectomy

Protocol document:
Prot_SAP_000.pdf: 
NRG ONCOLOGY 
 
NRG-LU006 
 
(ClinicalTrials.gov NCT #04158141) 
 
PHASE III RANDOMIZED TRIAL OF PLEURECTOMY/DECORTICATION PLUS 
SYSTEMIC THERAPY WITH OR WITHOUT ADJUVANT HEMITHORACIC 
INTENSITY-MODULATED PLEURAL RADIATION THERAPY (IMPRINT) FOR 
MALIGNANT PLEURAL MESOTHELIOMA (MPM) 
 
Amendment 2: April 13, 2022 


 
NRG-LU006 
1  
Version Date:  April 13, 2022 
 
NRG ONCOLOGY  
 
NRG-LU006 
(ClinicalTrials.gov NCT #04158141) 
 
PHASE III RANDOMIZED TRIAL OF PLEURECTOMY/DECORTICATION PLUS 
SYSTEMIC THERAPY WITH OR WITHOUT ADJUVANT HEMITHORACIC 
INTENSITY-MODULATED PLEURAL RADIATION THERAPY (IMPRINT) FOR 
MALIGNANT PLEURAL MESOTHELIOMA (MPM) 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Medical Group; and SWOG. 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (15-MAR-2022) 
Principal Investigator/Radiation 
Oncology 
Andreas Rimner, MD 
Memorial Sloan Kettering Cancer Center 
Department of Radiation Oncology 
1275 York Ave. 
New York, NY 10065 
212-639-6025/Fax:  929-321-7153 
Rimnera@MSKCC.ORG 
Radiation Oncology Co-Chair 
Charles B. Simone, II, MD 
Department of Radiation Oncology 
New York Proton Center 
225 East 126th Street 
New York, NY 10035 
646-968-9012 
csimone@nyproton.com  
Surgical Oncology Co-Chair 
Valerie W. Rusch, MD 
Memorial Sloan Kettering Cancer Center 
Department of Surgery 
1275 York Ave 
New York, NY, 10065 
212-639-5873/Fax:  646-422-2086 
ruschv@MSKCC.ORG 
Medical Oncology Co-Chair 
Marjorie G. Zauderer, MD 
Memorial Sloan Kettering Cancer Center 
Department of Medicine 
1275 York Avenue 
New York, NY 10065 
646-888-4656 
zauderem@MSKCC.org 
Radiology Co-Chair 
Ritu R. Gill, MD 
Beth Israel Deaconess Medical Center 
Department of Radiology 
330 Brookline Avenue 
Boston, MA  02215-5400  
rgill@bidmc.harvard.edu 
Medical Physics Co-Chair 
Ellen Yorke, PhD 
Memorial Sloan Kettering Cancer Center 
Department of Medical Physics 
1275 York Ave 
New York, NY, 10065 
212-639-8637 
yorkee@mskcc.org 
 


 
NRG-LU006 
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Version Date:  April 13, 2022 
 
NRG ONCOLOGY  
 
NRG-LU006 
(ClinicalTrials.gov NCT #04158141) 
 
PHASE III RANDOMIZED TRIAL OF PLEURECTOMY/DECORTICATION PLUS 
SYSTEMIC THERAPY WITH OR WITHOUT ADJUVANT HEMITHORACIC 
INTENSITY-MODULATED PLEURAL RADIATION THERAPY (IMPRINT) FOR 
MALIGNANT PLEURAL MESOTHELIOMA (MPM) 
 
Study Team continued 
Proton Physics Co-Chair 
Xiaoying Liang, PhD, DABR 
Mayo Clinic 
4500 San Pablo Rd. S. 
Jacksonville, FL 32224 
904-957-0456 
Liang.xiaoying@mayo.edu 
QOL Co-Chair 
Khinh Ranh Voong, MD MPH 
Sidney Kimmel Cancer Center  
Johns Hopkins Bayview 
300 Mason Lord Dr. 
Baltimore MD, 21224 
410-367-3205/Fax:  410-550-6598 
kvoong1@jhmi.edu 
Translational Science Co-Chair  
Tobias Peikert, MD 
Mayo Clinic Cancer Center 
Division of Pulmonary and Critical Care 
Medicine, 200 First Street 
Rochester, MN 55901 
507-284-4162 
Peikert.Tobias@mayo.edu 
Pathology Co-Chair 
Ming S. Tsao, MD 
University Health Network, Princess Margaret 
Cancer Center 
101 College St., 11th floor 
Toronto, ON M5G 1L7, Canada 
416-634-8721 
Ming.Tsao@uhn.ca 
Lead Statistician 
Chen Hu, PhD 
NRG Oncology Statistical and Data Mgmt Ctr 
& John Hopkins Univ School of Medicine 
50 South 16th Street, Ste. 2800 
Philadelphia, PA 19102 
215-940-4842/Fax:  215-928-0153 
HuC@NRGOncology.org 
 
 


 
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NRG ONCOLOGY 
NRG-LU006 
 
STUDY CHAMPIONS (15-MAR-2022) 
ECOG-ACRIN Champion 
John Varlotto, MD 
Department of Radiation Oncology 
Edwards Cancer Center – Marshall University 
1400 Hal Greer Blvd. 
Huntington, WV 25701 
304 399 6501/Fax: 304 399 6528 
varlotto@marshall.edu 
Alliance Champion 
Jeremy Brownstein, MD 
Department of Radiation Oncology 
Ohio State University 
460 W. 10th Ave., Ste. A206  
Columbus, OH 43210  
614-293-8415/Fax: 614-293-4044 
Jeremy.Brownstein@osumc.edu 
SWOG Champion 
Robert Samstein, MD, PhD 
Department of  
Icahn School of Medicine Mount Sinai 
1470 Madison Avenue, PO Box 208032 
New York, NY 10029 
212-241-4173 
robert.samstein@mountsinai.org 
 
 
 
NRG Oncology Contact Information (15-MAR-2022) 
Data Management 
For questions concerning eligibility or 
data submission 
Matthew Novak and Tammy Bausinger 
NRG Oncology 
50 South 16th Street, Ste. 2800 
Philadelphia, PA  19102 
215-574-3211 (Novak) / 215-574-3223 (Bausinger) 
NovakM@NRGOncology.org 
BausingerT@NRGOncology.org 
RTQA 
For questions concerning RT data 
submission 
Jennifer Presley, B.S., R.T.(R)(M)(T) 
IROC Philadelphia – RT QA Center 
ACR Center for Research and Innovation 
50 South 16th Street, Ste. 2800 
Philadelphia, PA  19102 
215-574-3153 
jpresley@acr.org 
RT Credentialing 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org 
RT data submission to TRIAD 
Triad-Support@acr.org 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & 
amendments 
Fran Bradley 
NRG Oncology  
50 South 16th Street, Ste. 2800  
Philadelphia, PA 19102 
215-940-8893/Fax: 215-928-0153 


 
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BradleyF@NRGOncology.org 
Lung Committee Chair 
Jeffrey D. Bradley, MD 
Department of Radiation Oncology 
Emory University School of Medicine 
Winship Cancer Institute 
Atlanta, Georgia 30322 
404-778-3630 
jeffrey.d.bradley@emory.edu 
 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Cisplatin 
Commercial 
119875 
Exempt 
N/A 
Carboplatin 
Commercial 
241240 
Exempt 
N/A 
Pemetrexed 
Commercial 
698037 
Exempt 
N/A 
 
 
 
Participating Sites (15-MAR-2022) 
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
 
 
Document History 
 
Version Date 
Amendment 2 
April 13, 2022 
Amendment 1 
March 15, 2022 
Initial 
January 2, 2020 
 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 


 
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CONTACT INFORMATION (15-MAR-2022) 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must be 
submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
(Sign in at https://www.ctsu.org, and 
select Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting that 
are unable to use the Portal should 
alert the CTSU Regulatory Office 
immediately by phone or email: 1-
866-651-CTSU (2878) or 
CTSURegHelp@coccg.org, to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-CTSU (2878) for 
regulatory assistance. 
Refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network 
(OPEN). OPEN is accessed 
at 
https://www.ctsu.org/OPEN_
SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help 
Desk with any OPEN-related 
questions by phone or email:  
1-888-823-5923, or 
ctsucontact@westat.com. 
 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Refer 
to the data submission 
section of the protocol 
for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page located on the CTSU members’ website 
(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 in with CTEP-IAM username and password.  
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI of 
the Lead Protocol Organization. 
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.  
 
 
 
 
 


 
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TABLE OF CONTENTS 
SCHEMA  ........................................................................................................................................8 
1.   OBJECTIVES ............................................................................................................................9 
1.1       Primary Objective ....................................................................................................9 
1.2       Secondary Objectives...............................................................................................9 
1.3       Exploratory Objectives ............................................................................................9 
2.   BACKGROUND .......................................................................................................................9 
2.1       Pleurectomy/Decortication and Adjuvant Conventional Hemithoracic 
Radiation Therapy ....................................................................................................9 
2.2       Systemic therapy ....................................................................................................10 
2.3       Hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) ............11 
2.4       Rationale for a randomized phase III study on IMPRINT .....................................12 
3.   PATIENT ELIGIBILITY AND INELIGIBILITY CRITERIA ..............................................14 
3.1 
Eligibility Criteria  .................................................................................................14 
3.2 
Ineligibility Criteria  ..............................................................................................15 
4.   REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  .................1 
5.   TREATMENT PLAN/REGIMEN DESCRIPTION..................................................................7 
5.1 
Surgery .....................................................................................................................7 
5.2 
Chemotherapy/ /Other Agent-Based Therapy .........................................................8 
5.3 
Radiation Therapy – Arm 2 only  ..........................................................................10 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................20 
5.5 
Duration of Therapy ...............................................................................................21 
6.   TREATMENT MODIFICATIONS/MANAGEMENT ...........................................................21 
6.1  Pemetrexed ..................................................................................................................21 
6.2  Cisplatin  .....................................................................................................................23 
6.3 Carboplatin ...................................................................................................................24 
7.   ADVERSE EVENTS REPORTING REQUIREMENTS .......................................................25 
7.1       Protocol Agents ......................................................................................................25 
7.2       Adverse Events and Serious Adverse Events ........................................................25 
7.3       Expedited Reporting of Adverse Events ................................................................26 
            7.4       Routine Reporting Requirements for Adverse Events ...........................................29 
            7.5       Pregnancy…….. .....................................................................................................29 
8.   REGISTRATION AND STUDY ENTRY PROCEDURES  ..................................................29 
            8.1       Cancer Trials Support Unit Registration Procedures .............................................30 
8.2 
RT-Specific Pre-Registration Requirement ...........................................................35 
8.3 
Patient Enrollment .................................................................................................37 
9.0 
     DRUG INFORMATION ..............................................................................................38 


 
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9.1 
Commercial Agent:  Pemetrexed  ..........................................................................38 
9.2 
Commercial Agent:  Cisplatin ...............................................................................38 
9.3 
Commercial Agent:  Carboplatin  ..........................................................................38 
10. 
Pathology/BIOSPECIMEN................................................................................................39 
10.1 
Optional Specimen Submissions ...........................................................................39 
11. 
SPECIAL studies (Non-Tissue) .........................................................................................41 
11.1 
Quality of Life........................................................................................................41 
11.2 
Quality of Life Primary and Exploratory Endpoints ..............................................44 
12. 
Modality Reviews ..............................................................................................................44 
12.1     Radiation Therapy Quality Assurance Reviews ....................................................44 
12.2     Medical Oncology Modality Quality Assurance Reviews.....................................44 
12.3     Surgical Quality Assurance Reviews .....................................................................45 
12.4     Imaging Retrospective Central Review .................................................................45 
13. 
DATA AND RECORDS ...................................................................................................45 
13.1     Data Management/Collection  ...............................................................................45 
13.2     Summary of Data Submission  ..............................................................................46 
13.3     Data Quality Portal  ...............................................................................................47 
13.4     Global Reporting/Monitoring  ...............................................................................48 
14. 
STATISTICAL CONSIDERATIONS...............................................................................48 
14.1 
Study Design  .........................................................................................................48 
14.2 
Study Endpoints .....................................................................................................48 
14.3 
Primary Objectives Study Design  .........................................................................48 
14.4 
Study Monitoring of Primary Objectives ...............................................................49 
14.5 
Accrual/Study Duration Considerations ................................................................50 
14.6 
Secondary or Exploratory Endpoints  ....................................................................50 
14.7 
Exploratory Hypothesis and Endpoints  ................................................................54 
14.8 
Gender/Ethnicity/Race Distribution ......................................................................57 
REFERENCES ..............................................................................................................................58 
APPENDIX A  ...............................................................................................................................62 
 
 
 
 
 
 
 
 
 
 
 


 
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NRG ONCOLOGY 
NRG-LU006 
 
PHASE III RANDOMIZED TRIAL OF PLEURECTOMY/DECORTICATION PLUS 
SYSTEMIC THERAPY WITH OR WITHOUT ADJUVANT HEMITHORACIC 
INTENSITY-MODULATED PLEURAL RADIATION THERAPY (IMPRINT) FOR 
MALIGNANT PLEURAL MESOTHELIOMA (MPM) 
 
SCHEMA (15-MAR-2022) 
Up to 4 cycles of neoadjuvant systemic therapy* 
 allowable before study entry. 
↓ 
STEP 1 REGISTRATION 
Pathologically confirmed clinical stage I-IIIA MPM (epithelioid or biphasic), 
amenable to macroscopic complete resection (MCR). 
 
Patients who did not receive 
neoadjuvant systemic therapy: 
 
Pleurectomy/Decortication**  
within 4 weeks of study entry 
↓ 
Pemetrexed + Cisplatin (or Carboplatin) 
4 to 8 weeks after surgery 
 
 
 
Patients who received neoadjuvant 
systemic therapy: 
 
Pleurectomy/Decortication**  
within 4 to 8 weeks of completion 
of systemic therapy 
 
STRATIFY 
- 
Systemic therapy:  chemotherapy vs immunotherapy +/- 
chemotherapy* 
- 
Cell type:  Epithelioid vs biphasic 
- 
Macroscopic complete resection: R0/R1 vs R2 
                                 
STEP 2 RANDOMIZATION 
(within 8 weeks after end of systemic therapy and/or P/D) 
                         
Arm 1 
No adjuvant RT  
 
Arm 2 
Hemithoracic Pleural RT  
 
*  Acceptable neoadjuvant systemic therapy options before study entry:  1) cisplatin/carboplatin + pemetrexed; 2) 
cisplatin/carboplatin + pemetrexed + anti-PD-1/L1 agents; or 3) ipilimumab/nivolumab 
 
** Pleurectomy/Decortication (P/D) to be performed with the goal of a macroscopic complete  resection (MCR). 
 
Randomization will be 1:1 to both arms.  NOTE:  Patients who cannot be randomized will be considered as having 
completed participation in NRG-LU006, and no additional data will be collected. 
 
Required Sample Size: 150 patients 
 


 
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1.   OBJECTIVES  
1.1       Primary Objective (15-MAR-2022) 
To detect an improvement in overall survival with the addition of adjuvant hemithoracic 
IMPRINT to surgery and systemic therapy compared to surgery and systemic therapy 
alone. 
 
1.2       Secondary Objectives (15-MAR-2022) 
• To determine local failure-free survival, distant-metastases-free survival, and 
progression-free survival with the addition of adjuvant hemithoracic IMPRINT to 
surgery and systemic therapy compared to surgery and systemic therapy alone. 
• To evaluate the treatment-related toxicities in both arms per CTCAE v5.0. 
• To detect a clinically meaningful 10-point change in global health status mean scores 
at 9 months after randomization with the addition of adjuvant IMPRINT as compared 
to surgery and systemic therapy alone.  
 
1.3       Exploratory Objectives (15-MAR-2022) 
• To evaluate the degree of under-staging, concordant and upstaging between centrally-
reviewed clinical staging (based on PET, CT and/or MRI) and pathologic staging. 
• To identify immunologic and pathologic biomarkers as predictors of response and 
potential targets for future combination trials. 
• To determine the magnitude of radiation dose escalation to gross residual disease 
based on combined modality imaging and associated local control rates with dose-
painting IMRT. 
• To determine the rate of R0/R1 and R2 resections, and type of procedures (extended 
Pleurectomy/Decortication (P/D), P/D and partial pleurectomy). 
• To evaluate the trajectory of EORTC QLQ-Q30 and LC13 symptoms in patients 
treated with IMPRINT by comparing the proportion of patients who respond with 
“quite a bit” or “very much” LC13 symptoms at 9-12 months post-randomization 
compared to at 3 months post-randomization. 
• To evaluate changes in health-related quality of life, functional domains, and 
symptoms over time with the addition of adjuvant IMPRINT as compared to surgery 
and systemic therapy alone.  
• To evaluate the prognostic values of center patient volume (≤10 versus >10 P/D/year) 
and systemic therapy type (Chemotherapy versus Immunotherapy). 
• To optimize quality assurance methodologies and processes for radiotherapy and 
imaging with machine learning strategies. 
 
2.   BACKGROUND  
2.1       Pleurectomy/Decortication and Adjuvant Conventional Hemithoracic Radiation    
Therapy 
This study builds on the promising initial experience with this novel pleural IMRT 
technique that was developed at MSKCC (Rosenzweig et al., 2012 and Rimner et al., 
2016) as well as the preliminary results of the ongoing expanded multicenter phase II 
study of chemotherapy +/- pleurectomy/ decortication (P/D) followed by IMRT 
(NCT00715611). Since one of the greatest issues with malignant pleural mesothelioma is 


 
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poor local disease control, much effort has focused on harnessing radiation to improve 
this. Historically, extrapleural pneumonectomy (EPP) has been the standard surgical 
procedure for MPM. However, locoregional recurrences still occur in up to 80% despite 
this aggressive resection. A phase II study performed at MSKCC demonstrated that the 
addition of 54 Gy of conventional hemithoracic RT could decrease that risk to 13% 
(Rusch et al., 2001). This study was followed by a multicenter phase II study that tested 
the combination of neoadjuvant cisplatin/pemetrexed followed by EPP and adjuvant 
hemithoracic radiation therapy (Krug et al., 2009). This approach led to a median survival 
of 16.6 months and a 2-year survival of 34%. However, EPP is associated with 
significant morbidity and mortality risks.  
 
P/D is an alternative lung-sparing surgical approach that involves a complete pleural 
resection but leaves the ipsilateral lung intact. A multi-institutional retrospective study 
initiated at MSKCC found on multivariable analysis that the adjusted hazard rate for 
death from EPP was 1.4 when compared to P/D (Flores et al., 2008). While not powered 
for an overall survival endpoint, the adjusted hazard rate in a recent randomized trial of 
EPP versus no resection was found to be 2.75 (Treasure et al., 2011).  While these studies 
indicate a potential survival advantage or at least no disadvantage of less extensive 
surgery, P/D potentially results in a less complete resection. Local failure of MPM in the 
chest is the major cause of morbidity and mortality in patients treated with lung-sparing 
treatment approaches. The extent of macroscopic resection appears to be of prognostic 
importance. Therefore, combination with additional local treatment modalities such as 
radiation therapy may significantly decrease the risk for locoregional recurrences. This 
paradigm was previously tested by adding adjuvant conventional radiation therapy to 
P/D. The results were disappointing, with a median overall survival of 13.5 months and 
one-year actuarial local control of 42%. In addition, this treatment was associated with a 
significant risk for radiation pneumonitis, including two patients with grade 5 toxicity 
(Gupta et al., 2005). Therefore, conventional radiation therapy cannot be delivered to 
patients with two intact lungs after P/D without an excessive risk of radiation 
pneumonitis. 
 
2.2       Systemic Therapy (15-MAR-2022) 
Conventional systemic therapy 
Until recently, the standard of care for systemic therapy for patients with resectable MPM 
was platinum-pemetrexed for up to 4 cycles of therapy (Vogelzang 2003).  
 
Immunotherapy 
Single-agent immunotherapy 
There is now evidence for activity of immunotherapy in MPM. The first data on the 
safety and activity of pembrolizumab in MPM were demonstrated in KEYNOTE-028 
which showed 20% grade 3 toxicities and a durable median response duration of 12 
months (Alley 2017). The majority of patients (72%) had stabilization of their disease, 
including 20% with a partial response. The Japanese phase 2 MERIT study demonstrated 
an objective response rate of 29% with a median response duration of 11.1 months and a 
68% disease control rate. (Okada 2019) The MAPS2 trial found a 12-week disease 
control in 44% of patients with nivolumab alone. (Scherpereel 2019) In the JAVELIN 


 
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trial single-agent avelumab achieved an objective response rate of only 9%, but with a 
median duration of response of 15.2 months and disease control rate of 58%, indicating 
the ability of even single-agent immunotherapy to achieve durable responses in a subset 
of patients. (Hassan 2019) 
 
Dual checkpoint inhibition (ipilimumab/nivolumab) 
In the second open-label non-comparative randomized of the MAPS2 trial the 
combination of ipilimumab plus nivolumab showed promising results of 12-week disease 
control in 50% of patients (Scherpereel 2019), This was followed by the CheckMate 743 
trial that compared first-line ipilimumab/nivolumab with standard platinum/pemetrexed 
chemotherapy in newly diagnosed mesothelioma patients (Baas 2021), This trial showed 
an OS benefit with a median OS of 18.1 months with ipilimumab-nivolumab versus 14.1 
months with chemotherapy (HR 0.74, p=0.002). Patients with biphasic or sarcomatoid 
histology benefitted the most with this particular dual checkpoint immunotherapy 
combination, while epithelioid patients derived a smaller benefit.   
 
