Clinical trial NCT01822496
Conditions: Stage III Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2013-11-04; Completion date: 2018-06-04
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with chemoradiation therapy works in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high energy x rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, etoposide, paclitaxel, 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. It is not yet known whether giving erlotinib hydrochloride is more effective than crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess whether patients with unresectable local-regionally advanced non-small cell lung cancer (NSCLC) treated with targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone.

SECONDARY OBJECTIVES:

I. To evaluate response rate. II. To assess toxicity. III. To assess overall survival. IV. To correlate clinical outcomes with tumor molecular aberrations identified from deep sequencing of selected kinomes in patients from whom adequate baseline tissue is available.

OUTLINE: Eligible patients are assigned to one of two cohorts based on pre-enrollment screening by the enrolling institution for two biomarkers: EGFR TK mutation and EML4-ALK fusion arrangement. Within each cohort, patients are randomized to either an experimental or control arm, resulting in a total of four treatment arms overall. Patients with both the EGFR mutation and ALK arrangement are placed in the ALK Cohort.

Planned Sample Size: 156 for the EGFR mutation cohort and 78 for the ALK translocation cohort

After completion of study treatment, patients are followed at 1 and 2 months, 4-6 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Arms: arm 1: Induction erlotinib for 12 weeks followed by chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. Patients who have had no response (partial or complete) after 6 weeks of induction therapy start chemoradiation therapy immediately. arm 2: Chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. arm 3: Induction crizotinib for 12 weeks followed by chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. Patients who have had no response (partial or complete) after 6 weeks of induction therapy start chemoradiation therapy immediately. arm 4: Chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy.
Interventions: intervention 1: Radiation Therapy intervention 2: Carboplatin intervention 3: Cisplatin intervention 4: Crizotinib intervention 5: Erlotinib intervention 6: Etoposide intervention 7: Paclitaxel
Intervention descriptions: intervention 1: 30 once-daily 2 Gy fractions over 6 weeks totaling 60 Gy of intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT). intervention 2: Concurrent: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable.

Consolidation: 4-6 weeks after completion of RT, AUC=6, IV, days 1 and 22. intervention 3: 50 mg/m2, IV (intravenous), on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, cisplatin will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable. intervention 4: 250 mg, orally, twice daily for four 3-week cycles (12 weeks in total) intervention 5: 150 mg, orally, once daily for four 3-week cycles (12 weeks in total) intervention 6: 50 mg/m2, IV, on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, etoposide will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable. intervention 7: Concurrent: 45 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable.

Consolidation: 4-6 weeks after completion of RT, 200 mg/m2, IV, days 1 and 22.

Protocol documents:
Prot_SAP_000.pdf: 
 
 1  
RTOG 1306, Version Date July 25, 2017 
 
NRG ONCOLOGY  
RTOG  1306 
A RANDOMIZED PHASE II STUDY OF INDIVIDUALIZED COMBINED MODALITY 
THERAPY FOR STAGE III NON-SMALL CELL LUNG CANCER (NSCLC) 
 
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 Research 
Foundation, Inc.; and SWOG. 
 
Study Team (11JULY2017) 
Principal Investigator/  
 
Medical Oncology (Alliance) 
Medical Oncology Co-Chair (Alliance) 
Ramaswamy Govindan, MD 
Olwen Hahn, MD 
Washington University School of Medicine 
University of Chicago Medical Center 
Box 8056, 660 S. Euclid Avenue 
5841 S. Maryland Ave., MC 2115 
St. Louis, MO 63132 
Chicago, IL 60637 
314-362-5737/FAX 314-362-7086 
773-702-5381/FAX 773-702-3163 
rgovinda@dom.wustl.edu 
ohahn@medicine.bsd.uchicago.edu 
 
 
Radiation Oncology Co-Chair (NRG Oncology) 
Medical Oncology Co-Chair (NRG 
Oncology/SWOG) 
Hak Choy, MD 
Anne S. Tsao, MD 
University of Texas Southwestern 
MD Anderson Cancer Center 
5801 Forest Park Road 
1515 Holcombe Blvd., Unit 432 
Dallas, TX 75390 
Houston, TX 77030 
214-645-7600/FAX 214-645-9193 
713-792-6363/FAX 792-1220 
Hak.Choy@utsouthwestern.edu 
astsao@mdanderson.org 
 
 
Radiation Oncology Co-Chair (NRG Oncology) 
Medical Oncology Co-Chair (ECOG-ACRIN) 
Billy W. Loo, MD, PhD 
Nisha A. Mohindra, MD 
Stanford Cancer Institute 
Northwestern Univ. Feinberg School of Medicine 
875 Blake Wilbur Drive 
676 N. St. Clair Street, Suite 850 
Stanford, CA 94305 
Chicago, IL 60611 
650-736-7143/FAX 650-725-8231 
312-695-6180/ FAX 312-695-2351 
BWLoo@Stanford.edu 
n-mohindra@northwestern.edu 
 
 
Radiation Oncology Co-Chair (SWOG) 
Translational Research Co-Chair (Alliance) 
Megan Daly, MD 
Pasi A. Jänne, MD, PhD 
University of California Davis 
Dana-Farber Cancer Institute 
4501 X Street, G-140 
450 Brookline Avenue, HIM223 
Sacramento, CA 95817 
Boston, MA 02215 
916-734-5428/FAX 916-703-5068 
617-632-6076/FAX 617-632-5786 
megan.daly@ucdmc.ucdavis.edu 
pjanne@partners.org 
 
 
Medical Physics Co-Chair (NRG Oncology) 
Pathology Co-Chair (NRG Oncology) 
Timothy D. Solberg, PhD, FASTRO, FACR, 
FAAPM, FACMP 
Professor and Vice Chair 
UCSF Department of Radiation Oncology 
1600 Divisadero Street, Suite H-1031 
San Francisco, CA 94115 
415-353-7190 
Timothy.solberg@ucsf.edu 
Kirk D. Jones, MD  
NRG Oncology Biospecimen Bank 
University of California San Francisco 
505 Parnassus Ave., Rm M545 
San Francisco, CA 94143-0102 
415-353-1696/FAX 415-353-1916 
kirk.jones@ucsf.edu 


 
 2  
RTOG 1306, Version Date July 25, 2017 
 
NRG ONCOLOGY  
 
RTOG 1306 
 
A RANDOMIZED PHASE II STUDY OF INDIVIDUALIZED COMBINED MODALITY 
THERAPY FOR STAGE III NON-SMALL CELL LUNG CANCER (NSCLC) 
 
 
 
Study Team Continued (11JULY2017) 
 
Senior Statistician (NRG Oncology) 
Senior Statistician (Alliance) 
James Dignam, PhD 
Xiaofei Wang, PhD 
NRG Oncology 
Duke University 
1818 Market Street, Suite 1720 
2424 Erwin Road, Suite 1102 
Philadelphia, PA 19103 
Durham, NC 27705 
215-574-3174/FAX 215-928-0153 
919-681-5406/FAX 919-681-8028 
dignamj@nrgoncology.org 
xiaofei.wang@duke.edu 
 
 
 
 
NRG Oncology Contact Information 
Data Manager: 
Jeffrey Serianni 
For questions concerning eligibility or data 
submission 
NRG Oncology 
1818 Market St., Ste. 1720 
Philadelphia, PA 19103 
215-574-3248/Fax: 215-940-8809 
SerianniJ@NRGOncololgy.org 
 
Amy Krystkiewicz, RN 
NRG Oncology 
1818 Market St., Ste. 1720 
Philadelphia, PA 19103 
267-940-9415/Fax: 215-940-8809 
KrystkiewiczA@NRGOncology.org 
 
 
RTQA Questions:  
Jennifer Presley, RT(R) (M) (T), ARRT  
For questions concerning RT data submission 
IROC Philadelphia – RT QA Center 
 
NRG Oncology 
 
1818 Market St., Ste. 1720 
 
Philadelphia, PA 19103 
 
215-574-3153 /Fax:   
 
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: 
Fran Bradley 
For questions concerning protocol and informed 
consent versions & amendments 
NRG Oncology  
1818 Market Street, Suite 1720 
Philadelphia, PA 19013 
215-940-8893/Fax: 215-928-0153 
BradleyF@NRGOncology.org 
 
 


 
 3  
RTOG 1306, Version Date July 25, 2017 
 
NRG ONCOLOGY  
 
RTOG 1306 
 
A RANDOMIZED PHASE II STUDY OF INDIVIDUALIZED COMBINED MODALITY 
THERAPY FOR STAGE III NON-SMALL CELL LUNG CANCER (NSCLC) 
 
NRG Oncology Contact Information Continued 
 
 
Lung Committee Chair: 
Jeffrey Bradley, MD 
 
 
 
Protocol Agent  
Agent 
Supply 
NSC # 
IND # 
erlotinib 
NCI 
718781 
63383 
crizotinib 
Commercial/Pfizer 
 
 N/A 
carboplatin 
Commercially available 
 
 N/A 
cisplatin 
Commercially available 
 
 N/A 
etoposide 
Commercially available 
 
 N/A 
paclitaxel 
Commercially available 
 
 N/A 
 
Participating Sites (7/29/13) 
 U.S. Only 
 Canada Only 
 U.S. and Canada 
 Approved International Member Sites 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 8 
July 25, 2017 
TBD 
Amendment 7 
July 11, 2017 
TBD 
Amendment 6 
May 16, 2016 
5/31/2016 
Amendment 5 
September 11, 2015 
October 8, 2015 
Amendment 4 
June 26, 2015 
July 13, 2015 
Amendment 3 
August 27, 2014 
September 8, 2014 
Update  
June 24, 2014 
June 24, 2014 
Amendment 2 
May 29, 2014 
June 19, 2014 
Activation 
September 4, 2013 
November 4, 2013 
Amendment 1 
September 4, 2013 
November 4, 2013 
Update  
July 29, 2013 
July 29, 2013 
Pre-Activation 
  March 27, 2013 
July 29, 2013 
 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
 
  
 
 
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. 


 
 4  
RTOG 1306, Version Date July 25, 2017 
 
NRG ONCOLOGY  
 
RTOG 1306 
 
 
A RANDOMIZED PHASE II STUDY OF INDIVIDUALIZED COMBINED MODALITY 
THERAPY FOR STAGE III NON-SMALL CELL LUNG CANCER (NSCLC) 
 
 
 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION (6/26/15) 
To submit site registration 
documents: 
For patient enrollments:  Submit study data   
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.
org (for submitting regulatory 
documents only) 
Please refer to Section 
5.0 of the protocol for 
instructions on using the 
OPEN system. 
 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com 
 
Data collection for this study will be done 
exclusively through Medidata Rave.  Please see 
the data submission section of the protocol for 
further instructions..  
 
 
Do not submit study data or forms to the CTSU 
Data Operations. Do not copy the CTSU on data 
submission. 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access to the CTSU 
members’ web site is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and password.  
For 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.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please review the 
CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ web site   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory and 
Monitoring Policy 
The CTSU web site is located at  https://www.ctsu.org 
 
 
 
 


 
 5  
RTOG 1306, Version Date July 25, 2017 
 
TABLE OF CONTENTS 
 
SCHEMA  ...................................................................................................................................................... 7 
ELIGIBILITY CHECKLIST ............................................................................................................................. 9 
1.0 
INTRODUCTION ............................................................................................................................. 13 
1.1  
Background ................................................................................................................................. 13 
1.2  
Why This Study Is Important ....................................................................................................... 14 
1.3  
Previous Studies ......................................................................................................................... 15 
1.4 
Translational Research ............................................................................................................... 16 
2.0 
OBJECTIVES .................................................................................................................................. 17 
2.1 
Primary Objective ........................................................................................................................ 17 
2.2 
Secondary Objectives ................................................................................................................. 17 
3.0 
 PATIENT SELECTION................................................................................................................... 17 
3.1 
Conditions for Patient Eligibility ................................................................................................... 17 
3.2 
Conditions for Patient Ineligibility ................................................................................................ 18 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT ..................................................................... 18 
4.1 
Highly Recommended Evaluations/Management ....................................................................... 18 
5.0 
REGISTRATION PROCEDURES ................................................................................................... 19 
5.1 
Phantom Irradiation for IMRT ...................................................................................................... 19 
5.2 
Digital RT Data Submission Using TRIAD .................................................................................. 20 
5.3  
Regulatory Pre-Registration Requirements ................................................................................ 20 
5.4 
Registration (5/29/14) .................................................................................................................. 21 
6.0 
 RADIATION THERAPY.................................................................................................................. 22 
6.1 
Dose Specifications ..................................................................................................................... 22 
6.2 
Technical Factors/Treatment Planning ....................................................................................... 22 
6.3 
Localization, Simulation, and Immobilization .............................................................................. 23 
6.4 
Target Volumes/Motion Management Target Volumes .............................................................. 23 
6.5 
Critical Structures ........................................................................................................................ 25 
6.6 
Documentation Requirements  .................................................................................................... 26 
6.7 
Compliance Criteria ..................................................................................................................... 26 
6.8 
R.T. Quality Assurance Reviews................................................................................................. 27 
6.9 
Radiation Therapy Adverse Events ............................................................................................ 27 
6.10 
Radiation Therapy Adverse Event Reporting .............................................................................. 28 
7.0 
 DRUG THERAPY ........................................................................................................................... 28 
7.1 
Treatment .................................................................................................................................... 28 
7.2 
Erlotinib (Tarceva®, OSI 774), IND #63383 ................................................................................ 30 
7.3 
Crizotinib (Xalkori®, PF-02341066)) ........................................................................................... 37 
7.4 
Cisplatin  ...................................................................................................................................... 42 
7.5  
Etoposide .................................................................................................................................... 42 
7.6 
Paclitaxel ..................................................................................................................................... 43 
7.7 
Carboplatin .................................................................................................................................. 44 
7.8 
Clinical Trials Agreement ............................................................................................................ 45 
7.9 
Dose Modification ........................................................................................................................ 46 
7.10 
Modality Review .......................................................................................................................... 54 
7.11 
Adverse Events ........................................................................................................................... 55 
7.12 
CTEP-AERS Expedited Reporting Requirements  ..................................................................... 56 
8.0 
 SURGERY ..................................................................................................................................... 59 
9.0 
 OTHER THERAPY ......................................................................................................................... 59 
9.1 
Permitted Supportive Therapy .................................................................................................... 59 
9.2 
 Non-permitted Supportive Therapy ............................................................................................ 59 
10.0 
TISSUE/SPECIMEN SUBMISSION ................................................................................................ 60 
10.1 
Tissue/Specimen Submission ..................................................................................................... 60 
10.2 
Tissue Submission for Retrospective Central Review of Biomarker Screening: Mandatory) ..... 60 
10.3 
Specimen Collection for Tissue Banking and Translational Research: Highly Recommended 
(but Optional)  ............................................................................................................................. 61 


 
 6  
RTOG 1306, Version Date July 25, 2017 
 
10.4 
Reimbursement ........................................................................................................................... 63 
10.5 
Confidentiality/Storage ................................................................................................................ 63 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 63 
11.1 
Study Parameters ....................................................................................................................... 63 
11.2 
Details of Evaluations .................................................................................................................. 63 
11.3 
Measurement of Response ......................................................................................................... 64 
11.4 
Measurement/Definition of Progression/Recurrence .................................................................. 65 
11.5 
Criteria for Discontinuation of Protocol Treatment ...................................................................... 65 
12.0 
DATA COLLECTION  ...................................................................................................................... 65 
12.1 
Summary of Data Submission .................................................................................................... 66 
12.2 
Summary of Dosimetry Digital Data Submission ........................................................................ 68 
See Section 5.0 for TRIAD account access and installation instructions. ............................................... 68 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 68 
13.1 
Primary Endpoint ......................................................................................................................... 68 
13.2 
Secondary Endpoints .................................................................................................................. 68 
13.3 
Sample Size ................................................................................................................................ 68 
13.4 
Patient Accrual ............................................................................................................................ 69 
13.5 
Statistical Design for Translational Research ............................................................................. 70 
13.6 
Analysis Plan ............................................................................................................................... 70 
13.7 
Gender and Minorities ................................................................................................................. 72 
REFERENCES ............................................................................................................................................ 73 
APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS ................................. 76 
APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT .......................... 77 
APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP...................................... 78 
APPENDIX II: ZUBROD PERFORMANCE SCALE .................................................................................... 79 
APPENDIX III: AJCC STAGING SYSTEM ................................................................................................. 80 
APPENDIX IV:  BIOSPECIMEN COLLECTION ......................................................................................... 82 
 
 
 
 
 
 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
NRG ONCOLOGY  
 
RTOG 1306 
 
A Randomized Phase II Study of Individualized Combined Modality Therapy 
 for Stage III Non-small Cell Lung Cancer (NSCLC) 
 
SCHEMA (5/29/14) 
 
Institution’s Screening for Biomarkers Prior to Randomization: Mandatory 
The enrolling institution is responsible for screening (must be done at CLIA certified 
lab) for documentation of EGFR TK mutation and EML4-ALK fusion arrangement. 
 
For EGFR mutation testing, any genotyping method to detect exon 19 deletion, L858, 
and T790M mutation may be used as long as it is performed in a CLIA certified 
laboratory. Note: The enrolling institution must provide the method of testing and the 
specific result (i.e. specific mutation). 
 
For ALK testing, the FDA approved Vysis dual color FISH assay must be used for the 
detection of an ALK rearrangement. Note: The enrolling institution must provide the 
testing laboratory and the specific result (% of positive cells). 
 
Patients with both the EGFR mutation and ALK arrangement will be placed in the ALK 
Cohort. See Section 10.0 for details of retrospective central review and biomarker 
analyses. 
 
Stratification 
Weight Loss 
 (in prior 6 mos.) 
Stage 
Chemotherapy 
1. ≤ 5% 
1. IIIA 
1. cisplatin & etoposide 
2. > 5% 
2. IIIB 
2. paclitaxel & carboplatin 
 
EGFR TK Mutation Cohort 
R 
 
 
A 
 
Concurrent 
N 
Arm 1: Induction Therapy:  
†chemotherapy  
D 
 Erlotinib, 150 mg/day  for 12 weeks* 
and IMRT or 3D-CRT 
O 
 
60 Gy in 30 fxs 
M 
 
 
I 
Arm 2: Concurrent †chemotherapy and 
 
Z 
radiation, 60 Gy 
 
E 
 
 
 
ALK Tran L Cohort 
R 
 
 
A 
Arm 3: Induction Therapy: 
Concurrent 
N 
Crizotinib, 250 mg/bid for 12 weeks* 
†chemotherapy  
D 
 
and IMRT or 3D-CRT 
O 
 
60 Gy in 30 fxs 
M 
Arm 4: Concurrent †chemotherapy and 
 
I 
radiation, 60 Gy 
 
Z 
 
 
E 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page 
 
 


 
 8  
RTOG 1306, Version Date July 25, 2017 
 
†Per treating physician’s discretion, a choice of 2 chemotherapy regimens: 
• Cisplatin and etoposide, every 4 weeks, for 2 cycles; 
• Paclitaxel and carboplatin weekly for 6 weeks followed by 2 cycles of consolidation. 
Consolidation chemotherapy will begin 4-6 weeks after completion of chemoradiation. 
• CT scans will be obtained 4-6 weeks after chemoradiation is completed and prior to 
consolidation chemotherapy administration. See Section 11.2.3 for additional monitoring. 
 
*If CT at 6 weeks into induction therapy does not show at least PR, the patient will proceed 
directly to concurrent chemotherapy and IMRT or 3D-CRT, provided there is no progression that 
would preclude definitive chemoradiotherapy, in which case the patient will go off protocol 
treatment  and be treated as appropriate for systemic disease . See Section 11.3 for definitions of 
responses. 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Histologically or cytologically confirmed non-squamous NSCLC; unresectable stage IIIA or IIIB disease; 
patients must be surgically staged to confirm N2 or N3 disease. 
 
 
Required Sample Size: 156 for the EGFR mutation cohort and 78 for the ALK translocation cohort 
  
 
 


 
 9  
RTOG 1306, Version Date July 25, 2017 
 
ELIGIBILITY CHECKLIST (6/26/15) 
(page 1 of 4) 
NRG Oncology Institution #   
 
RTOG 1306 
 
  
Case #  
 
 
 
 
 
 
  ____ (Y) 1.   
Does the patient have a histologically or cytologically confirmed, newly diagnosed non-
squamous NSCLC? 
 
______(Y) 2.   Does the patient have unresectable clinical stage IIIA or IIIB (AJCC, 7th ed.) disease?  
 
______(Y) 3.   Was the patient surgically staged to confirm N2 or N3 disease? 
 
______(Y) 4.    Does the patient have measurable disease? (as described in Section 3.1 of the  
 
 
 
protocol) 
 
___(Y/NA) 5.  
If the patient has a pleural effusion, does it meet the requirements as outlined in Section  
 
 
3.1 of the protocol? 
 
______(Y) 6. 
Did the patient have a pre-enrollment biomarker screening documenting the presence of  
 
 
an EGFR mutation, ALK arrangement, or both (as outlined in Section 3.1 of the   
 
 
protocol)? 
 
______(Y) 7. 
Did the patient have a complete history and physical within 45 days prior to registration? 
 
______(Y) 8. 
Did the patient have a whole body FDG-PET/CT, CT scan with contrast of the chest and 
upper abdomen to include liver and adrenals (unless medically contraindicated), and MRI 
of the brain with contrast (or CT scan with contrast if MRI medically contraindicated) 
within 30 days prior to registration? 
 
______(Y) 9. 
Did the patient have a Zubrod Performance Status of 0 or 1 within 14 days prior to  
 
 
registration? 
 
______(Y) 10. Was the patient at least 18 years old at the time of registration? 
 
______(Y) 11. Did the patient have a CBC/differential within 14 days prior to registration and meet all of  
 
 
the requirements as outlined in Section 3.1 of the protocol? 
 
______(Y) 12. Does the patient have adequate renal and hepatic function within 14 days prior to  
 
 
registration as described in Section 3.1 of the protocol? 
 
___(Y/NA) 13.  If the patient is a woman of childbearing potential, has she had a negative serum  
 
 
pregnancy test within 14 days prior to registration? 
 
______(Y) 14.  Has the patient provided a signed study specific informed consent prior to study entry  
 
 
including consent for mandatory screening of tissue? 
 
______(N) 15.  Does the patient have any component of small cell lung carcinoma? 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page 
 
 


 
10  
RTOG 1306, Version Date July 25, 2017 
 
ELIGIBILITY CHECKLIST (7/29/13) 
(page 2 of 4) 
NRG Oncology Institution #   
 
RTOG 1306 
 
  
Case #  
 
 
 
 
 
 
______(N) 16.  Does the patient have an exudative, bloody, or cytologically malignant effusion? 
 
______(N) 17.  Has the patient had a prior invasive malignancy (except non-melanomatous skin cancer)  
 
 
and not been disease free for the past 2 years? 
 
 
______(N) 18.  Has the patient had prior systemic chemotherapy for the study cancer? 
 
______(N) 19.  Has the patient had prior radiotherapy to the region of the study cancer that would result  
 
 
in an overlap of radiation therapy fields? 
 
______(N) 20.  Does the patient have any severe, active co-morbidities as defined in Section 3.2 of the  
 
 
protocol? 
 
______(N) 21.  Does the patient have atelectasis of the entire lung? 
 
______(N) 22. Does the patient have contralateral hilar node involvement? 
 
______(N) 23.  Has the patient had a prior allergic reaction to the study drug(s) involved in this protocol? 
 
 
The following questions will be asked at Study Registration:  
3D-CRT and/or IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION.  
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials (Last First Middle) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
 
 
 
 
 
 
 
 
Continued on next page 
 
 


 
11  
RTOG 1306, Version Date July 25, 2017 
 
ELIGIBILITY CHECKLIST (7/29/13) 
(page 3 of 4) 
NRG Oncology Institution #   
 
RTOG 1306 
 
  
Case #  
 
 
 
 
 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at a VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date 
 
 
         
18. 
Medical oncologist’s name  
 
              (Y/N) 19. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 20.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
              (Y/N) 22. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's 
disease, or heart disease).  
 
              (Y/N) 23. 
Have you obtained the patient's consent to allow someone from this institution to  
 
 
 
contact him or her in the future to take part in more research?  
  
 _______(N/Y)  24.        Use of IMRT. 
 
 
_____  25. 
Specify biomarker (EGFR TK mutation, EML4-ALK fusion arrangement, or both). 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page 
 
 
 
 


 
12  
RTOG 1306, Version Date July 25, 2017 
 
ELIGIBILITY CHECKLIST (7/29/13) 
(page 4 of 4) 
NRG Oncology Institution #   
 
RTOG 1306 
 
  
Case #  
 
 
 
 
 
 
 
            _____  26. 
Specify chemotherapy regimen that patient will receive (cisplatin & etoposide vs. 
paclitaxel & carboplatin) 
 
 
_____  27. 
Specify percent weight loss in prior 6 mos. (≤ 5% vs. > 5%). 
 
 
_____  28. 
Specify stage (IIIA vs. IIIB). 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, 
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated 
during an institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 


 
13  
RTOG 1306, Version Date July 25, 2017 
 
1.0 INTRODUCTION 
1.1  
Background  
Local-regionally advanced NSCLC is potentially curable with multi-modality therapy. For patients 
with stage III NSCLC, the standard treatment regimen consists of chemotherapy and radiation.   
Concurrent administration of platinum based doublet therapy in combination with thoracic 
radiation is superior to sequential administration of chemotherapy followed by thoracic radiation 
or thoracic radiation alone (Choy 2004, Blackstock 2007). More than a decade of research with 
older chemotherapy agents has clearly established that induction chemotherapy preceding 
concurrent chemoradiation or consolidation or maintenance therapy following chemoradiation 
does not offer additional improvements in overall survival over concurrent chemoradiation alone 
(Blackstock 2007). It has become apparent in the recent years that lung cancer, in particular 
adenocarcinoma, is a remarkably molecularly diverse disease (Wheatley-Price 2008). Although 
several pathways appear to be dysregulated at a given time, it is widely believed in some cases 
that cancer cells get addicted to a few pathways more than others (oncogene addiction). Better 
understanding of the molecular biology of cancer coupled with advances in drug development has 
led to significant progress recently (Romond 2005; DeMatteo 2009). The spectacular benefit seen 
with the use of imatinib for the treatment of patients with c-kit harboring Gastrointestinal Stromal 
Tumors (GIST) and trastuzumab in patients with Her-2 neu positive breast cancer should serve 
as ideal models for emulation (Romond 2005; DeMatteo 2009). There is a clear need for 
innovative strategies in the treatment of locally advanced NSCLC and integration of predictive 
biomarkers for novel targeted agents.    
 
The need for predictive biomarkers is clearly exhibited in the examples below. Despite the 
significant role played by molecularly targeted therapies, such as bevacizumab and erlotinib, in 
patients with metastatic NSCLC, results from clinical trials using these agents in the setting of 
unselected locally advanced NSCLC have not been particularly encouraging (Mok 2009; 
Shepherd 2005; Cappuzzo 2010; Sandler 2006). More specifically, use of maintenance therapy 
with gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) following 
chemoradiation is associated with inferior survival compared to placebo in a molecularly 
unselected patients with locally advanced NSCLC (Kelly 2008). Concurrent use of EGFR TKIs 
along with thoracic radiation with or without chemotherapy in patients with locally advanced 
NSCLC has not produced striking results, once again in a broad unselected group of patients with 
NSCLC (Ready 2010). Bevacizumab, a monoclonal antibody against vascular endothelial growth 
factor (VEGF) in combination with thoracic radiation has resulted in a few instances of tracheo-
esophageal fistula leading to early termination of many ongoing trials (Spigel 2010). 
 
The introduction of EGFR TK inhibitors for the treatment of advanced NSCLC and the recognition 
that the most dramatic responses with EGFR TK inhibitors are best observed in patients whose 
tumors harbor EGFR TK mutations mark a major milestone in the treatment of patients with 
NSCLC (Shepherd 2005; Paez 2004). EGFR TK inhibitors administered as monotherapy produce 
a 2 to 3-fold increase in the response rates, progression-free survival, and overall survival 
compared to chemotherapy alone in this subset of patients (Fong 2008). When erlotinib, an 
EGFR TK inhibitor, is administered following 4 cycles of platinum-based doublet therapy in the 
maintenance setting in patients with incurable advanced NSCLC, there was a significant 
improvement in the progression-free survival and overall survival of these patients (Hazards Ratio 
HR 0.10) (Cappuzzo 2010). 
 
It has been reported recently that the echinoderm microtubule-associated protein-like 4-
anaplastic lymphoma kinase (EML4-ALK) fusion gene plays an important role in some patients 
with NSCLC (Soda 2007). An inhibitor of the ALK fusion kinase, crizotinib, produced a response 
rate of 64% in 76 patients with advanced metastatic NSCLC who harbored the fusion gene (Kwak 
2010). The median progression-free survival has not been reached in this study. The side effects 
are minimal with the most frequent side effects being visual disturbances, elevated liver function 
tests, nausea, and vomiting. 
 


 
14  
RTOG 1306, Version Date July 25, 2017 
 
Taken together, these examples serve to illustrate the power of a rational drug development 
process and the impact of targeted therapies in molecularly selected patients. The impressive 
improvements seen with imatinib in advanced GIST and trastuzumab in metastatic breast cancer 
led to thoughtful development of these drugs not only in advanced stage disease but also in early 
stage disease to improve the cure rates. Post-operative trastuzumab improves overall survival by 
nearly 50% in patients with resected her-2 positive breast cancer. The American College of 
Surgical Oncology (ACOSOG) reported significant improvement in disease-free survival (primary 
endpoint) with adjuvant imatinib following resected GIST.  
 
To the best of our knowledge, no studies have been designed specifically targeting patients with 
an EGFR TK inhibitor with locally advanced NSCLC whose tumors cells have mutated EGFR TK. 
Given the impressive benefits seen with crizotinib in those with ALK fusion gene, we believe it is 
rational to study these 2 agents in the molecularly selected patients with locally advanced 
NSCLC. Tumors that exhibit mutations in the EGFR TK domain do not harbor ALK fusion gene 
and vice versa. We hypothesize that customized therapy in molecularly selected patients would 
significantly improve the progression-free survival and overall survival in patients with locally 
advanced NSCLC when used in addition to chemotherapy and thoracic radiation. Unlike the 
strategies employed before, we prefer to use targeted therapy (erlotinib or crizotinib) only in the 
induction phase in a carefully selected group of patients with locally advanced NSCLC whose 
tumors have known “sensitive” mutations in the EGFR TK domain (for erlotinib) or EML4-ALK 
fusion rearrangement (for crizotinib). The induction therapy will be followed by concurrent 
chemoradiation. We do not plan to use molecularly targeted therapy following chemoradiation in 
light of the discouraging data from SWOG 0023, even though the SWOG 0023 involved the use 
of gefitinib in a broad group of patients with locally advanced NSCLC without any molecular 
selection. 
 
1.2  
Why This Study Is Important  
Even though concurrent chemoradiation improves overall survival in patients with locally 
advanced NSCLC compared to sequential chemotherapy followed by radiation or thoracic 
radiation alone, more than 70% would die from recurrent disease. There is a significant need to 
improve the outcomes in patients with locally advanced NSCLC. 
 
Nearly 10% of all patients with NSCLC diagnosed in the western hemisphere have mutations in 
the EGFR TK domain. The proportion of patients with EGFR TK mutation increases dramatically 
to 30%-50% in a group of patients with Asian ethnicity and in those who report no history of 
tobacco smoking.  EGFR TK mutation positive NSCLC perhaps represents the most common 
molecularly defined subset of NSCLC. EGFR TK inhibitors produce striking response rates (70%-
90%) and progression-free survival (12-13 months) in metastatic NSCLC in this subset. Even by 
conservative estimates, these numbers represent a 2 to 3-fold improvement over chemotherapy 
alone. Use of EGFR TK inhibitors in a selected group of patients with molecularly vulnerable 
disease has a high likelihood of improving the outcomes. Moreover, there is extensive experience 
with regard to the safety and tolerability in advanced disease setting alone, in combination with 
chemotherapy and in combination with thoracic radiation. ALK fusion gene is present in 3-4% of 
all patients with NSCLC but probably ~10% in adenocarcinoma of the lung, roughly at the same 
prevalence rate as EGFR TK mutations. More importantly, the very same group of individuals 
(adenocarcinoma, light or never smokers) is likely to have one or the other molecular changes we 
are seeking for this study.  
 
Eligible patients for the proposed study include those with non-squamous NSCLC with EGFR TK 
mutations or EML4- ALK fusion gene product. Each enrolling institution is responsible for the 
biomarker screening, which must be done at a CLIA certified laboratory.  
 
If the proposed study meets its primary endpoints, this study itself would likely change the 
practice patterns. It is highly unlikely that another larger phase III study would be feasible in 
molecularly defined locally advanced NSCLC. Patients with local-regionally advanced NSCLC will 
be routinely screened for the presence of EGFR TK mutations (just as patients with breast cancer 


 
15  
RTOG 1306, Version Date July 25, 2017 
 
are screened for the presence of her-2 overexpression/amplification) and EML4-ALK fusion gene. 
Individualized therapy would then become the standard of care for patients with stage III NSCLC. 
Moreover, this study would provide the template for integration of emerging novel therapies for a 
molecularly defined subset of patients early in the drug development and early in the disease 
process, significantly enhancing the prospect of cure. It is worth keeping in mind that targeted 
therapies have not cured a single patient with NSCLC to date. It is critical that we develop rational 
approaches to cure more patients in early and locally advanced NSCLC with the use of 
molecularly targeted therapies. 
 
If the proposed study fails to meet its study objectives, cytotoxic chemotherapy will continue to be 
the standard of care even for patients with locally advanced NSCLC, despite having EGFR TK 
mutations or ALK fusion gene. Like all well-designed prospective multi-center trials, a negative 
outcome from this study at least will put to rest the idea that use of targeted therapies will improve 
survival even in this carefully selected molecularly defined subset. Empiric use of available 
agents such as EGFR TK inhibitors or ALK inhibitors even in molecularly selected patients could 
then be strongly discouraged in locally advanced NSCLC. 
 
1.3  
Previous Studies  
Erlotinib improves overall survival modestly in patients with advanced NSCLC (not based on 
EGFR mutation status) who have had progressive disease following platinum based 
chemotherapy (Shepherd 2005). Gefitinib, another EGFR TK inhibitor, has been shown to be 
non-inferior to docetaxel (an approved agent) in the second line therapy of NSCLC (Kim 2008). 
Gefitinib produces better progression-free survival over paclitaxel and carboplatin in patients with 
metastatic previously untreated NSCLC from Asia with no or limited history of tobacco smoking 
(Mok 2009). Specifically, the improvement is striking and significant only in those with EGFR TK 
mutation NSCLC. Similar results of striking benefit in EGFR TK mutation NSCLC have been 
reported from other studies (Cappuzzo 2010).  
 
CALGB 30106 studied the role of induction therapy with gefitinib, paclitaxel, and carboplatin 
followed by concurrent therapy with thoracic radiation with either gefitinib alone (stratum 1, poor 
risk group) or gefitinib and weekly paclitaxel, carboplatin (stratum 2, good risk group) (Ready 
2010). The median overall survival in the “good- risk” (stratum 2) group was a disappointing 13 
months, though surprisingly, was much better in the “poor-risk” group with a median overall 
survival of 19 months. Of the 45 specimens adequate for EGFR and KRAS mutation analysis, 13 
(29%) tumors had EGFR-activating mutations. Two of the tumors with L858R mutations also had 
T790M mutations that are known to confer resistance to gefitinib. Tumors with an EGFR gefitinib 
sensitive mutation without a resistance mutation were balanced between the 2 strata with five in 
poor-risk stratum 1 and six in good-risk stratum 2. The median overall survival was 5.7 months for 
exon 19 deletions and 28.4 months for exon 21 L858R mutations. These results have to be 
interpreted with caution given the extremely small numbers and the use of gefitinib in combination 
with chemotherapy in the “good- risk” group (stratum 2). 
 
Maintenance therapy with gefitinib following concurrent chemoradiation with cisplatin, etoposide, 
and consolidation docetaxel produced markedly inferior overall survival and a correspondingly 
decreased progression- free survival compared with placebo in molecularly unselected group of 
patients with locally advanced NSCLC in the SWOG study (Kelly 2008). 
 
RTOG 94-10 was the largest phase III trial from North America that compared sequential versus 
concurrent chemoradiation. The RTOG reported the results of this 3-arm trial that included 611 
patients. This trial demonstrated the superior outcome of concurrent chemoradiation therapy 
(Curran 2011).  Belani, Choy, and others explored the weekly paclitaxel and carboplatin in locally 
advanced NSCLC. (Belani 2005, Movsas 2005). The median survival ranges from 16.3 to 17.9 
months, which was comparable to other regimens. The toxicity was reasonable. 
 
Physicians will be allowed to choose either of the 2 most commonly used chemotherapeutic 
regimens in stage III NSCLC:  cisplatin and etoposide for 2 cycles concurrent with radiation or 


 
16  
RTOG 1306, Version Date July 25, 2017 
 
weekly doses of paclitaxel and carboplatin during radiation therapy followed by 2 additional cycles 
of consolidation therapy with paclitaxel and carboplatin administered every 3 weeks. 
 
1.4 
Translational Research (6/26/15) 
Paired frozen tumor tissue or formalin fixed paraffin embedded tissue and peripheral blood will be 
obtained from consenting patients in order to obtain genomic DNA. With the limited numbers of 
samples, it may not be possible to obtain enough high quality material from all the enrolled 
patients. Therefore, this correlative component should be viewed as an exploratory analysis. DNA 
will be subjected to custom array capture for targets representing all human tyrosine kinase 
exons and a subset of associated effector/modulator proteins downstream of EGFR activation 
pathway and those related to the fusion kinase activity conferred by novel EML4 ALK 
translocation.  Deep (> 200X coverage) re-sequencing will be performed to generate quantitative 
read counts of both high- and low-frequency somatic mutations among the targeted exons in 
each patient sample pair. The objective of the correlative study is to assess the feasibility of 
performing deep sequencing of selected kinomes in patients from whom adequate amount of 
tissue would be available. Identified genomic alterations (SNVs, InDels, and rearrangements) will 
be correlated response to therapy.   
 
Lung cancer is molecularly more complex than had been realized previously. Comprehensive 
sequencing efforts in lung cancer to date have reviewed a diversity of relatively low frequency 
mutations that may, nonetheless, have biological relevance. Of all the known genetic aberrations, 
EGFR mutations and ALK rearrangements are clinically highly significant and are targets for 
therapy. While the presence of these markers (EGFR TK mutation and ALK fusion) predict for 
response to some extent, more work needs to be done to identify mechanisms of both intrinsic 
and acquired resistance. Multiple (as yet undiscovered) genomic alterations may collectively 
contribute to the therapeutic response and survival. Identification secondary alterations in the 
same or other pathways is now known to contribute to therapeutic resistance to some extent in 
relation to EGFR TK inhibitors, though much less is known about the genomic evolution in 
relation to EML4 ALK inhibitors. Finally, because of intrinsic tumor cell heterogeneity and multi-
clonality, the “dosage” of a specific mutation, rather than simply its presence or absence in an 
undefined percentage of the cell population, may drive the magnitude of the therapeutic response 
and overall clinical outcome. 
 
Accordingly, we hypothesize that “deep” and quantitative re-sequencing of a selected set of 
genes in lung cancer will better define biomarkers that would more reliable predict response to 
existing therapies (such as erlotinib and crizotinib) and identify novel targets for future therapy. To 
test this hypothesis, we will combine array-based target capture and Illumina sequencing of the 
receptor tyrosine kinome (including EGFR) and the critical genes in the downstream pathways. 
Sequencing will be performed on patient-matched tumor and non-malignant DNAs for at least 
200X coverage to generate quantitative and sensitive data (“deep” read counts) to detect 
mutations that may occur in subpopulations of tumor cells. Samples will be bar-coded to allow 
multiplexed resequencing of samples, both to decrease cost and increase throughput of the 
analysis, with the goal of eventually developing this platform for a prospectively conducted ‘real-
time’ assay in subsequent integrated biomarker trials. As compared to more comprehensive 
whole exome or whole genome studies, this approach will allow us to perform “deeper” (more 
sensitive) sequencing of at least potentially actionable and thus, more clinically relevant gene 
targets on a larger number of cases. The relatively lower complexity of sequence data also will 
allow us to barcode and multiplex samples (lower assay cost) and more rapidly identify and 
validate true genomic alterations in independent tumor cohorts. Based on the data generated, we 
will be able to address whether alterations in the tyrosine kinome (in addition to or instead of the 
specific EGFR analyzed in the primary trial) contribute to therapeutic response and overall 
outcome. 
 


 
17  
RTOG 1306, Version Date July 25, 2017 
 
2.0 OBJECTIVES 
2.1 
Primary Objective 
2.1.1 
To assess whether patients with unresectable local-regionally advanced NSCLC treated with 
targeted agents based on molecular characteristics have a longer progression-free survival than 
those treated with standard care therapy alone 
 
2.2 
Secondary Objectives 
2.2.1 
To evaluate response rate; 
2.2.2 
To assess toxicity; 
2.2.3 
To assess overall survival; 
2.2.4 
To correlate clinical outcomes with tumor molecular aberrations identified from deep sequencing 
of selected kinomes in patients from whom adequate baseline tissue is available. 
 
3.0  
PATIENT SELECTION (5/29/14) 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED.  For 
questions concerning eligibility, please contact the study data manager. 
 
3.1 
Conditions for Patient Eligibility (6/26/15) 
3.1.1 
Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC;  
3.1.2 
Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 
disease. Patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, 
EBUS-TBNA, EUS, or VATS. 
3.1.3 
Patients with any T with N2 or N3 are eligible. Patients with T3, N1-N3 disease are eligible if 
deemed unresectable. Patients with T4, any N are eligible. 
3.1.4 
Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 
1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum 
size of 10 mm by CT scan (CT scan slice thickness no greater than 5 mm).  
3.1.5 
Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are 
eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field 
of radiotherapy. 
3.1.6 
If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, 
the patient will be eligible. Patients who develop a new pleural effusion after thoracotomy or other 
invasive thoracic procedure will be eligible. 
3.1.7 
The institution’s pre-enrollment biomarker screening at a CLIA certified lab documents presence 
 
of known “sensitive” mutations in EGFR TK domain (exon 19 deletion, L858) and/or EML4-
 
ALK fusion arrangement. Either the primary tumor or the metastatic lymph node tissue may be 
used  
for testing of mutations. 
3.1.8 
The institution’s pre-enrollment biomarker screening at a CLIA certified lab documents absence of 
 
T790M  mutation in the EGFR TK domain; 
3.1.9 
Appropriate stage for protocol entry, including no distant metastases, based upon the following 
 
minimum diagnostic workup: 
• 
History/physical examination, including recording of pulse, BP, weight, and body surface 
area, within 45 days prior to registration; 
• 
Whole body FDG-PET/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT 
must be negative for distant metastasis.  
• 
CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless 
medically contraindicated) within 30 days prior to registration; 
• 
MRI of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) 
within 30 days prior to registration. 
3.1.10 Zubrod Performance Status 0-1 within 14 days prior to registration; 
3.1.11 Age ≥ 18; 
3.1.12 CBC/differential obtained within 14 days prior to registration, with adequate bone marrow function 
defined as follows: 
• 
Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3;  
• 
Platelets ≥ 100,000 cells/mm3;  


 
18  
RTOG 1306, Version Date July 25, 2017 
 
• 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 
8.0 g/dl is acceptable.); 
3.1.13 Adequate renal and hepatic function, defined as follows: 
• 
Serum creatinine < 1.5 mg/dL or Calculated Creatinine Clearance ≥ 50 ml/min (by Cockroft-
Gault formula) within 14 days prior to registration; 
• 
AST/ALT ≤ 2.5 X ULN within 14 days prior to registration; 
• 
Bilirubin within normal institutional limits within 14 days prior to registration 
3.1.14 Negative serum pregnancy test within 14 days prior to registration for women of childbearing 
potential; 
3.1.15 Patient must provide study specific informed consent prior to study entry, including consent for 
mandatory screening of tissue. 
 
3.2 
Conditions for Patient Ineligibility (5/29/14) 
3.2.1 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a 
minimum of 730 days [2 years] (For example, carcinoma in situ of the breast, oral cavity, or cervix 
are all permissible); 
3.2.2 
Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different 
cancer is allowable;   
3.2.3 
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields; 
3.2.4 
Atelectasis of the entire lung; 
3.2.5 
Contralateral hilar node involvement;  
3.2.6 
Exudative, bloody, or cytologically malignant effusions; 
3.2.7 
Severe, active co-morbidity, defined as follows: 
• 
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 
months; 
• 
Transmural myocardial infarction within the last 6 months; 
• 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 
• 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration; 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; 
• 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, 
however, that HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because the treatments involved in this 
protocol may be significantly immunosuppressive.  Protocol-specific requirements may also 
exclude immuno-compromised patients. 
3.2.8 
Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception; this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic.  
3.2.9 
Prior allergic reaction to the study drug(s) involved in this protocol. 
 
 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT 
NOTE: This section lists baseline evaluations needed before the initiation of protocol treatment 
that do not affect eligibility. 
 
4.1 
Highly Recommended Evaluations/Management 
Note that these evaluations/interventions are highly recommended as part of good clinical care of 
patients on this trial but are not required.   
4.1.1 
Comprehensive pulmonary consultation and pulmonary function testing, including spirometry and 
diffusing capacity of carbon monoxide within 56 days prior to start of treatment; 
4.1.2 
EKG and/or echocardiogram within 56 days prior to start of treatment; 
4.1.3 
Quantitative lung ventilation/perfusion scan +/- CT scan within 56 days prior to start of treatment; 


 
19  
RTOG 1306, Version Date July 25, 2017 
 
4.1.4 
Nutritional assessment, including evaluation of the need for prophylactic gastrostomy tube 
placement (if the patient is ≥ 10% below ideal body weight or is unable to swallow pills) within 56 
days prior to start of treatment.  
 
5.0 REGISTRATION PROCEDURES (5/29/14) 
Access Requirements for OPEN, Rave, and TRIAD 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM account. 
This is the same account (user id and password) used for the CTSU members' web site. To 
obtain an active CTEP-IAM account, go to https://eapps-ctep.nci.nih.gov/iam. 
 