Combination systemic therapy plus immunotherapy 
The field of systemic therapy for MPM is currently very dynamic with several ongoing 
trials that may further establish the role of immunotherapy in multiple settings. Many 
ongoing efforts explore the combination of chemotherapy and immunotherapy, with 
some studies already completed. The DREAM (durvalumab in combination with first-
line chemotherapy in mesothelioma) trial already demonstrated the safety of combination 
chemo-immunotherapy with a median progression-free survival of 6.2 months. Of the 54 
patients followed for 6 months 46% achieved a partial response (Nowak 2020).  PrE0505 
enrolled 55 patients with combination of durvalumab and chemotherapy and 
demonstrated a median overall survival of 20.4 months. Fifty-six percent achieved partial 
response and 40% achieved stable disease (Forde 2020).  The promising results of the 
DREAM3R and PrE0505 trials led to the design of the DREAM3R trial (NCT04334759) 
which will study the addition of durvalumab to cisplatin/pemetrexed. 
Additional studies on the role of chemo-immunotherapy include a Canadian Cancer 
Trials Group study (NCT02784171) that evaluates the addition of pembrolizumab to 
platinum/pemetrexed chemotherapy. The BEATMeso trial (NCT03762018) investigates 
the addition of atezolizumab to platinum/pemetrexed/bevacizumab. These studies are 
likely going to further change the landscape of systemic treatment options for patients 
with MPM in the near future. 
As several neoadjuvant chemotherapy/immunotherapy combinations are commonly being 
delivered in the community, these will be permissible prior to study entry. On study only 
adjuvant platinum/pemetrexed will be delivered in patients who have not received 
neoadjuvant therapy. 
2.3       Hemithoracic intensity-modulated pleural radiation therapy (IMPRINT) (15-MAR-
2022) 
Consequently, a novel, highly conformal IMRT technique has been developed to treat the 
ipsilateral pleura with maximal sparing of the ipsilateral and contralateral lungs (Figure 


 
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1) (Rimner et al., 2012). Initially it was shown that this treatment technique was 
associated with a 20% risk of ≥ grade 3 radiation pneumonitis, which appears acceptable 
in this high-risk patient population and is comparable to pneumonitis risks for locally-
advanced non-small cell lung cancer (Rosenzweig et al., 2012). In resectable MPM 
patients (n=20), the 2-year overall survival rate of 53% was very promising, with a 
median survival of 26 months.  
 
 
A phase II trial at MSKCC and MDACC showed that out of 27 patients only 6 developed 
grade 2 and only 2 developed grade 3 radiation pneumonitis with no grade 4 or 5 
radiation-related toxicities observed (Rimner, Zauderer et al., 2016). The median 
progression-free and overall survival was 12.4 and 23.7 months, respectively. Thus, 
hemithoracic IMPRINT was deemed feasible and safe for selected centers with 
significant expertise. Currently this approach is being tested in a multicenter phase II 
study to examine the safety and exportability of this approach in a total of 5 centers 
(NCT00715611). 
 
Figure 1 
Example of an adjuvant IMRT plan after P/D to a total dose of 48.6 Gy (Rimner et al., 
2012). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This randomized phase III study, NRG-LU006, builds on this experience to date, with the 
goal to establish the IMPRINT technique as an essential component of a lung-sparing 
trimodality treatment approach. Therefore testing the impact of adjuvant IMPRINT in a 
randomized fashion is required to lead to a change in the standard of care for operable 
patients of P/D and systemic therapy alone.  
 
 
 
 
 
 
 
 
 
2.4       Rationale for a randomized phase III study on IMPRINT (15-MAR-2022) 
This trial is important because there is currently neither a uniform radiation field 
design/dose/technique to treat patients with MPM nor an established role of adjuvant 
hemithoracic IMPRINT. Most will agree that there is a role for maximal surgical 
debulking of MPM, and studies have suggested that a macroscopic complete resection is 
associated with prolonged outcomes in patients with MPM. The role of chemotherapy 
with cisplatin and pemetrexed is clearly established as the standard systemic therapy. 


 
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With the increasing use of lung-sparing P/D there is a need for improved locoregional  
control, as patients remain at high risk for local failure after lung-sparing P/D, despite 
frequently being the optimal surgical approach. The orthotopic presence of the ipsilateral 
lung represents a formidable challenge to the ability to deliver adjuvant radiation therapy 
without exceeding normal tissue dose constraints, especially the dose to the lungs. A new 
IMRT technique has been established that targets the entire hemithoracic pleura at risk 
for recurrence while avoiding the underlying ipsilateral lung tissue.  
 
A review of the current literature of the outcomes of P/D reveals that there is significant 
heterogeneity in the reported outcomes between studies. The endpoints are calculated 
from various time points, i.e. surgery, randomization, or diagnosis; patients of a variety of 
stages and histologic subtypes are included; adjuvant and neoadjuvant therapies are 
usually not specified or not accounted for, follow up is variable in terms of intervals 
between follow up visits and length of follow up. Overall survival has been reported to 
range from 7.1 months to 23 months, with the average across studies being about 12 to 15 
months. Outcomes of pleural IMRT have primarily been published by Memorial Sloan 
Kettering Cancer Center (MSKCC) and a cancer center in Aviano, Italy. To date, the 
reported OS from surgery or the start of RT have been very encouraging, ranging from 18 
to 33 months. It is therefore suggested that pleural IMRT may be associated with an 
overall survival benefit, possibly related to the ability to deliver a higher radiation dose 
than with conventional techniques and increased dose homogeneity with a lesser risk for 
areas of underdosing. 
 
Should this phase III trial result in an overall survival benefit associated with the use of 
IMPRINT, it would establish the multimodality approach of P/D, systemic therapy and 
adjuvant hemithoracic pleural IMRT as a new standard treatment paradigm for MPM. 
 
The phase II study utilized an induction chemotherapy approach in order to maximize 
resectability as well as patient selection for surgery and radiation therapy (Rimner, 
Zauderer et al., 2016). However, the response rate to induction chemotherapy was less 
than anticipated with 29% (n=13) partial responses among 27 evaluable patients. There 
were 15 patients (33.3%) who even progressed during induction chemotherapy, thus 
potentially having missed an opportunity for optimal tumor debulking and resection. 
While induction chemotherapy will be permitted, this study will preferentially use 
surgical resection as the initial treatment step followed by adjuvant chemotherapy and 
randomization to hemithoracic IMPRINT versus no IMPRINT. The prospective phase II 
study on the safety of adjuvant IMPRINT in combination with neoadjuvant chemotherapy 
+/- P/D showed a low rate of ≥ grade 3 radiation pneumonitis, with only two out of 27 
evaluable patients having experienced grade 3 pneumonitis. Six patients developed grade 
2 pneumonitis. All eight patients with radiation pneumonitis had resolution of their 
symptoms after standard management with systemic steroids. No grade 4 or 5 toxicities of 
any kind were observed. A failure pattern analysis of an expanded series of patients 
treated with this IMPRINT approach at MSKCC revealed that the majority of failures 
occur at sites of previous gross disease, with local failure being the first site of failure in 
30% of patients (Rimner et al., 2014). This indicates that (1) completeness of surgical 
resection is critical, and (2) a higher radiation dose to sites of gross residual disease may 


 
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be necessary to achieve higher local control rates in the pleural space. Therefore, this 
study allows a simultaneous integrated boost (SIB) using “dose-painting” IMRT to areas 
of gross residual disease without exceeding normal tissue constraints.  
 
3.   PATIENT ELIGIBILITY AND INELIGIBILITY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page). For radiation therapy-related eligibility 
questions, please contact RTQA (see protocol cover page).  
 
      Inclusion of Women and Minorities 
      NIH policy requires that women and members of minority groups and their subpopulations 
be included in all NIH-supported biomedical and behavioral research projects involving 
NIH-defined clinical research unless a clear and compelling rationale and justification 
establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the research.  
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification.  Cost is 
not an acceptable reason for exclusion except when the study would duplicate data from 
other sources.  Women of childbearing potential should not be routinely excluded from 
participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
3.1 
Eligibility Criteria (15-MAR-2022) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met.  
 
Prior to STEP 1 REGISTRATION – ALL PATIENTS 
3.1.1 Pathologically (histologically or cytologically) confirmed diagnosis of epithelioid or 
biphasic MPM;   
3.1.2 Imaging proof of clinical stage (AJCC 8th edition) I-IIIA MPM by PET/CT at diagnosis; 
• 
Diagnostic volumetric CT scan of the chest is preferred; however, the CT portion of 
the PET/CT may be used if CT imaging is of diagnostic quality. 
3.1.3   MPM is amenable to resection by P/D as determined by a thoracic surgeon; 
3.1.4    History/physical examination within 42 days prior to Step 1 Registration; 
3.1.5 Age ≥ 18;  
3.1.6    ECOG Performance Status 0-1 within 42 days prior to Step 1 Registration;  
3.1.7 Required Initial Laboratory Values prior to study entry (must be at least 14 days after last 
infusion of pre-study entry neoadjuvant therapy, if given): 
• 
Absolute neutrophil count ≥1500 cells/mm3; 
• 
Platelets ≥100,000 cells/mm3; 
• 
Hemoglobin ≥ 8.0 g/dL; 
• 
Serum total bilirubin ≤ 1.5 X ULN; 
• 
AST (SGOT) and ALT (SGPT) ≤ 3.0 X ULN;  
• 
Creatinine clearance ≥45 mL/min by the Cockcroft-Gault (C-G) equation: 


 
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CrCl (mL/min)  = [140 – age (years)] x weight (kg) {x 0.85 for female patients} 
 72 x serum creatinine (mg / dL) 
 
 
3.1.8    Negative urine or serum pregnancy test within 14 days of Step 1 Registration for women 
of childbearing potential; 
3.1.9 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months are eligible for this trial. Note: HIV testing is not required for eligibility 
for this protocol. 
3.1.10  The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry; 
 
Prior to STEP 1 REGISTRATION – PATIENTS WHO RECEIVED SYSTEMIC 
THERAPY BEFORE STUDY ENTRY 
3.1.10 The following systemic therapy and immunotherapy combinations are permissible:  1) 
cisplatin/carboplatin + pemetrexed; 2) cisplatin/carboplatin + pemetrexed + anti-PD-1/L1 
agents; and 3) ipilimumab/nivolumab. 
3.1.11  Patients must have received at least 2 cycles of neoadjuvant systemic therapy (as defined 
in section 5). 
 
Prior to STEP 2 RANDOMIZATION – ALL PATIENTS 
3.1.12  No evidence of progression as defined by PET/CT within 30 days prior to Step 2 
randomization.  Cases of possible progression or equivocal results must be discussed with 
Dr. Rimner prior to randomization.   
3.1.13 Patients must have received at least 2 cycles of systemic therapy and undergone a 
pleurectomy/decortication with the goal of macroscopic complete resection;  
3.1.14  ECOG Performance Status 0-1 within 30 days prior to Step 2 Randomization; 
3.1.15  History/physical examination within 30 days prior to Step 2 Randomization; 
 
3.2 
Ineligibility Criteria (15-MAR-2022) 
Patients with any of the following conditions are NOT eligible for this study. 
 
Prior to STEP 1 REGISTRATION – ALL PATIENTS 
3.2.1 Pregnancy or women who are breastfeeding and unwilling to discontinue. 
3.2.2    Participants of childbearing potential (participants who may become pregnant or who 
may impregnate a partner) unwilling to use highly effective contraceptives during and for 
six months after end of treatment because the treatment in this study may be significantly 
teratogenic. 
3.2.3    Diagnosis of sarcomatoid mesothelioma. 
3.2.4    Severe, active co-morbidity defined as follows: 
• NYHA Class III or IV heart failure 
• COPD requiring chronic oral steroid therapy of > 10 mg prednisone daily or 
equivalent at the time of registration. Inhaled corticosteroids are allowed;  
• Unstable angina requiring hospitalization and/or transmural myocardial infarction 
within the last 3 months;  
• Interstitial lung disease; 


 
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• Hemodialysis or peritoneal dialysis; 
• Concurrent active malignancy (with the exception of current or prior non-
melanomatous skin cancer or low-grade malignancies followed observantly for which 
treatment has not or does not have the potential to interfere with the safety or efficacy 
assessment of the investigational regimen) 
o If evidence of disease < 3 years, institution must consult with the Principal 
Investigator, Andreas Rimner, MD. 
• Hepatic impairment defined by ChildPugh Class (ChildPugh Class B & C); 
o For patients with evidence of chronic hepatitis B virus (HBV) infection, the 
HBV viral load must be undetectable on suppressive therapy within 30 days 
prior to registration, if indicated.  Note:  HBV viral testing is not required for 
eligibility for this protocol. 
o Patients with a history of hepatitis C virus (HCV) infection must have been 
treated and cured.  For patients with HCV infection who are currently on 
treatment, they are eligible if they have an undetectable HCV viral load within 
30 days prior to registration. 
• Active lung infection requiring IV antibiotics; 
• Patients on immunosuppressive therapy, for example with a history of organ or bone 
marrow transplant or other hematologic disorders that are expected to compromise 
life expectancy or tolerance of treatment;  
3.2.5  Prior nephrectomy on the contralateral side of MPM; 
3.2.6  Ipsilateral thoracic electronic implant, e.g. pacemaker, defibrillator, unless switched to 
the contralateral side prior to initiation of RT; 
3.2.7    Prior thoracic radiation therapy (patients with prior thoracic RT cannot be planned to 50-
60 Gy without exceeding normal tissue constraints); 
3.2.8    Use of bevacizumab or other antiangiogenic therapy to treat current mesothelioma (due to 
potential for increased complications from local therapy). 
3.2.9    For patients who received neoadjuvant systemic therapy prior to study entry, surgery 
planned to occur greater than 8 weeks following neoadjuvant systemic therapy. 
 
Prior to STEP 2 RANDOMIZATION – ALL PATIENTS 
3.2.10  Supplemental oxygen use;  
3.2.11  Third space fluid that cannot be controlled by drainage or insufficient lung expansion  
after P/D (this prevents targeting the pleura without exceeding normal tissue constraints);  
3.2.12  Prior intrapleural therapy (i.e. intrapleural chemotherapy, photodynamic therapy); 
pleurodesis is permitted; 
3.2.13  Bulky residual disease in the major fissure preventing pleural IMRT; 
3.2.14  Patients who have undergone extrapleural pneumonectomy; 
3.2.15  Patients with active infection that requires systemic I.V. antibiotics, antiviral, or      
antifungal treatments. 


 
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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP (13-
APR-2022) 
 
PRE-TREATMENT ASSESSMENTS  
 
Assessments 
Prior to Step 1 Registration  
Pathologic confirmation of epithelioid or 
biphasic MPM  
X 
History, physical examination (including 
weight), performance status, vital signs 
including O2 saturation, temperature, heart rate, 
blood pressure, and respiratory rate 
≤42 days 
Surgical confirmation that MPM is amenable to 
resection by P/D 
X 
PET/CT for staging 
At diagnosis 
Diagnostic volumetric CT scan of the chest* 
At diagnosis 
Functional MRI of the thorax or MRI of the 
chest (optional) 
≤42 days 
Urine or serum pregnancy test (women of 
childbearing potential) 
≤14 days 
CMP (Complete Metabolic Panel) and CBC 
with differential† 
Prior to study entry (must be at least 14 
days after pre-study entry neoadjuvant 
therapy if given, and within 42 days prior 
to Registration for patients who did not 
receive pre-study neoadjuvant therapy) 
 
 
* 
Diagnostic CT scan of the chest 1-3 mm slice thickness (intravenous contrast is preferred, 
CT volumetry, modified RECIST criteria). This can be obtained as part of PET/CT if CT 
imaging is of diagnostic quality. 
† 
CMP to include creatinine, total bilirubin, AST and ALT, electrolytes (potassium, sodium, 
and chloride).  CBC with differential to include absolute neutrophil count, lymphocyte 
count, platelet count, and hemoglobin. 
 
 


 
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ASSESSMENTS FOR PATIENTS RECEIVING SURGERY FOLLOWED BY 
CHEMOTHERAPY (SYSTEMIC THERAPY NOT RECEIVED 
BEFORE STUDY ENTRY) 
 
Assessments 
After 
Enrollment,  
Prior to Surgery 
After Surgery 
Prior to First 
Chemo. Cycle 
During Chemo. 
(prior to     
every cycle) 
History, physical 
examination (including 
weight), performance 
status, vital signs including 
O2 saturation, temperature, 
heart rate, blood pressure, 
and respiratory rate 
 
X 
X 
Toxicity Assessment Grade 
per NCI CTCAE, v 5.0 
 
X 
X 
Quantitative V/Q scan as 
indicated* 
Within 
30 days 
(may be prior to 
enrollment but 
must be within 30 
days prior to 
surgery) 
 
 
Pulmonary Function Tests 
(FEV1 and DLCO) 
Within 
30 days 
(may be prior to 
enrollment but 
must be within 30 
days prior to 
surgery) 
 
 
CMP (Complete Metabolic 
Panel) and CBC with 
differential† 
As clinically 
indicated 
Within 14 days 
prior to first cycle 
of chemotherapy 
X 
Urine or serum pregnancy 
test (women of child-
bearing potential) 
 
Within 14 days 
prior to first cycle 
of chemotherapy 
 
EORTC QLQ-C30 and 
QLQ-LC13 
X 
Within 30 days 
prior to first cycle 
of chemotherapy 
 
Biospecimen Collection:  
tissue and blood for future 
exploratory analysis – see 
Section 10 for details 
X 
 
 
 
 
* Preop quantitative V/Q scan strongly recommended for patients with ≤60% predicted post-op  


 
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FEV1 and/or DLCO. 
† CMP to include creatinine, total bilirubin, AST and ALT, electrolytes (potassium, sodium, and 
chloride).  CBC with differential to include absolute neutrophil count, WBC, lymphocyte count, 
platelet count, and hemoglobin.  Collection timeframes prior to treatment per institutional 
standards.  
 
 
ASSESSMENTS FOR PATIENTS RECEIVING SURGERY ONLY (SYSTEMIC 
THERAPY RECEIVED BEFORE STUDY ENTRY) 
 
Assessments 
After Enrollment,  
Prior to Surgery 
After Surgery 
(4 wks after surgery 
+\- 2 wks)  
History, physical examination 
(including weight), performance 
status, vital signs including O2 
saturation, temperature, heart rate, 
blood pressure, and respiratory rate 
X 
X 
Toxicity Assessment Grade per NCI 
CTCAE, v 5.0 
 
X 
Quantitative V/Q scan as indicated** 
Within 30 days 
(may be prior to enrollment 
but must be within 30 days 
prior to surgery) 
 
PET/CT  
Within 30 days 
(may be prior to enrollment 
but must be within 30 days 
prior to surgery) 
 
Pulmonary Function Tests (FEV1 and 
DLCO) 
Within 30 days 
(may be prior to enrollment 
but must be within 30 days 
prior to surgery) 
 
CMP (Complete Metabolic Panel) 
and CBC with differential * 
X 
 
 
EORTC QLQ-C30 and QLQ-LC13 
X 
 
Biospecimen Collection:  tissue and 
blood for future exploratory analysis 
– see Section 10 for details 
X 
 
 
 
 
* 
 
 
** 
 
CMP to include creatinine, total bilirubin, AST and ALT, electrolytes (potassium, sodium, 
and chloride).  CBC with differential to include absolute neutrophil count, WBC, 
lymphocyte count, platelet count, and hemoglobin.  
Preop quantitative V/Q scan strongly recommended for patients with ≤60% predicted post-
op FEV1 and/or DLCO. 
 
 


 
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ASSESSMENTS PRIOR TO RANDOMIZATION AND DURING RT  
(Patients who cannot be randomized will not be followed, and any assessment 
post-randomization will not apply) 
 
BOTH ARMS 
ARM 2 ONLY 
Assessments 
Step 2 
Randomization 
After Step 2 
Randomization,  
Prior to RT 
 
During RT  
History, physical 
examination (including 
weight), performance 
status, vital signs including 
O2 saturation, temperature, 
heart rate, blood pressure, 
and respiratory rate 
Within 30 days prior 
to randomization 
 
Weekly 
EORTC QLQ-C30 and 
QLQ-LC13 
Within 30 days prior 
to randomization 
 
 
Toxicity Assessment Grade 
per NCI CTCAE, v 5.0 
 
 
Weekly 
PET/CT 
Within 30 days prior 
to randomization 
 
 
Diagnostic volumetric CT 
scan of the chest* 
 
Within 30 days after 
randomization 
 
 
Pulmonary Function Tests 
(FEV1 and DLCO) 
Within 30 days after 
randomization 
 
 
CMP (Complete Metabolic 
Panel) and CBC with 
differential † 
 
Within 14 days after 
randomization 
If clinically 
indicated 
Renal scan in patients with 
impaired renal function 
(GFR<60)  
 
Within 30 days after 
randomization 
 
Urine or serum pregnancy 
test (women of 
childbearing potential) 
 
Within 14 days after 
randomization 
 
Biospecimen Collection:  
blood for future 
exploratory analysis – see 
Section 10 for details 
 
Within 14 days after 
randomization (prior 
to RT in Arm 2) 
 
 
 
* 
Diagnostic Chest CT with 1-3 mm slice thickness (1mm preferred; with intravenous contrast 
preferred), CT volumetry, modified RECIST criteria. This can be obtained as part of 
PET/CT if CT imaging is of diagnostic quality. 
† 
CMP to include creatinine, total bilirubin, AST and ALT, electrolytes (potassium, sodium, 
and chloride).  CBC with differential to include absolute neutrophil count, WBC, 
lymphocyte count, platelet count, and hemoglobin. 


 
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ASSESSMENTS IN FOLLOW UP 
(Patients who cannot be randomized will not be followed, and any assessment 
post-randomization will not apply)  
 
Assessments 
Arm 1 and 2:  From 
Randomization:  q3 mos. (+/- 2 
weeks) x 2 yrs., then q6 mos. 
(+/- 4 weeks) x 3 yrs.  
As clinically indicated 
History, physical 
examination (including 
weight), performance status, 
vital signs including O2 
saturation, temperature, heart 
rate, blood pressure, and 
respiratory rate 
X 
 
Diagnostic volumetric CT 
scan of chest* 
X as noted below: 
From Randomization:  q 3 mos. 
+/- 2 weeks x 2 yrs., then 6 mos. 
(if clinically indicated) then 
annually to yr. 5 and as clinically 
indicated 
 
CMP (Complete Metabolic 
Panel)** 
For Arm 2 patients –  
recommended (not mandatory) 
at 3 and 6 months ONLY 
 
All other time points as 
clinically indicated 
X 
(for Arm 1 patients) 
 
PET/CT 
 
X (if suspicious findings on 
CT chest) 
Toxicity Assessment Graded 
per NCI CTCAE, v 5.0† 
X 
 
EORTC QLQ-C30 and 
QLQ-LC13 
At 3, 9, 15, and 21 months from 
Randomization (+/- 2 weeks) 
 
Biopsy of recurrent disease 
 
X (if suspicious findings on 
CT and/or PET) 
Biospecimen Collection: 
blood for future exploratory 
analysis – see Section 10 for 
details 
3 months only 
 
 
 
* 
 
** 
Diagnostic Chest CT with 1-3 mm slice thickness (1mm preferred; with intravenous contrast 
preferred), CT volumetry, modified RECIST criteria.  
CMP to include creatinine, total bilirubin, AST and ALT, electrolytes (potassium, sodium, 
and chloride).   
† 
Report AEs reasonably related (possibly, probably, definitely) to protocol treatment and      
persistent AEs 


 
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Definition of Disease Assessments 
CT scan with contrast will be used for response assessment. In cases where PET-CT scans are 
being acquired, response assessment will be done in accordance with the EORTC criteria. 
Additionally, exploratory data from MRI scans and volumetric calculations from CT scans will 
be collected for exploratory analysis per section 13.3. DICOM data from imaging studies will be 
collected per section 13.3. 
 