See Section 5.2 for information on installing TRIAD for submission of digital RT data prior 
to enrolling patients. 
5.1 
Phantom Irradiation for IMRT (5/29/14) 
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. The Imaging and Radiation Oncology Core (IROC) Houston QA Center 
(formerly the Radiological Physics Center [RPC]) will be the entity to notify your institution when 
all credentialing requirements have been met and the institution is RT credentialed to enter 
patients onto this study.   
 
 
RT Credentialing 
Requirements 
 
Web 
Link 
for 
Procedures 
and 
Instructions:  
http://irochouston.mdanderson.org   
 
Treatment 
Modality 
Key Information 
 
Photons 
  
Facility Questionnaire 
✓ 
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. 
Credentialing Status 
inquiry form 
✓ 
To determine whether your institution needs to complete any 
further credentialing requirements, please complete the 
“Credentialing Status Inquiry Form” found under credentialing 
on the IROC Houston web site, 
http://irochouston.mdanderson.org 
Phantom Irradiation 
 ✓ 
An IMRT phantom study provided by IROC Houston must be 
successfully completed. Instructions for requesting and 
irradiating the phantom are found on the IROC Houston web 
site,  http://irochouston.mdanderson.org. Note that only the 
most sophisticated technique needs to be credentialed, e.g., 
if credentialed for IMRT, 3DCRT may be used. 
Credentialing Notification 
IROC Houston will notify the institution and NRG Oncology 
that all desired requirements have been met. 


 
20  
RTOG 1306, Version Date July 25, 2017 
 
5.2 
Digital RT Data Submission Using TRIAD (5/29/14) 
  
TRIAD is the American College of Radiology’s (ACR’s) image exchange application, and 
it is used by the NRG Oncology. TRIAD provides sites participating in NRG Oncology 
clinical trials a secure method to transmit DICOM RT and other objects.  TRIAD 
anonymizes and validates the images as they are transferred. 
 
TRIAD Access Requirements 
• 
Site physics staff who will submit images through TRIAD will need to be registered with The 
Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and 
Access Management (IAM) account. Please refer to Section 5.0 of the protocol for 
instructions on how to request a CTEP-IAM account. 
• 
To submit images, the site physics user must have been assigned the 'TRIAD site user' role 
on the relevant NCI National Clinical Trial Network. Users should contact your site Lead RA 
to be added to your site roster. Users from other cooperative groups should follow their 
procedures for assignment of roster roles. 
• 
RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations 
When a user applies for a CTEP-IAM account with proper user role, he/she will 
need to have the TRIAD application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be found on the NRG 
Oncology/RTOG web site Core lab tab.    
 
This process can be done in parallel to obtaining your CTEP IAM account username and 
password. 
 
If you have any questions regarding this information, please send an e-mail to the TRIAD 
Support mailbox at TRIAD-Support@acr.org. 
 
5.3  
Regulatory Pre-Registration Requirements (6/24/14) 
5.3.1 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Prior to the recruitment of a patient for this study, investigators must be registered members of a 
lead protocol organization.  Each investigator must have an NCI investigator number and must 
maintain an “active” investigator registration status through the annual submission of a complete 
investigator registration packet (FDA Form 1572 with original signature, current CV, 
Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original 
signature) to the Pharmaceutical Management Branch (PMB), CTEP, DCTD, NCI. These forms 
are 
available 
on 
the 
CTSU 
web 
site: 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. For questions, please 
contact the CTEP Investigator Registration Help Desk by e-mail at pmbregpend@ctep.nci.nih.gov  
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-IAM application to 
register (both initial registration and annual re-registration) with CTEP and to obtain a user 
account. Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) An active 
CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support 
Unit) websites and applications, including the CTSU members’ web site. Additional information 
can 
be 
found 
on 
the 
CTEP 
web 
site 
at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  For questions, please contact 
the CTEP Associate Registration Help Desk by email at ctepreghelp@ctep.nci.nih.gov. 


 
21  
RTOG 1306, Version Date July 25, 2017 
 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can enroll patients. Study centers can check the status of their registration packets by 
querying the Regulatory Support System (RSS) site registration status page of the CTSU 
member web site by entering credentials at https://www.ctsu.org . For sites under the CIRB 
initiative, IRB data will automatically load to RSS. 
 
Site registration forms may be downloaded from the RTOG-1306 protocol page located on the 
CTSU members’ web site.  Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the (state organization type e.g. P2C, CITN, NCTN Groupname) link to expand, then 
select trial protocol, RTOG-1306 
• 
Click on the Site Registration Documents link 
 
Requirements for RTOG-1306 site registration: 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
• 
CTSU RT Facilities Inventory Form (if applicable) 
NOTE: Per NCI policy, all institutions that participate on protocols with a radiation therapy 
component must participate in the IROC Houston monitoring program.  If this form has been 
previously submitted to CTSU, it does not need to be resubmitted unless updates have occurred 
at the RT facility. 
• 
IRB/REB approval letter  
• 
IRB/REB approved consent (English version)  
• 
IRB/REB assurance number renewal information, as appropriate 
• 
See the additional pre-registration requirements in Sections 5.1 and 5.2. 
5.3.2 
Pre-Registration Requirements for the Initial Shipment of Crizotinib  
 
All pre-registration requirements must be met before registering the first case. Institutions must 
electronically complete (versus hand write) a Study Agent Shipment Form (SASF) available on 
the NRG Oncology/RTOG web site, www.rtog.org, under protocol-specific materials/regulatory 
resources. Institutions must fax the SASF to the CTSU Regulatory Office (Fax 215-569-0206) as 
soon as the individual responsible for the study agent has been identified. The completed SASF 
document also may be e-mailed to the CTSU at CTSURegulatory@ctsu.coccg.org. 
 
5.4 
Registration (6/26/15) 
 
All patients must consent to screening of tissue for EGFR mutation analysis and ALK fusion 
arrangement at a CLIA certified laboratory. Only patients with EGFR TK mutation or EML4-ALK 
fusion arrangement will be enrolled. All patients can be registered after completing the Eligibility 
Checklist via online registration; see the text below for online registration instructions. 
5.4.1  
OPEN Registration Instructions 
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.   
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). 
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
< 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. See Section 5.0 for obtaining a CTEP-IAM account. All site staff will use 
OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise System for 
regulatory and roster data and, upon enrollment, initializes the patient position in the Rave 
database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ web site https://www.ctsu.org. 


 
22  
RTOG 1306, Version Date July 25, 2017 
 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. Site staff should 
use the registration forms provided on the group or CTSU web site as a tool to verify 
eligibility. 
• 
All patients have signed an appropriate consent form and HIPPA authorization form (if 
applicable).  
 
The OPEN system will provide the site with a printable confirmation of registration and treatment 
information.  Please print this confirmation for your records.  
 
Further instructional information is provided on the CTSU members' web site OPEN tab or within 
the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
In the event that the OPEN system is not accessible, participating sites can contact web support 
for assistance with web registration: websupport@acr.org or call the Registration Desk, at (215) 
574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax 
in the eligibility checklist and will need the registering individual’s e-mail address and/or return fax 
number. This information is required to assure that mechanisms usually triggered by the OPEN 
web registration system (e.g. drug shipment and confirmation of registration) will occur.  
 
6.0  
RADIATION THERAPY (5/29/14) 
 
See Section 5.2 for information on installing TRIAD for submission of digital RT data prior 
to enrolling patients. 
 
 
NOTE: FOR THIS STUDY, EITHER IMRT OR 3D-CRT IS REQUIRED.   
 
 
The use of IGRT is highly encouraged but not required. No margin reduction will be 
allowed whether IGRT is used or not, and separate IGRT credentialing will not be required. 
 
Institutions must complete the pre-registration credentialing requirements in Sections 5.1 
through 5.3 before registering patients on this study. 
 
Protocol treatment must begin on day 1 of cycle 1 of chemotherapy. 
 
6.1 
Dose Specifications  
6.1.1 
The total dose will be 60 Gy in 30 fractions of 2 Gy. Radiation treatment will be administered 5 
days per week, 1 fraction per day. It is recommended that radiation treatment begin on a Monday, 
Tuesday, Wednesday, or Thursday. There are no field reductions. All fields must be treated daily 
and the entire PTV must be treated daily.  Radiation therapy (RT) commences on day 1 of 
chemotherapy. On days when chemotherapy is given concurrently with RT, chemotherapy should 
be administered prior to RT. 
6.1.2 
The treatment plan will be normalized such that 95% of the PTV is covered by the prescription 
dose. No more than 0.03 cc of the PTV may receive > 120% of the prescription dose (maximum 
dose constraint). The maximum and minimum doses within the PTV (defined as the minimum 
dose to the hottest 0.03 cc volume and the maximum dose to the coldest 0.03 cc volume, 
respectively) will be reported.   
 
6.2 
Technical Factors/Treatment Planning (5/29/14) 
6.2.1 
Beam Energy:  6 - 10 MV will be used.  
6.2.2 
Beam Shaping:  Multi-leaf collimation (MLC) or individually-shaped divergent custom blocks will 
be used to spare normal tissues outside of the target volume. 
6.2.3 
3D Conformal Radiation Therapy (3D-CRT) or Intensity-Modulated Radiation Therapy (IMRT): 
The PTV is to be treated with any combination of coplanar or noncoplanar fields optimized to 
deliver the specified dose while restricting the dose to the normal tissues. Each field is to be 
treated daily with no revisions throughout the course of treatment. See Section 5.2 for details of 


 
23  
RTOG 1306, Version Date July 25, 2017 
 
3D-CRT credentialing. IMRT is allowed as long as the participating institution is credentialed for 
intra-thoracic IMRT treatments. See Section 5.1 for details of IMRT credentialing. 
6.2.4 
Heterogeneity Corrections: All radiation doses will be calculated with heterogeneity corrections 
that take into account the density differences within the irradiated volume (e.g., air, soft tissue, or 
bone). The acceptable heterogeneity correction dose calculation algorithms can be found on the 
IROC Houston web site at http://irochouston.mdanderson.org. Non-validated dose calculation 
algorithms (e.g. Clarkson or pencil beam) will not be allowed for this study. Dose calculations 
should be performed on a non-contrast enhanced CT. Alternatively, if calculations are performed 
on a contrast-enhanced scan, areas of contrast enhancement adjacent to the target volumes or 
nearby critical structures should be over-ridden with soft tissue density. 
 
6.3 
Localization, Simulation, and Immobilization (6/26/15) 
6.3.1 
Immobilization to assure reproducibility of the setup is necessary. Each patient will be positioned 
in an immobilization device in the treatment position on a flat table. 
6.3.2 
A volumetric treatment planning CT study will be required to define gross tumor volume (GTV), 
clinical target volume (CTV), and planning target volume (PTV)(see definitions below).  
Contiguous CT slices, having no more than 3 mm thickness through the regions harboring gross 
tumor and grossly enlarged lymph nodes and no more than 10 mm thickness of the remaining 
regions are to be obtained starting from the level of the cricoid cartilage and extending inferiorly 
through the entire liver volume.  The GTV, CTV, and PTV and normal organs will be outlined on 
all appropriate CT slices. 
6.3.3 
A treatment planning FDG PET/CT scan (or FDG-PET alone) with the patient in the treatment 
position is encouraged for treatment planning.  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.   
6.3.4 
Intravenous (i.v.) contrast during the planning CT is optional provided a diagnostic chest CT was 
done with contrast to delineate the major blood vessels.  If not, i.v. contrast should be given 
during the planning CT. If contrast is used, the densities can be over-ridden or the contrast scan 
must be registered to a non-contrast scan for planning purposes. 
6.3.5 
The use of four-dimensional radiation treatment planning is highly encouraged.  Acceptable 
methods of accounting for tumor motion include:  design of the PTV to cover the excursion of the 
primary and involved nodal CTV during free breathing (motion inclusive), or the more limited 
excursion during a voluntary or automatic breath-hold (e.g., Elekta ABC device) or a gating 
approach (e.g., Varian RPM system) 
 
6.4 
Target Volumes/Motion Management Target Volumes (5/29/14) 
 
Note: All required structures must be labeled as listed below in Table 6.5.6 for digital RT 
data submission.  Resubmission of data may be required if labeling of structures does not 
conform to the DICOM Standard Name listed. 
6.4.1 
Target Volumes: The definitions of volumes will be in accordance with the 1993 ICRU Report 
#62. 
• 
Definition of the GTV:  The primary tumor and clinically positive lymph nodes seen either on 
the pretreatment or the planning CT (> 1 cm short axis diameter) or pretreatment PET scan 
(maximum SUV > 3) will constitute the GTV. Pathologically involved nodes not meeting 
radiographic criteria also should be included in the GTV. The volume(s) may be disjointed.  In 
the event of a collapsed lobe or lung segment, the use of PET to distinguish tumor from 
fluid/atelectasis is encouraged.  
 
 
 
For patients on Arms 1 and 3, all initially involved sites as determined on CT and/or PET/CT 
prior to induction therapy will be targeted. At sites of stable disease or partial response to 
induction therapy, the residual disease/radiologic abnormality (primary or nodal) or residual 
nodal tissue will constitute the GTV. At nodal sites of complete response to induction therapy 
with no residual nodal tissue, there will be no GTV but the CTV will be defined as below.  
• 
Definition of the CTV:  The CTV is defined to be the GTV plus a 0.5 cm to 1 cm margin as 
appropriate to account for microscopic tumor extension. However, the CTV should not cross 
natural anatomic barriers to tumor extension such as fissures or fascial planes unless these 


 
24  
RTOG 1306, Version Date July 25, 2017 
 
structures are directly abutted or invaded by the GTV. Elective treatment of the mediastinum 
and supraclavicular fossae will not be done. 
 
 
For patients on Arms 1 and 3, at nodal sites of complete response to induction therapy with 
no residual nodal tissue, the CTV is defined to be the pretreatment GTV plus a 0.5 to 1 cm 
margin, but edited to remain within the anatomic boundaries of the respective nodal stations 
as seen on the post-induction treatment planning scan (ie, should not extend into lung 
parenchyma or mediastinal organs unless originally grossly involved). 
• 
Definition of the PTV:  The internal target volume (ITV) is defined to be the CTV plus an 
internal margin (IM) to account for target/organ motion. The final PTV is defined to be the ITV 
plus a setup margin (SM) to account for patient positioning uncertainty and machine 
tolerance. These margins are determined as described below. 
6.4.2 
Margin Determination Based on Motion Management Approaches 
• 
Free-breathing 3-D CT Planning (i.e. standard CT simulation without 4DCT, fusion of 
inhalation and exhalation scans, or fluoroscopy):  The internal motion (IM margin) will be at 
least 1 cm in the superior-inferior direction, and 0.5 cm in the axial plane. For institutions not 
using 4DCT, the use of fluoroscopy to determine the margin for motion in the inferior-superior 
direction is encouraged. 
• 
Breath-hold or gating 3-D CT Planning: For breath-hold (assisted, such as the Elekta ABC 
device, or voluntary) or gated CT simulation (such as the Varian RPM device), a single 3-D 
CT image will be acquired at a pre-determined respiration level. The IM will be 0.5 cm in the 
superior-inferior direction and 0.3 cm in the axial plane. If this approach is adopted, the 
institution must use breath-hold or respiratory-gated treatment delivery. Treatment delivery 
under free-breathing conditions without gating is not acceptable for this approach. 
• 
Abdominal Compression: 3-D CT planning: If abdominal compression is used during CT 
simulation, the IM will be 0.8 cm in the superior-inferior direction and 0.5 cm in the axial 
plane.  
• 
4-D CT planning: 4-D CT may be employed (ideally with the acquisition additionally of 3-D CT 
images at natural end-inhale and end-exhale). The ITV is the union of the CTV volumes 
(primary tumor and nodes) contoured on each component 3-D CT data set from the 4-D CT 
acquisition to form the envelope that encompasses the motion of the CTV for a complete 
respiratory cycle. The portion of the ITV corresponding to tumors completely surrounded by 
lung parenchyma may be formed by first contouring the maximum intensity projection (MIP) 
of the GTV, then applying the GTV to CTV margin expansion as described above in 
“Definition of the CTV”. 
• 
Setup Margin (SM): The SM will be 0.5 cm in all directions. No margin reduction will be 
allowed, even when using IGRT. The final PTV is constructed by expanding the ITV (CTV + 
IM) by the SM. 
 
 
 


 
25  
RTOG 1306, Version Date July 25, 2017 
 
Table 6.4.2: PTV Margin Summary (see above for detailed descriptions) 
 
Motion 
management 
Internal margin (cm) 
Setup margin 
(cm, uniform) 
Total PTV margin (cm) 
Sup-Inf 
Axial 
Sup-inf 
Axial 
Free 
breathing 
1 
0.5 
0.5 
1.5 
1 
Breath hold or 
gating 
0.5 
0.3 
0.5 
1 
0.8 
Abdominal 
compression 
0.8 
0.5 
0.5 
1.3 
1 
4D CT 
Union of CTVs 
Union of CTVs 
0.5 
Union of CTVs 
+ 0.5 cm 
Union of CTVs 
+ 0.5 cm 
 
 
6.5 
Critical Structures (7/29/13) 
 
Note: All required structures must be labeled as listed below in Table 6.5.6 for digital RT 
data submission.  Resubmission of data may be required if labeling of structures does not 
conform to the DICOM standard name listed. 
 
Normal tissue constraints shall be prioritized in the following order for treatment planning:  
1=spinal cord, 2=lungs, 3=esophagus, 4=brachial plexus, and 5=heart. Critical structures should 
be 
contoured 
according 
to 
the 
lung 
contouring 
atlas 
(available 
at 
http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx). 
6.5.1 
Spinal Cord: The spinal cord should be contoured based on the bony limits of the spinal canal 
from the top of C1 to the bottom of L2. The spinal cord dose limit is the highest priority dose 
constraint and thus must be met irrespective of other constraints. No more than 0.03 cc of the 
spinal cord may receive greater than 50.5 Gy total dose (“direct” plus “scatter” dose). 
6.5.2 
Lungs: The total lung volume is defined as the sum of the volume of both lungs minus the GTV. 
The dose-volume constraint to the lungs is the second highest priority and must be met, except if 
it conflicts with the cord dose constraints.  The proportion of total lung volume that receives more 
than 20 Gy (V20) should not exceed 37%.  Additionally, the mean lung dose should not exceed 
20 Gy.     
 
 
If either of these constraints is exceeded, for the 3D-CRT cases, one might increase the 
weighting of any AP/PA fields  and reduce any oblique fields. This can be done as long as the 
cord dose (above), which takes precedence, is not exceeded. For 3D-CRT or IMRT cases, one 
can reduce the CTV to the minimum range suggested above especially near the spinal cord.  
6.5.3 
Esophagus: The esophagus contour should include the mucosal, submucosa, and all muscular 
layers out to the fatty adventitia, from the bottom of the cricoid cartilage to the gastroesophageal 
junction. No more than 0.03 cc of the esophagus may receive > 63 Gy. The mean dose to the 
esophagus should be ≤ 34 Gy. The esophagus should not be circumferentially irradiated with > 
60 Gy (i.e., the 60 Gy isodose line should not encompass the entire axial cross-section of the 
esophagus at any level). The V60 (% volume of esophagus exceeding 60 Gy) should be 
calculated for each patient. 
6.5.4 
Brachial Plexus: The ipsilateral brachial plexus should be contoured for upper lobe tumors. No 
more than 0.03 cc of the brachial plexus may receive > 63 Gy.  
6.5.5 
Heart: The heart and pericardium should be contoured together from the base to the apex of the 
heart. The following limits are recommended:  V60 to <1/3, V45 to <2/3, and V40 to <100% of the 
heart. 
 
 


 
26  
RTOG 1306, Version Date July 25, 2017 
 
6.5.6 
DICOM Standard Names for Required Structures for Digital RT Data Submission (5/29/14) 
All required RT structures must be labeled using the DICOM Standard Name shown in the table 
below and submitted digitally.  
 
Table 6.5.6 
Structure 
DICOM Standard Name 
 
Gross Tumor Volume 
GTV 
Not required if complete response 
to induction therapy with no 
residual nodal tissue for patients 
on Arms 1 or 3. See Section 6.4.1 
for details 
Clinical Target Volume 
CTV 
  
Internal Target Volume 
ITV 
IM = internal margin 
SM = setup margin 
Planning Target Volume 
PTV_6000 
 
Right Lung 
Lung_R 
 
Left Lung 
Lung_L 
 
Spinal Cord 
SpinalCord 
 
Lungs  
Lungs 
Both Lungs minus GTV 
Esophagus 
Esophagus 
 
Brachial Plexus 
BrachialPlexus 
 
Heart 
Heart 
 
 
6.6 
Documentation Requirements (7/29/13) 
Portal image of each field of 3-D radiotherapy or orthogonal images that localize the isocenter 
placement for IMRT must be obtained on the first day of therapy but should not be submitted 
6.6.1  
Weekly verification or orthogonal isocenter images are required to be taken, but not submitted. 
This verification information also can be gathered with cone-beam CT or other CT devices that 
are present in the treatment room. 
6.6.2  
Isodose plans and DVHs of GTV, CTVs, PTVs, and critical normal structures for IMRT. 
6.6.3 
The “RTOG 1306 Datasheet” is available in the Forms section of the of the NRG Oncology/RTOG 
web site, http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1306. 
 
 
Sites will record dose-volume values for all required structures on this datasheet. The datasheet 
must be completed and submitted with the digital RT data via TRIAD for review. 
 
6.7 
Compliance Criteria (6/26/15) 
6.7.1 
Variations of Dose Prescription: 
• 
Per Protocol: See Section 6.1.  
• 
Variation Acceptable: Variations of this magnitude are acceptable only when the geometrical 
arrangement of the target and critical structures is challenging. Minimum and maximum 
doses are defined using a sampling volume of 0.03 cc as described above in Section 6.1.2. 
➢ PTV: The prescribed dose can cover less than 95% of the PTV provided it covers at least 
90% of the PTV. The minimum dose can fall below 93% of the prescribed dose provided 
it is at least 90% of the prescription dose, if the areas of underdosing are confined to 
regions of overlap with critical structures. The maximum dose within the PTV may exceed 
120% of the prescribed dose provided it is no more than 125% of the prescription dose, 
and the areas exceeding 110% of the prescription dose are confined within the GTV and 
do not overlap with critical structures.  
➢ Spinal cord: Maximum dose ≤ 52 Gy. 
➢ Lungs: V20 ≤ 40%, MLD ≤ 22 Gy (after all strategies described in section 6.5.2 have 
been attempted). 


 
27  
RTOG 1306, Version Date July 25, 2017 
 
➢ Esophagus: Maximum dose ≤ 66 Gy, mean dose ≤ 35 Gy. It is recommended that 
circumferential irradiation to > 60 Gy for no more than 0.5 cm length (e.g., if the CT slice 
spacing is 0.3 cm, the 60 Gy isodose line may encompass the cross-section of the 
esophagus on one slice but not on any adjacent slices.) 
➢ Brachial plexus: Maximum dose ≤ 66 Gy. 
• 
Deviation Unacceptable:  Dose distributions falling in this category are not acceptable, and 
plan modifications should be attempted to improve results. A Deviation Unacceptable occurs 
if any of the Variation Acceptable dose limits stated above are exceeded. Additionally, a 
Deviation Unacceptable is assigned if more than 1 cm3 of tissue outside the PTV receives ≥ 
110% of the prescribed dose.      
 
Table 6.7.1: Summary of Protocol Constraints and Compliance Criteria 
(see Sections 6.1, 6.5, and 6.7.1 for detailed definitions) 
 
Structure 
Metric 
Per protocol 
Variation 
acceptable 
Deviation 
unacceptable 
PTV 
V60Gy 
≥ 95% 
≥ 90% 
< 90% 
 
Min dose (0.03 cc) 
≥ 55.8 Gy (93%) 
≥ 54 Gy (90%) 
< 54 Gy 
 
Max dose (0.03 cc) 
≤ 72 Gy (120%) 
≤ 75 Gy (125%) 
> 75 Gy 
Spinal cord 
Max dose (0.03 cc) 
≤ 50.5 Gy 
≤ 52 Gy 
> 52 Gy 
Lungs 
(minus GTV) 
V20Gy 
≤ 37% 
≤ 40% 
> 40% 
 
Mean dose 
≤ 20 Gy 
≤ 22 Gy 
> 22 Gy 
Esophagus 
Max dose (0.03 cc) 
≤ 63 Gy 
≤ 66 Gy 
> 66 Gy 
 
Mean dose 
≤ 34 Gy 
≤ 35 Gy 
> 35 Gy 
 
 
 
 
 
Brachial plexus 
Max dose (0.03 cc) 
≤ 63 Gy 
≤ 66 Gy 
> 66 Gy 
 
6.7.2 
Missed Treatment Days/Elapsed Days  
• 
Per Protocol: Treatment break (other than holidays, weekends) 0-2 days; treatment duration: 
< 45 days;  
• 
Variation Acceptable:  Treatment break (other than holidays, weekends) 3-7 days; treatment 
duration: 45-51 days;  
• 
Deviation Unacceptable: Treatment break (other than holidays, weekends) >7 days; 
treatment duration: > 51 days. 
 
 
6.8 
R.T. Quality Assurance Reviews (5/29/14) 
The NRG Oncology Radiation Oncologist Co-Chairs, Hak Choy, MD, and Billy W. Loo, MD, PhD, 
will oversee quality assurance RT reviews as complete RT data is received. These case reviews 
will be ongoing and facilitated by IROC Philadelphia RT. The reviews will be performed remotely 
or at RTOG Headquarters.  
 
6.9 
Radiation Therapy Adverse Events 
6.9.1  
Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and esophagitis are 
expected side effects of radiation therapy. Radiation induced myocarditis or transverse myelitis 
rarely occur at doses lower than 50 Gy. Radiographic evidence of radiation change and 
subsequent fibrosis of the lung will occur within lung volume receiving ≥ 20 Gy, usually within the 
first 6 months after initiation of treatment. It is essential to spare as much normal lung as possible 
in order to avoid symptomatic lung injury. 
6.9.2 
Esophagitis 
Esophageal complaints are common with combined modality therapy. Esophagitis does not 
constitute a reason to interrupt or delay radiotherapy or chemotherapy provided oral intake is 
sufficient to maintain hydration. Patients should be advised to avoid alcoholic, acidic, or spicy 
foods or beverages. Viscous Xylocaine, Carafate, or other medications should be used for 
symptomatic relief. Occasionally, narcotics may be required. 


 
28  
RTOG 1306, Version Date July 25, 2017 
 
 
It is not necessary to biopsy acute esophagitis in the first 2 weeks of combined therapy since it 
is rarely due to underlying viral or fungal disease. Acute esophagitis may persist for 4-6 weeks. 
If Grade 4 (CTCAE, v. 4) esophagitis occurs, and a treatment interruption is being considered, 
every effort should be made to limit it to 3 treatment days or less. Patients requiring 
hospitalization because of esophagitis may have their treatment interrupted.  In this event, please 
notify Drs. Choy or Loo. 
 
Esophagitis Grading System (CTCAE, v. 4) 
 
Grade 
Clinical Scenario 
1 
Asymptomatic; clinical or diagnostic observations only; intervention not indicated  
2 
Symptomatic; altered eating/swallowing; oral supplements indicated       
3 
Severely altered eating/swallowing; tube feeding, TPN or hospitalization indicated 
4 
Life-threatening consequences; urgent operative intervention indicated 
5 
Death 
 
Treatment should be interrupted for grade 4 or greater dysphagia or odynophagia. Acute 
esophageal toxicity, which typically can occur within two weeks of the initiation of treatment and 
manifests as dysphagia, odynophagia, reflux symptoms, etc. should be pharmacologically 
managed with the following approach and should be initiated at the first signs or symptoms of 
esophageal toxicity.  Recommended treatments are provided in the table below. 
 
Management of Radiation Esophagitis 
 
1) Ketoconazole 200 mg PO q day OR 
2) Fluconazole 100 mg PO q day until the completion of radiation 
3)    Mixture of: 2% viscous lidocaine: 60 cc 
Mylanta: 30 cc 
sucralfate (1 gm/cc): 10 cc  
Take 15-30 cc PO q3-4 hrs. prn. 
(Contraindications: pts on Dilantin, Cipro, Digoxin) 
4) Ranitidine 150 mg PO BID (or other H2 blocker or a proton pump inhibitor such as 
omeprazole) until the completion of radiation 
5) Grade 4 esophagitis:  hold RT + chemotherapy until grade 2 or less.  We expect a 
significant portion of patients will experience grade 3 esophagitis.   
 
6.10 
Radiation Therapy Adverse Event Reporting  
See Section 7.11 and Section 7.12. 
 
7.0  
DRUG THERAPY (5/29/14) 
Protocol treatment must begin within 2 weeks after registration. 
 
7.1 
Treatment  
All chemotherapy doses will be calculated based on actual body weight. All standard of care 
chemotherapy is administered as per respective institutional guidelines.  All treating physicians 
will need to declare their treatment choice before randomization of patients on the trial.    
 
In the cohorts randomized to induction erlotinib or crizotinib, radiographic imaging for re-staging 
will occur at the 6-week time point of induction therapy. Note: Any patients who have had no 


 
29  
RTOG 1306, Version Date July 25, 2017 
 
response (partial or complete) after 6 weeks of induction targeted agent will immediately proceed 
to chemoradiation. 
7.1.1 
Control Arm for Both Cohorts (Arms 2 and 4) (9/4/13) 
 
 
 
Patients will be treated with the treating physicians’ choice of chemotherapy. The treating 
physician will choose from one of the 2 regimens detailed below and declare the choice prior to 
patient randomization. Chemotherapy will be administered concurrently with thoracic radiation 
beginning on day 1 of cycle 1. Any treatment delays or dose reductions should proceed as per 
institutional guidelines for good medical practice. 
 
Treatment regimen choices are as follows: 
• 
Cisplatin (50 mg/m2) on days 1, 8, 29, and 36 from start of protocol treatment, and etoposide 
(50 mg/m2) on days 1-5 and 29-33 from the start of protocol treatment administered 
intravenously for two 4-week cycles;  
• 
Paclitaxel (50 mg/m2) and carboplatin (AUC-2) on days 1, 8, 15, 22, 29, and 36 from start of 
protocol treatment, intravenously weekly during thoracic radiation for one 6-week cycle. Two 
cycles of consolidation treatment will begin 4-6 weeks after completion of radiation therapy 
with paclitaxel (200 mg/m2) and carboplatin (AUC 6) on days 1 and 22 administered 
intravenously.  
7.1.2 
EGFR TK Mutation Cohort (Arm 1) (9/4/13) 
 
Patients will receive 12 weeks (four 3-week cycles) of induction therapy with oral erlotinib (150 
mg/day) followed by a combination of chemotherapy with thoracic radiation beginning on day 1 of 
cycle 1 of chemotherapy. Erlotinib induction therapy will be completed 2 weeks prior to initiation 
of concurrent chemoradiation. Treating physicians will declare the chemotherapy regimen choice 
prior to randomization.  
 
 
Treating physicians can choose from 2 chemotherapy regimens: 
• 
Cisplatin (50 mg/m2) on days 1,8, 29, and 36 from start of protocol treatment, and etoposide 
(50 mg/m2) on days 1-5 and 29-33  from start of protocol treatment administered 
intravenously for two 4-week cycles;  
• 
Paclitaxel (50 mg/m2) and carboplatin (AUC-2) on days 1, 8, 15, 22, 29, and 36 from start of 
protocol treatment, intravenously weekly during thoracic radiation for one 6-week cycle. Two 
cycles of consolidation treatment will begin 4-6 weeks after completion of radiation therapy 
with paclitaxel (200 mg/m2) and carboplatin (AUC 6) on days 1 and 22 administered 
intravenously.  
7.1.3 
EML4-ALK Fusion Arrangement Cohort (Arm 3) (9/4/13) 
 
Patients will receive 12 weeks (four 3-week cycles) of induction therapy with oral crizotinib (250 
mg twice daily) followed by a combination of chemotherapy with thoracic radiation  beginning on 
day 1 of cycle 1 of chemotherapy. Crizotinib induction therapy will be completed 2 weeks prior to 
initiation of concurrent chemoradiation. Treating physicians will declare the chemotherapy 
regimen choice prior to randomization.   
 
Treating physicians can choose from 2 chemotherapy regimens: 
• 
Cisplatin (50 mg/m2) on days 1, 8, 29, and 36 from start of protocol treatment , and etoposide 
(50 mg/m2) on days 1-5 and 29-33 from start of protocol treatment administered intravenously 
for two 4-week cycles;  
• 
Paclitaxel (50 mg/m2) and carboplatin (AUC-2) on days 1, 8, 15, 22, 29, and 36 from start of 
protocol treatment, intravenously weekly during thoracic radiation for one 6-weekcycle. Two 
cycles of consolidation treatment will begin 4-6 weeks after completion of radiation therapy 
with paclitaxel (200 mg/m2) and carboplatin (AUC 6) on days 1 and 22 administered 
intravenously. 
7.1.4 
In the unlikely event of a patient having both EGFR TK mutation and EML4-ALK fusion 
rearrangement and if they are randomized to experimental therapy, patients will be assigned to 
receive crizotinib induction therapy followed by chemoradiation.  


 
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7.2 
Erlotinib (Tarceva®, OSI 774), IND #63383 (11JULY2017) 
To supplement the toxicity information provided in the protocol, investigators must obtain the 
current version of the Investigator Brochure for comprehensive pharmacologic and safety 
information. The Investigator’s Brochure may be obtained from NCI’s Pharmaceutical 
Management Branch (PMB); see Section 7.2.9 below. 
7.2.1 
Erlotinib is an orally active antitumor agent (Tyrosine Kinase inhibitor) developed for the treatment 
of non-small cell lung cancer (NSCLC), pancreatic cancer, and other solid tumors. OSI 
Pharmaceuticals, Inc., Genentech, Inc., and F. Hoffmann-La Roche Ltd are co-developing 
erlotinib globally. In the U.S., erlotinib 150 mg daily is approved for use as maintenance therapy 
in patients with advanced or recurrent NSCLC who have not progressed after 4 cycles of first-line 
platinum-based doublet chemotherapy.  
7.2.2 
How Supplied 
Erlotinib tablets are provided by Astellas Pharma and distributed by the Pharmaceutical 
Management Branch, DCTD/NCI as 25 mg, 100 mg, and 150 mg white film-coated immediate-
release tablets packaged in high-density polyethylene (HDPE) bottles.  Each bottle contains 30 
tablets.  
 
The tablets are round and convex without markings.  The 25 mg tablets are 1/4 inches (6 mm); 
the 100 mg tablets are 11/32 inches (9 mm); and the 150 mg tablets are 13/32 inches (10 mm). 
Erlotinib excipients include lactose monohydrate, hypromellose, hydroxypropyl cellulose, 
magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate 
and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C 
Yellow No. 6 (25 mg only) for product identification. 
 
In 2017 there will be a transition to Erlotinib tablets with a different finished appearance.  The new 
Erlotinib tablets are manufactured to the same specifications, and are packaged in 60 mL HDPE 
bottles.  The tablets are round, with a biconvex face, straight sides, and white film-coated.  Each 
strength will be plain on one side, with print on the opposite side: 
• 
25 mg – “T” and “25” in orange print 
• 
100 mg – “T” and “100” in gray print 
• 
150 mg – “T” and “150” in maroon print 
7.2.3 
Route of Administration  
 
Oral 
7.2.4 
Method of Administration 
• 
Tablets should be taken once daily preferably in the morning with up to 200 mL of water one 
hour before or two hours after food. 
• 
Administration through G-tube: Dissolve the dose in 100 mL of sterile water, and shake it 
vigorously to form a uniform suspension.  Draw suspension into a syringe and administer 
through the G-tube port.  Repeat the transfer until the entire volume has been administered.  
Add small volume (40 mL) of sterile water to the container used to dissolve the tablets.  
Shake the residual suspension, aspirate it into a syringe, and administer.  Repeat this last 
step to ensure the entire dose is administered.  The total volume of delivery/rinse is ~180 mL.  
7.2.5 
Potential Drug Interaction 
Erlotinib is highly protein bound (92% to 95% in humans).  Erlotinib is metabolized primarily via 
CYP3A4 and to a lesser extent by CYP1A2, and the pulmonary isoform CYP1A1.  Dose Erlotinib 
cautiously with agents that are highly protein bound or are metabolized by, or are inhibitors or 
inducers of these enzymes. 
 
Significant interactions with the clearance of other CYP3A4 substrates are unlikely. 
 
CYP Iso-Enzymes Inhibitors/Inducers: 
o 
Potent CYP3A4 or combined CYP3A4/CYP1A2 Inhibitors:  Use alternative drug.  
Alternatively, reduce Erlotinib dose in the event of drug interaction (if permitted by the 
protocol).  


 
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RTOG 1306, Version Date July 25, 2017 
 
o 
Potent CYP3A4 inducers:  Use alternative drug.  If an alternative treatment is 
contraindicated, consider increasing the Erlotinib dose (see Section 7.9.2).   
o 
Potent and moderate CYP1A2 inducers:  concomitant use with Erlotinib should be 
avoided. 
 
Food-drug interaction:  Avoid grapefruit /grapefruit juice (potent CYP3A4) while taking Erlotinib. 
 
Smoking:  Advise smokers to stop smoking while Erlotinib.  Smoking induces CYP1A2 enzymes 
and has been shown to reduce Erlotinib exposure by 50% to 60%. 
 
Anticoagulant:  Concomitant NSAIDs, warfarin or warfarin-derivatives may increase bleeding and 
PT /INR. Dose adjustment may be needed.  
 
Proton Pump Inhibitor:  Erlotinib’s solubility decreases as the pH increases. Co-administration of 
omeprazole with Erlotinib will increase the AUC and Cmax by 46% and 61%, respectively.  
 
H2-antagonist: Avoid concomitant use of Erlotinib with gastric acid reducing agents if possible.  
When ranitidine 300 mg is given with Erlotinib, Erlotinib AUC and Cmax  decrease by 33% and 
54%, respectively.  Increasing the dose of Erlotinib will not compensate the loss of exposure.  
However, if an H2-antagonist receptor is needed, take Erlotinib at least 2 hours before or 10 
hours following the H2-antagonist administration.  Dosing such, Erlotinib loss of exposure is 
minimized to AUC of 15% and Cmax of 17%.   
 
Statins:  The combination of erlotinib and a statin may increase the potential for statin-induced 
myopathy, including rhabdomyolysis, which was observed rarely.  
 
Gastrointestinal perforation:  Concomitant use of anti-angiogenic agents, corticosteroids, NSAIDs, 
and/or taxane-based chemotherapy, or patients with prior medical history with peptic ulcers or 
diverticular disease are at high risk of GI perforation while on erlotinib treatment.  Discontinue 
erlotinib if GI perforation manifests. 
7.2.6 
Storage 
 
Storage:  Store at 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F). 
7.2.7 
Patient Care Implications 
If patient vomits after taking the tablets, readminister the dose only if the tablets can actually be 
seen and counted. 
 
Recommend patients to use sunscreen protection, and wear hat and long sleeve shirts as 
sunlight can exacerbate skin reactions. 
 
Women of childbearing potential must use effective contraception during treatment and for one 
month after the last dose of Erlotinib. 
 
 
 
 
 
7.2.8     Adverse Events (25July2017) 
A comprehensive list of AEs possibly related to erlotinib is provided in the CAEPR.  Additional 
information can also be found in the Investigator’s Brochure.  A few common or serious AEs are 
described below. 
 
Interstitial lung disease (ILD): Cases of ILD-like events, including fatalities, have been reported 
uncommonly in patients receiving erlotinib for treatment of non-small cell lung cancer (NSCLC), 
pancreatic cancer, or other advanced solid tumors.  In pivotal study BR 21, in NSCLC, the 
incidence of serious ILD-like events was 0.8% in each of the placebo and erlotinib arms.  In the 
pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 
2.5% in the erlotinib plus gemcitabine group versus 0.4% in the placebo plus gemcitabine-treated 
group.  The overall incidence in patients treated with erlotinib from all studies (including 
uncontrolled studies and studies with concurrent chemotherapy) is approximately 0.6%.  Some 
examples of reported diagnoses in patients suspected of having ILD-like events include 


 
32  
RTOG 1306, Version Date July 25, 2017 
 
pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, 
interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress 
syndrome, lung infiltration and alveolitis.  These ILD-like events started from a few days to 
several months after initiating erlotinib therapy.  Most of the cases were associated with 
confounding or contributing factors such as concomitant or prior chemotherapy, prior 
radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary 
infections.  In patients who develop acute onset of new and/or progressive unexplained 
pulmonary symptoms, such as dyspnea, cough and fever, erlotinib therapy should be interrupted 
pending diagnostic evaluation.  If ILD is diagnosed, erlotinib should be discontinued and 
appropriate treatment initiated as necessary. 
 
Rash or dermatosis: Rash or dermatosis (grades 1-3) has been reported in many subjects 
(~50%) during the first several days of treatment, although severity diminishes after 4 weeks of 
therapy.  The use of topical agents (i.e., diphenhydramine, corticosteroids) and oral antibiotics 
(tetracycline) has been instituted in some patients with variable results.  In patients with severe 
rash, treatment has been discontinued or the study drug dose reduced.  The etiology of the rash 
is still unknown, but may be related to the mechanism of action of erlotinib.  
 
Diarrhea, dehydration, and electrolyte imbalance: Diarrhea has occurred in patients on 
erlotinib, and moderate or severe diarrhea should be treated with loperamide.  In some cases, 
dose reduction may be necessary.  In the event of severe or persistent diarrhea, nausea, 
anorexia, or vomiting associated with dehydration, erlotinib therapy should be interrupted and 
appropriate measures should be taken to treat the dehydration.  There have been rare reports of 
hypokalemia and renal failure (including fatalities).  Some reports of renal failure were secondary 
to severe dehydration due to diarrhea, vomiting and/or anorexia while others were confounded by 
concomitant chemotherapy.  In more severe or persistent cases of diarrhea, or cases leading to 
dehydration, particularly in groups of patients with aggravating risk factors (concomitant 
medications, symptoms or diseases or other predisposing conditions including advanced age), 
erlotinib therapy should be interrupted and appropriate measures should be taken to intensively 
rehydrate the patients intravenously.  In addition, renal function and serum electrolytes including 
potassium should be monitored in patients at risk of dehydration. 
 
Hepatotoxicity with or without hepatic impairment: Hepatic failure and hepatorenal syndrome 
(including fatal cases) can occur with erlotinib treatment in patients with normal hepatic function; 
the risk of hepatic toxicity is increased in patients with baseline hepatic impairment.  Perform 
periodic liver testing (transaminases, bilirubin, and alkaline phosphatase) during treatment with 
erlotinib.  Increased frequency of monitoring of liver function is required for patients with pre-
existing hepatic impairment or biliary obstruction.  Withhold erlotinib in patients without pre-
existing hepatic impairment for total bilirubin levels >3 x institutional upper limit of normal (ULN) 
or transaminases >5 x ULN.  Withhold erlotinib in patients with pre-existing hepatic impairment or 
biliary obstruction for doubling of bilirubin or tripling of transaminases values over baseline.  
Discontinue erlotinib in patients whose abnormal liver tests meeting the above criteria do not 
improve significantly or resolve within three weeks. 
 
Renal insufficiencies: Cases of hepatorenal syndrome, acute renal failure (including fatalities), 
and renal insufficiency have been reported.  Some were secondary to baseline hepatic 
impairment while others were associated with severe dehydration due to diarrhea, vomiting, 
and/or anorexia, or concurrent chemotherapy use.  In the event of dehydration, particularly in 
patients with contributing risk factors for renal failure (e.g., pre-existing renal disease, medical 
conditions or medications that may lead to renal disease, or other predisposing conditions 
including advanced age), erlotinib therapy should be interrupted and appropriate measures 
should be taken to intensively rehydrate the patient.  Withhold erlotinib in patients developing 
severe renal impairment until renal toxicity is resolved.  Perform periodic monitoring of renal 
function and serum electrolytes during erlotinib treatment. 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
Gastrointestinal perforation: Gastrointestinal perforation (including fatal cases) can occur with 
erlotinib treatment.  Patients receiving concomitant anti-angiogenic agents, corticosteroids, 
NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or 
diverticular disease may be at increased risk of perforation.  Permanently discontinue erlotinib in 
patients who develop gastrointestinal perforation. 
 
Bullous and exfoliative skin disorders: Bullous, blistering, and exfoliative skin conditions, 
including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, which in 
some cases were fatal, can occur with erlotinib treatment.  Discontinue erlotinib treatment if the 
patient develops severe bullous, blistering or exfoliating conditions. 
 
Myocardial infarction/ischemia: In the pancreatic carcinoma trial, six patients (incidence of 
2.1%) in the erlotinib/gemcitabine group developed myocardial infarction/ischemia.  One of these 
patients died due to myocardial infarction.  In comparison, three patients in the 
placebo/gemcitabine group developed myocardial infarction (incidence 1.1%), and one died due 
to myocardial infarction.  The pooled incidence of myocardial infarction/ischemia in the three 
monotherapy lung cancer studies was 0.2% in the erlotinib arms and 0.4% in the control arms. 
 
Cerebrovascular accident: In the pancreatic carcinoma trial, seven patients in the 
erlotinib/gemcitabine group developed cerebrovascular accidents (incidence: 2.5%).  One of 
these was hemorrhagic and was the only fatal event.  In comparison, in the placebo/gemcitabine 
group there were no cerebrovascular accidents.  The pooled incidence of cerebrovascular 
accident in the three monotherapy lung cancer studies was 0.6% in the erlotinib arms and 0.9% in 
the control arms. 
 
Microangiopathic hemolytic anemia with thrombocytopenia: The pooled incidence of 
microangiopathic hemolytic anemia with thrombocytopenia in the three monotherapy lung cancer 
studies was 0% in the erlotinib arms and 0.1% in the control arms.  The incidence of 
microangiopathic hemolytic anemia with thrombocytopenia in the pancreatic cancer study was 
1.4% in the erlotinib plus gemcitabine arm and 0% in the control arm. 
 
Ocular disorders: Corneal perforation or ulceration can occur with erlotinib treatment.  Other 
ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have 
been observed with erlotinib treatment and are known risk factors for corneal 
ulceration/perforation.  Interrupt or discontinue erlotinib therapy if patients present with 
acute/worsening ocular disorders such as eye pain. 
 
Embryo-fetal toxicity: Based on its mechanism of action, erlotinib can cause fetal harm when 
administered to a pregnant woman.  When given during organogenesis, erlotinib administration 
resulted in embryo-fetal lethality and abortion in rabbits at doses approximately 3 times the 
recommended human daily dose of 150 mg.  If erlotinib is used during pregnancy, or if the patient 
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to 
a fetus.  Advise females of reproductive potential to use highly effective contraception during 
therapy, and for at least 2 weeks after the last dose of erlotinib.  Advise patients to contact their 
healthcare provider if they become pregnant, or if pregnancy is suspected, while taking erlotinib. 
 