Response and progression will be evaluated in this study by using the modified Response 
Evaluation Criteria in Solid Tumors (Byrne et al., 2004).  Changes in the largest diameter (LD) 
(unidimensional measurement) of the tumor lesions perpendicular to the chest wall or 
mediastinal structures at two levels and three sites are used in the mRECIST criteria. The 
measurement of lymph nodes is in accordance with RECIST criteria.  
 
The following terms and definitions may guide investigators but official mRECIST criteria 
should be employed for all study evaluations.  
 
Complete Response (CR)  
Disappearance of the target lesion; this determination will be made based on CT image 
evaluation.  
 
Partial Response (PR)  
At least a 30% decrease in the LD of the target lesion, taking as reference the baseline LD; this 
determination will be made based on CT image evaluation.  
 
Stable Disease (SD)  
Neither sufficient shrinkage to qualify for CR/PR above nor sufficient increase to qualify for LE 
below, taking as reference the smallest LD since the treatment started  
 
Local Enlargement (LE)  
At least a 20% increase in the LD of target lesions, taking as reference the smallest LD recorded 
since the treatment started; this determination will be made based on CT image evaluation  
 
Local Failure (LF)  
Refers to progression of pleural tumor thickness or appearance of a site of pleural thickness 
greater than 5 mm in the site of treated tumor.  
 
For outcome analysis: modified RECIST criteria (mRECIST) will be used to assess progression 
free survival and Overall survival. 
 
Evaluation of Non-Target Lesions  
Marginal Failure (MF)  
Refers to the appearance of a new measurable site of pleural tumor greater than 5mm within the 
treated site or enlarging tumor dimensions corresponding to a 20% increase in the longest diameter 
compared to initial appearance on imaging evaluation.  
 


 
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Regional Failure (RF)  
Refers to the appearance of measurable tumor or lymph nodes along the natural lymphatic drainage 
typical for the location of the treated primary disease only with dimension of at least 1.0 cm on 
imaging studies (preferably CT scans) within the hilum, and the mediastinum. Equivocally appearing 
enlarged lymph nodes should be positive on PET imaging or biopsied to confirm involvement with 
carcinoma.  
 
Metastatic Dissemination (MD)  
Refers to the appearance of cancer deposits characteristic of metastatic dissemination from 
Mesothelioma. Appropriate evaluations for making this determination include physical examination 
and imaging studies. PET scan OR biopsy to confirm MD is encouraged but not required. 
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION (15-MAR-2022) 
Participants will undergo surgical resection with P/D as the initial treatment step, within 4 weeks 
after study entry.  Participants who did not receive neoadjuvant systemic therapy prior to study 
entry will receive an adjuvant chemotherapy regimen of pemetrexed and cisplatin (or 
carboplatin), 4 to 8 weeks after surgery.   
 
Patients who received neoadjuvant systemic therapy prior to study enrollment will undergo 
surgical resection with P/D within 4 to 8 weeks of completion of neoadjuvant systemic 
treatment.  Note:  neoadjuvant systemic therapy is defined as 2 to 4 cycles of one of the 
following regimens:  1) Platinum/pemetrexed; 2) platinum/pemetrexed + anti-PD-1/L1 agent; or 
3) ipilimumab/nivolumab.  No additional systemic therapy will be given on the study for these 
patients. 
 
Randomization occurs after the second treatment modality (chemotherapy or P/D).  Participants 
randomized to Arm 1 will receive no further treatment, and participants randomized to Arm 2 
will receive photon radiation using Intensity-Modulated Radiation Therapy (IMRT) or Pencil 
Beam Scanning (PBS) Proton Therapy to the hemithoracic pleura.   
  
5.1 
Surgery (15-MAR-2022) 
For patients who received neoadjuvant systemic therapy as the initial treatment, surgery (P/D) 
must take place within 4 to 8 weeks from the end of neoadjuvant systemic therapy.  For patients 
who undergo adjuvant chemotherapy, it must begin within 8 weeks after surgery. 
 
5.1.1 Technique, timing, other  
Complete surgical resection of all gross tumor (i.e. " macroscopic complete resection", also 
termed "MCR") via a lung-sparing procedure is required.  
 
Prior to surgery, FEV1 and DLCO values must be: 
• Post-operative predicted FEV1>40%;  
• Post-operative predicted DLCO >40% (corrected for Hgb). 
 
The approach to achieving MCR is dictated by the extent of disease at exploration and may 
include partial pleurectomy, pleurectomy/decortication (P/D) or extended pleurectomy/ 
decortication (EPD) as described in guidelines developed by the IASLC (Rice et al., 2011). The 


 
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procedure performed should be accompanied by lymph node sampling or dissection of all 
peribronchial / hilar / mediastinal lymph node stations according to the AJCC / UICC lymph 
node map described in the 7th and 8th editions of the international staging systems for malignant 
pleural mesothelioma.  Intraoperative adjunctive therapies such as heated intrapleural 
chemotherapy or photodynamic therapy are NOT allowed in this study.  
 
Procedure 
Description 
Trial eligibility 
Extra Pleural 
Pneumonectomy (EPP) 
en bloc resection of the parietal and 
visceral pleura with the ipsilateral 
lung, pericardium, and diaphragm. In 
cases where the pericardium and/or 
diaphragm are not involved by tumor, 
these structures may be left intact. 
Not eligible 
Extended 
Pleurectomy/Decortication 
(extended P/D) 
parietal and visceral pleurectomy to 
remove all gross tumor with resection of 
the diaphragm and/or pericardium. 
Eligible 
Pleurectomy Decortication 
(P/D) 
parietal and visceral pleurectomy to 
remove all gross tumor without 
diaphragm or pericardial resection. 
Eligible 
Partial 
Pleurectomy/Decortication 
(partial (P/D) 
partial removal of parietal and/or visceral 
pleura for diagnostic or palliative 
purposes but leaving gross tumor behind. 
Eligible 
(Only minimal residual 
gross disease) 
 
5.2 
Chemotherapy/ /Other Agent-Based Therapy (15-MAR-2022) 
For patients who underwent P/D as the initial treatment, adjuvant chemotherapy protocol 
treatment must begin within 4 to 8 weeks after surgery.  The combination of pemetrexed 
and cisplatin (or carboplatin) will be given every 3 weeks for 4 cycles. 
                       
5.2.1    Pemetrexed based chemotherapy with cisplatin (or carboplatin) 
            Recommended administration guidelines or per institutional standard 
 
500 mg/m2 administered by IV over 10 minutes on Day 1 of a 21-day cycle with cisplatin 
or carboplatin. Doses can be rounded per institution policy.  
 
            When given in combination with platinum-based therapy, administer the pemetrexed 
prior to the platinum.  Cisplatin is preferred over carboplatin. However, pre-existing renal 
impairment, hearing deficit and/or neuropathy may be acceptable reasons to use 
carboplatin instead of cisplatin.   
 
Recommended pre-medications or per institutional standard 
NOTE: Pemetrexed administration requires vitamin supplementation initiated one week 
prior to first dose of pemetrexed 
     
• Vitamin Supplements to be started 7 days prior to initial pemetrexed dose:  
a. Vitamin B12:  Patients should receive one intramuscular (IM) injection of 
1000 mcg vitamin B12 seven days prior to the first pemetrexed dose then 


 
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every 3 cycles thereafter. Subsequent vitamin B12 injections may be 
administered on the same day as pemetrexed.  
b. Folic acid:  Folic acid 400-1000 mcg PO once daily started seven days prior to 
pemetrexed dose, continued during treatment, and for 21 days after last 
pemetrexed dose. 
• Premedications 
a. Pemetrexed has low emetic risk but use of dexamethasone is required to 
prevent cutaneous reactions, doses may vary per institutional standard, the 
following are two options:  
i. 
Dexamethaxone 4 mg PO twice daily for 3 days, starting the day 
before pemetrexed administration. 
ii. 
Dexamethasone 8-12 mg PO/IV once prior to pemetrexed infusion. 
b. Other premedications can be used per institutional standard. 
         
5.2.2    Cisplatin  
            Recommended administration guidelines or per institutional standard 
75 mg/m2 IV once every 3 weeks (on Day 1 of a 21-day cycle with pemetrexed), as a 60-
minute infusion. Prepare and administer per institution policy. Doses can be rounded per 
institution policy. 
            
Recommended pre-medications or per institutional standard 
             
• Cisplatin anti-emetic administration guidelines:  5-HT3 antagonists (e.g. ondansetron 
8 mg IV/PO +.  Dexamethasone 10-20 mg IV 30 minutes prior to chemotherapy).  
(Note: can give pre-medications by oral route 60 minutes prior to infusion).  Continue 
ondansetron 8 mg PO twice a day for three days then as needed.  Rescue antiemetic 
such prochlorperazine 10 mg PO up to four times a day should be provided. Use of 
other anti-nausea meds such as fosaprepitant/aprepitant, metoclopramide, or 
olanzapine is left to the discretion of the investigator. 
• Cisplatin pre-hydration guidelines: Pre-hydration with 0.45 % sodium chloride 1000 
mL with 16 mEq magnesium sulfate infused over 2 hours prior to cisplatin.  
• Cisplatin post-hydration guidelines: Following the end of the cisplatin administration, 
an additional give 0.9% sodium chloride 1000 mL with 20 mEq potassium chloride 
and 16 mEq magnesium sulfate infused over 2 hours. Patients should be encouraged 
to self-hydrate throughout the week with frequent fluid intake with non-caffeinated 
beverages.  Patients unable to orally self-hydrate should be considered for additional 
IV hydration on these days with NS. 
 
5.2.3    Carboplatin  
Recommended administration guidelines or per institutional standard 
See Appendix A for the carboplatin dosing worksheet 
AUC=5 once every 3 weeks (on Day 1 of a 21-day cycle after pemetrexed infusion is 
completed), over 60 minutes. Prepare and administer per institution policy. Doses can be 
rounded per institution policy. Carboplatin dose will be calculated using the Calvert 
formula:  Carboplatin dose (mg) = target AUC x (GFR + 25).  
 


 
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For the purposes of this protocol, the glomerular filtration rate is considered equivalent to 
the creatinine clearance calculated by Cockcroft-Gault and is capped at 125 mL/min. 
Actual body weight should be used unless patient is greater BMI > 25, then use an 
adjusted body weight.  Lower limit of serum creatinine should be the lower limit of assay 
– i.e. usually = 0.7 mg/dL: 
 
Clcr (mL/min) = 
[140 – age (years)] x weight (kg) {x 0.85 for female patients} 
 72 x serum creatinine (mg / dL) 
 
Recommended pre-medications or per institutional standard 
• Antiemetic regimen including a 5HT3-antagonist and steroid as described above in 
5.2.2. 
5.3 
Radiation Therapy – Arm 2 only (15-MAR-2022) 
Radiation therapy protocol treatment must begin within 4 to 8 weeks from the end of Step 1 
treatment.  Radiation therapy will be administered 5 days/week over approximately 6 weeks at 
45 to 50.4 Gy (RBE), with RBE = 1.1 for protons and RBE = 1.0 for photons, in 25-28 fractions.  
Note that Gy for photons and Gy (RBE) for protons are used interchangeably in this protocol as 
applicable for each modality.  An optional concomitant boost to 60 Gy (maximum dose per 
fraction of 2.4 Gy) for gross residual disease may be incorporated if normal tissue constraints can 
be met. 
 
A Contouring Atlas has been developed by Memorial Sloan Kettering Cancer Center that offers 
general guidance for delineation of targets for epithelioid or biphasic malignant pleural 
mesothelioma in the context of intensity-modulated pleural radiation therapy.  The Atlas is 
posted on the NRG-LU006 page of the CTSU website and is to be used as a reference for 
treatment planning.  All pre-treatment radiation therapy quality assurance reviews will be 
assessed based on conformity to Atlas structures. 
 
Pre-treatment review is required for all patients randomized to Arm 2 prior to delivery of 
radiation treatment. The patient cannot start treatment until they have received approval from 
the Imaging and Radiation Oncology Core (IROC)-Philadelphia.  Due to the complexity of the 
RT planning, the Pre-Treatment review process is accomplished in two steps.  Step 1 is a 
preliminary contour review where all required structures are submitted and evaluated for 
protocol compliance.  Once the contour review is approved, Step 2 is a pre-treatment review of 
the full planning dataset to confirm contours and evaluate the plan for dose compliance is done.  
Each of these steps requires 3 business days from the receipt of complete data via TRIAD.  If 
revisions are required, the process begins again. 
 
5.3.1 Treatment Technology 
Intensity Modulated Radiation Therapy (IMRT) will be used for all photon therapy; permitted 
delivery platforms include conventional linear accelerators (both fixed gantry IMRT and 
Volumetric Arc Therapy techniques at discretion of prescribing physician), MR-linacs and 
TomoTherapy units. A photon beam energy of 6-10 MV will be used.  In these platforms, multi-
leaf collimation (MLC) will be used to spare normal tissues outside of the target volume. 
 
Pencil beam scanning (PBS), commonly referred to as intensity-modulated-proton-therapy 


 
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(IMPT), will be used for all proton beam therapy; permitted optimization techniques include 
single-field-uniform-dose (SFUD) or single-field optimization (SFO); or multi-field optimization 
(MFO). 
 
Daily image guided radiation therapy (IGRT) using orthogonal X-rays, MV CT or MR guidance 
and weekly volumetric imaging, including kV cone-beam CT, helical MV CT (e.g.  
TomoTherapy), or CT-in-room must be used for all patients, regardless of radiation treatment 
techniques.   
 
5.3.2 Immobilization and Simulation  
Immobilization 
Proper immobilization is critical for this protocol.  Patient setup reproducibility must be achieved 
using appropriate clinical devices.  Alpha cradles, Vac-Lok, or similar devices are used for 
shoulder immobilization.  Immobilization of proton therapy patients should be performed such 
that beam range variations due to daily differences of patient settling into the immobilization 
devices are minimized.  Arms should be abducted bilaterally with hands above the head and 
setup must be reproducible daily. 
 
Simulation Imaging  
Simulation CTs should be CT slices of no more than 3 mm slice thickness starting from the level 
of the cricoid cartilage and extending inferiorly to the iliac crest.  Administration of intravenous 
(I.V.) contrast during simulation CT is preferred.  A 4D scan capturing all phases of the 
respiratory motion should be obtained.  Images to be used for proton therapy treatment planning 
should be acquired prior to IV contrast injection.  If available, an FDG-PET study in the 
treatment position should be performed.  Otherwise a diagnostic PET scan prior to RT start 
should be used for fusion and treatment planning.  This PET scan (and associated DICOM 
registration file if applicable) will be submitted with digital RT treatment planning data as part of 
the pre-treatment review. 
 
Motion Management Technique 
A motion assessment (4D scan) or management technique must be used and documented. The 
use of four-dimensional radiation treatment planning is preferred to account for respiratory 
motion in the treatment planning process.  Other methods permitted are treatment in breath hold 
(using Active Breathing Coordinator (ABC), Real-Time Position Management (RPM), surface 
imaging or otherwise supervised breath hold) and abdominal compression.  The motion 
management scans should include the entire thorax, extending from above the lung apex to the 
bottom of the lungs with at least 2 cm margin, typically around L2 inferiorly.     
 
For PBS treatment delivery, in addition to those methods listed above, use of layer- or volume-
repainting techniques is strongly encouraged.  Other methods to reduce interplay effect of PBS 
delivery include limiting max spot MU and increasing spot size by use of range shifters. 
 
5.3.3 Imaging for Structure Definition and Image Registration 
A volumetric treatment planning CT study and a recent, registered FDG-PET scan will be 
required to define gross tumor volume (GTV), internal target volume (ITV) (if 4D scan is used), 
clinical target volume (CTV), and planning target volume (PTV) (see definitions in Section 5.3.4 


 
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below).  Contiguous CT slices, having no more than 3 mm thickness are to be obtained starting 
from the level of the cricoid cartilage and extending inferiorly through the iliac crest.  The GTV, 
CTV, and PTV and critical structures will be outlined on all appropriate CT slices.  In the case 
where the PET/CT is obtained in the treatment position, the CT from this study may be used as 
the planning CT scan.  Otherwise, a diagnostic PET/CT used for staging could be used for target 
delineation with image co-registration with the planning CT.   
 
5.3.4 Definition of Target Volumes and Margins 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable.  Resubmission of data may be required if labeling of structures does 
not conform to the standard DICOM name listed.  Capital letters, spacing and use of underscores 
must be applied exactly as indicated. 
 
If residual disease is identified, it will be delineated as GTV. On slices containing GTV, the 
outer and inner CTV (CTV_Outer and CTV_Inner) must include a 3mm margin surrounding the 
GTV. On slices containing normal lung, the CTV_Outer and CTV_Inner must be delineated at 
the lung/chest wall interface. Below the level of the diaphragm, the CTV_Outer is typically only 
a single crescent-shaped contour which is named CTV_Outer and needs to be manually 
expanded to cover the pleura towards the sternum, the diaphragm and diaphragmatic crura to 
midline anteriorly and the paravertebral space posteriorly.  
 
An internal target volume (ITV_Inner and ITV_Outer) will be delineated as an expansion of the 
CTV_Inner and CTV_Outer to account for respiratory and cardiac motion seen on the 4D-CT 
study.  If breath-hold or compression are used for motion management, if the institution’s 
experience indicates there is minimal residual motion in their application, there may be no ITV 
(ITV and CTV will be identical).  The instructions below refer to the ITV approach. These 
volumes will then be expanded and combined to form an equivalent PTV as follows.  
 
On slices where the ITV is the region between outer and inner contours, PTV_Outer is defined as 
the ITV_Outer plus 1 cm externally into the chest wall.  Where necessary, the PTV_Outer will 
be further adjusted to cover the entire thickness of the chest wall, including the ribs and 
intercostal muscles. It will be expanded to the lateral edge of the sternum or midline anteriorly, 
to include the costovertebral joint and the lateral edge of the vertebral body, the 
costodiaphragmatic and costomediastinal recess and the crus of the diaphragm.  Below the level 
of the diaphragm use only PTV_Outer as this will be a crescent shaped structure and there is no 
lung internally to avoid. Typically, the volumes extend inferiorly to about the bottom of the L2 
vertebral body. 
 
This volume will exclude the external skin surface and stay 5mm off of the spinal cord medially 
bounded by the vertebral body edge.  The PTV_Outer may be shaved off the spinal canal where 
necessary. 
 
PTV_Inner is the ITV_Inner with 6mm expansion into the lung parenchyma for photons or a 
comparable margin to account for range uncertainties and uncertainties in the stopping power for 


 
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protons. The PTV for planning purposes is the volume between PTV_Outer and PTV_Inner, 
represented by the Boolean structure PTV_Outer minus PTV_Inner. A detailed target volume 
contouring description is provided in Table 5.3.4 below.  
 
Table 5.3.4 
Target Structure Definitions 
 
Gross Tumor Volume (GTV)   
• Gross tumor based on CT and PET scan 
 
Clinical Target Volume (CTV) 
• CTV_Inner: lung/chest wall interface on slices without GTV; 3mm internal 
margin surrounding the GTV on slices with GTV 
• CTV_Outer: lung/chest wall interface on slices without GTV; 3mm external 
margin surrounding the GTV on slices with GTV 
 
Internal Target Volume (ITV) 
• ITV_Inner: internal expansion (i.e. shrinkage) of the CTV_Inner to account for 
respiratory and cardiac motion seen on 4DCT scan 
• ITV_Outer: external expansion of the CTV_Outer to account for respiratory 
and cardiac motion seen on 4DCT scan 
 
Planning Target Volume (PTV)* 
• PTV_Inner: 6mm internal expansion of the ITV_Inner 
• PTV_Outer: 10mm external expansion of the ITV_Outer; where necessary, the 
PTV_Outer will be further adjusted to cover the entire thickness of the chest 
wall, including the ribs and intercostal muscles; it will be expanded to the 
lateral edge of the sternum or midline anteriorly, the costovertebral joint and 
the lateral edge of the vertebral body, the costodiaphragmatic and 
costomediastinal recess and the crus of the diaphragm 
 
 
If desired, gross residual disease may be treated with a Simultaneous Integrated Boost to 60 Gy 
while respecting normal tissue constraints. The involved structures shall be named GTV_6000, 
ITV_6000 (if ITV approach is used), CTV_6000 (3mm margin), and PTV_6000 (5mm margin).  
 
For target structures, users will consult the Contour Atlas that is posted on the NRG-LU006 page 
of the CTSU website.  
 
5.3.5 
Definition of Critical Structures and Margins 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable.   
 
Resubmission of data may be required if labeling of structures does not conform to the standard 


 
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DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
Standard Name 
 
Description 
Validation 
Required/Required 
when applicable 
GTV 
Target Structure Delineation descriptions 
found above in Table 5.2.4 
Required when 
Applicable 
CTV_Inner 
Required 
CTV_Outer 
Required 
ITV_Inner 
Required when 
Applicable (with 
use of 4DCT ITV 
approach) 
ITV_Outer 
Required (with use 
of 4DCT ITV 
approach) 
PTV_Inner 
Required 
PTV_Outer 
Required 
PTV_Out-PTV_In 
PTV_Outer minus PTV_Inner 
Required 
PTV 
Volume between PTV_Outer and 
PTV_Inner 
Required 
Bolus_x.x cm 
Scar bolus 0.5cm to 1.0 cm maximum, if 
used; x.x = thickness of bolus  
Required when 
Applicable 
GTV_6000 
Tumor Volumes for optional Simultaneous 
Integrated Boost (SIB) if used for planning 
additional dose to gross residual disease 
Required when 
Applicable (SIB) 
CTV_6000 
Required when 
Applicable (SIB) 
ITV_6000 
Required when 
Applicable (SIB 
with ITV approach) 
PTV_6000 
Required when 
Applicable (SIB ) 
SpinalCord 
Spinal Cord (spinal canal from most 
superior slice to 3 slices inferior of PTV) 
Required 
Lungs 
Combined Right and Left Lungs 
Required 
Lungs-GTV 
Combined lungs minus GTV 
Required when 
applicable 
Lung_R 
Right Lung 
Required 


 
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Lung_R-GTV 
Right lung minus GTV 
Required when 
applicable 
Lung_L 
Left Lung 
Required 
Lung_L-GTV 
Left lung minus GTV 
Required when 
applicable 
Esophagus 
Esophagus (entire esophagus from cricoid 
cartilage to stomach) 
Required 
Heart 
Heart (pericardial sac; superior border at 
level of the right pulmonary artery crossing 
to the right side of the mediastinum) 
Required 
BrachialPlexus_L 
 
Left Brachial Plexus 
Required 
BrachialPlexus_R 
Right Brachial Plexus 
Required 
BrachialPlexus 
Combined Brachial Plexus 
Required 
Liver 
Liver 
Required 
Liver-GTV 
Liver minus GTV 
Required when 
applicable 
Spc_Bowel 
Space occupied by large bowel and small 
bowel 
Required 
Kidney_L 
 
Left Kidney 
Required 
Kidney_R 
Right Kidney 
Required 
Kidneys 
Combined Kidneys 
Required 
Stomach-PTV 
Stomach minus PTV 
Required 
E-PTV 
All tissue within the external contour minus 
PTV 
Required 
 
5.3.6 Dose Prescription  
The prescribed dose per fraction is 1.8 Gy and the total prescribed dose is 50.4 Gy. An optional 
concomitant boost to 60 Gy for gross residual disease may be incorporated if normal tissue 
constraints can be met with a maximum dose per fraction of 2.4 Gy.  See table below for 
examples of optional boost fractionation.  
 
Total Fractions 
Dose Per Fraction 
Total Prescribed Dose 
Optional Boost 
Total Boost Dose 
25 
1.8 Gy 
  45.0* 
2.40 Gy 
60 Gy 
26 
1.8 Gy 
46.8   
2.30 Gy 
60 Gy 
27 
1.8 Gy 
48.6  
2.22 Gy 
60 Gy 
28 
1.8 Gy 
50.4  
2.14 Gy 
60 Gy 


 
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*The total prescribed dose may be reduced to a minimum of 45 Gy (in 1.8 Gy increments) if required to 
satisfy the normal tissue constraints, while aiming for the highest dose within dosimetric constraints. 
 
The total prescribed dose may be reduced to a minimum of 45 Gy (in 1.8 Gy increments) if 
required to satisfy the normal tissue constraints, while aiming for the highest dose within 
dosimetric constraints. An optional bolus of clinically appropriate thickness (0.5 cm to 1.0 cm 
maximum) may be applied to the scar. If bolus is utilized, a contour to represent the bolus site 
will be included in the treatment plan and submitted.  This structure will be labeled as indicated 
in Section 5.3.5 above. 
 
5.3.7    Planning Constraints 
Planning constraints are tabulated below.  All doses are in Gy.  Note that the heart constraints are 
different for a left-versus right-sided target.  
 
Structure Name 
Dosimetric 
Parameter 
Per  
Protocol 
Variation 
 Acceptable 
Deviation  
Unacceptable 
GTV 
D95%[%] 
>=95 
>=90 
< 90 
 
 
 
 
 
PTV 
D95%[%] 
>=94 
>=90 
< 90 
V95%[%] 
>=94    
>=90 
< 90  
D5%[%] 
<=115 
<=120 
>120 
D0.03cc[%] 
<= 130 
 
<=150 
>150 
 
 
 
 
 
GTV_6000 * 
D95%[Gy] 
>= Rx Dose 
and <=60 
Gy 
N/A 
< Rx Dose 
 
 
 
 
 
Lungs-GTV 
(if no GTV, use Lungs) 
V20Gy[%] 
<=37 
<=40 
>40 
Mean[Gy] 
<=20.5 
N/A   
>20.5 
 
 
 
 
 
Lung_R 
Lung_L 
(Ipsi-lateral) 
V40Gy[%] 
<=67 
<=90 
>90 
 
 
 
 
 
Lung_R 
Lung_L 
(Contralateral) 
V5Gy [%] 
<=50 
<=80 
>80 
Mean [Gy] 
<=8 
<=10 
>10 
V20Gy[%] 
<=5 
<=7 
>7 
 
 
 
 
 
Esophagus 
Mean[Gy] 
<=34 
<=38 
>38 
V60Gy [%] 
<=17 
<=18 
>18 
  
 
 
 
 
SpinalCord 
D0.03cc[Gy] 
<=50   
N/A 
>50  
 
 
 
 
 
Kidney_R 
V18Gy[%] 
<=33 
<=50 
>50 


 
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Kidney_L 
 
 
 
 
 
 
Kidneys 
V18Gy[%] 
<=33 
<=50 
>50 
 
 
 
 
 
Stomach-PTV 
Mean[Gy] 
<=30 
<=32 
>32 
  
 
 
 
 
Spc_Bowel 
D0.03cc[Gy] 
<=55 
<=56 
>56 
D5cc[Gy] 
<=45 
<=50 
>50 
 
 
 
 
 
BrachialPlexus_R 
BrachialPlexus_L  
D0.03cc[Gy] 
<=65 
N/A 
>65 
 
 
 
 
 
Liver-GTV 
(if no GTV, use Liver) 
Mean[Gy] 
<=30 
<=31 
>31 
V30Gy [%] 
<=45 
<=50 
>50 
 
 
 
 
 
Heart 
(right meso) 
V40Gy[%] 
<=25 
<=35 
> 35 
Mean [Gy] 
<=30 
N/A 
>30 
 
 
 
 
 
Heart 
(left meso) 
V40Gy[%] 
<=35 
<=37 
 
>37 
V30Gy[%] 
<=50 
N/A 
>50 
Mean [Gy] 
<=30  
N/A 
>30 
 
 
 
 
 
E-PTV 
D0.03cc[%] 
<=110 
<=115 
>115 
Hotspots exceeding 110% of prescription (Variation Acceptable 115%) should be inside the PTV;  
 
*Boost to GTV is optional.  If no boost is intended, use the constraints for GTV.  If optional 
concomitant boost to 60 Gy is intended, use structure GTV_6000 and follow the constraints in 
Table 5.3.7. 
 
Dose Calculations 
Acceptable choices of algorithm are listed at http://irochouston.mdanderson.org.  Any algorithm 
used for this study must be credentialed by IROC Houston. 
 
Photon dose calculations 
For Convolution/Superposition type algorithms, dose should be reported as computed inherently 
by the given algorithm.   For Monte Carlo or Grid Based Boltzmann Solver algorithms, 
conversion of Dm (dose-to-medium) to Dw (dose-to-water) should be avoided.  Dm, computed 
inherently by these algorithms, should be reported.  
 
Proton dose calculations 
Monte Carlo dose calculation algorithm is required for final dose calculations in this protocol. 
 
Primary dataset for dose calculation 


 
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The primary dataset for dose calculation must be a free-breathing CT that was acquired along 
with 4DCT, an average intensity pixel CT (AveIP) generated from the 4DCT or the breath-
hold/gated CT, or the CT acquired with compression.  Maximum Intensity Pixel (MIP) generated 
images from 4DCTs may not be used as the primary dose calculation dataset. In the case in 
which contrast is present during the treatment planning CT, the density of the contrast should be 
overridden to a representative background electron density. 
 
Dose matrix resolution 
Dose grid size should be ≤ 3 mm in all directions. 
 
5.3.8   Daily Treatment Localization/IGRT 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate accuracy 
and precision throughout its entire process from target and normal tissue delineation, to radiation 
delivery, to adaptation of therapy to anatomic and biological changes over time in individual 
patients. In this section we use the terminology IGRT to focus on image-guidance at the time of 
radiation delivery to ensure its adherence to the planned treatment. 
 
Daily image guidance that allows for 3D shifts is a requirement for this trial.  Acceptable image 
guidance consists of daily orthogonal radiographs (2D imaging) matched on the spine for setup 
verification (or their equivalent per department guidelines) supplemented by weekly volumetric 
imaging at the treatment machine, which may include kV cone-beam CT, MV CT, CT-on- rails. 
More frequent volumetric imaging can be done per departmental guidelines when applicable.   
 
Guidelines for LINAC-based treatment planning (when applicable) 
The isocenter is approximately at the center of the treatment field. It is set by centering it on a 
field that ranges from the top of T1 to the bottom of L2, the contralateral edge of the vertebral 
body to lateral flash on the chest wall. Treatment is delivered with 6 to 10 MV photon beams, 
either static-gantry intensity modulated with the dynamic multi leaf collimator (DMLC or sliding 
window) technique or arc therapy (VMAT). Suggested beam angles for static-gantry IMRT are 6 
to 9 beam directions, approximately equispaced over a range of 190 to 200 degrees and chosen to 
avoid the contralateral lung as much as possible. Suggested beam angles for arc therapy are 4-6 
partial arcs going from 181 degrees to 20 degrees (right side) or 179 degrees to 340 degrees (left 
side) and determined by the shape of the lungs (the “lung limit”). Arc 1 should start from anterior 
oblique. 
 
Guidelines for proton therapy treatment planning: 
Proton therapy treatment plans should likewise use 2 – 4 treatment fields when field size limit 
allows.  Treatment fields should not traverse the base frame of patient head immobilization 
device, unless a proton therapy-compatible head immobilization device, such as a base-of-skull 
frame, is used.  Fields should not traverse through treatment table corners.   Beam-specific PTVs 
may be implemented for single-field-optimization (SFO) or single-field-uniform-dose (SFUD) 
plans or for multi-field optimization (MFO) with appropriate distal and proximal margins to 
ensure robustness of the treatment plans.  Alternatively, IMPT plans may be created using robust 
optimization on dose coverage objectives using robust optimization criteria that include range 
uncertainties >=5% and setup errors >=5 mm on CTV.  Robust optimization using the same 
robustness criteria should be applied to high risk critical organs, such as the spinal cord, if such 


 
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OARs are expected to receive near their maximum tolerance doses.  Care must be taken to assure 
that appropriate dose fall-off gradients are introduced in the field or target sub-volume junction 
regions to assure junction line dose homogeneity in the presence of setup errors.  If necessary, 
the maximum extent of diaphragm movement may be contoured and overridden with tissue HU 
value as appropriate, with distal and proximal margins of fields traversing through the 
diaphragms selected to assure adequate target coverage on reconstructed CT sets with and 
without diaphragm HU overrides.  When such tissue overrides are used, OAR doses should be 
reported from a verification plan on the AveIP CT set with no overrides.  Alternatively, 4D 
robust optimization that accounts for additional image sets, like the maximum inhale and exhale 
phases, may be used.  Air cavities within the ipsilateral lung should be reviewed for need to 
override during planning likewise, in a manner similar to that of diaphragm movements.  Beam 
angles tangential to periodically moving chestwall should be avoided due to potential range 
perturbations caused by chestwall movements.  Range shifters should be considered as needed.   
Motion mitigation techniques for proton therapy treatment planning and delivery should be 
evaluated and selected based on organ motion magnitude and follow recommendations of the 
PTCOG Thoracic Work Group Consensus Guidelines document (Chang et al., IJROBP 2017). 
 
For proton therapy treatments, pleural effusion filling variations and other anatomical changes 
that might occur through the course of patient treatment should be evaluated weekly, using either 
in-room volumetric imaging techniques (CBCT, CT-on-rail) that prompts for repeat CT imaging, 
or repeat imaging on the simulation CT.  Dose distributions should be re-calculated on the repeat 
CT scans to assure adequate target coverage and normal organ protection, and treatment plans 
should be modified when necessary. 
 
The robustness of PBS treatment plans, optimized either using or not using robust optimization 
algorithms, should be evaluated.  Due to the large volume and geometric complexity of the 
target, as well as the higher likelihood of patient anatomy changes through the case of treatment, 
the following evaluation scenarios should be used: 
Scenario 
% Range Error 
Setup Error (mm) 
X 
Y 
Z 
1 
5.0 % 
0 
0 
0 
2 
5.0 % 
0 
0 
0 
3 
0 
5.0 
0 
0 
4 
0 
-5.0 
0 
0 
5 
0 
0 
5.0 
0 
6 
0 
0 
-5.0 
0 
7 
0 
0 
0 
5.0 
8 
0 
0 
0 
-5.0 
 
For plan robustness evaluation, at least 6 of 8 scenarios should achieve CTV coverage >=95% 
and all scenarios should achieve CTV coverage >=90%.  One to 2 scenarios <90% CTV 
coverage is an acceptable variation.  More than 2 scenarios with <90% CTV coverage is an 
unacceptable deviation. 
 
5.3.9    RT Case Review  
Pre-treatment reviews are required for all cases.  Due to the complexity of the RT planning, the 


 
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Pre-Treatment review process is accomplished in two steps.  Step 1 is a preliminary contour 
review where all required structures are submitted and evaluated for protocol compliance.  Once 
the contour review is approved, Step 2 is a pre-treatment review of the full planning dataset to 
confirm contours and evaluate the plan for dose compliance.  Each of these steps requires 3 
business days from the receipt of complete data via TRIAD.  If revisions are required, the 
process begins again.  See Section 12 for specifics on submission process and requirements.  RT 
may not begin until full plan approval is received.   
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
5.4.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
5.4.2    Prohibited or Restricted Medications 
            Cisplatin 
Use caution with other renally excreted drugs or other nephrotoxic and ototoxic drugs.   
 
Carboplatin 
Use caution with concomitant administration with, IV contrast dye, iohexol, 
aminoglycosides or other nephrotoxic medications. 
 
Pemetrexed 
Ibuprofen may reduce pemetrexed clearance. Ibuprofen therapy should be held 2 days 
prior to pemetrexed administration, during therapy, and for 2 days after last pemetrexed 
dose in patients with a CrCl between 45-79 mL/minute. If ibuprofen must be continued 
during pemetrexed therapy, monitor for myelosuppression, renal, and gastrointestinal 
toxicity. Other NSAIDs (e.g. naproxen, diclofenac, ketorolac) should also be used with 
caution. 
 
            Avoid concomitant use with BCG, cladribine, deferiprone, dipyrone, natalizumab, 
pimecrolimus, topical tacrolimus, and live vaccines. 
5.4.3    Participation in Other Trials  
Concurrent participation in other therapeutic trials is not permissible. However, trials that 
do not add experimental agents are allowed (e.g. imaging trials, quality of life, etc). 
Patients developing recurrence after treatment on NRG-LU006 may participate in other 
trials.  
5.4.4    Herbal and Nutritional Supplements 
The concomitant use of herbal therapies is not recommended, as their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown. However the 
use of general nutritional foundation supplements will be allowed including: calcium 
with vitamin D and/or minerals, Omega 3’s (fish oil), Vitamin B6, Vitamin B12, a basic 
multivitamin , L-glutamine, or probiotics oral supplements will be permitted at long as at 
or below the FDA approved recommended dose allowance (RDA) by a healthcare 
provider.   Herbal-based multivitamins are not allowed. Any additional supplements will 
need prior review and approval by the Medical Oncology Co-Chair Marjorie G. Zauderer, 
MD. 


 
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5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
▪ 
Disease progression, 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable adverse event(s), as described in Section 7 
▪ 
Patient decides to withdraw consent for participation in the study, or 
▪ 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT (15-MAR-2022) 
Please note that institutions are permitted to follow their local institutional standards for dose 
modifications as standard of care, and in accordance with package insert guidelines for these 
agents. 
 
When chemotherapy related toxicity is observed, dose delays and/or reductions in drug 
administration are allowed per package insert and institutional standards as described below.  
 
6.1  Pemetrexed 
Parameters to use: 
• ANC ≥1,500/mm3 and platelets ≥100,000/mm3 
• CrCl ≥45 mL/minute by the Cockcroft-Gault equation  
• Recovery of non-hematologic toxicity to ≤ grade 2 
 
       Dose Modifications 
Renal dose adjustment is not necessary for CrCl ≥45 mL/minute. Use is not recommended 
with CrCl <45 mL/minute.  
 
There are no recommended dose adjustments for hepatic impairment.  
 
  Potential Adverse Drug Reactions (and management) or refer to Institutional   
Standard 
 
Hematologic Toxicity 
 
Pemetrexed Dose Modification/Management 
ANC <1500/mm3 
Hold until ANC ≥1,500/mm3 
Resume pemetrexed at same dose 
ANC <500/mm3 and 
platelets ≥50,000/mm3 
 
Hold therapy until ANC ≥1,500/mm3 and platelets 
≥100,000/mm3 
Administer 375 mg/m2 
Platelets <100,000/mm3 
without bleeding 
Hold therapy until platelets ≥100,000/mm3 
Resume pemetrexed at same dose 
Platelets <50,000/mm3 
without bleeding 
Hold therapy until platelets ≥100,000/mm3  
Administer 375 mg/m2 


 
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Platelets <50,000/mm3 with 
bleeding 
Hold therapy until platelets ≥100,000/mm3 
Administer 250 mg/m2 
Recurrent Grade 3 or 4 
Myelosuppression after two 
dose reductions 
Discontinue pemetrexed 
 
Non-Hematologic Toxicity 
 
Pemetrexed Dose Modification/Management 
Diarrhea (any grade) 
requiring hospitalization, 
grade 3 or 4 diarrhea 
Hold until toxicity recovers to grade ≤ 2 
Administer 375 mg/m2 
Grade 3 or 4 Mucositis 
 
Hold until toxicity recovers to grade ≤ 2 
Administer 250 mg/m2 
 
Grade 3 or 4 Neurotoxicity 
 
Discontinue pemetrexed 
 
Skin toxicity 
 
Pre-treatment administration of dexamethasone is required 
to reduce incidence of serious and occasionally fatal 
dermatologic toxicities. Cases of Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been 
reported.  
 
Permanently discontinue pemetrexed if severe/life-
threatening bullous, blistering, or exfoliating dermatologic 
toxicity occurs. 
Pulmonary toxicity 
 
Withhold pemetrexed and evaluate patient in setting of 
acute onset new or progressive pulmonary symptoms (e.g. 
dyspnea, cough, or fever). 
 
If interstitial pneumonitis is confirmed, permanently 
discontinue pemetrexed. 
All other Grade 3 or 4 non-
hematologic toxicities  
Hold until toxicity recovers to grade ≤ 2 
Administer 375 mg/m2 
Recurrent Grade 3 or 4 non-
hematologic toxicities after 
two dose reductions 
Discontinue pemetrexed 
 
 
Management of hypersensitivity reactions or refer to institutional standard 


 
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Hypersensitivity reactions include anaphylactic-like reactions. Tachycardia, 
bronchoconstriction, hypotension, facial edema and erythema may occur and should be 
should be treated with antihistamine, corticosteroids, and epinephrine as per institutional 
hypersensitivity management protocol. These reactions typically occur in patients with prior 
exposure to the drug. For future doses, pretreat with the same medications.  
 
6.2  Cisplatin (15-MAR-2022) 
      Parameters to use: 
• Absence of pre-existing grade 2 neuropathy or hearing loss 
• Creatinine clearance > 50 mL/min  
• ANC  ≥ 1500 mm3 
• Hg ≥ 8 g/dL 
• Platelets ≥ 100 K/mm3 
 
     Dose modifications (based on organ function; toxicity) 
 
Dosage with renal impairment:  In general, patients should not be retreated with cisplatin 
until serum creatinine is below 1.5 mg/dL. According to the FDA and manufacturer, cisplatin 
is contraindicated in patients with preexisting renal impairment. 
 
Creatinine 
clearance 
% previous dose 
Dose to 
administer 
46-60 
75% 
56 mg/m2 
30-45 
50% 
38 mg/m2 
<30 
Do not give 
Do not give 
 
Dosage with hepatic impairment:  There are no dosage adjustments provided in the 
manufacturer’s labeling. Dosage adjustment is likely not necessary as cisplatin is believed to 
undergo spontaneous degradation in the bloodstream and is not hepatically metabolized. 
Cisplatin is predominantly eliminated by the kidneys. 
 
     Dosage with toxicity: 
• 
Grade 2 neurotoxicity/ototoxicity 
Reduce to 56 mg/m2 
• 
Grade 3 or 4 neurotoxicity/ototoxicity 
Discontinue 
• 
Other grade 3 non-hematologic/organ toxicity 
Reduce to 56 mg/m2  
• 
Other grade 4 non-hematologic/organ toxicity 
Discontinue 
• 
Hemolysis, optic neuritis, arterial thromboembolism, severe 
hypersensitivity reactions, grade 3 or 4 increased LFTs 
 
Discontinue 
• 
Grade 4 platelets, grade 4 ANC >/= 5 days, 
thrombocytopenic bleeding or febrile neutropenia  
 
Reduce to 56 mg/m2 


 
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Potential Adverse Drug Reactions:  Adverse effects include myelosuppression, 
nausea/vomiting, peripheral neuropathy, nephrotoxicity, ototoxicity, alopecia, and 
hypersensitivity. For management please refer to institutional standard. 
 
Hypersensitivity reactions include anaphylactic-like reactions:  Tachycardia, 
bronchoconstriction, hypotension, facial edema and erythema may occur and should be 
should be treated with antihistamine, corticosteroids, and epinephrine as per institutional 
hypersensitivity management protocol. These reactions typically occur in patients with prior 
exposure to cisplatin. For future doses, pretreat with the same medications.  
 