Women of childbearing potential must use effective contraception during treatment and for one 
month after the last dose of Erlotinib. 
 
 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Erlotinib (Tarceva, NSC 718781) 


 
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RTOG 1306, Version Date July 25, 2017 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3622 patients. Below is the CAEPR for Erlotinib 
(Tarceva).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.6, June 20, 20171 
 
 Adverse Events with Possible  
 Relationship to Erlotinib (Tarceva) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Disseminated intravascular 
coagulation2 
  
 
 
Hemolytic uremic syndrome2 
  
 
 
Thrombotic thrombocytopenic 
purpura2 
  
CARDIAC DISORDERS 
  
 
 
Myocardial infarction2 
  
EYE DISORDERS 
  
 
Conjunctivitis 
 
 Conjunctivitis (Gr 2) 
 
Dry eye 
 
 Dry eye (Gr 2) 
 
 
Eye disorders - Other (corneal 
perforation) 
  
 
Eye disorders - Other (eyelash 
in-growth and/or thickening) 
 
  
 
 
Keratitis 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal hemorrhage3 
 
  
 
 
Gastrointestinal perforation4 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
 Infection5 (Gr 3) 
INVESTIGATIONS 
  


 
35  
RTOG 1306, Version Date July 25, 2017 
 
 
 Adverse Events with Possible  
 Relationship to Erlotinib (Tarceva) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased 
(Gr 3) 
 
 
INR increased (in patients 
taking Coumadin) 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular2 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
Pneumonitis 
 
 Pneumonitis (Gr 4) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
 
Nail loss 
 
 Nail loss (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2The risk of myocardial infarction, cerebrovascular accident, and microangiopathic hemolytic anemia is 
increased in patients with pancreatic cancer who were treated concomitantly with gemcitabine. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 


 
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RTOG 1306, Version Date July 25, 2017 
 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Adverse events reported on erlotinib (Tarceva) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that erlotinib (Tarceva) caused the adverse 
event: 
 
EYE DISORDERS - Blurred vision; Eye disorders - Other (orbital cellulitis); Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Colitis; Constipation; Duodenal ulcer; Dysphagia; Esophagitis; 
Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (pneumatosis intestinalis); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs 
HEPATOBILIARY DISORDERS - Cholecystitis 
INVESTIGATIONS - Creatinine increased; Lymphocyte count decreased; Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hypocalcemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Dizziness; Peripheral sensory neuropathy 
PSYCHIATRIC DISORDERS - Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Pharyngolaryngeal pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: Erlotinib (Tarceva) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
Note:  Erlotinib (Tarceva®)-induced diarrhea and/or vomiting has been associated with dehydration, 
hyperkalemia; hypocalcemia; hypokalemia; hypomagnesemia; hyponatremia; hypophosphatemia, 
increased creatinine, and renal failure. 
 
Note:  Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during 
use of erlotinib (Tarceva®) in patients with or without baseline hepatic impairment.  
 
7.2.9 
Supply:  
This study will be conducted under an IND to be held by NCI and will require FDA submission 
and approval as part of the IND. Erlotinib tablets are provided by Astellas Pharma and distributed 
by the DCTD/NCI. Erlotinib will be supplied to patients on study free of charge. 
 
7.2.10 This study will be conducted under an NCI IND. The Erlotinib and the associated Investigator 
Brochure will be provided by the Pharmaceutical Management Branch (PMB). 
 
The Principal Investigator (or authorized designee listed by the Investigator on the site’s most 
recent Supplemental Investigator Data Form [IDF] on file with the PMB) at each participating 
institution may request erlotinb from NCI’s Pharmaceutical Management Branch (PMB). The 
updated version (11/10/03) of each institution’s Drug Authorization Review and Tracking System 
(DARTS) will require selecting a designee from the individuals listed on the IDF. The information 
on the IDF is linked to the Investigator during the annual Investigator registration process. This 
process must be completed before a drug order can be entered for that investigator. Any changes 


 
37  
RTOG 1306, Version Date July 25, 2017 
 
to this information will require updating the first two pages of the IDF, having the Investigator sign 
the revised IDF, and returning it to the PMB via fax at 240-276-7893. Questions about the 
process should be directed to the PMB at 240-276-6575 Monday through Friday from 8:30 am–
4:30 pm Eastern Time. PMB policy requires that drug be shipped directly to the institution where 
the patient is to be treated.   
 
PMB does not permit the transfer of agents between institutions unless prior approval from PMB 
is obtained. Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees must submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application. Access to the OAOP application and the associated training 
guide is available at the following link: https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx . 
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an "active" 
account status and a "current" password. For questions about drug orders, transfers, returns, or 
accountability, call 240-276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or 
e-mail PMBAfterHours@mail.nih.gov anytime. 
 
The Investigator Brochure (IB), if available, for this drug will be supplied by the PMB/NCI. All 
requests 
for 
IBs 
should 
be 
e-mailed 
to 
ibcoordinator@mail.nih.gov 
<mailto:ibcoordinator@mail.nih.gov> or the IB Coordinator may be contacted at 240-276-6575. 
Please refer to the Pharmaceutical Management Branch, CTEP, DCTD, NCI “Policy and 
Guidelines 
for 
Investigational 
Agent 
Distribution” 
at 
the 
following 
link: 
http://www.rtog.org/ResearchAssociates/QualityControlSiteAudits/PMBPolicy.aspx. 
NRG 
Oncology applies these policies to all provided drug. 
 
Agent Inventory Records: The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the inventory and disposition of all agents received from DCTD 
using the NCI Oral Drug Accountability Record Form (DARF).  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
7.3 
Crizotinib (Xalkori®, PF-02341066) (8/27/14) 
Refer to the package insert for detailed pharmacologic and safety information.  
7.3.1 
Crizotinib is a selective ATP-competitive small-molecule inhibitor of the anaplastic lymphoma 
kinase (ALK) and c-Met/hepatocyte growth factor receptor (HGFR) receptor tyrosine kinases and 
their oncogenic variants (eg, c-Met/HGFR mutations or ALK fusion proteins). It is manufactured 
by Pfizer and is FDA approved for use in EML 4 ALK translocated patients with NSCLC. 
7.3.2 
Formulation 
 
Formulated Capsules: Crizotinib is formulated as a 200 mg or 250 mg capsule. The product 
consists of crizotinib and compendial excipients in a hard gelatin capsule. Crizotinib is packaged 
in 60-ct bottles. 
7.3.3 
Administration 
 
Oral, 250 mg twice daily; Sites will follow standard practice as detailed in the package insert for 
use with caution in the setting of concomitant drugs.   
7.3.4 
Storage and Stability 
 
Crizotinib as hard gelatin capsules is supplied in high-density polyethylene (HDPE) bottles. 
Crizotinib should be stored in accordance with labeled conditions. 
7.3.5     Adverse Events  (25July2017) 
 
 
 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Crizotinib (PF-02341066, NSC 749005) 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 2058 patients. Below is the CAEPR for Crizotinib 
(PF-02341066). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.2, April 21, 20171 
 
 Adverse Events with Possible  
 Relationship to Crizotinib (PF-02341066) 
 (CTCAE 4.0 Term) 
[n= 2058] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
Sinus bradycardia 
 
  
EYE DISORDERS 
  
Eye disorders - Other (vision 
disorders)2 
 
 
 Eye disorders - Other (vision 
disorders)2 (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
  
 
 
Esophagitis 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Edema face 
 
 
 Edema face (Gr 2) 
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
General disorders and 
administration site conditions - 
Other (generalized edema) 
 
 
  
Localized edema 
 
 
 Localized edema (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 


 
39  
RTOG 1306, Version Date July 25, 2017 
 
 
 Adverse Events with Possible  
 Relationship to Crizotinib (PF-02341066) 
 (CTCAE 4.0 Term) 
[n= 2058] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
 
Blood bilirubin increased 
  
 
Creatinine increased 
 
  
 
 
Electrocardiogram QT corrected 
interval prolonged 
  
 
Lymphocyte count decreased 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased 
(Gr 2) 
 
White blood cell decreased 
 
 White blood cell decreased 
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Musculoskeletal and connective 
tissue disorder - Other (muscle 
spasms) 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
Nervous system disorders - 
Other (neuropathy)3 
 
 Nervous system disorders - 
Other (neuropathy)3 (Gr 2) 
 
 
Syncope 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Periorbital edema 
 
 
 Periorbital edema (Gr 2) 
 
Rash4 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Vision disorders may include the following: Chromatopsia, Diplopia, Halo vision, Photophobia, Photopsia, 
Vision blurred, Visual acuity reduced, Visual brightness, Visual impairment, Vitreous floaters, and Visual 
perseveration. 
 
3Neuropathy may include the following:  Acute polyneuropathy, Amyotrophy, Areflexia, Autoimmune 
neuropathy, Autonomic failure syndrome, Autonomic neuropathy, Axonal neuropathy, Biopsy peripheral 
nerve abnormal, Burning feet syndrome, Burning sensation, Decreased vibratory sense, Demyelinating 
polyneuropathy, Dysesthesia, Electromyogram abnormal, Formication, Gait disturbance, Genital 
hypoesthesia, Guillain-Barre syndrome, Hyperesthesia, Hypoesthesia, Hyporeflexia, Hypotonia, Ischemic 
neuropathy, Loss of proprioception, Miller Fisher syndrome, Mononeuritis, Mononeuropathy, 
Mononeuropathy multiplex, Motor dysfunction, Multifocal motor neuropathy, Muscle atrophy, Muscular 
weakness, Myelopathy, Nerve conduction studies abnormal, Nerve degeneration, Neuralgia, Neuritis, 
Neuromuscular toxicity, Neuromyopathy, Neuropathy peripheral, Neuropathy vitamin B6 deficiency, 


 
40  
RTOG 1306, Version Date July 25, 2017 
 
Neurotoxicity, Paresthesia, Peripheral motor neuropathy, Peripheral nerve lesion, Peripheral nerve palsy, 
Peripheral nervous system function test abnormal, Peripheral sensorimotor neuropathy, Peripheral 
sensory neuropathy, Peroneal muscular atrophy, Peroneal nerve palsy, Phrenic nerve paralysis, 
Polyneuropathy, Polyneuropathy chronic, Polyneuropathy idiopathic progressive, Radiation neuropathy, 
Sensorimotor disorder, Sensory disturbance, Sensory loss, Skin burning sensation, Temperature 
perception test decreased, Tinel’s sign, Toxic neuropathy, and Ulnar neuritis. 
 
4Treatment-related rash may include erythematous rash, rash maculo-papular, and pruritus. 
 
 
Adverse events reported on crizotinib (PF-02341066) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that crizotinib (PF-02341066) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(basophilia); Disseminated intravascular coagulation; Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac arrest; Myocarditis; 
Pericardial effusion; Supraventricular tachycardia 
EYE DISORDERS - Blurred vision; Cataract; Optic nerve disorder; Papilledema 
GASTROINTESTINAL DISORDERS - Colitis; Colonic perforation; Dysphagia; Esophageal ulcer; Gastric 
ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (gastrointestinal amyloidosis); 
Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Fever; General disorders and 
administration site conditions - Other (failure to thrive); Malaise; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (cholestasis); Hepatobiliary disorders - 
Other (hepatitis); Hepatobiliary disorders - Other (hepatotoxicity) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder 
INFECTIONS AND INFESTATIONS - Abdominal infection; Infections and infestations - Other 
(peridiverticular abscess); Kidney infection; Lung infection; Sepsis; Skin infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Spinal fracture; Wound complication 
INVESTIGATIONS - CPK increased; GGT increased; Investigations - Other (blood lactate 
dehydrogenase increased); Investigations - Other (blood testosterone decreased); Investigations - Other 
(eosinophil count increased); Investigations - Other (monocyte count increased); Investigations - Other 
(platelet count increased); Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hypermagnesemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Musculoskeletal and 
connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal and connective tissue disorder 
- Other (myopathy); Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (hemorrhage, intratumoral); Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Ischemia cerebrovascular; Pyramidal tract 
syndrome; Seizure; Stroke 
PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS - Fetal death 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Euphoria 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Renal and urinary disorders - 
Other (renal cyst); Renal calculi; Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Dyspnea; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (respiratory distress); 
Respiratory, thoracic and mediastinal disorders - Other (traumatic lung injury) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Skin and subcutaneous tissue disorders - Other 
(drug eruption) 
VASCULAR DISORDERS - Hematoma; Hypotension; Phlebitis; Thromboembolic event; Vasculitis 


 
41  
RTOG 1306, Version Date July 25, 2017 
 
 
 
Note: Crizotinib (PF-02341066) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.3.6 
Supply:  
Pfizer will supply crizotinib free of charge to patients on study in the U.S. Crizotinib is an 
approved, marketed drug that is considered investigational in the context of this clinical trial; 
however, this clinical investigation of crizotinib meets the criteria for IND exemption as described 
under title 21 CRF312.2 (b). 
7.3.7 
Drug Ordering and Accountability  
Crizotinib will be distributed by Biologics, Inc. Drug accountability records must be maintained at 
all sites according to good clinical practices and NCI guidelines. 
 
 
The Study Agent Shipment Form (SASF); available on the NRG Oncology/RTOG web site, 
www.rtog.org  under protocol-specific materials/regulatory resources for U.S. sites must be 
submitted to the CTSU Regulatory Office (Fax 215-569-0206) as soon as the individual 
responsible for the study agent has been identified. The completed SASF document may also be 
e-mailed to the CTSU at CTSURegulatory@ctsu.coccg.org.    
 
The drug supply will not be shipped by Biologics, Inc. until the patient has been registered. NRG 
Oncology will notify Biologics, Inc. to initiate each of these shipments after registration of the 
patient. Biologics, Inc. will ship a supply of crizotinib sufficient for the entire treatment for patients 
randomized to Arm 3. Each shipment will include three 60-ct bottles of crizotinib 250 mg 
capsules. If the patient dose reduces, contact Biologics for a supply of 200 mg capsules. 
Biologics, Inc. will ship drug according to the following schedule: 
 
RTOG 1306 Shipment Schedule 
Patient 
Randomized 
Initial e-order 
sent by RTOG 
Initial e-order 
received by 
Biologics, Inc. 
(before  2 p.m. 
EST) 
Initial order shipped 
by Biologics, Inc. 
Initial order received 
at site 
Monday 
Monday 
Monday 
 Monday 
  Tuesday 
Tuesday 
Tuesday 
Tuesday 
 Tuesday 
 Wednesday 
Wednesday 
Wednesday 
Wednesday 
 Wednesday 
 Thursday  
Thursday 
Thursday 
Thursday 
 Thursday 
 Friday  
Friday 
Friday 
Friday 
 Monday 
 Tuesday 
 
Biologics, Inc. will ship the order “same day” for all orders received before 2 p.m. EST, Monday 
through Thursday via FedEx Priority Overnight. Orders received after 2 p.m. EST, Monday 
through Thursday will be processed and shipped the next business morning.  
 
Drug deliveries are restricted during weekends and holidays. Biologics, Inc. observes the 
following holidays: New Year’s Day, Memorial Day, July 4th, Labor Day, Thanksgiving Day, the 
Friday following Thanksgiving Day, Christmas Eve, and Christmas Day. Sites should plan ahead 
to accommodate patients being treated during restricted times. 
 
Upon notification of a new patient enrollment, Biologics, Inc. will place an outbound call to the site 
contact to confirm that the site’s shipment is being processed. Biologics’ distribution team will 
monitor packages throughout the duration of transit via the FedEx web site and FedEx One Call 
Solution (live support). Real-time monitoring enables Biologics to mitigate potential delivery 
delays. 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
Please contact the drug distributor listed in the protocol directly for shipment tracking 
information and anticipated delivery dates or if a shipment has not been received by the 
expected date.  
 
At the completion of the study, unused supplies will be destroyed at the site according to the 
institution's policy for drug destruction.  Sites should complete the drug destruction form located 
on the NRG Oncology/RTOG web site www.rtog.org 
 under 
protocol-specific 
materials/regulatory resources and send the form to Biologics (see below for contact information). 
 
Questions about supply and delivery should be directed to:  
 
Elliott Lee, Clinical Research Program Manager  
Biologics, Inc. 
Clinical Research Services 
120 Weston Oaks Court 
Cary, NC 27513-2256 
Email: elee@biologicsinc.com or clinicaltrials@biologicsinc.com 
Phone:  919-459-4990 / Toll Free 800-693-4906 
Fax: 919-256-0794 
 
 
7.4 
Cisplatin (7/29/13) 
Refer to the package insert for detailed pharmacologic and safety information 
7.4.1 
Formulation: Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, 
and hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The 
pH range will be 3.5 to 4.5. Cisplatin injection also is available from the manufacturer in aqueous 
solution, each ml containing 1 mg cisplatin and 9 mg NaCl and HCL or NaOH to adjust pH. 
Cisplatin also is available in vials containing 50mL or 100mL of a 1mg/mL solution.   
7.4.2 
Mechanism of Action: The dominant mode of action of cisplatin appears to be inhibition of the 
incorporation of DNA precursors, although protein and RNA synthesis are also inhibited. This 
drug forms DNA adducts and cross-links. 
7.4.3 
Administration: After administering appropriate antiemetics, cisplatin will be infused over 1-2 
hours along with vigorous hydration. 
7.4.4 
Storage and Stability: 
Reconstituted solution of cisplatin is stable for 20 hours when stored at 
27°C and should be protected from light if not used within 6 hours. The vials and injection should 
not be refrigerated. Cisplatin has been shown to react with aluminum needles, producing a black 
precipitate within 30 minutes.  
7.4.5 
Adverse Events: Human toxicity includes nausea, vomiting, anaphylaxis, neuropathies, ocular 
disturbances, renal toxicity (with an elevation of BUN and creatinine and impairment of 
endogenous creatinine clearance, as well as renal tubular damage, which appears to be 
transient), ototoxicity (with hearing loss that initially is in the high-frequency range, as well as 
tinnitus), and hyperuricemia. Much more severe and prolonged toxicity has been observed in 
patients with abnormal or obstructed urinary excretory tracts.  Myelosuppression, often with 
delayed erythrosuppression, is expected. 
7.4.6 
Supply: Cisplatin is commercially available.  
 
 
7.5  
Etoposide (7/29/13) 
Refer to the package insert for detailed pharmacologic and safety information 
7.5.1 
Formulation 
 
For i.v. use, etoposide is supplied in 100-1000 mg vials at a concentration of 20 mg/ml.  Each 100 
mg vial also contains anhydrous citric acid 10 mg, benzyl alcohol 150 mg polysorbate 80 purified 
400 mg, polyethylene glycol, and absolute alcohol.  The manufacturer recommends etoposide 
dilution to a concentration of 0.2 or 0.4 mg/ml with either 0.9% Normal Saline, USP or 5% 
Dextrose Injection, USP.  Diluted to these concentrations, it yields a product that is stable for 96 
and 48 hours respectively, at room temperature (25°C), and under normal room fluorescent light 
in both glass and plastic containers. 


 
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RTOG 1306, Version Date July 25, 2017 
 
7.5.2 
Administration:  Intravenous on days 1-5 every 4 weeks for 2 cycles; infuse etoposide over at 
least 45-60 minutes. Infusions of 30 minutes or less greatly increase the risk of hypotension.  
7.5.3 
Storage:  Store intact vials at 15°C to 30°C (59°F to 86°F).  Protect from light. 
7.5.4 
Adverse Events   
Hematologic Toxicity:  Myelosuppression is dose related and dose limiting with granulocyte nadirs 
occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after 
drug administration.  Bone marrow recovery is usually complete by day 20.  Acute myeloid 
leukemia has been reported in rare instances. 
 
Gastrointestinal Toxicity: Nausea and vomiting are the major gastrointestinal toxicities.  Nausea 
and vomiting can usually be controlled with standard antiemetic therapy. 
 
Hypotension:  Transient hypotension following rapid intravenous administration has been 
reported in 1% to 2% of patients.  It has not been associated with cardiac toxicity or 
electrocardiographic changes.  No delayed hypotension has been noted. 
 
Allergic Reactions:  Anaphylactic-like reactions characterized by chills, fever, tachycardia, 
bronchospasm, dyspnea and hypotension have been reported to occur in less than 1% of the 
patients treated with the oral capsules.  These reactions have usually responded promptly to the 
cessation of the drug and to the administration of pressor agents, corticosteroids, antihistamines 
or volume expanders as appropriate.  One fatal acute reaction associated with bronchospasm 
has been reported. 
 
Alopecia:  Reversible alopecia, sometimes progressing to total baldness was observed in up to 
66% of patients. 
 
Other Toxicities:  The following adverse reactions have been infrequently reported:  aftertaste, 
hypertension, rash, fever, pigmentation, pruritus, abdominal pain, constipation, dysphagia, 
transient cortical blindness, and a single report of radiation recall dermatitis. 
7.5.5 
Supply: Etoposide is commercially available.  
 
7.6 
Paclitaxel (7/29/13) 
Refer to the package insert for detailed pharmacologic and safety information. 
7.6.1 
Paclitaxel is a poorly soluble plant product from the western yew, Taxus brevifolia. The injection is 
a clear, colorless to slightly yellow viscous solution.  Improved solubility requires further dilution 
with either 0.9% sodium chloride or 5% dextrose in water.  All solutions of paclitaxel exhibit a 
slight haziness directly proportional to the concentration of drug and the time elapsed after 
preparation, although when prepared as described below, solutions of paclitaxel (0.3-1.2 mg/ml) 
are physically and chemically stable for 27 hours at ambient temperature (27°C). 
7.6.2 
Preparation 
Paclitaxel injection is a sterile solution concentrate, 6 mg/ml in 5, 16.7, and 50 ml vials (30, 100, 
and 300 mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol, 
USP, 50%. Paclitaxel will be diluted to a final concentration of 0.3 to 1.2 mg/ml in D5W, NS, or 
D5NS , in glass or polyolefin containers due to leaching of diethylhexphthalate (DEHP) plasticizer 
from polyvinyl chloride (PVC) bags and intravenous tubing by the Cremophor vehicle in which 
paclitaxel is solubilized. Each bag/bottle should be prepared immediately before administration. 
NOTE: Formation of a small number of fibers in solution (NOTE: acceptable limits established by 
the USP Particular Matter Test for LVPs) have been observed after preparation of paclitaxel. 
Therefore, in-line filtration is necessary for administration of paclitaxel solutions. In-line filtration 
should be accomplished by incorporating a hydrophilic, microporous filter of pore size not greater 
than 0.22 microns (e.g.: Millex-GV Millipore Products) into the intravenous fluid pathway distal to 
the infusion pump. Although particulate formation does not indicate loss of drug potency, 
solutions exhibiting excessive particulate matter formation should not be used. 
7.6.3 
Administration 
All patients should be premedicated prior to paclitaxel administration in order to prevent severe 
hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO 
administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 
50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 
to 60 minutes before paclitaxel. 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
Paclitaxel, at the appropriate dose and dilution, will be given as an infusion as per standard of 
care guidelines. The paclitaxel is administered using an in-line filter with a maximum size of 0.22 
micron. Paclitaxel will be administered via an infusion control device (pump) using non-PVC 
tubing and connectors, such as the intravenous administration sets (polyethylene or polyolefin) 
that are used to infuse parenteral nitroglycerin. Nothing else is to be infused through the line 
through which paclitaxel is administered.  
Caution is warranted when paclitaxel is concomitantly administered with known substrate or 
inhibitors of CYP2C8 and CYP3A4.   
7.6.4 
Storage 
Paclitaxel vials should be stored between 20-25C (68°-77°F).  
7.6.5 
Adverse Effects 
Hematologic: Myelosuppression;Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain; 
Heart: Arrhythmias, heart block, hypertension; Neurological: Sensory and peripheral neuropathy; 
Allergy: Severe anaphylactic reactions; Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, 
infiltration (erythema, induration, tenderness, rarely ulceration), hypotension, irritation to the 
injection site, mucositis 
7.6.6 
Supply 
Paclitaxel is commercially available.  
 