 6.3 Carboplatin (15-MAR-2022) 
      Parameters to use 
• Creatinine Clearance 
• PLT ≥ 100 K/mm3 
 
     Dose modifications (based on organ function; toxicity) 
• Renal impairment 
o Dose determination with Calvert formula uses GFR or estimated CrCl and 
inherently adjusts for renal dysfunction (see Appendix A) 
• Hepatic impairment: There are no dosage adjustments provided in the manufacturer’s 
labeling 
• Adjustment for toxicity 
o Platelets < 50,000 cells/mm3 or ANC < 500 cells/mm3: dose reduced to AUC=4  
 
Potential Adverse Drug Reactions Recommended Management or refer to Institutional 
Standard 
• Myelosuppression 
o Monitor blood counts closely 
o Reduce dosage and/or delay cycles until WBC and platelet counts have recovered 
o Anemia may require blood transfusion 
• Nausea and vomiting 
o Pretreatment with antiemetics is recommended 
• Ototoxicity 
o Clinically significant hearing loss reported in pediatric patients 
o Long-term audiology monitoring is recommended if patient experiences changes 
in hearing during chemotherapy 
• Nephrotoxicity 
o Use caution with concomitant administration with aminoglycosides or other 
nephrotoxic medications 
• Vision loss 
o Discontinue carboplatin; usually reversible within weeks of discontinuation 
• Electrolyte wasting 
o Monitor closely and replace as indicated by IV or PO supplementation 


 
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      Management of hypersensitivity reactions or refer to institutional standard 
      Hypersensitivity reactions include anaphylactic-like reactions. Tachycardia, broncho-
constriction, hypotension, facial edema and erythema may occur and should be treated with 
antihistamines, corticosteroids, and epinephrine as per institutional hypersensitivity 
management protocol. These reactions typically occur in patients with prior exposure to 
platinum therapy. For future doses, consider desensitization protocol or alternative 
medication. 
      
7.       ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1       Protocol Agents 
            Commercial Agents:  The commercial agents in NRG-LU006 are pemetrexed, cisplatin 
and carboplatin. 
 
 
7.2       Adverse Events and Serious Adverse Events 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.2.3 Adverse Events for Pemetrexed 
Refer to the package insert for detailed pharmacologic and safety information 
 
7.2.4 Adverse Events for Cisplatin 
Refer to the package insert for detailed pharmacologic and safety information 
 
7.2.5 Adverse Events for Carboplatin 
Refer to the package insert for detailed pharmacologic and safety information 
                                                                                                                                                                                    


 
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7.3       Expedited Reporting of Adverse Events (15-MAR-2022) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made NRG Oncology by phone at 1-215-574-3191.  An electronic report must be 
submitted immediately upon re-establishment of the Internet connection. 
 
While CTEP-AERS may be used for this study, please note that reports submitted to this 
database will neither be reviewed nor submitted to the FDA by NCI, as this study is not 
being conducted under a CTEP-held IND. 
 
7.3.1 Expedited Reporting Methods 
• Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERS-24 Hour 
Notification must be submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS-24-hour notification must be followed by a complete report within 5 
days.  
• Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Deidentified supporting source documentation should be 
uploaded to the Source Document Portal via the CTEP-AERS integration.  
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
7.3.2 Expedited Reporting Requirements for Adverse Events  
 
 Step 1:  Surgery and Adjuvant Chemotherapy  


 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor 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. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
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: 
• 
Unexpected Grade 4 and all Grade 5 AEs 
 
Arm 2:  Any Phase Study Utilizing Radiation Therapy (including chemoRT studies)1 
 


 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor 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 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
 
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 protocol treatment and are related to 
treatment, i.e. have an attribution of possible, probable, or definite to protocol treatment, require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 3 adverse events 
 
7.3.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
 
7.3.4 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent be reported via CTEP-AERS. In addition, secondary malignancies 
following radiation therapy must be reported via CTEP-AERS. Three options are 
available to describe the event: 


 
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• 
Leukemia secondary to oncology chemotherapy (e.g., acute 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 
AE reporting unless otherwise specified. 
 
7.4 
Routine Reporting Requirements for Adverse Events 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
7.5 
Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be 
completed and submitted to CTEP.  Any pregnancy occurring in a patient or patient’s 
partner from the time of consent to 6 months after the end of study treatment must be 
reported and then followed for outcome.  Newborn infants should be followed until 30 
days old.  Please see the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on 
how to report pregnancy and its outcome to CTEP.  
 
8. REGISTRATION AND STUDY ENTRY PROCEDURES (15-MAR-2022) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.   
 
RCR utilizes five person registration types. 
• IVR — MD, DO, or international equivalent; 
• NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the, Roster Update Management System (RUMS), OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 


 
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• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) 
with limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR AP 
A 
AB 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
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 Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs 
and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval. 
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN must be rostered at the 
enrolling site with a participating organization.  
 
Additional information is located 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. 
 
8.1    Cancer Trials Support Unit Registration Procedures (13-APR-2022) 
         This study is supported by the NCI CTSU.  
 
         IRB Approval  
         For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 


 
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Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if the 
study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• Holds an Active CTEP status; 
• Active status at the site(s) on the IRB/REB approval on at least one participating 
organization’s roster; 
• If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
 
          Additional Requirements for Protocol NRG-LU006 Site Registration 
          Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• Surgeon credentialing (see Section 8.1. 3); 


 
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• IRB/REB approved consent (International and/or Canadian sites only: English and 
native language versions*);  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
*Translation of documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB approved consent, must be 
provided in English and in the native language. Certification of the translation is optimal 
but due to the prohibitive costs involved NRG will accept, at a minimum, a verified 
translation. A verified translation consists of the actual REB approved consent document 
in English and in the native language, along with a cover letter on organizational 
letterhead/stationery that includes the professional title, credentials, and signature of the 
translator as well as signed documentation of the review and verification of the 
translation by a neutral third party. The professional title and credentials of the neutral 
third party translator must be specified as well. 
 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site 
must be aligned to an RTI provider. To manage provider associations or to add or remove 
associated providers, access the Provider Association page from the Regulatory section 
on the CTSU members’ website at https://www.ctsu.org/RSS/RTFProviderAssociation. 
Sites must be linked to at least one Imaging and Radiation Oncology Core (IROC) 
provider to participate on trials with an RTI component. Enrolling sites are responsible 
for ensuring that the appropriate agreements and IRB approvals are in place with their 
RTI provider. An individual with a primary role on a treating site roster can update the 
provider associations, though all individuals at a site may view provider associations. To 
find who holds primary roles at your site, view the Person Roster Browser under the 
RUMS section on the CTSU website. 
 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston 
to verify credentialing status or to begin a new modality credentialing process.  
 
To complete protocol-specific credentialing the RTI provider or enrolling site should 
follow instructions in protocol Section 8.2 to submit documentation or other materials to 
the designated IROC Quality Assurance (QA) center. Upon the IROC QA center 
approving the RTI provider for the study modality, IROC will automatically send the 
approval to the Regulatory Support System (RSS) to comply with the protocol-specific 
requirement, unless otherwise noted at the bottom of the IROC Credentialing Approval 
notification. IROC will continue to copy the provider and/or enrolling site on modality 
approvals. 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject 
in the OPEN credentialing screen and may need to answer additional questions related to 
treatment in the eligibility checklist.   
 


 
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8.1.1 Additional Requirements for sites in Canada 
 
All institutions in Canada must conduct this trial in accordance with International 
Conference on Harmonization-Good Clinical Practice (ICH-GCP) Guidelines [per section 
6.2.5 of ICH E6(R2)]. This trial is being conducted under a Clinical Trial Application 
(CTA) with Health Canada. As a result essential documents must be retained for 25 years 
following the completion of the trial at the participating site (25 years post final analysis, 
last data collected, or closure notification to REB, whichever is later), or until notified by 
the sponsor, NRG Oncology, that documents no longer need to be retained [per C.05.012 
(4) of the FDR].  In addition, upon request by the auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct 
access [per section 4.9.7 of ICH].  Prior to clinical trial commencement, sites in Canada 
must also complete and submit the following documents to NRG Regulatory (regulatory-
phl@NRGOncology.org): 
• Clinical Trial Site Information Form,  
• Qualified Investigator Undertaking Form,  
• Research Ethics Board Attestation Form. 
• Protocol Signature Page 
• Delegation of Task Log (DTL)   
• List of Laboratories  
• SIV/Training Confirmation of Completion Form – Research Associate (please 
refer to the activation memo for details)  
• SIV/Training Confirmation of Completion Form – Qualified Investigator (please 
refer to the activation memo for details)  
• IRB/REB approved consent (English and native language versions; submitted to 
NRG Regulatory for review prior to IRB/REB submission). 
 
The following items are collected by NRG Oncology Regulatory on a yearly or biyearly 
basis:   
• IRB/REB Membership Roster  
• Laboratory Certificates and Normal Values  
• CVs for Qualified Investigator and Sub-Investigators noted on the DTL log 
 
8.1.2 Additional Pre-Registration Requirements FOR INTERNATIONAL 
INSTITUTIONS  
• IRB/REB approved consent (English and native language versions*) 
*Note: International Institutions must submit their consent form in English to 
NRG Regulatory (regulatory-phl@NRGOncology.org) for review prior to IRB 
submission (initial and amendments).  Certification/verification of IRB/REB 
consent translation is also required (described below).  
 
8.1.3 Surgeon Credentialing 
Participating surgeons must complete and sign a credentialing form prior to their 
institutions entering any patients onto this study.  This form can be accessed on the 
protocol-specific page of the CTSU website.  The study Research Associate will email 
the completed form to Surgical Oncology Co-Chair Dr. Valerie Rusch 


 
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(ruschv@MSKCC.ORG) for review and approval.  Dr. Rusch will email approval to 
NRG Data Management and the Research Associate, then the Research Associate 
submits the form to the Regulatory Submission Portal on the CTSU website.  Institutions 
should allow adequate processing time (7-10 days) before registering the first patient.   
 
8.1.4    Site P/D Volume 
            Sites must complete a Site P/D Volume Form indicating the number of                          
pleurectomy/decortication procedures performed at the site per year.  The form can be 
found on the protocol-specific page of the CTSU website, and should be submitted to the 
Regulatory Submission Portal using the instructions below (see Submitting Regulatory 
Documents). 
 
8.1.5    Downloading Site Registration Documents:    
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and staff 
on a participating roster. To view/download site registration forms:   
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol 
tree, or 
o Click on the By Lead Organization folder to expand, then select NRG 
Oncology and protocol number [NRG-LU006]; 
• Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB initiative, IRB data will load automatically to 
CTSU.) 
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal, log in to the CTSU members’ website, to 
the Regulatory section and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email:  1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction and 
support. 
 
Checking Your Site’s Registration Status:  
Site registration status may be verified on the CTSU members’ website.   
 


 
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• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status given only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks.  
 
8.2 
RT-Specific Pre-Registration Requirements (15-MAR-2022) 
For detailed information on the specific technology requirement required for this study, 
please refer to the table below and utilize the web link provided for detailed instructions. 
The check marks under the treatment modality columns indicate whether that specific 
credentialing requirement is required for this study. Specific credentialing components 
may require you to work with various QA centers; however, IROC Houston will notify 
your institution when all credentialing requirements have been met and the institution is 
RT credentialed to enter patients onto this study.  The credentialing notification 
document (sent as an email) must be uploaded by the site to the CTSU Regulatory 
Submission Portal for RSS to be updated.   
 
Proton centers wishing to participate in this study must comply with the NCI proton 
guidelines for the Use of Proton Radiation Therapy in NCI Sponsored Cooperative Group 
Clinical Trials, which are available on the IROC Houston 
(http://irochouston.mdanderson.org) and IROC (https://www.irocqa.org) websites.  These 
requirements include, but are not limited to, completion of a proton facility questionnaire, 
a successful IROC site visit, which identifies the proton technique(s) which can be used, 
annual monitoring of the proton beam calibration, e.g. IROC Houston’s monitoring 
program, and successful digital data submission to TRIAD. Once these requirements are 
successfully met, the proton center is approved to use proton therapy in NCI sponsored 
clinical trials. Each trial may require additional proton therapy credentialing steps prior to 
being allowed to enter a patient treated with protons onto a specific study. IROC Houston 
will coordinate the completion of the proton therapy use approval process in conjunction 
with the appropriate other IROC QA Centers for any additional protocol specific 
credentialing requirements.  See the table below for the credentialing requirements of this 
study. 
 
RT   
Credentialing 
Requirements 
Web Link for Credentialing Procedures and Instructions 
http://irochouston.mdanderson.org 
Treatment Modality 
Proton 
Photon 
Key Information 


 
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Credentialing 
Status 
Inquiry Form 
X 
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). 
Facility 
Questionnaire 
X 
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 
X 
An IMRT or proton lung 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).  
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 NRG 
Headquarters that all desired 
credentialing requirements have been 
met. 
 
8.2.1 Digital Radiation Therapy Data Submission Using Transfer of Images and Data 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 
images as they are transferred. 
TRIAD Access Requirements: 
• A valid Cancer Therapy Evaluation Program (CTEP-) Identity and Access 
Management (IAM) (CTEP-IAM) account.  
• Registration type of:  Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR).  Refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM account 
and complete registration in RCR. 
• TRIAD Site User role on an NCTN or ETCTN roster.  
 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 
to TRIAD, and may submit images for credentialing purposes, or for enrollments to 


 
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which the provider is linked in OPEN. 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
 
This process can be done in parallel to obtaining your CTEP-IAM account  and 
RCR registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.3 
Patient Enrollment (15-MAR-2022) 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/ randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
 
Requirements for OPEN access:   
• A valid CTEP-IAM account; 
• To perform enrollments:  Must be on a LPO roster, ETCTN corresponding roster, or 
participating organization roster with the role of Registrar. Registrars must hold a 
minimum of an Associate Plus (AP) registration type;  
• Surgeon credentialing for appropriate site staff prior to enrollment; 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  
 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your records.  


 
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Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
9.0      DRUG INFORMATION  
 
9.1 
Commercial Agent:  Pemetrexed (15-MAR-2022) 
 
 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information.  
 
9.1.1 Adverse Events 
 
Please refer to the package insert. 
 
9.1.2 Availability/Supply  
 
Please see Section 5.2.1 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 
 
9.2 
Commercial Agent:  Cisplatin (15-MAR-2022) 
 
 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information.  
 
9.2.1 Adverse Events 
 
Please refer to the package insert. 
 
9.2.2 Availability/Supply  
 
Please see Section 5.2.2 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 
 
9.3 
Commercial Agent:  Carboplatin (15-MAR-2022) 
 
 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information.  
 
9.3.1 Adverse Events 
 
Please refer to the package insert. 
 
9.3.2 Availability/Supply  
 
Please see Section 5.2.3 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 


 
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10. PATHOLOGY/BIOSPECIMEN 
 
10.1 
Optional Specimen Submissions (15-MAR-2022) 
Patients must be offered the opportunity to consent to optional specimen collection. If the patient 
consents to participate, the site is required to submit the patient’s specimens as specified per 
protocol. Sites are not permitted to delete the specimen component from the protocol or from the 
sample consent.   
 
See detailed specimen collection/processing/shipping instructions on the protocol-specific 
page of the CTSU website. 
 
This study will include collection of biospecimens for future analyses. An amendment for any 
correlative science studies to be performed on biological samples will be submitted to CTEP, 
NCI for review and approval according to NCTN guidelines or via the Navigator portal after the 
trial has been reported. Amendments to the protocol and/or proposals for use of banked tissue or 
blood samples will include the appropriate background, experimental plans with assay details, 
and a detailed statistical section. Samples for testing will not be released for testing until the 
appropriate NCI approvals have been obtained. 
 
Specimen Collection for Banking for Future Research 
• Required Forms: ST form, pathology reports.  All forms must be completely filled out 
with an NRG Label including the Study #, Case #, NRG Institution name and # or 
Institution NCI ID, and patient initials. The pathology accession number and date of 
procedure must remain visible on the pathology report but all other PHI information must 
be redacted/removed. 
• Kits are available for Frozen biospecimens from the NRG Oncology Biospecimen Bank 
at San Francisco (NRGBB-SF). Sites should include the following information in their 
email:  Ship to Fed Ex address with room number, confirm site has IRB approval for 
study, how many patients site enrolled in past month.  
Detailed Processing and shipping instructions are provided on the protocol-specific page 
of the CTSU website.   
• Shipping days for Frozen Specimens: Monday-Wednesday (U.S. sites); Monday-Tuesday 
(Canada and Non-North American). International sites must contact the NRGBB-SF 
before shipping. Check NRG Broadcasts for bank holiday closures. We are unable to 
accept shipments on Saturdays or holidays. Check Fed Ex site for storm delays and do 
not ship during severe weather. 
• Shipping costs: A single use prepaid Fed Ex label is provided for each case in LU006 kits 
provided to the site (U.S. sites only) for batch shipping frozen biospecimens to the 
NRGBB-SF. Ship all Biospecimens to: 
NRG Oncology Biospecimen Bank – San Francisco 
2340 Sutter Street- Room S341 
UCSF  
San Francisco, CA 94115 
415-476-7864/Fax 415-476-5271 
Email: NRGBB@ucsf.edu 


 
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For questions about banking biospecimens contact:  
NRG Oncology Biospecimen Bank – San Francisco 
NRGBB@ucsf.edu   
415-476-7864/Fax 415-476-5271 
 
Specimen Type 
Collection Time Points 
Collection Information 
and  Requirements/ 
Instructions for Site 
Shipping 
H&E slide(s) of 
Primary tumor  
 
Pre-treatment (including 
neoadjuvant therapy): 
obtained as part of routine 
diagnostic procedures 
 
H&E stained slide, ST 
form and pathology report. 
H&E slide can be a 
duplicate cut slide, does 
not have to be the 
diagnostic slide. 
Ship ambient to 
NRGBB-SF 
FFPE Block 
 
Pre-treatment (including 
neoadjuvant therapy): 
obtained as part of routine 
diagnostic procedures 
Site should make every 
effort to submit the block 
that corresponds to the 
H&E for this study. If Site 
is unable to submit a 
Block then the following 
alternative is acceptable:  
A) Two 2mm (or 3mm) 
punches (tumor size 
dependent) embedded 
in paraffin with a 
corresponding H&E. 
(Punch kits available 
from NRGBB-SF 
upon request.). If sites 
are unable to embed 
the punches they may 
send the punches to 
the biobank to be 
embedded. 
 
Ship to NRGBB-SF 
 (use cold packs during 
warm weather) 
Plasma- EDTA 
tube 
 
 
Pre-treatment after 
enrollment and prior to  
surgery  
 
 
  
 
For all randomized 
patients: after 
randomization (prior to 
RT for Arm 2 patients) 
and at 3 month follow up 
visit only 
 
Process and aliquot a 
minimum of 0.5 ml into 
each of five 1 ml 
cryovials. Freeze and store 
at -80°C and ship frozen 
on dry ice. 
Forms: ST form 
 
Ship on Dry Ice by 
Priority Overnight 
Courier to NRGBB-SF 


 
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Serum- Red top 
tube 
Pre-treatment after 
enrollment and prior to 
surgery  
 
For all randomized 
patients: after 
randomization (prior to 
RT for Arm 2 patients) 
and at 3 month follow up 
visit only 
 
Process and aliquot a 
minimum of 0.5 ml into 
each of five 1ml cryovials. 
Freeze and store at -80°C 
and ship frozen on dry ice. 
Forms: ST form 
 
Ship on Dry Ice by 
Priority Overnight 
Courier to NRGBB-SF 
Whole Blood- 
EDTA tube 
 
Pre-treatment after 
enrollment and prior to 
surgery    
 
For all randomized 
patients:  after 
randomization (prior to 
RT for Arm 2 patients) 
and at 3 month follow up 
visit only 
Sites collect and mix 
blood and aliquot a 
minimum of 1.5 mls blood 
into three 2ml cryovials. 
 
Freeze and Store at -80C 
and ship frozen on dry ice. 
 
Forms: ST forms 
Ship on Dry Ice by 
Priority Overnight 
Courier to NRGBB-SF  
 
11.       SPECIAL STUDIES (NON-TISSUE) 
 
11.1 
Quality of Life (15-MAR-2022) 
 
11.1.1 Background/Rationale for Studying Patient Report Outcome Measures (PROMs) in 
NRG-LU006 
 
NRG-LU006 is the first randomized phase III study that evaluates the benefit of lung-
sparing trimodality therapy in patients with malignant pleural mesothelioma.  Given the 
rarity of MPM and the recently demonstrated feasibility of hemithoracic pleural IMRT 
(Rimner 2016), there exists no data describing the impact of hemithoracic pleural RT on 
well-being and symptoms from a patient’s perspective.   
 
Patient reported outcome measures (PROMs) report health status and symptoms directly 
from the patient without the influence of clinicians.  PROMs complement physician-
reported treatment effects.  Furthermore, patient-reported symptoms are more closely 
associated with cancer patients’ overall function and well-being when compared to 
physician-reported treatment toxicity (Basch 2009).  PROMs in NRG-LU006 provide a 
unique and exciting opportunity to understand the impact of pleural IMRT on patients’ 
quality of life, function, and symptoms.  Importantly, these patient reports of pleural 
IMRT’s impact would serve as the benchmark for understanding the effect of lung-
sparing trimodality therapy in the treatment of this rare disease entity.  
 
Only two PROMs have been validated in malignant pleural mesothelioma (Nowak 2004, 
Hollen 2006).  The European Organization for Research and Treatment of Cancer quality 
of life core questionnaire (EORTC QLQ-C30), supplemented with the lung cancer 


 
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specific module (QLQ-LC13), has been extensively used in malignant pleural 
mesothelioma trials.  EORTC QLQ-C30 and QLQ-LC13 were originally developed and 
validated for lung cancer patients, and subsequently validated for malignant 
mesothelioma patients (Nowak 2004).  The EORTC QLQ-C30 covers global quality of 
life (QOL), 5 functional domains (physical, role, cognitive, emotional, social), 3 
symptom domains (fatigue, pain, nausea/vomiting) and specific symptoms (dyspnea, 
appetite loss, insomnia, diarrhea, constipation, financial impact).  A higher score for 
functional domain indicates better health status, whereas a lower score for symptoms 
domains and single-items indicates fewer symptoms.  The EORTC QLQ-LC13 is a 
supplementary module that includes additional evaluation of cancer-specific symptoms 
and treatment-related side effects, including use of pain medication.  Specific symptoms 
evaluated include: cough, hemoptysis, dyspnea, pain, sore mouth, dysphagia, peripheral 
neuropathy, and alopecia.  A lower QLQ-LC13 score indicates fewer symptoms.  We will 
collect this information alongside QLQ-C30, to better understand baseline-specific 
symptoms and treatment-related side effects throughout management of this rare disease 
entity.   
 
EORTC QLQ functional domain and symptom scales capture changes in a patient’s well-
being and predicted for survival in malignant pleural mesothelioma patients who received 
chemotherapy.  In cohort study of 53 MPM patients with measurable disease who 
received platinum doublet chemotherapy, baseline global health was reported at 50% of a 
normal healthy reference population and questionnaire compliance was 82% 
approximately 6 months after start of chemotherapy. On average during treatment, there 
was an absolute numeric decline in patient-reported global health status by 5 points and a 
statistically significant decline from baseline in multiple functional domains (physical: -3, 
social: -9, and cognitive: -11 points, respectively; all p<0.05) (Nowak 2004).  Functional 
domains (physical, role, cognitive, emotional) and specific symptoms (QLQ-C30 fatigue, 
pain, and dyspnea), but not global quality of life, predicted for overall-survival after 
chemotherapy.  Patient-reported dyspnea correlated with forced vital capacity, a measure 
of pulmonary function.   
 
EORTC quality of life questionnaires show improved global quality of life in patients 
with MPM after P/D and chemotherapy.  In a retrospective study of 36 patients with 
MPM who underwent extended P/D, of which 78% underwent adjuvant 
platinum/pemetrexed chemotherapy and no adjuvant radiation was given, global quality 
of life increased 5 to 25 points on average 7-8 months after P/D (Burkholder 2015).  In a 
similar cohort of n=28 patients who underwent P/D, EORTC QLQ-C30 showed 
improved fatigue in all patients at 9 months post P/D. In the subset of these patients 
initially presenting with symptoms (ECOG 1) at baseline, patients had improvement in 
QOL and dyspnea after P/D (Mollberg 2012).  This analysis excluded 25% (n=6 of 28 
patients) who had significant disease progression at 5-6 (n=1) and 8-9 months (n=5), in 
whom follow-up was not continued.  
 
A description of the effect of IMPRINT on well-being from the patient’s perspective is  
critical to informing patients and oncologists about the impact of adjuvant lung-sparing 
radiation. There is no current understanding of the additional impact of IMPRINT on 


 
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quality of life, functional status, and symptoms after the addition of IMPRINT compared 
to P/D and systemic therapy alone. 
 
Quality of life between EPP and P/D have been directly compared.  In a retrospective 
study of 77 patients with stage I and II MPM who received P/D or EPP associated with 
multimodality treatment, only patients who received P/D returned to their baseline QOL 
at 12 months (Rena 2012).  QOL has been evaluated after receipt of the different types of 
pleurectomy and decortication (extended P/D, P/D, and partial P/D). A prospective 
observational series of 28 patients with MPM treated with extended P/D (Burkholder 
2015) and a randomized trial of partial P/D versus talc pleurodesis (Rintoul 2014) have 
both demonstrated a higher QOL score reported at 6-12 months after P/D compared to 
baseline.  However, a direct QOL comparison between the different types of P/D has not 
been performed. Thus, it is not known if there exists a QOL difference between the 
different types of P/D. We do not expect QOL to be different between the different types 
of P/D in NRG-LU006, but we will be able to account for types of P/D in the NRG-
LU006 QOL analysis. 
 
11.1.2 Administration of NRG-LU006 EORTC QLQ 
Time Points 
See Section 4 Assessment Tables for details.  EORTC QLQ performed at randomization 
will serve as the baseline assessment for the secondary endpoint QOL analysis.  
 
EORTC QLQ performed at randomization will serve as the baseline assessment for the 
exploratory QOL analysis.  EORTC QLQ assessments during follow up may be 
evaluated in relation to EORTC QLQ assessments at randomization and assessments 
collected prior to receipt of surgery and receipt of systemic therapy to improve the 
understanding of quality of life, function, and symptoms throughout management of this 
rare disease entity. 
 
Recall Period 
The recall period is stipulated by the EORTC quality of life questionnaires.  Most items 
use a “past week” recall period.   
 
Instructions  
Questionnaires may be completed on paper at the appropriate patient visit.  
Questionnaires are to be administered at follow-up visits, so that when a follow-up visit is 
delayed, completion of the EORTC QLQ-C30 and LC-13 assessments may also be 
delayed.  These assessments should be administered during an office visit if at all 
possible, preferably while the patient is waiting to be seen.  Once the questionnaires are 
completed by the patient, the staff member should review it to ensure that no items were 
unintentionally left blank.  When absolutely necessary, it may also be administered by 
mail or phone.  The completed form will then be data entered into Medidata Rave.    
 
If a patient declines to complete a scheduled QLQ-C30 and LC-13 form or if the 
questionnaires are not completed for any other reason (and cannot be completed by phone 
or mail), the QOL coversheet must be completed in Medidata Rave.   


 
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11.1.3 Quality of Life Patient Population 
All patients enrolled in NRG-LU006 who understand English, Spanish or French will be 
required to participate in the QOL study.   
 
11.2 
Quality of Life Primary and Exploratory Endpoints (15-MAR-2022)  
 
For the primary QOL endpoint: We hypothesize that addition of IMPRINT will improve 
disease control that will translate into an improvement in the overall health status at the 9 
month time point after randomization.  
 
EORTC QLQ performed at randomization will serve as the baseline for QOL analysis, 
since the primary endpoint as the purpose of this study is to evaluate the effect of the 
addition of IMPRINT to surgery and systemic therapy.  EORTC QLQ assessments will 
also be collected prior to receipt of surgery and receipt of systemic therapy to improve 
the understanding of quality of life, function, and symptoms throughout management of 
this rare disease entity. 
 
For the exploratory QOL analyses:  We hypothesize that for patients receiving IMPRINT, 
there will be a lower proportion of patients responding with “quite a bit” or “very much” 
EORTC QLQ-C30 and LC13 treatment-related specific symptoms at 9-12 months post-
randomization when compared to 3 month post-randomization. 
 
We will also descriptively explore the effect of IMPRINT on overall health-related 
quality of life, functional domains (physical, role, cognitive, emotional) and symptoms 
over time from the patient’s perspective. 
 
12.       MODALITY REVIEWS 
12.1     Radiation Therapy Quality Assurance Reviews (15-MAR-2022) 
The Principal Investigator, Dr. Rimner, or study Co-Chair Dr. Simone, will perform a 
Pre-Treatment Radiation Therapy quality assurance review of all treatment plans for 
those patients randomized to Arm 2. This will be conducted in two parts.  Step 1 is the 
contour review and Step 2 is the full plan review to confirm contours and evaluate the 
dose compliance of protocol dose constraints.  Three (3) business days are to be allotted 
for each step of the pre-treatment review once all required data are received for each in 
completion as indicated in Section 5.3. 
 
12.2     Medical Oncology Modality Quality Assurance Reviews (15-MAR-2022) 
The Medical Oncology Co-Chair, Dr. Zauderer, will perform a Chemotherapy Assurance 
Review of all patients who receive or are to receive systemic therapy in this trial.  The 
goal of the review is to evaluate protocol compliance.  The review process is contingent 
on timely submission of chemotherapy treatment data as specified in Section 12.1. The 
scoring mechanism is: 1) Per Protocol, 2) Acceptable Variation, 3) Unacceptable 
Deviation, and 4) Not Evaluable.  Systemic therapy delivered prior to study entry will 
not be included in this review.  
 


 
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Dr. Zauderer will perform a Quality Assurance Review after NRG Headquarters has 
received complete data for the first 20 cases enrolled. Dr. Zauderer will perform the next 
review after NRG Headquarters has received complete data for the next 100 cases 
enrolled. The final cases will be reviewed within 3 months after this study has reached 
the target accrual or as soon as NRG Headquarters has received complete data for all 
cases enrolled, whichever occurs first.   
 
12.3     Surgical Quality Assurance Reviews  
The Surgical Oncology Co-Chair, Dr. Rusch, will perform a Quality Assurance Review 
for verification of protocol compliance, on a continuous basis. For this review, sites must 
submit an operative report, pathology report and discharge summary for each patient.  
The final cases will be reviewed within 3 months after this study has reached the target 
accrual or as soon as NRG Headquarters has received complete data for all cases 
enrolled, whichever occurs first. 
 
12.4     Imaging Retrospective Central Review 
Upon completion of this study and at the time of final analysis, the Radiology Co-Chair, 
Dr. Ritu Gill, will perform a retrospective central review of the NRG-LU006 Diagnostic 
Imaging Data via MIM software (or similar IROC-DI platform) on the NRG Oncology 
CITRIX-XEN environment.   
 
13.       DATA AND RECORDS 
13.1     Data Management/Collection (13-APR-2022) 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments.  
 
Requirements to access Rave via iMedidata: 
• 
A valid  CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
 
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must hold a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site staff must either click on 
the link in the email or log in to iMedidata via the CTSU members’ website under Data 


 
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Management > Rave Home and click to accept the invitation in the Tasks pane located in 
the upper right-corner of the iMedidata screen. Site staff will not be able to access the 
study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the eLearnings link in the Tasks pane located in the upper right-
corner of the iMedidata screen. If an eLearning is required for a study and has not yet 
been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com.                                                   
             
13.2     Summary of Data Submission (15-MAR-2022) 
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 the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Sections 7.3 and 7.4 for information about expedited and 
routine reporting.   
 
Summary of All Data Submission: Refer to the CTSU website. 
 
See Section 8.2.1 for TRIAD account access and installation instructions. 
 
   See RT data submission table for TRIAD below. 
 
DICOM files to export 
from Treatment Planning 
System to TRIAD 
Step 1: Preliminary Contour Review 
• 
DICOM Planning CT 
• 
DICOM Baseline PET or PET/CT 
(used for tumor volume delineation) 
• 
DICOM RT Structure 
Step 2: Full Plan Review (after approval 
for Step 1 is given) 
• 
DICOM Planning CT  
• 
DICOM RT Structure  
• 
DICOM RT Dose   
• 
DICOM RT Plan   
Must submit and receive 
approval of full plan review 
prior to start of RT 
 
TRIAD Time Point:  
      RT Digital Plan 


 
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All required structures must be labeled per the tables in Sections 5.3.4 and 5.3.5 
Upon submission of the RT digital data via TRIAD, complete an online Digital Data Submission  
Information Form (DDSI): 
https://www.irocqa.org/Resources/TRIAD 
NOTE:  ALL SIMULATION AND PORTAL IMAGES WILL BE KEPT BY THE INSTITUTION 
AND ONLY SUBMITTED IF REQUESTED. 
 
   See Diagnostic Imaging submission table for TRIAD below. 
 
DICOM files to export 
to TRIAD 
 
Baseline 
TRIAD Time Point:  
• PET/CT  
• CT Chest 
• See Section 4 Pre-Treatment 
Assessments table 
• MRI Scans if 
Available  
 
 
During Treatment 
 
• CT Chest 
• Quantitative V/Q 
scan 
• See Section 4 Assessments If Surgery 
Is First table and also Prior to 
Randomization and During RT table 
• PET/CT 
• See Section 4 Assessments If 
Systemic therapy Is First table and 
also Prior to Randomization and 
During RT table 
• CT Chest 
• Renal scan 
• See Section 4 Assessments Prior to 
Randomization and During RT table 
 
 
F/U Scans 
 
• CT Chest 
• PET/CT 
See Assessments in Follow Up table 
All required structures must measure and be labeled per the tables in Section 5.3. 
 
13.3     Data Quality Portal (15-MAR-2022) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status and 
timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 


 
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the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
 
13.4     Global Reporting/Monitoring (15-MAR-2022) 
Required submission of patient demographic data for this study will be submitted 
automatically via OPEN.   
 
Note: Serious adverse events must be submitted via CTEP-AERS per protocol 
guidelines. 
 
14.       STATISTICAL CONSIDERATIONS 
14.1 
Study Design (15-MAR-2022) 
The study is an open-label, randomized, phase III trial to evaluate the addition of 
adjuvant hemithoracic IMPRINT to surgery and systemic therapy compared to surgery 
and systemic therapy alone for malignant pleural mesothelioma patients.  Patients will be 
enrolled prior to any modality treatment (step 1) and randomized 1:1 between IMPRINT 
and observation after systemic therapy or pleurectomy/decortication (P/D).  Patients who 
cannot be randomized will not be followed post-randomization, and will not be included 
in any endpoint analyses.  
 
14.2 
Study Endpoints 
14.2.1  Primary Endpoint 
The primary endpoint is overall survival (OS), which is defined as the time between the 
date of randomization and the date of death due to any cause.  
 
14.2.2 Secondary Endpoints 
• Local-failure-free survival, defined as the time from randomization to local disease 
progression (per Section 4) or death due to any cause, whichever occurs first. 
• Distant-metastases-free survival, defined as the time from randomization to distant 
metastases (per Section 4) or death due to any cause, whichever occurs first.  
• Progression-free survival, defined as the time from randomization to any documented 
progression or death due to any cause, whichever occurs first. 
• Treatment-related toxicity 
• Quality of life as measured by EORTC quality of life questionnaires 
 
14.3 
Primary Objectives Study Design (15-MAR-2022) 
14.3.1 Primary Hypothesis and Endpoints 
The primary objective of this randomized phase III trial is to determine whether the 
addition of adjuvant hemithoracic IMPRINT to surgery and systemic therapy (Arm 2) 
will improve OS as compared to surgery and systemic therapy alone (Arm 1) for 
malignant pleural mesothelioma patients.  Based on Shaikh et al. (J Thorac Oncol. 2017), 
the median OS in Arm 1 is assumed to be 12 months, and a hazard ratio of 0.6 


 
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(approximately equivalent to improving the median OS from 12 months to 20 months 
[H1]).   
 
14.3.2 How Primary Endpoints Will Be Analyzed 
The primary analysis for OS will be performed on an intent-to-treat (ITT) basis, such that 
all randomized cases will be included in the treatment arm to which they were 
randomized regardless of what treatment the patients actually received. This is the 
primary dataset for analyses of demography, baseline characteristics, and efficacy 
outcome research.   
 
 
 
OS is defined as the time from randomization to death due to any cause.  Patients without 
documented death at the time of analysis will be censored at the date of last known 
contact.  The primary analysis of OS will occur when at least 105 deaths are available, 
and the study will be considered as “positive” if the log-rank test statistics Z-value > 
1.721 (1-sided p<0.043), which is the threshold adjusted for type 1 error using group 
sequential methods.   
 
We will compare the distributions of OS between treatment arms using a one-sided 
stratified log-rank test (using stratification factors as strata).  The rates at various 
timepoints (e.g., every 6 months after randomization) and medians of OS for each arm 
will be estimated using the Kaplan-Meier method.  The associated 90% confidence 
interval (CI) will be calculated using Greenwood’s formula and based on a log-log 
transformation applied on the survival function.  Hazard ratios will be estimated using a 
stratified Cox regression model.  Results from an unstratified analysis will also be 
provided.  If any stratum has less than 5 events, the stratification factor which contains 
the level with the smallest number of patients will be removed from the stratified 
analyses. 
 
14.3.3 Sample Size and Power Calculations:  
We hypothesize a hazard ratio (HR) of 0.6 (Arm 1 is the reference level), which is 
equivalent to an improvement in median OS from 12 months to 20 months [H1].  With 
132 randomized patients and at least 105 deaths, the study provides at least 80% power to 
detect a HR of 0.6 at a 1-sided significance level of 0.05.  Due to the rarity of the disease, 
we make a practical compromise for feasibility by setting the type 1 error at 1-sided level 
of 0.05, instead of the conventional level of 0.025.  Guarding against a lack-of-data rate 
of up to 5.5%, a total of 140 patients will be randomized at step 2. Assuming about 6% of 
all patients may be unable to be randomized after receiving systemic therapy/PD, we 
project to accrue 150 patients at step 1 registration. 
 
14.4 
Study Monitoring of Primary Objectives 
Two interim analyses for both efficacy and futility of OS are planned.  The results of the 
analyses will be reported to the NRG Oncology DMC for its review and 
recommendations.  The efficacy early stopping boundary is based on the Lan-DeMets 
implementation of O’Brien-Fleming boundary, and the futility early stopping boundary is 
based on Freidlin et al., 2010.  These analyses will occur when approximately 53 deaths 
(50% information) and 79 deaths (75% information) have been reported, with the 


 
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corresponding early-stopping boundary for efficacy set at 2.524 and 2.013, and the early-
stopping boundary for futility set at 0.037 and 0.251 (all boundaries in Z-value scale), 
respectively.  If there are any deviations from the assumptions, group sequential methods 
will be used to properly adjust for the stopping boundary based on cumulative 
information. 
 
Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. An interim study summary report will 
be prepared at each meeting accordingly until the initial study results have been released.  
In general, the interim reports will contain information about patient accrual rate, a 
projected completion date for the accrual phase, distributions of pretreatment 
characteristics and important prognostic baseline variables, and the frequencies and 
severity of treatment-related adverse events.  The interim reports will not contain the 
results from the treatment comparisons with respect to the primary or any secondary 
endpoints, with the exception of reporting of adverse events. The DMC also will review 
the study on an “as needed” basis.  
 
14.5 
Accrual/Study Duration Considerations 
 
During the first 6 months following activation, little accrual is anticipated while the trial 
is being approved by institutional review boards (IRBs). We assume a uniform monthly 
accrual rate of 3.4 patients (3 patients to be randomized) following the 6 month ramp-up 
period.  Based on the design parameters in Section 14.3.3, study accrual is projected to 
last 50 months (4.2 years).  The final analysis is anticipated to occur approximately 68 
months (5.7 years) after study initiation.   
 
The above projected study durations are based on the hypothesized design parameters.  If 
the actual study parameters deviate from the hypothesized ones, the actual study duration 
may be different from the projection. In this case the protocol will be amended 
accordingly to reflect the revised duration.  
 
14.6 
Secondary or Exploratory Endpoints (including correlative science aims) (15-MAR-
2022) 
14.6.1 Secondary Endpoints:  
• Local-failure-free survival, defined as the time from randomization to local disease 
progression (per Section 4) or death due to any cause, whichever occurs first. 
• Distant-metastasis-free survival, defined as the time from randomization to distant 
metastases (per Section 4) or death due to any cause, whichever occurs first.  
• Progression-free survival, defined as the time from randomization to any documented 
progression or death due to any cause, whichever occurs first. 
• Treatment-related toxicity 
• The change quality of life at 9 months from randomization, as measured by EORTC 
quality of life questionnaires 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed  
 


 
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Local-Failure-Free Survival, Distant-Metastases-Free Survival, and Progression-Free 
Survival 
Local-failure-free survival (LFFS) is defined as the time from randomization to local 
disease progression or death due to any cause, whichever occurs first.  Distant-
metastases-free survival (DMFS) is defined as the time from randomization to distant 
metastases or death due to any cause, whichever occurs first.  Progression-free survival 
(PFS) is defined as the time between the date of randomization and the first date of 
documented progression or death due to any cause, whichever occurs first.  For these 
endpoints, disease progression will be determined per Section 4.  Subjects who do not 
progress or die will be censored on the date of their last evaluable tumor assessment as 
determined with radiographic evidence.  Subjects who do not have any on-study tumor 
assessments and do not die will be censored on the second day of their date of 
randomization.  As the disease management will change once local failure or distant 
metastasis occurs, for the purpose of evaluating the role of adjuvant IMPRINT, we use 
the following analysis plans: for LFFS, patients are censored when a distant metastasis as 
the sole progression occurs as the first progression event; for DMFS, patients are 
censored when a local failure as the sole progression occurs as the first progression event.  
For these endpoints, intent-to-treat (ITT) population will be used.  We will compare the 
distributions of LFFS, DMFS and PFS between treatment arms using a one-sided 
stratified log-rank test (using stratification factors as strata).  The rates at various 
timepoints (e.g., every 6 months after randomization) and medians of LFFS, DMFS and 
PFS for each arm will be estimated using the Kaplan-Meier method (1958).  The 
associated 95% confidence interval (CI) will be calculated using Greenwood’s formula 
and based on a log-log transformation applied on the survival function.  Hazard ratios for 
LFFS, DMFS and PFS will be estimated using a stratified Cox regression model.  Results 
from an unstratified analysis will also be provided.  If any stratum has less than 5 events, 
the stratification factor which contains the level with the smallest number of patients will 
be removed from the stratified analyses.   
 
Treatment-Related Toxicity 
Adverse events (AEs) will be graded with CTCAE version 5.0.  For the purpose of 
evaluating the role of adjuvant IMPRINT, the As-Treated (AT) patient population will be 
used for the analysis of safety data in this study.  The AT population consists of all 
randomized subjects based on the treatment they actually received after randomization.  
Treatment-related adverse events observed after randomization will be summarized as 
assessed by the investigator.  The worst overall grade per patient will be tabulated for 
both arms.  Other toxicities of interest will also be assessed as necessary.  All adverse 
events, adverse events leading to withdrawal, interruption or modification of protocol 
treatment, Grade ≥ 3 adverse events, and serious adverse events will be summarized.  
Deaths and cause of death will be summarized.  The rate of treatment-related adverse 
events will be reported with the frequency and severity (e.g., type, grade, and attribution) 
by arm.   
 
Quality of Life (QOL)/Patient-reported Outcome (PRO) 
EORTC quality of life scores are transformed to a 0-100 point scale and interpreted using 
a minimally important difference approach.  Differences in means scores is commonly 


 
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presented, which allows comparison between cohorts or from baseline within the same 
cohort of patients (Nowak 2004).  A clinically meaningful or modest effect is defined as a 
difference of 10 to 20 points in a HRQOL parameter (Osoba et al., 1998).  A large effect 
is defined as changes of ≥20 points.   
 