7.7 
Carboplatin (7/29/13) 
 
Refer to the package insert for detailed pharmacologic and safety information. 
7.7.1 
Formulation 
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150 
mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and 
mannitol. Carboplatin also is available as a 10 mg/mL solution in 50, 150, and 450 mg vials. 
7.7.2 
Dose Calculation  
The dose of carboplatin is calculated as follows, using the Calvert formula based on creatinine 
clearance: Total dose (mg) = Target AUC (in mg/mL per min) x (Estimated GFR + 25) 
 
The GFR should not exceed 125 ml/min. If the calculated GFR based on the Calvert formula is 
greater than 125 ml/min, a GFR of 125 ml/min should be used. The maximum carboplatin dose 
for an AUC = 2 should not exceed 300 mg. 
 
In the absence of new renal obstruction or other renal toxicity greater than or equal to grade 2 
(CTCAE, v. 4) (serum creatinine >1.5 x ULN), the dose of carboplatin will not be recalculated for 
subsequent cycles, but will be subject to dose modification as noted. In patients with an 
abnormally low serum creatinine (≤ 0.6 mg/dl), due to reduced protein intake and/or low muscle 
mass, the creatinine clearance should be estimated using a minimum value of 0.6 mg/dl. If a 
more appropriate baseline creatinine value is available within 4 weeks of treatment that may also 
be used for the initial estimation of GFR. 
 
Note:  The carboplatin dose is calculated in mg, not mg/m2. For the purposes of this protocol, the 
GFR is considered equivalent to the creatinine clearance. Creatinine clearance (CrCL) 
can either be measured or estimated using the formula: 
 
(140-age) wt (kg)    x (0.85 if female) 
72 x creatinine (mg/dl) 
7.7.3 
Adverse Events  
Hematologic: Myelosuppression is the major dose-limiting toxicity. Thrombocytopenia, 
neutropenia, leucopenia, and anemia are common but typically resolve by day 28 when 
carboplatin is given as a single agent.  
Allergic reactions: Hypersensitivity to carboplatin has been reported in 2% of patients receiving 
the drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely bronchospasm and 
hypotension. The reactions can be successfully managed with standard epinephrine, 
corticosteroid, and antihistamine therapy. Desensitization per the allergy team is allowed. 


 
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RTOG 1306, Version Date July 25, 2017 
 
Neurologic: Peripheral neuropathies have been observed in 4% of patients receiving carboplatin 
with mild paresthesia being the most common. 
Gastrointestinal: Nausea and vomiting are the most common gastrointestinal events; both usually 
resolve within 24 hours and respond to antiemetics. Other gastrointestinal events include 
diarrhea, weight loss, constipation, and gastrointestinal pain.  
Hepatic toxicity: Elevated alkaline phosphatase, total bilirubin, and SGOT have been reported. 
Other: Pain and asthenia are the most common miscellaneous adverse events. Alopecia has 
been reported in 3% of the patients taking carboplatin. 
7.7.4 
Preparation  
When available, prediluted vials of carboplatin should be utilized. Otherwise, the preparation of 
carboplatin should proceed as described below: 
 
Immediately before use, the contents of a carboplatin vial must be reconstituted with either sterile 
water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP. The 
following shows the proper diluent volumes to be used to obtain a carboplatin concentration of 10 
mg/mL: 
Vial size 
Diluent volume 
50 mg 
5mL 
150 mg 
15 mL 
450 mg 
45 mL 
 
Carboplatin reacts with aluminum to form a precipitate and cause a loss of potency. Therefore, 
needles or intravenous sets containing aluminum parts that may come in contact with the drug 
must not be used for the preparation or administration of carboplatin. 
7.7.5 
Administration 
 
Carboplatin will be infused intravenously as per standard of care guidelines. The dose of 
carboplatin is area under the curve (AUC) = 2.   
7.7.6 
Storage and Stability  
Intact vials of carboplatin are stable for the period indicated on the package when stored at room 
temperature (15-30˚C or 59-86˚F) and protected from light. When prepared as described above, 
carboplatin solutions are stable for 8 hours at room temperature if protected from light. The 
solution should be discarded after 8 hours since no antibacterial preservative is contained in the 
formulation. 
7.7.7 
Supply  
 
Carboplatin is commercially available.  
 
 
7.8 
Clinical Trials Agreement 
 
Protocols that involve agent(s) covered by a collaborative agreement with a biotech/pharma 
 
company(ies) must incorporate the NCI/ DCTD Collaborative Agreement Language shown below. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 


 
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RTOG 1306, Version Date July 25, 2017 
 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
 
E-mail: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
7.9 
Dose Modifications (6/26/15) 
7.9.1 
Arm 3: Patients in ALK Rearrangement Cohort  


 
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RTOG 1306, Version Date July 25, 2017 
 
These patients are randomized to receive 12 weeks of induction with crizotinib. The following 
table should be used when reducing crizotinib doses for toxicity.  Missed/vomited doses should 
not be made up but should be recorded in the comments section of the Medidata Rave drug form. 
There will be no dose reduction of crizotinib below dose level -2. 
 
 
Dose Level 
 
Dose of crizotinib 
0 (starting dose) 
250 mg BID 
-1 
200 mg BID 
-2 
250 mg daily 
 
 
The grades of adverse events below refer to CTCAE, v. 4. 
 
 
• Ocular Toxicity 
 
For ≥  grade 2 new or worsening eye pain, interrupt crizotinib until pain resolves to ≤ grade 1, 
and then resume at the previous dose. If after 14 days the eye pain does not resolve to ≤ 
grade 1, discontinue crizotinib.  
 
 
For ≥  grade 2 keratitis, discontinue crizotinib.  
 
 
For ≥  grade 2 ocular surface disease (conjunctivitis), interrupt crizotinib until toxicity improves 
to ≤  grade 1. Once the conjunctivitis resolves to ≤ grade 1, resume and reduce the dose by 50 
mg/day. 
 
• GI Toxicity: Nausea, Diarrhea, and/or Vomiting 
 
Grade 1 or 2: Continue crizotinib at the same dose level and institute treatment for diarrhea 
(loperamide at 4mg at the first onset, followed by 2 mg every 2-4 hours until diarrhea free for 
12 hours) and/or oral emetic therapy of physician’s choice for nausea/vomiting. If grade 2 
toxicity persists over 48-72 hours despite optimal medical management, decrease crizotinib by 
1 dose level. 
 
 
Grade 3: Hold crizotinib and institute treatment for diarrhea (loperamide at 4mg at the first 
onset, followed by 2 mg every 2-4 hours until diarrhea free for 12 hours) and/or oral emetic 
therapy of physician’s choice for nausea/vomiting. Once toxicity resolves to ≤  grade 2, resume 
with one dose level reduction. If crizotinib is held for ≥ 21 days, discontinue crizotinib. 
 
Grade 4: Discontinue crizotinib. 
 
• Hematologic Toxicity 
The ANC must be ≥ 1,000/mcl and platelet count must be ≥ 100,000/mcl on day 1 of each 
cycle for treatment to continue. Treatment with crizotinib may be delayed for up to 2 weeks for 
neutropenia and/or thrombocytopenia. If counts do not return to these levels within 2 weeks 
patients must discontinue therapy. 
 
Patients developing febrile neutropenia of any duration must be dose reduced to dose level –2 
for the subsequent cycle 
 
• Pulmonary Toxicity 
 
Patients with worsening pulmonary symptoms including new onset of or worsening dyspnea, 
cough or fever should be promptly evaluated for interstitial pneumonitis and treated as 
clinically indicated, including the use of corticosteroids. 
 
 
Crizotinib should be held pending diagnosis of the pulmonary disorder, and discontinued if a 
diagnosis of interstitial pneumonitis is confirmed. 
 
• Hepatic Toxicity 


 
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Give the following doses for crizotinib only: 
 
SGOT (AST) 
 
Bilirubin 
Crizotinib 
≤ 5 x ULN 
and 
≤ 3 x ULN 
Same dose level 
> 5 x ULN 
or 
> 3 x ULN 
Hold* 
 
*Hold crizotinib until AST ≤ 5 x ULN and bilirubin ≤  3 x ULN, then resume treatment at one 
dose level lower.  If crizotinib is held for ≥ 14 days, discontinue crizotinib therapy. 
 
• Other Toxicities 
Grade 3: Hold crizotinib until toxicity resolves to ≤  grade 2, then resume with a one dose level 
reduction. If crizotinib is held ≥  21 days, discontinue crizotinib. 
 
Grade 4: Discontinue crizotinib. 
 
7.9.2 
Arm 1: Patients in EGFR TK Mutation Cohort  
These patients are randomized to receive 12 weeks of induction with erlotinib. The recommended 
dose of single-agent erlotinib is 150 mg/day. Missed/vomited doses should not be made up but 
should be recorded in the comments section of the Medidata Rave drug form. 
 
For toxicity that is thought to be related to erlotinib, the daily dose of erlotinib will be decreased 
according to the schedule displayed in the Table 1. 
a) 
Patients with unresolved toxicity after 2 weeks should be taken off study.  However, if it is 
the treating physician’s opinion that the patient may benefit from continued treatment, the 
patient may continue on study.   
b) 
Patients may have a second dose reduction for toxicity; however, patients requiring a third 
dose reduction should be taken off study unless, in the opinion of the treating physician, 
there is reason to believe the patient may benefit from continued treatment.  
c) 
Once a dose has been reduced for a patient, it should not be subsequently increased. 
 
Table 1: Erlotinib Dose Level Reduction 
 
Starting Dose 
Dose (-1) 
Dose (-2) 
Dose (-3) 
150 mg/day 
100 mg/day 
75 mg/day 
50 mg/day 
 
 
 


 
49  
RTOG 1306, Version Date July 25, 2017 
 
Table 2: Erlotinib Dosage Modification Criteria for Erlotinib-Related Toxicities 
 
Toxicity 
Grade 
Erlotinib dosage 
modification* 
Guideline for management 
Keratitis 
1 
None 
No intervention 
2 (if <14 days) 
None 
Preservative-free artificial tears, 
ointments, and/or other therapies as 
clinically indicated, with a follow-up 
examination within 2 weeks 
2 (if >14 days) 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level 
>3 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level* 
Diarrhea  
1 
None 
No intervention 
2 
• None if tolerable 
• If not tolerable, hold until 
resolution to grade <1, 
then resume at the same 
dose.  
• If intolerable grade 2 
recurs after resumption, 
hold until resolution to 
grade <1 and resume with 
1 dose reduction.  
Loperamide (4 mg at first onset, 
followed by 2 mg every 2–4 hrs until 
diarrhea free for 12 hrs) 
>3 
(despite optimal 
loperamide use) 
Hold until recovery to < 
grade 1  
And then 
Reduce 1 dose level* 
Rash 
1 
None 
No intervention 
2 
• None if tolerable 
• If not tolerable, hold until 
resolution to grade <1, 
then resume at the same 
dose.  
• If intolerable grade 2 
recurs after resumption, 
hold until resolution to 
grade <1 and resume with 
1 dose reduction.  
Any of the following: minocycline+, 
topical tetracycline or clindamycin, 
topical silver sulfadiazine, 
diphenhydramine, oral prednisone 
(short course) 
>3 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level 
 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
Toxicity 
Grade 
Erlotinib dosage 
modification* 
Guideline for management 
Bilirubin 
 
(for patients 
without pre-
existing liver 
dysfunction) 
 
3 x ULN 
Withhold erlotinib. 
Discontinue if levels do not 
improve significantly or 
resolve within three weeks. 
 
(for patients with 
pre-existing liver 
dysfunction) 
 
≥2 x baseline  
 
Liver 
trans-
aminase 
(for patients 
without pre-
existing liver 
dysfunction) 
 
>5 x ULN 
Withhold erlotinib 
Discontinue if levels do not 
improve significantly or 
resolve within three weeks. 
 
(for patients with 
pre-existing liver 
dysfunction) 
 
≥3 x baseline 
 
Signs and symptoms of 
interstitial pneumonitis 
Hold pending diagnosis 
Permanently discontinue if 
diagnosis is confirmed and 
considered possibly related 
to erlotinib 
Patient should be thoroughly 
evaluated, closely monitored, and 
supported as clinically indicated 
Other 
toxicity 
>2 prolonged 
clinically significant 
toxicity 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level* 
Treatment as appropriate 
*if dose has been previously held for grade 2 rash or diarrhea, and grade 2 symptoms recur, OR if the 
patient finds the symptoms unacceptable, hold dose until recovery to < grade 1 and then reduce dose 
one level  
 
Additional erlotinib dose modification guidelines include: 
 
Discontinue erlotinib for:  
• 
Severe hepatic toxicity that does not improve significantly or resolve within three weeks. 
• 
Gastrointestinal perforation. 
• 
Severe bullous, blistering or exfoliating skin conditions. 
• 
Corneal perforation or severe ulceration. 
  
Withhold erlotinib:  
• 
For severe (grade 3 to 4) renal toxicity, and consider discontinuation of erlotinib. 
• 
For acute/worsening ocular disorders such as eye pain, and consider discontinuation of erlotinib. 
 
Reduce erlotinib by 50 mg decrements: 
• 
If severe reactions occur with concomitant use of strong CYP3A4 inhibitors (such as atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandomycin [TAO], voriconazole, or grapefruit or grapefruit juice) or when using 
concomitantly with an inhibitor of both CYP3A4 and CYP1A2 (e.g., ciprofloxacin). Avoid 


 
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RTOG 1306, Version Date July 25, 2017 
 
concomitant use if possible. 
• 
When restarting therapy following withholding treatment for a dose-limiting toxicity that has 
resolved to baseline or grade ≤1.  
 
Increase erlotinib by 50 mg increments as tolerated for: 
• 
Concomitant use with CYP3A4 inducers, such as rifampin, rifabutin, rifapentine, phenytoin, 
carbamazepine, phenobarbital, or St. John’s wort.  Increase doses by 50 mg increments at 2-
week intervals to a maximum of 450 mg.  Avoid concomitant use, if possible. 
• 
Concurrent cigarette smoking.  Increase by 50 mg increments at 2-week intervals to a maximum 
of 300 mg.  Immediately reduce the dose of erlotinib to the recommended dose (150 mg or 100 
mg daily) upon cessation of smoking. 
 
Drugs affecting gastric pH 
• 
Avoid concomitant use of erlotinib with proton pump inhibitors if possible.  Separation of doses 
may not eliminate the interaction since proton pump inhibitors affect the pH of the upper 
gastrointestinal (GI) tract for an extended period. 
• 
If treatment with an H2-receptor antagonist such as ranitidine is required, erlotinib must be taken 
10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the 
H2-receptor antagonist. 
• 
Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid 
dose and the erlotinbi dose should be separated by several hours, if an antacid is necessary. 
 
7.9.3 
Arms 2 and 4: For Both Cohorts Receiving Concurrent Chemotherapy and Radiation 
(6/26/15) 
The grades of adverse events below refer to CTCAE, v. 4. 
 
Cisplatin (50 mg/m2) on Days 1 and 8 and Etoposide (50 mg/m2) on Days 1-5 administered 
intravenously q4 weeks for 2 cycles 
 
If dose reduction is required during chemoradiation, no re-escalation is allowed in subsequent 
chemoradiation cycles.  
 
 
If cisplatin and/or etoposide are held for greater than 2 consecutive weeks, the drugs will be held 
permanently for the duration of concurrent therapy.  
 
The following dose levels are used for dose modifications during both the concurrent 
chemoradiation phase. Missed/vomited doses should not be made up but should be recorded in 
the comments section of the Medidata Rave drug form.  There will be no dose reduction below 
level -1. 
 
Dose Level 
Cisplatin 
Etoposide 
0 
50 mg/m2 
50 mg/m2 
-1 
40 mg/m2 
40 mg/m2 
 
• Hematologic Toxicity 
Dose modification on d1 of a new cycle during concurrent chemoradiation (cycles 1-4) 
 
ANC 
 
Platelet 
Cisplatin and Etoposide Dose 
≥ 1,000/mcl 
and 
≥ 100,000/mcl 
Continue w/ previous dose 
< 1,000/mcl 
or 
< 100,000/mcl 
Hold* 
 
*Check weekly and resume therapy at previous dose (no dose reduction) when counts recover 
to ANC ≥ 1,000 and platelets ≥ 100,000/mcl.  
 


 
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RTOG 1306, Version Date July 25, 2017 
 
Febrile neutropenia occurring during chemoradiation will result in a decrease of the cisplatin 
and etoposide dose level by –1. Febrile neutropenia occurring despite dose reduction during 
chemoradiation will result in discontinuation of chemotherapy. Radiation therapy is held for 
neutropenia (ANC < 500/mcl); radiation therapy may be restarted when the ANC ≥ 500/mcl. 
• Renal Toxicity 
Based on day 1 of each cycle for cisplatin and etoposide: 
 
CrCl < 50 ml/min 
Hold therapy. Administer fluids and repeat 
creatinine in one week. 
If after one week CrCl ≥ 50 ml/min 
Administer both cisplatin and etoposide at full 
dose. 
If after one week CrCl < 50 ml/min 
Discontinue chemotherapy. 
 
• Hepatic Toxicity 
Give the following doses for etoposide only: 
 
Bilirubin 
Etoposide 
< 1.5 mg/dl 
Same dose level 
1.5 -3.0 mg/dl 
 1 dose level 
≥  3.0 mg/dl 
Hold* 
 
• Gastrointestinal Toxicity 
Nausea/Vomiting: For ≥  grade 3 nausea or vomiting despite maximum antiemetics, decrease 
cisplatin by one dose level for the next dose. If nausea and vomiting improve, cisplatin dose 
should be re-escalated to the previous dose, if possible. 
 
• Neurotoxicity (Peripheral) 
Cisplatin doses should be modified for neurologic toxicity (see below). Serum magnesium and 
calcium levels should be checked; vitamin B12 levels may need to be evaluated especially in 
older patients.  
 
Grade 1: Give cisplatin at full dose. 
 
Grade ≥  2: Hold cisplatin until neurotoxicity resolves to  ≤  grade 1, then resume with one 
dose level reduction. Continue treatment with etoposide. If cisplatin is held for ≥ 21 days, 
discontinue cisplatin. 
 
• Ototoxicity: Discontinue cisplatin for ≥ grade 3 ototoxicity. 
 
• Hypomagnesemia and Hypokalemia: is not an indication for stopping therapy. Oral and 
parenteral supplementation is indication for serum levels < LLN. 
 
• All Other Treatment-Related Toxicities that Exceed grade 2: (except alopecia, nausea, 
vomiting, fatigue and anorexia), hold cisplatin and etoposide until the toxicities have resolved 
to grade 2 or less and resume cisplatin and etoposide with one dose level reduction. 
 
Paclitaxel (50 mg/m2) and Carboplatin (AUC-2) intravenously weekly during thoracic 
radiation for 6 weeks followed 4-6 weeks later by 2 cycles of Paclitaxel (200 mg/m2) and 
Carboplatin (AUC-6) intravenously q 3 weeks for 2 cycles 
 
If dose reduction is required during chemoradiation, no re-escalation is allowed in subsequent 
chemoradiation cycles. However, paclitaxel and carboplatin will be started at dose level 0 after 
the completion of radiation therapy. 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
If paclitaxel and/or carboplatin are held for greater than 2 consecutive weeks, the drugs will be 
held permanently for the duration of concurrent therapy.  
 
The following dose levels are used for dose modifications during both the concurrent 
chemoradiation phase. There will be no dose reduction below level -1. 
 
Dose Level 
Paclitaxel 
Carboplatin 
0 
50 mg/m2 
AUC = 2 
-1 
40 mg/m2 
AUC = 1 
 
The following dose levels are used for dose modifications during the consolidation phase. There 
will be no dose reduction below level -1. 
 
Dose Level 
Paclitaxel 
Carboplatin 
0 
200 mg/m2 
AUC = 6 
-1 
150 mg/m2 
AUC = 4.5 
 
• 
Hematologic Toxicity 
 
Dose Modification during Concurrent Chemoradiation: 
 
ANC 
 
Platelet 
Carboplatin and Paclitaxel Dose 
≥ 1,000/mcl 
and 
≥ 100,000/mcl 
Continue w/ previous dose 
< 1,000/mcl 
or 
< 100,000/mcl 
Hold* 
 
*Check weekly and resume therapy at previous dose (no dose reduction) when counts 
recover to ANC ≥ 1,000 and platelets ≥ 100,000/mcl. If, after 3 weeks of holding drugs ANC < 
1,000/mcl or platelet < 100,000/mcl, contact Drs Govindan, Hahn, or Tsao. 
 
Febrile neutropenia occurring during chemoradiation will result in a decrease of the 
carboplatin and paclitaxel dose level by –1. Febrile neutropenia occurring despite dose 
reduction during chemoradiation will result in discontinuation of carboplatin, but continuation 
of paclitaxel at the previous dose (-1 dose level). Radiation therapy is held for neutropenia 
(ANC < 500/mcl); radiation therapy may be restarted when the ANC ≥500/mcl. 
 
Dose Modification on Day 1 of a New Cycle during Consolidation Therapy: 
 
ANC 
 
Platelet 
Chemotherapy 
≥ 1,000/mcl 
and 
≥ 100,000/mcl 
Continue w/ previous dose 
< 1,000/mcl 
or 
< 100,000/mcl 
Hold* 
 
*Check weekly and resume therapy at previous dose (no dose reduction) when counts 
recover to ANC ≥ 1,000 and platelets ≥ 100,000/mcl. If, after 3 weeks of holding drugs ANC < 
1,000/mcl or platelet < 100,000/mcl, contact the Drs. Govindan, Hahn, or Tsao. 
 
Febrile neutropenia occurring during consolidation will result in a decrease of both the 
carboplatin and paclitaxel doses by 1 dose level. 
 
• 
Renal Toxicity: There are no dose modifications for renal toxicity. It is not necessary to 
change the dose of carboplatin unless the calculated dose changes by ≥ 10%. 
 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
 
• 
Neurotoxicity (Peripheral) 
Paclitaxel doses should be modified for neurologic toxicity (see below). Serum magnesium 
and calcium levels should be checked; folate and vitamin B12 levels may need to be 
evaluated especially in older patients.  
 
Grade 1: Give paclitaxel at full dose. 
 
Grade ≥ 2: Hold paclitaxel until neurotoxicity resolves to  ≤  grade 1, then resume with one 
dose level reduction. Continue treatment with carboplatin. If paclitaxel is held for  ≥  21 days, 
discontinue paclitaxel, but continue treatment with carboplatin. 
• 
Hepatic Toxicity:  
Give the following doses for paclitaxel only: 
 
SGOT (AST) 
 
Bilirubin 
Paclitaxel 
≤ 2.5 x ULN 
and 
< 1.5 mg/dl 
Same dose level 
2.5 – 5.0 x ULN 
and 
< 1.5 mg/dl 
 1 dose level 
> 5 x ULN 
or 
≥ 1.5 mg/dl 
Hold* 
 
*Hold paclitaxel until AST ≤ 5 x ULN and bilirubin < 1.5 mg/dl, then resume treatment at 
one dose level lower. (Continue treatment with carboplatin. If paclitaxel is held for ≥ 21 
days, discontinue paclitaxel therapy (continue treatment with carboplatin. 
 
• 
Hypersensitivity to Carboplatin 
Grade 1: Slow the infusion until symptoms resolve, then restart the infusion at the initial 
planned rate. 
 
Grade 2: Stop the infusion. Administer H1 and/or H2 blockers +/- dexamethasone, 
according to physician discretion/institutional guidelines. Restart carboplatin when 
symptoms resolve and pretreat before all subsequent doses of carboplatin. 
 
Grade 3 or 4: Patient should be removed from all protocol therapy. 
 
• 
Hypersensitivity to Paclitaxel 
Grade 1: Slow the infusion until symptoms resolve, then restart the infusion at the initial 
planned rate. 
 
Grade 2: Stop the infusion. Administer H1 and/or H2 blockers +/- dexamethasone 
according to physician discretion/institutional guidelines. Restart when symptoms resolve 
and pretreat before all subsequent doses. 
 
Grade 3 or 4: Discontinue therapy with paclitaxel. 
 
• 
All Other Treatment-Related Toxicities that Exceed grade 2: (except alopecia, nausea, 
vomiting, fatigue and anorexia), hold paclitaxel and carboplatin until the toxicities have 
resolved to grade 2 or less and resume carboplatin and paclitaxel with one dose level 
reduction. 
 
7.10 
Modality Review 
The Alliance Co-Principal Investigator/Medical Oncologist, Ramaswamy Govindan, MD, and the 
NRG Oncology and Alliance Medical Oncology Co-Chairs, Anne Tsao, MD, and Olwen Hahn, 
MD, will perform a Chemotherapy Assurance Review of all patients who receive or are to receive 
chemotherapy 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 


 
55  
RTOG 1306, Version Date July 25, 2017 
 
Section 12.1. The scoring mechanism is: Per Protocol/Acceptable Variation, Unacceptable 
Deviation, and Not Evaluable.  A report is sent to each institution once per year to notify the 
institution about compliance for each case reviewed in that year. 
   
Drs. Govindan, Tsao, and Hahn will perform a Quality Assurance Review after complete data for 
the first 20 cases enrolled has been received at NRG Oncology. They will perform the next review 
after complete data for the next 20 cases enrolled has been received at NRG Oncology. The final 
cases will be reviewed within 3 months after this study has reached the target accrual or as soon 
as complete data for all cases enrolled has been received at NRG Oncology, whichever occurs 
first. 
 
7.11 
Adverse Events (5/29/14) 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP website at                           
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be 
reported via the CTEP-AERS (the CTEP Adverse Event  Reporting System) application accessed 
via 
either 
the 
CTEP 
web 
site 
(https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613).  
 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
the NRG Oncology Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet 
fails. Once internet connectivity is restored, an AE report submitted by phone must be entered 
electronically into CTEP-AERS. 
7.11.1 Adverse Events (AEs)  
Definition of an 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). [CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements. February 29, 2012; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf] 
7.11.2 Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited 
reporting criteria defined in the table in section 7.12 will be reported via CTEP-AERS.  SAEs that 
require 24 hour CTEP-AERS notification are defined in the expedited reporting table in section 
7.12.  Contact the CTEP-AERS Help Desk if assistance is required.  
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in 
any of the following outcomes: 
• 
Death; 
• 
A life-threatening adverse drug experience; 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
• 
A persistent or significant disability/incapacity; 
• 
A congenital anomaly/birth defect; 
• 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition.  
 
 
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.7.11.3 
Acute 
Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 


 
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RTOG 1306, Version Date July 25, 2017 
 
 
AML or MDS that is diagnosed during or subsequent to treatment in patients on NCI/CTEP-
sponsored clinical trials must be reported via the CTEP-AERS within 30 days of AML/MDS 
diagnosis.  
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
 
7.12 
CTEP-AERS Expedited Reporting Requirements (5/29/14) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via CTEP-AERS, the CTEP Adverse Event  Reporting System, 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 NRG Oncology and satisfies NRG 
Oncology requirements for expedited adverse event reporting. 
 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only 
pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
the NRG Oncology Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet 
fails. Once internet connectivity is restored, an AE report submitted by phone must be entered 
electronically into CTEP-AERS. 
 
• 
CTEP-AERS-24 Hour Notification requires that an CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 
24-hour notification must be followed by an CTEP-AERS 5 Calendar Day Report. Serious 
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table below. 
• 
Supporting source document is not mandatory.  However, if the CTEP-AERS report indicates 
in the Additional Information section that source documentation will be provided, then it is 
expected.  If supporting source documentation accompanies a CTEP-AERS report, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and 
fax supporting documentation to both the NCI at 301-230-0159 and the NRG Oncology 
dedicated SAE FAX, 215-717-0990. 


 
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RTOG 1306, Version Date July 25, 2017 
 
• 
A serious adverse event that meets expedited reporting criteria outlined in the following table 
but is assessed by the CTEP-AERS as “expedited reporting NOT required” must still be 
reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT 
Required” assessment; the CTEP-AERS allows submission of all reports regardless of the 
results of the assessment.  
 
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials conducted under an 
IND as described in the table below. Please refer to the erlotinib SPEER for exclusions to 
expedited reporting. Important: All AEs reported via CTEP-AERS also must be reported on the 
AE section of the appropriate case report form (see Section 12.1). 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Arm 1 under an IND/IDE for Erlotinib within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
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 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
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. 


 
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RTOG 1306, Version Date July 25, 2017 
 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 
(5/29/14) Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials Utilizing an Agent under a CTEP-IND  
The following are protocol-specific exceptions to expedited reporting via CTEP-AERS. Report the 
following AEs in an expedited manner only if the AEs exceed grade 2 (CTCAE, v. 4): Esophagitis, 
dysphagia. 
  
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials utilizing commercial agents 
as described in the table below. Please refer to the additional instructions or exceptions to expedited 
reporting immediately following the table below. Important: All AEs reported via CTEP-AERS also must 
be reported on the AE section of the appropriate case report form (see Section 12.1). 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies Utilizing Commercially Available Agents within 30 Days of the Last 
Administration of the Commercial Agent 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 


 
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RTOG 1306, Version Date July 25, 2017 
 
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 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 
(5/29/14) Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials Utilizing an Agent under a Non-CTEP-IND   
The following are protocol-specific exceptions to expedited reporting via CTEP-AERS. Report the 
following adverse events (AEs) in an expedited manner only if the AEs exceed grade 3 (CTCAE, v. 4): 
Nausea, vomiting, diarrhea, and dehydration. Report the following AEs in an expedited manner only if the 
AEs exceed grade 2 (CTCAE, v. 4): Esophagitis, dysphagia. 
 
 
8.0  
SURGERY 
Not applicable to this study. 
 
9.0  
OTHER THERAPY  
9.1 
Permitted Supportive Therapy 
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. Herbal and nutritional supplements are 
allowed, provided they do not interact with the CYP34A pathway. 
 
9.2 
 Non-permitted Supportive Therapy 
 
During concomitant chemoradiation, hematopoietic growth factors are contraindicated. 
 
 
 


 
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10.0 
TISSUE/SPECIMEN SUBMISSION (6/26/15) 
NOTE: Patients must be offered the opportunity to participate in the correlative 
components of the study, such as the optional tissue/specimen submission for banking 
and translational research.  
 
If the patient consents to participate in the tissue/specimen component of the study, the site is 
required to submit the patient’s specimens as specified in Section 10.0 of the protocol. Note: 
Sites are not permitted to delete the tissue/specimen component from the protocol or from the 
sample consent. 
 
10.1 
Tissue/Specimen Submission (6/26/15) 
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and 
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved 
through careful block storage and processing. The NRG Oncology encourages participants in 
protocol studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank 
– San Francisco provides tissue specimens to investigators for translational research studies. 
Translational research studies integrate the newest research findings into current protocols to 
investigate important biologic questions. Note: The NRG Oncology Biospecimen Bank – San 
Francisco will provide collection kits and instructions at no charge for the submission of 
specimens in this protocol. 
 
In this study, it is required that each enrolling institution screen the patient’s tissue for at 
least EGFR TK domain (exon 19 deletion, L858, and T790M) mutation and EML4-ALK 
fusion arrangement (must be done in a CLIA certified lab). The enrolling institution also must 
document the method of testing and the specific result and submit 5 unstained slides (5 micron 
thickness) to the NRG Oncology Biospecimen Bank – San Francisco for retrospective central 
review and biomarker analyses. Once all patients have been enrolled, these specimens will be 
used for EGFR and ALK testing, performed using a uniform diagnostic assay (the specific assay 
will be determined at a future date, as it may evolve during the course of this trial). 
  
For the institution’s EGFR mutation testing, any genotyping method to detect exon 19 deletion or 
L858R mutation may be used as long as it is performed in a CLIA certified laboratory. Note: The 
enrolling institution must provide the method of testing and the specific result to the Biospecimen 
Bank (i.e. specific mutation).  
 
For the institution’s ALK testing, the FDA approved Vysis dual color FISH assay must be used for 
the detection of an ALK rearrangement. Note: The enrolling institution must provide the testing 
laboratory and the specific result (% of positive cells). 
 
In addition, it is highly recommended (but optional) that archival tissues and blood specimens 
be submitted to the NRG Oncology Biospecimen Bank for banking for future translational 
research. The NRG Oncology Biospecimen Bank provides tissue specimens to investigators for 
approved studies. Translational research studies integrate the newest research findings into 
current protocols to investigate important biologic questions.   
 
 
10.2 
Tissue Submission for Retrospective Central Review of Biomarker Screening: Mandatory 
(6/26/15) 
All patients must consent to pre-entry biomarker screening of tissue for EGFR mutation 
analysis and ALK fusion arrangement by the enrolling institution (must be done in a CLIA 
certified lab).  
 
The institution must provide the following material to the NRG Oncology Biospecimen 
Bank – San Francisco for retrospective central review of biomarker screening within 42 
calendar days of enrolling the patient:  
10.2.1 One H & E stained slide per positive biopsy site (slide can be a duplicate cut stained H&E; it does 
not have to be the diagnostic slide); 


 
61  
RTOG 1306, Version Date July 25, 2017 
 
10.2.2 Five 5 micron unstained sections cut onto positive charged slides; 
 
The slides must correspond to one of the H&Es being submitted and must be clearly labeled with 
the pathology identification number that corresponds to the Pathology Report and the block id. 
10.2.3 A Pathology Report documenting that the submitted slides contain tumor; the report must include 
the NRG Oncology protocol number and the patient’s case number. The patient’s name and/or 
other identifying information should be removed from the report. The surgical pathology numbers 
and date of procedure information must NOT be removed from the report. 
• 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.2.4 A Specimen Transmittal (ST) Form stating that the tissue is being submitted for central review 
and biomarker analysis. The Form must include the NRG Oncology protocol number, the patient’s 
case number, the method used by the institution for biomarker screening, and the specific result. 
10.2.5 Retrospective central review of EGFR TK domain mutations and EML4-ALK fusion arrangement 
will be performed by the Pathology Co-Chair, Dr. Jones for patients who have been enrolled to 
the study. 
 
10.3 
Specimen Collection for Tissue Banking and Translational Research: Highly 
Recommended (but Optional) (6/26/15) 
For patients who have consented to participate in the tissue/blood component of the study (See 
sample consent). 
 
Patients must be offered the opportunity to participate in the tissue/specimen collection for 
banking and translational research. If the patient consents to participate in this component, the 
site is required to submit the patient’s specimens as specified below. Note: Sites are not 
permitted to delete the tissue/specimen component from the protocol or from the sample consent 
form. 
 
See Section 1.4 for the proposed translational research studies for this trial. 
 
The following must be provided in order for the case to be evaluable for the Biospecimen Bank:  
10.3.1 One H&E stained slide ((slide can be a duplicate cut stained H&E; it does not have to be the 
diagnostic slide)  
10.3.2 Corresponding paraffin-embedded tissue block (the block must match the H&E being submitted) 
or two 3 mm punch biopsies embedded in a new paraffin block along with a corresponding H&E 
slide of the punch block. Fifteen 5 micron unstained slides are acceptable for sites unable to 
submit blocks/punches. 
 
Note: A kit with the punch, tube, and instructions can be obtained free of charge from the NRG 
Oncology Biospecimen Bank. Block, core or slides must be clearly labeled with the pathology 
accession number and block id that corresponds to the Pathology Report. 
• 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.3.3 A Pathology Report documenting that the submitted block or core contains tumor. The report 
must include the NRG Oncology protocol number and patient’s case number. The patient’s name 
and/or other identifying information should be removed from the report. The surgical pathology 
numbers and information must NOT be removed from the report. 
10.3.4 A Specimen Transmittal Form clearly stating that tissue is being submitted for the NRG Oncology 
Biospecimen Bank- San Francisco; if for translational research, this should be stated on the form. 
The form must include the NRG Oncology protocol number and patient’s case number.  
10.3.5 Serum, Plasma, Whole Blood (see Appendix IV for collection, processing, and kit information) 
 
Prepaid labels are provided with kits. Kits can be requested from NRGBB@ucsf.edu. The 
following materials must be provided to the NRG Oncology Biospecimen Bank: A Specimen 
Transmittal (ST) Form documenting the date of collection of the biospecimen; the NRG Oncology 


 
62  
RTOG 1306, Version Date July 25, 2017 
 
protocol number, the patient’s case number, time point of study, and method of storage, for 
example, stored at -80 C, must be included.] 
10.3.6 Storage Conditions 
 
Store frozen specimens at -80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available:  
• 
Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one 
week (please ship out Monday-Wednesday only). 
OR: 
• 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only). 
OR: 
• 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only;). 
 
Please indicate on ST Form the storage conditions used and time stored. 
10.3.7 Specimen Collection Summary: 
Specimens for Central Review of Biomarker Screening (Mandatory) 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E 
stained slides of the 
primary tumor 
Pre-treatment 
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
Five 5 micron unstained 
sections cut onto positive 
charged slides 
Pre-treatment 
Five 5 micron 
unstained sections cut 
onto positive charged 
slides 
Slides shipped 
ambient. (with a cold 
pack during summer) 
 
Specimens for Banking/Translational Research (Recommended) 
Representative H&E 
stained slides of the 
primary tumor 
Pre-treatment 
H&E stained slide (can 
be additional or same 
as mandatory central 
review specimens 
listed above) 
 
Slide shipped ambient 
A paraffin-embedded 
tissue block of the 
primary tumor taken 
before initiation of 
treatment or two 3 mm 
diameter core of tissue, 
punched from the tissue 
block with a punch tool 
embedded in paraffin  
Pre-treatment 
Paraffin-embedded 
tissue block or two 
3mm punch biopsies 
embedded in paraffin  
Note: 15 unstained 
slides are acceptable 
for sites unable to 
submit blocks/punches 
(can be additional or 
same as Central 
Review specimens) 
Block or punch shipped 
ambient (with a cold 
pack during summer) 
 
SERUM: 5-10 mL of 
whole blood in red top 
tube  and centrifuge 
Pre-treatment 
Frozen serum samples 
containing 0.5 mL per 
aliquot in 1 mL 
cryovials (five to eight) 
Serum sent frozen on 
dry ice via overnight 
carrier 
PLASMA: 5-10 mL of 
anticoagulated whole 
blood in EDTA tube #1 
(purple/ lavender top) 
and centrifuge 
Pre-treatment 
Frozen plasma 
samples containing 0.5 
mL per aliquot in 1 mL 
cryovials (five to eight) 
Plasma sent frozen on 
dry ice via overnight 
carrier 
Whole blood for DNA: 5-
10 mL of anticoagulated 
Pre-treatment 
 
Frozen whole blood 
samples containing  1 
Whole blood sent 
frozen on dry ice via 


 
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RTOG 1306, Version Date July 25, 2017 
 
whole blood in EDTA 
tube #2 (purple/ lavender 
top) and mix 
Note: If site missed this 
collection time point, 
the site may collect 
whole blood for DNA at 
a later time point but 
must note this on the 
ST Form. 
ml per aliquot in 1ml 
cryovials (three to five) 
overnight carrier 
 
10.3.8 Submit materials for Central Review, Tissue Banking, and Translational Research as follows: 
 
Courier Address (FedEx, UPS, etc.): For Central Review and Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
Questions: 415-476-7864/FAX 415-476-5271;  NRGBB@ucsf.edu 
 
10.4 
Reimbursement (5/29/14) 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per 
the requirements/methods specified by the new NCTN Program. This information will be made 
available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) 
portal system. OPEN will serve as the registration system for all patient enrollments onto NCI-
sponsored NCTN trials, including this study, which will be transitioned into the new Program from 
the NCI-sponsored Cooperative Group Clinical Trials Program. 
 
10.5 
Confidentiality/Storage  
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further details.) 
10.5.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient’s 
case number only. The NRG Oncology Biospecimen Bank database only includes the following 
information: the number of specimens received, the date the specimens were received, 
documentation of material sent to a qualified investigator, type of material sent, and the date the 
specimens were sent to the investigator. No clinical information is kept in the database. 
10.5.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for the 
translational research component of this protocol will be retained until the study is terminated, 
unless the patient has consented to storage for future studies. If at any time the patient withdraws 
consent to store and use specimens, the material will be returned to the institution that submitted 
it. 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters  
 
See Appendix I for a summary of assessments and time frames. See the section below for  
 
details of evaluations and exceptions. 
 
11.2 
Details of Evaluations (6/26/15) 
11.2.1 Pre-treatment Evaluation  
• Tumor measurements: Measure in at least 1 dimension and record the longest dimension as ≥ 
10 mm with CT scan of the chest and upper abdomen. 
• 
History and physical examination must include recording of pulse, BP, weight, and body 
surface area. 
• 
A CT scan with contrast of the chest and upper abdomen to include liver and adrenals is 
required unless medically contraindicated. 
• 
A CT scan of the brain with contrast can be substituted if an MRI of the brain with contrast is 
medically contraindicated. 


 
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RTOG 1306, Version Date July 25, 2017 
 
• 
Nutritional assessment should include evaluation of the need for prophylactic gastrostomy 
tube placement if the patients is ≥ 10% below ideal body weight or is unable to swallow pills. 
11.2.2 Evaluation During Treatment  
• 
Tumor measurements: Measure in at least 1 dimension and record the longest dimension as 
≥ 10 mm with CT scan of the chest and upper abdomen.  
• 
History and physical examination must include recording of pulse, BP, weight and body 
surface area. Note: It is not necessary to change drug doses due to changes in the patient’s 
body surface area unless the calculated dose changes by ≥ 10%. 
• 
For patients on Arms 1 and 3: a CT scan of the chest and upper abdomen should be 
completed after 6 weeks of oral induction therapy and at the completion of oral induction 
therapy. 
• 
Patients on Arms 1 and 3 should have a CBC, platelets, serum creatinine, bilirubin, AST/ALT, 
alkaline phosphatase every 3 weeks during erlotinib or crizotinib. 
• 
Patients receiving paclitaxel and carboplatin should have a CBC, platelets, serum creatinine, 
and bilirubin weekly. 
• 
Patients receiving paclitaxel and carboplatin should have a CT scan of the chest and upper 
abdomen 4-6 weeks after completion of chemoradiation.  This should occur prior to 
consolidation chemotherapy.   
• 
Patients receiving cisplatin and etoposide should have a CBC, platelets, and serum 
creatinine on weeks 1, 2, 5, and 6. 
• 
For patients on Arms 1 and 3: Weekly adverse event evaluations may be done over the 
phone by the study nurse/CRA. 
11.2.3 Evaluation in Follow Up 
• 
History and physical examination must include recording of pulse, BP, weight and body 
surface area. 
• 
All patients: A CT scan of the chest and upper abdomen should be completed 4-6 weeks 
after completion of chemoradiation therapy. 
• 
All patients: After the first follow-up scan obtained 4-6 weeks after completion of 
chemoradiation therapy, a CT scan of the chest and upper abdomen should be completed 
every 3 months for 2 years, every 6 months for 3 years, then annually.  
• 
For patients on Arms 2 and 4: Adverse event evaluations 2 months after completion of 
therapy may be done over the phone by the study nurse/CRA. 
 
11.3 
Measurement of Response  
Response will be evaluated in this study using the revised RECIST guideline, v. 1.1 [European 
Journal of Cancer. 45: 228-247, 2009] will be used as a guideline to determine study eligibility. 
See http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf for further details. 
 
  
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  
 
 
• 
Measurable disease - the presence of at least one measurable lesion; If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
• 
Measurable lesions - Must be accurately measured in at least 1 dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 10 mm by 
CT scan (CT scan slice thickness no greater than 5 mm). 
• 
Non-measurable lesions - All other lesions, including small lesions (longest diameter <10 
mm or pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-
measurable lesions. Lesions considered truly non-measurable include: pleural or pericardial 
effusion, lymphangitic involvement of lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques 
 
 
 


 
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Response Criteria: Evaluation of Target Lesions 
 
  
Complete 
Response 
(CR): 
Disappearance of all target lesions; Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the 
smallest sum diameters while on study 
 
 
11.4 
Measurement/Definition of Progression/Recurrence  
 
Progression is defined as changes in known lesions that are not related to post-chemoradiation-
induced inflammation, as defined below: 
• At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study); in 
addition to the relative increase of 20%, the sum also must demonstrate an absolute 
increase of at least 5 mm. 
• Appearance of ≥ 1 new lesions also is considered progression. 
• Local progression is defined as progression within the PTV. 
• Regional progression is defined as progression outside of the PTV but within the same lobe 
of the lung as the primary tumor or in regional lymph nodes as defined by the AJCC 7th 
edition nodal stations.  
• Distant progression is defined as progression at any other site, including development of a 
malignant pleural or pericardial effusion. 
 
 
11.5 
Criteria for Discontinuation of Protocol Treatment 
• 
Unacceptable toxicity; see Section 6.0 and Section 7.0 for further information. 
• 
Progression of disease; 
• 
Development of a 2nd primary upper aerodigestive tract malignancy (eg, lung cancer, 
esophagus cancer, 2nd primary head and neck cancer);  
• 
A delay in protocol treatment, as specified in Sections 6.0 and/or 7.0. Treatment breaks, if 
necessary, ideally should not exceed 5 treatment days at a time and 10 treatment days total. 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
 
 
 
12.0 
DATA COLLECTION (5/29/14) 
This study will utilize Medidata Rave® for remote data capture (RDC) of all data. 
 
Access to the trial in Rave is granted through the iMedidata application to all persons with the 
appropriate roles in RSS.  To access iMedidata/Rave, see Section 5.0 of the protocol.     
 
Each person responsible for data entry must be on the NRG Oncology roster in order to receive 
access to Medidata Rave®.  
 