For the purpose of evaluating the role of adjuvant IMPRINT, the QOL analyses for any 
changes between two timepoints will be performed based on all randomized patients with 
assessments at both timepoints, compared between the treatment arms to which they were 
randomized regardless of what treatment the patients actually received.  The primary 
QOL endpoint is whether a patient experiences a clinically meaningful improvement 
(CMI) in EORTC-QLQ global health status score (≥10 points), from randomization to 9 
months after randomization.  The rates of patients experiencing a CMI changes will be 
compared between Arm 1 and Arm 2 using Cochran-Mantel-Haenszel test, with the 
exception that if at least one cell has counts less than 5, a Fisher’s exact test will be used.  
The associated 90% confidence interval will be calculated for each arm using Clopper-
Pearson method.  Results from an as-treated analysis will also be provided.   
 
As a sensitivity analysis, a mixed effects model will be used to assess changes of 
EORTC-QLQ global health status score across time using all available data while 
adjusting for stratification variables and other baseline characteristics. Mixed models are 
a general class of models for analyzing repeated measures data, which allow modeling of 
the covariance among the repeated measures as well as random effects such as patient-
specific intercepts and slopes and can incorporate fixed and time-varying covariates. 
Fixed effects will consist of stratification factors and potentially other baseline covariates 
of interest. Since missing data is expected, patients with missing data will be compared to 
patients with complete data at each follow-up time with respect to baseline 
characteristics. If any of these characteristics are found to be significantly different, then 
they will be incorporated into the mixed effects model. Prior to performing analyses, an 
evaluation of the amount, reasons and patterns of missing data will be performed, using 
the well-known categories of missing completely at random (MCAR), missing at random 
(MAR) and missing not at random (MNAR) (Fairclough 2010, Verbeke 2000). If missing 
data are MCAR or MAR, then a mixed model using maximum likelihood is sufficient 
because all available data can be used. A joint model that allows a shared parameter 
between the repeated measurements and time to death or drop out can be used if 
considered MNAR due to the high number of patient deaths or dropouts (Rizopoulos 
2012). Other options for MNAR data are pattern mixture and selection models 
(Fairclough 2010, Little 1995). Sensitivity analyses will be performed to compare the 
results of different analytic strategies (Fairclough 1998).  
 
14.6.3 Interim Analysis for Pneumonitis in Patients Receiving Immunotherapy 
In addition to monitoring severe adverse events and unexpected adverse events closely 
and having them reviewed at the semi-annual DMC meetings, as described in section 
14.4, treatment-related grade 3 or higher pneumonitis in patients who have received 
immunotherapy and then receive radiation therapy will be closely monitored by the study 
team.  For the first 24 eligible patients randomized to Arm 2 who received 
immunotherapy, the frequency of treatment-related grade 3 or higher pneumonitis will be 


 
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continuously monitored.     
Special safety interim analyses of grade 3 or higher treatment-related pneumonitis that 
does not improve to grade 0-2 within 4 weeks of onset will be conducted when 6, 9, 12, 
15, 18, 21 and 24 patients become analyzable (e.g., patients who have been treated with 
immunotherapy at any time, have received at least 1 fraction of RT, and have been 
observed for at least 4 months after RT completion).  Based on the following Bayesian 
toxicity monitoring rule, if the rate is considered as concerning, the study team and group 
leaders will discuss with CTEP about the most appropriate actions to mitigate the 
potential risks, including a possible major modification to study design or accrual 
suspension.  Based on rates of grade 3 or higher treatment-related pneumonitis from 
IMPRINT trial and existing immunotherapy trials, we assume a priori that Arm 2 has an 
average grade 3 or higher pneumonitis rate of approximately 8% and that there is an 
approximately 14% chance that the risk will be 18% or higher (e.g., 10% or more 
increase), which corresponds to a Beta (0.08, 0.92) prior distribution.  We then consider 
the rate of toxicity to be concerning if the posterior probability of the grade 3 or higher 
pneumonitis rate ≥18% is more than 70%.  Table 14.1 summarizes the Bayesian 
monitoring rule when the 6th, 9th, 12th, 15th, 18th, 21st and 24th patients become analyzable.  
Table 14.1 Bayesian Toxicity Monitoring Rule 
Total # of analyzable patients 
6 
9 
12 
15 
18 
21 
24 
# patients with grade 3 or 
higher pneumonitis 
2 
3 
4 
4 
5 
6 
6 
Table 14.2 summarizes the operating characteristics based on 5,000 simulations with 12 
patients in terms of how frequent Arm 2 may be considered “alarming” for accrual 
suspension.  
Table 14.2 Operating characteristics of the monitoring rule 
Underlying risk 
0.1 
0.15 
0.2 
0.25 
0.3 
% of time stopping considered 
14.7% 
33.6% 
54.8% 
73.3% 
86.9% 
 
14.6.4 Power Calculations for Quality of Life (QOL) Research:  
The primary QOL hypothesis is that the proportion of  patients in Arm 2 who experience 
clinically meaningful improvement (CMI) in QOL at 9 months after randomization (p2) 
is larger than that in the control arm (p1), e.g., p2>p1.  This hypothesis will be tested at a 
1-sided type 1 error of 5%, using Fisher’s exact test to compare the proportions of 
patients experiencing CMI between the two arms. 
 
By definition, only participants who are alive at 9 months after randomization could 
potentially be analyzable for QOL analysis. Based on the primary hypothesis of OS, the 
survival rate at 9 months is approximately 59% under H0, and 73% under H1.  We define 
patients as analyzable if they are randomized and have assessments at both timepoints (at 
randomization and 9 months post-randomization).  While great efforts will be made to 
minimize patients’ attrition such that the number of analyzable cases can be maximized, 
it is well acknowledged that uncertainty still exists in the total number of analyzable 


 
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cases.  Furthermore, to our best knowledge, there are no existing data available in this 
population that can be used for the control group, nor a widely accepted difference in 
patients experiencing CMI.  Therefore, we argue the sample size of the QOL component 
should not be determined by detecting a fixed difference between patients’ proportions of 
experiencing CMI.  Instead, we demonstrate that, under reasonable assumptions, it is 
reasonable and justifiable to offer QOL to all patients to detect non-trivial differences in 
proportions of patients experiencing CMI.  The following table assumes 85% of 
randomized patients who remain alive at 9 months after randomization are analyzable 
(e.g., an attrition rate of 15%).  When the attrition rate is lower, e.g., smaller than 15%, 
greater power is expected to detect same differences in CMI proportions. 
 
Table 14.3: Power of Comparing Primary QOL Endpoint 
at 9 months post-randomization 
% Experienced CMI 
in Arm 2 (p2) 
% Experienced CMI 
in Arm 1 (p1) 
Power  
30% 
10% 
62% 
40% 
10% 
90% 
40% 
20% 
52% 
50% 
20% 
84% 
 
14.7 
Exploratory Hypothesis and Endpoints (15-MAR-2022) 
14.7.1  Exploratory endpoints 
• The degree of under-staging, concordant and upstaging between centrally-reviewed 
clinical staging (based on PET, CT and/or MRI) and pathologic staging 
• Immunologic and pathologic biomarkers as predictors of response 
• Association between radiation dose to gross residual disease and local control 
• Rate of R0/R1 and R2 resections, by type of procedures (extended 
Pleurectomy/Decortication (P/D), P/D and partial pleurectomy) 
• EORTC QLQ-Q30 and LC13 symptoms in patients treated with IMPRINT who 
respond with “quite a bit” or “very much” LC13 symptoms at 9-12 months post-
randomization and at 3 months post-randomization 
• Changes in health-related quality of life, functional domains, and symptoms over time 
with the addition of adjuvant hemithoracic IMPRINT as compared to surgery and 
systemic therapy alone. 
• Prognostic values of center patient volume (≤10 versus >10 P/D/year) and systemic 
therapy type (chemotherapy vs immunotherapy). 
• Optimization of quality assurance methodologies and processes for radiotherapy and 
imaging with machine learning strategies   
 
14.7.2  Analysis plans for exploratory endpoints 
For each subject, the centrally-reviewed clinical staging (based on PET, CT and/or MRI) 
will be compared with pathologic staging to determine whether it is under-staging 
(clinical staging is more extensive than pathologic staging), concordant (clinical staging 
is same as pathologic staging), or upstaging (clinical staging is less extensive than 
pathologic staging).  The proportion of under-staging, concordant and upstaging, along 


 
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with the associated 95% confidence intervals, will be reported.  
 
For each immunologic and pathologic biomarker of interest, response status between 
patients with and without respective biomarker will be summarized and compared. Chi-
square test will be used for univariate comparisons between biomarker positive and 
negative cases.  Assessment of potential prognostic factors will be evaluated in 
multivariable analyses using logistic regression. A stepwise model selection approach 
will be used to identify all significant risk factors. Each step of model building will 
contain the main effect for each biomarker as well as treatment arm. Factors which are 
significant at a 5% level will be kept in the final model. The potential interactions 
between the main effect and all significant risk factors, as well as treatment arm, will be 
tested.  
 
Gross residual disease and local failure will be analyzed as competing risk data (death 
without gross residual disease or death without local failure as the respective competing 
event). Association between radiation dose to gross residual disease and local failure will 
be evaluated similarly in multivariable analyses using Fine-Gray regression model.   
 
Proportions of R0/R1 and R2 resections, by type of procedures (extended 
Pleurectomy/Decortication (P/D), P/D and partial pleurectomy), along with 95% 
confidence intervals, will be reported.  
  
A mixed effects model will be used to assess changes in health-related quality of life, 
functional domains, and symptoms over time using all available data while adjusting for 
stratification variables and other baseline characteristics, as elaborated in Section 14.6.2. 
 
Prognostic values of center patient volume (≤10 versus >10 P/D/year) and systemic 
therapy type (Chemotherapy versus Immunotherapy), with respect to OS and PFS, will be 
determined using Cox regression model.  
 
Radiotherapy and imaging with machine learning strategies 
MPM treatment planning is difficult and complex due to the presence of large target 
volumes (PTVs), the possibility of concurrent integrated boost, and attempts to spare 
many organs at risk (OARs) (eg, spinal cord, lung, esophagus, heart, brachial plexus, 
liver, bowel, kidneys, stomach and other organs at risk). Both the delineation of target and 
organ-at-risk structures and the planning of radiation are complicated. IMRT/IMPT 
optimization is iterative in nature in order to fulfill the treatment planning process's 
objectives. The time required to construct a decent plan and the plan's quality are both 
dependent on the planner's experience; thus, variance in the quality of plans and the time 
required for planning is always recognized (efficiency). 
 
The Center for Innovation in Radiation Therapy (CIRO) and the Imaging and Radiation 
Oncology Core's (IROC) radiation therapy quality assurance center (RTQA) will use 
machine learning technologies to assess the quality of radiotherapy plans and to enhance 
them. Machine learning and artificial intelligence models will be trained using multi-
institutional data to help ensure the consistency and quality of MPM radiation. 


 
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14.8 
Gender/Ethnicity/Race Distribution (15-MAR-2022) 
 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
2 
0 
0 
2 
Asian 
0 
7 
0 
0 
7 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
2 
10 
0 
0 
12 
White  
24 
86 
1 
3 
114 
More Than One Race 
0 
0 
0 
0 
0 
Total 
26 
105 
1 
3 
135 
 
 
 
 
 
Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
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 
0 
1 
0 
0 
1 
White  
3 
10 
0 
1 
14 
More Than One Race 
0 
0 
0 
0 
0 
Total 
3 
11 
0 
1 
15 
 
 
 
 
 
 
 


 
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Baas P, Scherpereel A, Nowak A, et al.  First-line nivolumab plus ipilimumab in unresectable 
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Byrne MJ and Nowak AK.  Modified RECIST criteria for assessment of response in malignant 
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Chang JY, Xiaodong Z, Knopf A, et al.  Consensus Guidelines for Implementing Pencil-Beam 
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Fairclough D. Design and analysis of quality of life studies in clinical trials (2nd ed.). Boca 
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Flores RM, Pass HI, Seshan VE, et al.  Extrapleural pneumonectomy versus pleurectomy/ 
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Forde, PM, Anagnostou V, Sun Z, et al.  Durvalumab with platinum-pemetrexed for unresectable 
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Freidlin B, Korn EL, Gray R.  A general inefficacy interim monitoring rule for randomized 
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Gupta V, Mychalczak B, Krug L, et al.  Hemithoracic radiation therapy after 
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Hassan R, Thomas A, Nemunaitis JJ, et al.  Efficacy and Safety of Avelumab Treatment in 
Patients With Advanced Unresectable Mesothelioma - Phase 1b Results From the JAVELIN 
Solid Tumor Trial.  JAMA Oncol.  2019;5(3):351-357. 
 
Hollen PJ, Gralla RJ, Liepa AM, et al.  Support Care Cancer. 2006 Jan;14(1):11-21; PMID: 
15999264. 
 
Krug LM, Pass HI, Rusch VW, et al.  J Clin Oncol 2009; 27(18): 3007-3013; PMCID: 
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Lan KK and DeMets DL.  Discrete sequential boundaries for clinical trials. Biometrika 1983; 70: 
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Little RA. Modeling the Drop-out Mechanism in Repeated-Measures Studies. J Am Stat Assoc. 
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Mollberg NM, Vigneswaran Y, Kindler HL, et al.  Ann Thorac Surg. 2012 Oct;94(4):1086-92. 
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Nowak AK, Lesterhuis WJ, Kok PS, et al.  Durvalumab with first-line chemotherapy in 
previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, 
phase 2 trial with a safety run-in.  Lancet Oncol.  2020 Sep;21(9):1213-1223. 
 
Okada M, Kijima T, Aoe K, et al.  Clinical Efficacy and Safety of Nivolumab: Results of a 
Multicenter, Open-label, Single-arm, Japanese Phase II study in Malignant Pleural 
Mesothhelioma (MERIT).  Clin Cancer Res. 2019 Sep 15;25(18):5485-5492. 
 
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Rimner A and Rosenzweig K.  Novel radiation therapy approaches in malignant pleural 
mesothelioma.  Ann Cardiothorac Surg 2012; 1(4):457-461; PMCID: PMC3741784. 
 
Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural 
mesothelioma: a harmful procedure. Lung Cancer. 2012 Jul;77(1):151-5; PMID: 22244608. 
Rice D, Rusch V, Pass H, et al.  Recommendations for uniform definitions of surgical techniques 
for malignant pleural mesothelioma: a consensus report of the international association for the 
study of lung cancer international staging committee and the international mesothelioma interest 
group.  J Thorac Oncol, 2011; Aug;6(8):1304-12. 
 
Rice D, Rusch V, Pass H, et al.  Recommendations for Uniform Definitions of Surgical 
Techniques for Malignant Pleural Mesothelioma: A Consensus Report of the International 
Association for the Study of Lung Cancer International Staging Committee and the International 
Mesothelioma Interest Group.  Journal of Thoracic Oncology.  Vol 6(8);Aug 2011:1304-1312. 
 
Rimner A, Zauderer MG, Gomez DR, et al.  J Clin Oncol 2016; 34(23):2761-2768; PMCID: 
PMC5019761. 
 
Rimner A, Spratt DE, Zauderer MG, et al.  Int J Radiation Oncol Biol Phys 2014; 90(2):394-401; 
PMCID: PMC5560169. 
 
Rintoul RC, Ritchie AJ, Edwards JG, et al. Lancet. 2014 Sep 20;384(9948):1118-27; PMID: 
24942631. 
 
Rizopoulos D. Joint models for longitudinal and time-to-event data with applications in R. Boca 
Raton, FL: Chapman & Hall/CRC; 2012 
Rosenzweig KE, Zauderer MG, Laser B, et al.  Int J Radiation Oncol Biol Phys 2012; 
83(4):1278-1283; PMCID: PMC4359620. 
 
Rusch VW, Rosenzweig K, Venkatraman E, et al.  A phase II trial of surgical resection and 
adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.  J Thorac 
Cardiovasc Surg 2001; 122:788-795. 
 
Shaikh F, Zauderer MG, von Reibnitz D, et al.  Improved Outcomes with Modern Lung-Sparing 
Trimodality Therapy in Patients with Malignant Pleural Mesothelioma.  J Thorac Oncol. 2017 
Jun;12(6):993-1000.  
 
Scherpereel A, Mazieres J, Greillier L, et al.  Nivolumab or nivolumab plus ipilimumab in 
patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, 
open-label, randomised, non-comparative, phase 2 trial.  Lancet Oncol. 2019 Feb;20(2):239-253. 
 
Travis WD, Asamura H, Bankier AA, et al.  The IASLC Lung Cancer Staging Project:  
Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-
Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer.  J 
Thorac Oncol. 2016 Aug;11(8)1204-1223.  
 


 
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Treasure T, Lang-Lazdunski L, Waller D, et al.  Lancet Oncol 2011; 12:763-772; PMCID: 
PMC3148430. 
 
Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. New York, NY: 
Springer-Verlag; 2000. 
 
Vogelzang NJ, Rusthoven JJ, Symanowski J, et al.  Phase III study of pemetrexed in 
combination with cisplatin versus cisplatin alone in patients with malignant pleural 
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Zauderer MG and Krug LM. .Ann Cardiothorac Surg 2012; 1(4):487-490; PMCID: 
PMC3741800.


 
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APPENDIX A (15-MAR-2022) 
CARBOPLATIN DOSE CALCULATION INSTRUCTIONS 
 
1) The Cockcroft-Gault formula will be used in NRG Oncology trials. 
 
Dosing of Carboplatin: 
1) The carboplatin dose will be calculated to reach a target area under the curve (AUC) 
according to the Calvert formula using creatinine clearance (mL/min) from the Cockcroft-
Gault formula. 
 
2) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dL.   
 
3) The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity 
greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring 
dose modification, the dose of carboplatin will not need to be recalculated for subsequent 
cycles, but will be subject to dose modification for toxicity as noted in the protocol. 
 
4) Carboplatin doses are required to be recalculated if the patient has a weight change of greater 
than or equal to 10%. Patients are permitted to have systemic therapy doses recalculated for < 
10% weight changes. 
 
5) At the time of dose modification, if the patient’s age had changed (the patient has had a 
birthday), the site can use the current age. 
 
 
CALVERT FORMULA: 
Carboplatin dose (mg) = target AUC x (GFR [or estimated CrCl] + 25) 
 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
 
The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg 
AUC 5 = 750 mg 
AUC 4 = 600 mg 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (mL/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
 
Creatinine Clearance (mL/min) =    [140-Age (years)] x actual body Weight* (kg)   {x 0.85 if 
female}  
                                                                
72 x serum creatinine (mg/dl)  
 
Notes: 


 
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1) Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient.   
 
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25. 
 
c.*Adjusted weight should be used for estimation of GFR for patients with BMI of greater 
than or equal to 25  
 
d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) (+ 45.5 females) or (+ 50 for men)  
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
At the time of a dose modification for toxicity: 
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the time 
of a dose modification is higher than the creatinine used to calculate the previous dose, use 
the current (higher) creatinine. This will ensure that the patient is actually receiving a dose 
reduction. 

ICF_001.pdf: 
NRG ONCOLOGY 
 
NRG-LU006 
 
(ClinicalTrials.gov NCT #04158141) 
 
PHASE III RANDOMIZED TRIAL OF PLEURECTOMY/DECORTICATION PLUS 
SYSTEMIC THERAPY WITH OR WITHOUT ADJUVANT HEMITHORACIC 
INTENSITY-MODULATED PLEURAL RADIATION THERAPY (IMPRINT) FOR 
MALIGNANT PLEURAL MESOTHELIOMA (MPM) 
 
Amendment 2: April 13, 2022 


Protocol Version Date: 04/13/22                                                                                                           NRG-LU006 
 
                                                                                                                                                              Page 1 of 19 
Research Study Informed Consent Document 
 
(15-MAR-2022) 
Study Title for Participants:  Testing the addition of targeted radiation therapy to surgery 
and the usual systemic therapy treatment for malignant pleural mesothelioma (MPM) 
 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  NRG-
LU006, “Phase III Randomized Trial of Pleurectomy/Decortication Plus Systemic Therapy 
With or Without Adjuvant Hemithoracic Intensity-Modulated Pleural Radiation Therapy 
for Malignant Pleural Mesothelioma (MPM),” (NCT #04158141)  
 
 
Overview and Key Information  
 
What am I being asked to do? 
We are asking you to take part in a research study.  This study has public funding from the 
National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United 
States Department of Health and Human Services. We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer. 
 
We are asking you to take part in this research study because you have malignant pleural 
mesothelioma (MPM), cancer in the lining of the lungs, and you are a candidate for a type of 
surgery called pleurectomy/ decortication that involves removing the affected lung lining and all 
visible masses, but not the affected lung itself. 
 
Taking part in this study is your choice.  
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
Why is this study being done? (15-MAR-2022) 
This study is being done to answer the following question: Can we extend your life by adding a 
type of radiation therapy that targets the lining of the lung to the usual treatment of surgery and 
chemotherapy?  This type of radiation avoids the healthy lung tissue as much as possible and 
could extend your life.   
 
We are doing this study because we want to find out if this approach is better or worse than the 
usual approach for your cancer.  The usual approach is defined as care most people get for MPM. 


Protocol Version Date: 04/13/22                                                                                                           NRG-LU006 
 
                                                                                                                                                              Page 2 of 19 
 
What is the usual approach to my malignant pleural mesothelioma? (15-MAR-2022) 
The usual approach for patients who are not in a study is treatment with surgery and 
chemotherapy.  Recently, the Food and Drug Administration (FDA) approved immune therapy 
treatment in MPM.  The chemotherapy drugs used in this study are approved by the FDA and 
commonly used with lung surgery.  For patients who get the usual approach for this cancer, 
about 60 patients out of 100 live longer than one year.   
 
What are my choices if I decide not to take part in this study? 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose not to be treated for cancer. 
• You may choose to only get comfort care to help relieve your symptoms and not get 
treated for your cancer.   
 
What will happen if I decide to take part in this study? (15-MAR-2022) 
If you received chemotherapy and/or immune therapy before entering the study: 
If you decide to take part in this study, you will have surgery.   
 
If you have not received any treatment before entering the study: 
If you decide to take part in this study, you will have surgery followed by 12 weeks of 
chemotherapy. 
 
All Participants: 
After you finish your study treatment, your doctor will reevaluate you to see if you can still take 
part in this study.  If you no longer meet the study criteria after surgery and chemotherapy, your 
participation in the study will end.  If you meet study criteria you will get placed in one of the 
two study groups.  One group will receive radiation therapy and one group will not. 
 
For all participants, your doctor will continue to follow your condition for about 5 years and 
watch you for side effects.  They will see you in the clinic every 3 months for 2 years, then every 
6 months for 3 more years.   
 
What are the risks and benefits of taking part in this study? (15-MAR-2022) 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision.     
 
Risks 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
 
If you choose to take part in this study, there is a risk that the usual approach plus radiation 
therapy may not be as good as the usual approach alone for helping you live longer.   
 


Protocol Version Date: 04/13/22                                                                                                           NRG-LU006 
 
                                                                                                                                                              Page 3 of 19 
There is also a risk that you could have side effects from the radiation treatment.  These side 
effects are in addition to and different from those you would get with the usual approach for your 
cancer.   
 
Some of the most common side effects that the study doctors know about are: 
• Tiredness 
• Peeling of skin 
• Sores in esophagus (swallowing tube) which may cause temporary difficulty swallowing  
• Cough 
• Shortness of breath 
• Infection 
• Nausea, vomiting 
• Loss of appetite or weight loss 
• Anemia  
 
There may be some risks that the study doctors do not yet know about.   
 
Benefits 
There is evidence that adding radiation therapy to surgery and drug therapy may be effective in 
stabilizing your type of cancer. It is not possible to know now if the addition of radiation will 
extend your life compared to the usual approach.  This study will help the study doctors learn 
things that will help people in the future. 
 
If I decide to take part in this study, can I stop later? 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  It’s important that you stop 
safely.  This may mean slowly stopping the chemotherapy and the radiation therapy so that there 
is not a sudden unsafe change, risk to your health, etc.  If you stop, you can decide if you want to 
keep letting the study doctor know how you are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
Are there other reasons why I might stop being in the study? 
Yes.  The study doctor may take you off the study if: 
• Your health changes and the study is no longer in your best interest. 
• New information becomes available and the study is no longer in your best interest. 
• You do not follow the study rules. 
• For women: You become pregnant while on the study. 
• The study is stopped by the National Cancer Institute (NCI), Institutional Review Board 
(IRB), Food and Drug Administration (FDA), or study sponsor (NRG Oncology). The 
study sponsor is the organization who oversees the study.   
 


Protocol Version Date: 04/13/22                                                                                                           NRG-LU006 
 
                                                                                                                                                              Page 4 of 19 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
What is the purpose of this study? (15-MAR-2022) 
The purpose of this study is to compare the usual treatment alone to having radiation that targets 
the diseased area of the lung lining and avoids the healthy lung tissue as much as possible plus 
the usual treatment.  The addition of this radiation therapy to the usual treatment could help you 
live longer.  But, it could also cause side effects, which are described in the risks section below.  
 
This study will help the study doctors find out if this different approach is better than the usual 
approach.  To decide if it is better, the study doctors will be looking to see if the study approach 
increases the life of patients by 6 months or more compared to the usual approach.   
 
What are the study groups? (15-MAR-2022) 
This study has two study groups.   
 
All study participants will have surgery. 
 
• Participants who received chemotherapy and/or immune therapy before enrolling in the 
study will have surgery 4-8 weeks after the last drug therapy. 
 
• Participants who did not receive chemotherapy and/or immune therapy before enrolling 
in the study will get the usual chemotherapy drugs used to treat this type of cancer 4-8 
weeks after surgery.  You will get these drugs through a vein in the arm every 3 weeks 
for up to 4 cycles.  Each cycle lasts 21 days. 
 
It does not matter what order you have these treatments (surgery followed by chemotherapy or 
chemotherapy and/or immunotherapy before study enrollment then surgery once you enroll), but 
you must have both types of treatment. 
 
Four to eight weeks after you complete surgery and chemotherapy you will be assigned to one of 
the study groups. 
 
• Group 1  
If you are in this group, your treatment will be complete and you will be carefully 
monitored by the doctor and regularly assessed.   
 
There will be up to 70 people in this group. 
 
• Group 2  
If you are in this group, you will receive radiation to the lining of your lung 5 days/week 
for about 6 weeks.  You will be carefully monitored by the doctor and regularly assessed. 
 
You will not get additional doses of drugs during this time, or radiation after the 6 weeks. 
 


Protocol Version Date: 04/13/22                                                                                                           NRG-LU006 
 
                                                                                                                                                              Page 5 of 19 
There will be up to 70 people in this group. 
 
We will use a computer to assign you to one of the study groups.  This process is called 
“randomization.”  It means that your doctor will not choose and you cannot choose which study 
group you are in.  You will be put into a group by chance. You will have an equal chance of 
being in Group 1 or Group 2. 
 
Another way to find out what will happen to you during this study is to read the chart below. 
Start reading at the top and read to the bottom, following the lines and arrows.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
What exams, tests, and procedures are involved in this study? (15-MAR-2022) 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study.  
 
You may have received chemotherapy and/or immune therapy            
before you enroll in this study. 
You agree to take part in the study and sign this consent form. 
You will have surgery and if you did not have chemotherapy or immune 
therapy before you enrolled in this study, you will have chemotherapy 
after surgery.   
Randomize – 
The computer will randomly put you in a study group. 
Group 1 
 
Close monitoring 
Group 2 
 
Radiation therapy to the 
lining of your lung 


Protocol Version Date: 04/13/22                                                                                                           NRG-LU006 
 
                                                                                                                                                              Page 6 of 19 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only.  
 
Quality of Life Study 
If you speak and understand English, Spanish or French, you will be asked to fill out 2 forms 
with questions about your physical and emotional well-being.  Researchers will use this 
information to better understand how patients feel during treatments and what effects the 
treatments are having.    
 
Since these forms are being used for research, the responses you provide will not be shared with 
your study doctor.  If you have any serious health issues or other concerns, please talk with your 
doctor or nurse right away. 
 
If you received drug therapy before starting the study, you will be asked to fill out these forms 6 
times as follows:  
• Before surgery 
• After surgery  
• At 3, 9, 15 and 21 months after randomization 
 
If you did not receive drug therapy before starting the study, you will be asked to fill out these 
forms at 7 times as follows:  
• Before surgery 
• After surgery before drug therapy 
• After surgery and drug therapy  
• At 3, 9, 15 and 21 months after randomization 
 
Each form will take about 5 minutes to complete for a total of 10 minutes to complete the forms 
each time.  The forms will ask about your overall health, your ability to do activities, and things 
like tiredness and shortness of breath.  You don’t have to answer any question that makes you 
feel uncomfortable.  
What risks can I expect from taking part in this study? (15-MAR-2022) 
 
General Risks 
If you choose to take part in this study, there is a risk that the usual treatment plus radiation 
therapy may not be as good as the usual approach for your cancer at shrinking or stabilizing your 
cancer.     
 
You also may have the following discomforts: 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
 
The chemotherapy and radiation therapy used in this study could be very harmful to an unborn or 
newborn baby.  There may be some risks that doctors do not yet know about.  It is very 
important that you check with your study doctor about what types of birth control or pregnancy 
prevention to use during the study and for 1 month after you have completed the study.  You 


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must let your study doctor know about any pregnancy that occurs at any time during the study 
and within 6 months after you have completed the study. 
 
Side Effect Risks 
The drugs and radiation therapy used in this study may affect how different parts of your body 
work such as your liver, kidneys, heart, and blood.  The study doctor will test your blood and let 
you know if changes occur that may affect your health. 
 
There is also a risk that you could have other side effects from the surgery. 
 
Here are important things to know about side effects: 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
3. Some side effects may make it hard for you to have children. 
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
Drug Risks 
 
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
Study Group 1 and Group 2 – Possible side effects of pemetrexed, cisplatin and carboplatin are 
listed in the tables below.  These drugs are part of the usual approach for treating this type of 
cancer: 
Possible Side Effects of Pemetrexed (Table Version Date: June 3, 2021) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Pemetrexed, more than 20 and up to 100 may have: 
• Nausea, loss of appetite, weight loss 
• Tiredness 
 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Pemetrexed, from 4 to 20 may have: 
• Damage to the lungs which may cause shortness of breath 
• Scarring of the lungs 
• Swelling of the body 
• Infection, possibly in the blood, especially when white blood cell count is low 
• Bruising, bleeding 
• Anemia which may cause tiredness, or may require blood transfusions 
• Kidney damage which may cause swelling, may require dialysis 
• Sores in mouth which may cause difficulty swallowing 
• Constipation, vomiting, diarrhea, belly pain 
• Radiation Recall Syndrome which may cause swelling and redness of the area of radiation 
• Numbness and tingling of the arms and legs 
• Fever 
• Rash, itching, blisters, peeling of skin 
• Hair loss 
 
RARE, AND SERIOUS 
In 100 people receiving Pemetrexed, 3 or fewer may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• Blockage of the bowels 
• Stevens-Johnson syndrome which may cause severe skin rash with blisters and peeling 
which can involve mouth and other parts of the body 
Possible Side Effects of Cisplatin (Table Version Date:  August 6, 2021) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, more than 20 and up to 100 may have: 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Anemia which may cause tiredness, or may require blood transfusions 
• Kidney damage which may cause swelling, may require dialysis 
• Hearing loss including ringing in the ears 
• Nausea, vomiting 
• Confusion 
• Numbness, pain and tingling of the fingers, toes, arms and/or legs, loss of balance 
 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, from 4 to 20 may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• Diarrhea 
• Change in taste 
• Hair loss 
 
RARE, AND SERIOUS 
In 100 people receiving Cisplatin, 3 or fewer may have: 
• Brain damage, Posterior Reversible Encephalopathy syndrome, which may cause 
headache, seizure, blindness 
• Seizure 
• A new cancer, including leukemia, resulting from treatment of a prior cancer 
Possible Side Effects of Carboplatin (Table Version Date:  October 18, 2021) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, more than 20 and up to 100 may have: 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Anemia which may cause tiredness, or may require blood transfusions 
• Vomiting, nausea 
• Hair loss 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Carboplatin, from 4 to 20 may have: 
• Diarrhea, constipation, belly pain 
• Changes in taste 
• Numbness and tingling in fingers and toes 
• Weakness 
• Swelling, redness, and pain at the site of the medication injection 
 
RARE, AND SERIOUS 
In 100 people receiving Carboplatin, 3 or fewer may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 


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RARE, AND SERIOUS 
In 100 people receiving Carboplatin, 3 or fewer may have: 
• Visual loss 
• Difficulty hearing 
 
Study Group 1 and Group 2 – Possible side effects of surgery are listed in the table below.  
This surgery is part of the usual approach for treating this type of cancer: 
 
SURGERY: 
Common side effects of surgery include (but are not limited to) pain, bleeding, infection, wound 
healing difficulties, and injury to surrounding areas. The table below lists some of the common 
side effects of surgery depending on the type and location of your surgery. Prior to your surgery, 
you will need to sign a surgical consent form provided by your doctor, which is separate from 
this trial and specific to the type of surgery you will undergo. The surgical consent will include 
risks specific to the type and location of your surgery. When you sign the surgical consent and 
during discussions with your surgeon, you should ask your surgeon about those risks.  
 
COMMON, SOME MAY BE SERIOUS 
 
In 100 people undergoing surgery, more than 20 and up to 100 may have: 
• Nausea, anorexia (loss of appetite) 
• Pain 
 
OCCASIONAL, SOME MAY BE SERIOUS 
 
In 100 people undergoing surgery, from 4 to 20 may have: 
• Damage to the liver may result in liver damage that can causes yellowing of the 
skin and eyes, bleeding/bruising, fluid in the abdominal, tiredness, confusion, and 
itching 
• Bleeding 
• Infection 
• Lung collapse 
• Fluid around the lungs 
• Wound healing difficulties 
• Swelling of the body 
• Injury to the nerves causing numbness 
 


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RARE, AND SERIOUS 
 
In 100 people undergoing surgery, 3 or fewer may have: 
• Prolonged need to be on a breathing machine with a breathing tube in place, and/or 
prolonged need to have a tube in the chest because of damage to the lung  
• Injury to the areas near the site of surgery including: 
▪ Injury to the bowels resulting in the need for a “bag” so that the bowels 
drain outside of the body 
▪ Kidney damage 
▪ Pancreas injury 
 
Study Group 2 - In addition to side effects listed above, people who are in Group 2 may also 
have some side effects from the radiation therapy.  These side effects are listed below. 
 
Possible Side Effects of Lung Radiation 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving lung radiation, more than 20 and up to 100 may have: 
• Swelling and redness, tanning, thickening, numbness, or peeling of the skin in the area 
of radiation 
• Difficulty and/or pain with swallowing 
• Hair loss in the treatment area, may be permanent 
• Shortness of breath 
• Cough with or without increased phlegm production 
• Tiredness 
• Diarrhea, nausea 
• Anemia, which may require blood transfusion 
• Infection, especially when white blood cell count is low 
• Bleeding, bruising 
• Rib pain, increased risk of rib fracture 
 
 


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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving lung radiation, from 4 to 20 may have: 
• Inflammation of the lung that may cause difficulty breathing and can be life-threatening 
• Narrowing of the throat which may cause vomiting, difficulty swallowing 
• Scarring in the lung  
• Lung collapse 
• Fluid around lungs 
• Bleeding from the lungs which may cause coughing up blood  
• Fever  
• Narrowing of the esophagus 
• Pain in chest wall 
 
 
RARE, AND SERIOUS 
In 100 people receiving lung radiation, 3 or fewer may have: 
• Abnormal opening in internal organs which may cause pain and bleeding 
• Irritation of the heart causing heart failure, heart attack, chest pain, abnormal heartbeat, 
shortness of breath, swelling of ankles, cough or tiredness 
• Transverse myelitis – irritation of the spinal cord causing weakness, tingling or numbness 
of the lower body and legs, or paralysis of the lower half of the body 
• Brachial plexopathy – irritation of the nerves controlling the arm, causing weakness or 
paralysis 
• Bleeding from the airway (windpipe) 
• Narrowing of the airway causing shortness of breath 
• Death 
• Lung damage, may be life threatening 
• Damage to the large blood vessels surrounding the heart, which could cause coughing up 
of blood and possibly death  
• Sores and skin damage causing bleeding and severe pain and may lead to an open wound 
 
What are my responsibilities in this study? 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
 


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For women: Do not get pregnant or breastfeed while taking part in this study and for one month 
after end of treatment.  For men: Do not father a baby while taking part in this study and for 1 
month after end of treatment.  For all:  Tell your study doctor right away if you think that you or 
your partner have become pregnant during the study or within 6 months after completing the 
study.  
 
What are the costs of taking part in this study? (15-MAR-2022) 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for your cancer.  This includes: 
 
• the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety and prevent and treat side effects.   
• the costs of getting the surgery, the chemotherapy drugs (if you are receiving 
chemotherapy after surgery), and if you are in Group 2, the radiation therapy. 
• your insurance co-pays and deductibles. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor, nurse or research coordinator for help finding the right person to talk to if you 
are unsure which costs will be billed to you or your insurance provider.  
 
You and/or your insurance provider will not have to pay for exams, tests, and procedures done 
for research purposes only or that are covered by the study. These include: 
• Quality of life assessments. 
 
Taking part in this study may mean that you need to make more visits to the clinic or hospital 
than if you were getting the usual approach to treat your cancer.  You may: 
 
• Have more travel costs. 
• Need to take more time off work. 
• Have other additional personal costs. 
 
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment 
 
What happens if I am injured because I took part in this study? 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 


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If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database.  
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at or receive copies of some of the information in your 
study records.  Your health information in the research database also may be shared with these 
organizations.  They must keep your information private, unless required by law to give it to 
another group.   
 
Some of these organizations are: 
 
• NRG Oncology and any company supporting the study now or in the future.  
• The NCI Central IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study.  
• The Food and Drug Administration and the groups it works with to review research. 
• The NCI and the groups it works with to review research, including the Cancer Trials 
Support Unit (CTSU). 
• The NCI’s National Clinical Trials Network and the groups it works with to conduct 
research.   
 
In addition to storing data in the study database, data from studies that are publicly funded may 
also be shared broadly for future research with protections for your privacy. The goal of this data 
sharing is to make more research possible that may improve people’s health. Your study records 
may be stored and shared for future use in public databases.  However, your name and other 
personal information will not be used.   
 
Some types of future research may include looking at your information and information from 
other patients to see who had side effects across many studies or comparing new study data with 
older study data.  However, right now we don’t know what research may be done in the future 
using your information.  This means that: 
 
• You will not be asked if you agree to take part in the specific future research studies 
using your health information.   


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• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your 
information.  
 
Where can I get more information?   
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor _____________________________ 
(insert name of study doctor[s]) at ______________________________________________ 
(insert telephone number, and email address if appropriate). 
 
For questions about your rights while in this study, call the  ____________________ (insert 
name of organization or center) Institutional Review Board at   
(insert telephone number). 
 
Optional studies that you can choose to take part in 
This part of the consent form is about optional studies that you can choose to take part in.  They 
are separate from the main study described above.  These optional studies will not benefit your 
health.  The researchers leading these optional studies hope the results will help other people 
with your type of cancer in the future.  The results will not be added to your medical records and 
you or your study doctor will not know the results. 
 
Taking part in these optional studies is your choice.  You can still take part in the main study 
even if you say “no” to these studies.  There is no penalty for saying “no.” You and your 
insurance company will not be billed for these optional studies.  If you sign up for, but cannot 
complete this study for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for the following study. 
 
Optional sample collections for known laboratory studies and/or storage for possible 
future studies (15-MAR-2022) 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 


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straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
Unknown future studies 
If you choose to take part in this optional study, blood will be collected from a vein in your arm 
and stored.  Storing samples for future studies is called “biobanking.”  The biobank is being run 
by NRG Oncology and is supported by the NCI.  Also, any health-related information, such as 
your response to cancer treatment, results of study tests, and medicines you took, will be stored 
for future use.  This is a publicly funded study. Samples from publicly funded studies are 
required to be shared as broadly as possible. However, we will protect your privacy. The goal of 
this is to make more research possible that may improve people’s health.  
 
The biobank is a public research resource. It has controlled access.  This means that researchers 
who want to get samples and data from it must submit a specific research request. The request 
identifies who they are and what their planned research project is.  Before getting the samples 
and data, the researchers must agree to keep the data private, only use it for their planned 
research project, and never use it to try to identify you. 
 
Right now, we don’t know what research may be done in the future using your blood.  This 
means that: 
 
• You will not be asked if you agree to take part in the future research studies.   
• You and your study doctor will not be told when or what type of research will be done. 
•  You will not get reports or other information about any research that is done using your 
samples.  
 
Unknown future research studies may include sequencing of all or part of your DNA.  This is 
called genomic sequencing.  Sequencing allows researchers to identify your genetic code. 
Changes in your genetic code may just be in your tumor tissue.  These are called somatic 
changes.  Changes may also be in your normal tissue and passed down through your family.  For 
example, these genetic changes may be passed down to your children in the same way that eye 
and hair color are passed down. These are called germline changes.  If only tumor tissue is 
sequenced, we will not know if a genetic change in your tumor is also in your normal tissue.  
This is why sometimes both normal tissue and tumor tissue are sequenced.  This helps 
researchers understand if a genetic change happened only in your cancer tissue, or in your 
normal tissue as well.   
What is involved in this optional sample collection?  
If you agree to take part, here is what will happen next: 
 
1. After you enroll in this study, about 4 tablespoons of blood will be collected from a vein 
in your arm before treatment prior to surgery, after randomization (before radiation for 
participants in Group 2), and at your 3 month follow up visit.  A sample from the tissue 
that was collected at the time of your surgery will be sent to the biobank.   


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2. Your samples will be stored in the biobank.  There is no limit on the length of time we 
will keep your samples and research information.  The samples will be kept until they are 
used for research or destroyed. 
3. Researchers can only get samples from the biobank after their research has been 
approved by experts.  Researchers will not be given your name or contact information.   
4. Some of your genetic and health information may be placed in central databases for 
researchers to use.  The databases will not include your name or contact information.   
 
What are the risks in this optional sample collection? 
• The most common risks related to drawing blood from your arm are brief pain and maybe 
a bruise.   
• Generally, hospitals will keep some of your tissue. This tissue may be used to help treat 
your cancer in the future.  There is a small risk that when this tissue sample is submitted 
to the biobank for this optional sample collection, your tissue could be used up.     
• Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace information 
in a database back to you.  They could use that information in a way that could harm you.  
Researchers believe the chance that someone could access and misuse your information is 
very small.  However, the risk may increase in the future as people find new ways of 
tracing information.  
• In some cases, this information could be used to make it harder for you to get or keep a 
job and get or keep health insurance.  There are laws against the misuse of genetic 
information, but they may not give full protection. For more information about the laws 
that protect you, ask your study doctor or visit:  https://www.genome.gov/10002328/  
 
How will information about me be kept private? 
Your privacy is very important to the study researchers and biobank.  They will make every 
effort to protect it.  Here are just a few of the steps they will take: 
 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your sample and information will not know who you are.   They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 
What are the benefits to taking part in this optional sample collection? 
You will not benefit from taking part. 
 
The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
Are there any costs or payments to this optional sample collection? 


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There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment. 
 
What if I change my mind about this optional sample collection? 
If you decide you no longer want your samples to be used, you can call the study doctor, 
_________________, (insert name of study doctor for main trial) at 
________________________ (insert telephone number of study doctor for main trial) who will 
let the biobank know.  Then, any sample that remains in the biobank will be destroyed or 
returned to your study doctor.  This will not apply to any samples or related health information 
that have already been given to or used by researchers. 
 
What if I have questions about this optional sample collection? 
If you have questions about the use of your samples for research, contact the study doctor, 
________________, (insert name of study doctor for main trial), at _____________________ 
(insert telephone number of study doctor for main trial). 
Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
 
Samples for unknown future studies: 
I agree that my samples and related health information may be kept in a biobank for use in future 
health research. 
 
 
YES 
 
NO 
 
Contact for Future Research 
I agree that my study doctor, or someone on the study team, may contact me or my doctor to see 
if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
 
 


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My signature agreeing to take part in the study 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.  I also agree to take part in any additional studies where I circled 
“yes”. 
 
Participant’s signature 
 
 
 
 
Date of signature 
 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
 
Date of signature