Upon initial site registration approval for the study in RSS (Regulatory Support System), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata (iMedidata-Notification@mdsol.com) to activate their account.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner 
of the iMedidata page.  Once an account is activated, eLearning modules will be available for 
Rave RDC instructions. Please note, site users will not be able to access the study in Rave until 


 
66  
RTOG 1306, Version Date July 25, 2017 
 
all required Medidata and study specific trainings are completed.  Trainings will be listed in the 
upper right pane of the iMedidata screen.   
Users that have not previously activated their iMedidata/Rave accounts will also receive a 
separate invitation from iMedidata to activate their account.  Account activation instructions are 
located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave is 
available on the CTSU website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
12.1 
Summary of Data Submission (6/24/14) 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will 
be used (first-last). Last names with apostrophes will be identified by the first letter of the last 
name. 
 
Folder 
Form/Item 
Registration via the OPEN System 
• Subject Enrollment 
Enrollment 
When pushed into RAVE there will 
be 4 forms representing 
registration 
 
• 
Eligibility Checklist 
• 
Step Information 
• 
Treatment Assignment  
• 
Demography 
 
 
Baseline 
 
• 
Baseline Labs 
• 
Diagnostic Staging 
• 
Exclusion Criteria 
• 
Lymph Node Assessment 
• 
Pathology Report 
• 
Patient History (formerly known as the A5) 
• 
Work Up 
 
RT Plan Upload 
• Digital Data-(Upload of e-mail confirmation 
from TRIAD submission required) 
 
 
Concomitant Medications 
 
• 
Concomitant Medication (only required if 
patient is taking concomitant medications) 
 
 
Week 3 (Induction)* 
 
Week 6 (Induction)* 
 
Week 9 (Induction)* 
 
Week 12 (Induction)* 
 
*Arms 1 and 3 only 
 
• 
Any Adverse Events? 
• 
Adverse Events – if any adverse events? = 
‘yes’ 
• 
Erlotinib – if enrolled to Arm 1 
• 
Crizotinib – if enrolled to Arm 3  
• 
On Treatment Labs 
• 
Patient Pill Diary–completed every 3 weeks 
by patient (print from RTOG web site) and 
uploaded to Crizotinib or Erlotinib form  
 
Concurrent Treatment 
 
• 
RT Administration 
• 
RT Treatment-if was radiation therapy given 
= ‘yes’ 
• 
RT Treatment Record- if was radiation 
therapy given = ‘yes’ (Upload of  copy of 
Daily RT Treatment Chart required) 


 
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RTOG 1306, Version Date July 25, 2017 
 
• 
Any Adverse Events? 
• 
Adverse Events – if any adverse events? = 
‘yes’ 
• 
Carboplatin (if selected during registration) 
• 
Paclitaxel (if selected during registration) 
• 
Cisplatin (if selected during registration) 
• 
Etoposide (if selected during registration) 
• 
On Treatment Labs 01 (up to 11 additional 
weeks may be added by user if needed) 
 
Consolidation Treatment* 
 
*Only appears if paclitaxel and carboplatin 
are selected during registration 
• 
Any Adverse Events? 
• 
Adverse Events – if any adverse events? = 
‘yes’ 
• 
Carboplatin 
• 
Paclitaxel 
• 
On Treatment Labs 01 (up to 11 additional 
weeks may be added by user if needed) 
 
End of All Treatment 
 
• 
End of All Treatment (this form should be 
completed for all patients after their final day 
of all protocol treatment) 
Year 1 
Follow Up 01 (month 1 post tx) 
Follow Up 02 (month 2 post tx) 
Follow Up 03 (month 3 post tx) 
Follow Up 04 (month 6 post tx) 
Follow Up 05 (month 9 post tx) 
Follow Up 06 (month 12 post tx) 
 
Year 2 
Follow Up 07 (month 15 post tx) 
Follow Up 08 (month 18 post tx) 
Follow Up 09 (month 21 post tx) 
Follow Up 10 (month 24 post tx) 
 
Years 3-5 
Follow Up 11 (month 30 post tx) 
Follow Up 12 (month 36 post tx) 
Follow Up 13 (month 42 post tx) 
Follow Up 14 (month 48 post tx) 
Follow Up 15 (month 54 post tx) 
Follow Up 16 (month 60 post tx) 
 
Years 6-10 
Follow Up 17 (month 72 post tx) 
Follow Up 18 (month 84 post tx) 
Follow Up 19 (month 96 post tx) 
Follow Up 20 (month 108 post tx) 
Follow Up 21 (month 120 post tx) 
• 
Any Adverse Events? 
• 
Adverse Events – if any adverse events? = 
‘yes’ 
• 
Patient Contacted 
• 
Follow-up - if Patient able to be Contacted 
= ’yes’ 
• 
Disease Assessment- if Documented 
clinical assessment = ‘yes’ 
• 
New Primary Cancer- If New Primary 
Cancer= ‘yes’ 
• 
Non-Protocol Treatment- if non-protocol 
cancer therapy= ‘yes’ 
• 
Pulmonary Function Tests – if PFTs 
performed = ‘yes’ 
• 
Primary Cause of Death – If Vital Status = 
‘dead’ 
 
 
CTEP-AERS 
• 
CTEP-AERS Upload Form – used by HQ to 
upload CTEP-AERS reports, sites have read 
only access to this folder/form 
Source Documentation 
• 
Source Documentation Upload – used by the 
sites in the event that source documentation 
needs to be uploaded to HQ 


 
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12.2 
Summary of Dosimetry Digital Data Submission (5/29/14) 
 
See Section 5.0 for TRIAD account access and installation instructions. 
 
Item 
Due 
Preliminary Dosimetry Information  
 
Digital Data Submission – Treatment  
Within 1 week of start of 
RT  
Digital data submission includes the following, all in DICOM format: 
 
• 
CT data, critical normal structures, all GTV, CTV, and PTV 
contours (CT Files, RT Structure File) 
 
• 
Digital beam geometry beam sets (RT Plan File) 
 
• 
Doses for  concurrently treated beams (RT Dose File) 
 
• 
Digital DVH data for all required critical normal structures, GTV, 
CTV, and PTVs for total dose plan  
• 
All required structures MUST be labeled per Table 6.5.6. 
• 
The “RTOG 1306 Datasheet” is available in the Forms section of 
the of the NRG Oncology/RTOG web site, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx
?study=1306. Submit via TRIAD with the digital data listed above. 
 
 
 
 
 
Upon submission of digital RT data via TRIAD, complete an online Digital 
Data Submission Form (DDSI Form), found on the NRG Oncology/RTOG 
web 
site 
under 
the 
‘Core 
Lab’ 
section,  
http://www.rtog.org/CoreLab/TRIAD.aspx 
 
Note: All simulation and portal films and/or digital film images will be kept 
by the institution and only submitted if requested. ) 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Primary Endpoint 
13.1.1 Progression-free survival (PFS); failure is defined as occurrence of local or regional progression, 
distant metastases, or death from any cause from the time of randomization to the occurrence of 
one of the failure events, whichever occurs first. 
 
13.2 
Secondary Endpoints 
13.2.1 Evaluation of response rates; 
13.2.2 Grade 3-5 (CTCAE, v. 4) adverse events; 
13.2.3 Overall survival (OS); failure is defined as death from any cause. 
13.2.4 Other progression-related endpoints, such as local-regional progression, distant progression; 
13.2.5 Correlation between clinical outcomes and tumor molecular aberrations identified from deep 
sequencing of selected kinomes in patients from whom adequate baseline tissue is available.  
 
13.3 
Sample Size  
The primary objective of this randomized phase II trial is to assess whether patients with 
unresectable stage III NSCLC treated with individualized therapy based on molecular 
characteristics have a longer progression-free survival (PFS) than those treated with standard 
care therapy alone. Only patients with EGFR TK mutation or EML4-ALK fusion rearrangement will 
be enrolled and randomized 1:1 to a standard arm (Arm 2 if EGFR cohort; Arm 4 if ALK cohort) or 
experimental arm (Arm 1 if EGFR cohort; Arm 3 if ALK cohort). Patients with both the EGFR 
mutation and ALK arrangement will be placed in the ALK Cohort. Patients will be stratified by 
weight loss (≤ 5% vs.  > 5%), stage (IIIA vs. IIIB), and chemotherapy (cisplatin and etoposide vs. 
paclitaxel and carboplatin). On the standard arm, patients will be treated with a combination of 


 
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chemotherapy and thoracic radiation. On the experimental arm, patients with EGFR mutation will 
be treated with erlotinib followed by concurrent chemotherapy and radiation, and patients with 
ALK translocation will be treated with crizotinib followed by concurrent chemotherapy and 
radiation. PFS is defined as the time from randomization to first documentation of progression or 
death due to any cause. Patients last known to be alive and progression free are censored at the 
date of last clinical assessment.  For both EGFR mutation and ALK translocation cohorts, the 
PFS rates for the standard arms, as well as the rates of non-analyzable (if any) may be carefully 
monitored and re-estimated at interim analysis if needed. 
 
The total number of patients to be randomized is 148 for the EGFR mutation cohort and 74 for the 
ALK translocation cohort. Taking into account 5% of registered patients who are deemed 
ineligible and withdraw from the study before randomization, we plan to enroll approximately 
156 patients to the EGFR mutation cohort and 78 patients to the ALK translocation cohort. 
13.3.1 Sample Size Justification for the EGFR Mutation Cohort 
The goal is to determine the PFS superiority of the experimental therapy relative to the standard 
therapy. In CALGB 30407 (the immediate preceding study conducted by CALGB in IIIA or IIIB 
unresectable NSCLC), the median PFS is approximately 12 months for patients on the 2 trial 
arms (chemoradiation and chemoradiation plus cetuximab). This trial aims to demonstrate a 65% 
improvement in median PFS, or 19.8 months, for the patients with an EGFR mutation on 
experimental therapy compared to patients with an EGFR mutation on standard therapy. 
Assuming constant hazards (exponential survival times), these median PFS times for patients 
with an EGFR mutation on experimental therapy (E1) and patients with an EGFR mutation on 
standard therapy (E2) correspond to a hazard ratio λE1/λE2 = 0.606 (40% relative hazard 
reduction). A design with 90% power and one-sided 15% type I error rate would require 89 
progression events to detect this effect size. Assuming approximately uniform accrual of 6 
patients per month over a 25-month period, this would result in 148 EGFR mutation patients (74 
per arm). The required 89 progression events for the superiority test will be observed within 1 
additional year of follow up after accrual completion. 
 
13.3.2 Sample Size Justification for the ALK Cohort 
The goal is to determine the PFS superiority of the experimental therapy relative to the standard 
therapy. In CALGB 30407, the median PFS is about 12 months for patients on the 2 trial arms. 
This trial aims to demonstrate that there is a 65% improvement in median PFS, or 19.8 months, 
for patients with an EML4-ALK translocation on experimental therapy relative to the same group 
of patients on standard therapy. Under constant hazards (exponential survival times), this median 
PFS times for patients with EML4-ALK translocation on experimental therapy (A1) and the same 
group of patients on standard therapy (A2) correspond to a hazard ratio  λA1/λA2  = 0.606. A 
design with 80% power and one-sided 15% type I error rate would require 58 progression events 
to detect the specified hazard ratio. Assuming approximately uniform accrual of 3 patients per 
month over a 25-month period, for a total of 74 patients with EML4-ALK translocation (37 per 
arm), the required 58 progression events for the superiority test would be observed by 1.75 
additional years of follow-up after accrual completion. 
 
13.4 
Patient Accrual  
CALGB 30407 accrued approximately 50 patients per year or 4-5 patients per month. RTOG 
0617 (phase III trial for stage III A/B NSCLC) accrued approximately 10 patients per month. With 
an increasing interest in molecular-guided lung cancer trials in  NRG Oncology and the Alliance, 
and the endorsement from other cancer cooperative groups as indicated above, we expect to 
enroll 6 patients to the EGFR mutant cohort and 3 patients to the ALK translocation cohort to the 
study per month. The prevalence rates in North America are ~10% for EGFR mutation and ~5% 
for EML4-ALK translocation. Once the target accrual is met for each mutation type, a notice 
suspending accrual for that cohort will be issued. 
 
We project that the accrual during the first 6 months will be negligible, in part due to the process 
of IRB approval and logistical arrangement for the mandatory screening of the relevant tumor 
biomarkers.  After the initial 6 month period, the accrual will be monitored on a quarterly basis 
and reviewed semi-annually by the NRG Oncology Data Monitoring Committee (DMC).  Despite 


 
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RTOG 1306, Version Date July 25, 2017 
 
our confidence that accrual goals will be met, the low prevalence of patients with EGFR mutant 
and ALK translocation tumors warrants that we closely monitor accrual, and the projected accrual 
for both cohorts may be re-estimated during the study. The study Senior Statistician will re-
evaluate the feasibility of trial completion, and make recommendations regarding corrective 
actions or closure to DMC accordingly. The trial will be considered for modification or closure due 
to poor accrual if any of the following conditions occur: 
• 
zero patients have been randomized by quarter 4; 
• 
≤ 6 patients have been randomized to the EGFR mutation cohort or ≤ 3 patients have 
been randomized to the ALK cohort by quarter 6; 
• 
≤ 18 patients have been randomized to the EGFR mutation cohort or ≤ 9 patients have 
been randomized to the ALK cohort by quarter 8. 
 
13.5 
Statistical Design for Translational Research  
The number of randomized patients with useable specimens for genomic sequencing will be 
determined, and reasons for unusable specimens will be documented. Due to the exploratory 
nature of the corrective sciences study, no formal power analysis is performed. Types and 
proportions of genomic alterations in evaluable paired specimens (tumor vs. germline DNA from 
peripheral blood) will be described. Fisher’s exact tests (Agresti 2002) will be used to compare 
the response rates between patients with and without alternations. Kaplan-Meier curves and log 
rank tests will be used to characterize the differences in OS and PFS between alterations 
subgroups. In view of the fact that approximately 20 genomic alterations subgroups could be 
potentially detected and analyzed, p-values ≤ 0.0025 would be deemed statistically significant 
using the Bonferroni method (Dunn 1961) for multiple comparisons. Alteration-alteration and 
alteration-treatment interactions may be performed depending on the limitations of sample 
size/number of events using logistic regression for response rate and Cox proportional hazard 
models for OS and PFS. A detailed plan for any additional translational research investigations 
will be submitted as an amendment to the protocol for CTEP review prior to commencement of 
such studies. 
 
13.6 
Analysis Plan  
13.6.1 Statistical Methods 
 
For the primary analysis, ineligible patients or patients who withdrew before receiving any 
protocol treatment will be excluded.  The primary endpoint is PFS, which is defined as the time 
from randomization to disease progression or death of any cause, whichever occurs first.  
 
 
The primary endpoint is progression-free survival (PFS). A rigorous definition of PFS is provided 
in Section 11.4.  Due to the limitations of PFS in solid tumors (Bhattacharya 2009), efforts will be 
made to minimize any potential bias introduced in assessment during study conduct, and 
appropriate sensitivity analyses (FDA 2007) may be conducted accordingly to assure the 
robustness of analysis results. Separate set of analysis will be conducted for each mutation type 
with comparison to the respective control arm.  
 
For these time-to-event endpoints (PFS and OS), the product limit estimator developed by Kaplan 
and Meier (1958) will be used to characterize outcomes by treatment arm. From the product limit 
estimates, median PFS and OS and 12-month PFS and OS as well as their 95% confidence 
intervals will be estimated. Comparisons between arms will be conducted using a log rank test. 
Cox proportional hazards model will be used to estimate the hazard ratio and their 95% 
confidence intervals of Arm 2 relative to Arm 1 (EGFR cohort) or Arm 4 relative to Arm 3 (ALK 
cohort) with and without adjusting for stratification factors. As an exploratory analysis, the survival 
and PFS endpoints will be related to prognostic factors, such as treatment, tumor size, 
performance status, pulmonary dysfunction, age, and weight loss, using the Cox proportional 
hazards model or an appropriate alternative in the case of model assumption violations. A step-
down procedure that consists of dropping the least significant covariates, one at a time, will be 
used to obtain a more parsimonious model. Other time to event endpoints, such as local-regional 
progression-free survival (LRPFS) and distant progression-free survival (DPFS) will be similarly 
analyzed. For these endpoints, appropriate methods for competing risks will be applied, 


 
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RTOG 1306, Version Date July 25, 2017 
 
specifically cumulative incidence functions (Kalbfleisch 2002) for estimation of cumulative cause 
specific event probabilities with associated testing for differences (Gray 1988), and regression 
methods for cause-specific hazards (Kalbfleisch 1978) and subdistribution hazards underlying 
cumulative incidence functions  (Fine 1999) may be applied accordingly for exploratory purposes.  
RPFS is defined as the time from randomization to local-regional progression or death, whichever 
occurs first, and DPFS is defined as the time from randomization to distant progression or death, 
whichever occurs first.  
 
 
The proportion of patients who respond (completely or partially) to each treatment will be 
estimated as well as their 95% confidence intervals. Response rates will be tested using Fisher’s 
exact test and using a logistic regression model (Agresti 2002) to incorporate other prognostic 
covariates. Similar analysis will be done for primary tumor control rate. 
 
The type and grade of treatment-related toxicity associated with each treatment regimen will be 
summarized using frequency table methods. 
 
The primary analysis will be based on local assessments of mutation status, which determines if 
a patient is eligible and can be randomized. The extent of agreement and cross-classification 
pattern will be evaluated between local assessment and central review for EGFR and ALK 
mutations. 
13.6.2 Interim Analysis for Futility 
 
An interim analysis for the futility hypothesis that the experimental arm is not effective as or 
unlikely to be more effective than the standard arm will be performed after half of the require 
events (44 for EGFR and 29 for ALK) has been reached. At the futility analysis, we will compare 
the distribution of the PFS of the experimental and the standard arm for each cohort. If the 
observed hazard ratio (experimental/standard) is greater than or equal to 1.0, then the 
corresponding cohort will be terminated early at the interim analysis for futility (i.e., the 
experimental arm will be considered ineffective in this disease population) and the results will be 
reported. If the observed hazard ratio of the experimental arm relative to the standard arm is less 
than 1.0, then the trial will continue to the full target accrual. Under reasonable assumptions, 
termination of the corresponding cohort for futility at the interim analysis using this rule is found to 
result in minimal loss of power (less than 2%) for the primary hypothesis test (Wieand 1994). If 
the observed hazard ratio (experimental/standard) is ≥ 1.0, a decision about whether to terminate 
accrual to the specific marker cohort and release the results will be made after consultation with 
the NRG Oncology Data Monitoring Committee (DMC) and NCI/CTEP. 
13.6.3 Toxicity Monitoring 
Erlotinib has been used extensively in the treatment of NSCLC over the past 5 years. Even 
though crizotinib has been approved for use in the United States for patients with advanced 
NSCLC whose tumor cells harbor EML4-ALK translocation, available evidence indicates that it is 
well tolerated and severe therapy-related complications are quite low. In this study, patients 
enrolled to the experimental arm will be receiving either single agent erlotinib or crizotinib before 
chemoradiation. We do not feel that it is necessary to conduct weekly monitoring for toxicities.  
13.6.4 Interim Analyses to Monitor Study Progress 
Interim reports with statistical analyses are prepared every 6 months until the initial manuscript 
reporting the treatment results has been submitted.  The reports contain: 
• 
Patient accrual rate with projected completion date (while the study is still accruing); 
• 
Total patients accrued; 
• 
Distributions of important pretreatment and prognostic baseline variables 
• 
The frequencies and severity of adverse events by treatment arm 
• 
Compliance rates of treatment delivery 
The interim reports will not contain the results from the treatment comparisons with respect to the 
efficacy endpoints (PFS, OS, etc.).  The NRG Oncology Data Monitoring Committee (DMC) will 
review the accrual to the study and the rate of adverse events on the study at least twice per year 
until the initial results of the study have been presented to the scientific community. 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative 
CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 
30, July 31, and October 31. 
 
13.7 
Gender and Minorities  
 
 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
3 
4 
7 
Not Hispanic or Latino 
91 
136 
227 
Ethnic Category: Total of all subjects 
94 
140 
234 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
3 
3 
6 
Black or African American 
10 
13 
23 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
81 
122 
203 
Racial Category: Total of all subjects 
94 
140 
234 
  


 
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RTOG 1306, Version Date July 25, 2017 
 
REFERENCES 
 
Agresti A. Categorical Data Analysis. Wiley; 2002. 
 
Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin 
for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality 
protocol. J Clin Oncol. 2005; 23(25):5883-91. Epub 2005 Aug 8. 
 
Bhattacharya, S., Fyfe, G., Gray, R. J., and Sargent, D. J. Role of sensitivity analyses in assessing 
progression-free survival in late-stage oncology trials. J Clin Oncol. 2009; 27, 5958-5964. 
 
Blackstock AW, Govindan R. Definitive chemoradiation for the treatment of locally advanced non small-
cell lung cancer. J Clin Oncol. 2007;25:4146-52. 
 
Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-
cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 
2010;11:521-9. 
 
Choy H, MacRae R, Milas L. Basic concepts of chemotherapy and irradiation interaction. In: Halperin EC, 
Perez CA, Brady LW, Schmidt-Ullrich RK, eds. Principles and practice of radiation oncology. 4th ed. 
Baltimore: Lippincott Williams and Wilkins; 2004: 736-756. 
 
Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-
small cell lung cancer: Randomized phase III trial RTOG 9410. J  Natl Cancer Inst. 2011 103(19):1452-
60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012; 104 (1):79.   
 
DeMatteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, 
primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 
2009;373:1097-104. 
 
Dunn, O.J. Multiple comparisons among means. J Am Stat Assoc.1961; 56, 52-64. 
 
Eberhard DA, Giaccone G, Johnson BE. Biomarkers of response to epidermal growth factor receptor 
inhibitors in Non-Small-Cell Lung Cancer Working Group: Standardization for use in the clinical trial 
setting. J Clin Oncol. 2008; 26: 983-94. 
 
FDA  Guidance for industry: Clinical trial endpoints for the approval of cancer drugs and biologics. 2007 
Accessed November 2011, available at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.
pdf 
 
 
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat 
Assoc. 1999; 94:496–509. 
 
Fong T, Morgensztern D, Govindan R. EGFR inhibitors as first-line therapy in advanced non-small cell 
lung cancer. J Thorac Oncol. 2008; 3: 303-10. 
 
Govindan R, Bogart J, Wang X, et al. Phase II study of pemetrexed, carboplatin, and thoracic radiation 
with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: 
CALGB 30407. J Clin Oncol. (Meeting Abstracts) 2009; 27: 7505. 
 
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann 
Statistics. 1988; 16:1141-1143. 
 
 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
REFERENCES (Continued) 
Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest 
radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung 
cancer: The Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008. 
 
Heinzerling JH, Hughes RS, Govindan R, et al. A phase I study of pemetrexed plus carboplatin or 
cisplatin with concurrent chest radiation therapy (CRT) for patients with locally advanced non-small cell 
lung cancer (LANSCLC). J Clin Oncol. (Meeting Abstracts) 2009; 27: 7545. 
 
Kalbfleisch JD, Prentice RL, Peterson AV Jr, et al. Analysis of failure times in presence of competing 
risks. Biometrika. 1978; 34:541–554. 
 
Kalbeisch,JD, Prentice RL. The Statistical Analysis of Failure Time Data, 2nd Edition, 2002; New York: 
Wiley-Interscience. 
 
Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent 
chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG 
S0023. J Clin Oncol. 2008; 26: 2450-6. 
 
Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer 
(INTEREST): a randomised phase III trial. Lancet. 2008; 372:1809-18. 
 
Klein J, Moeschberger M. Survival Analysis: Techniques for Censored and Truncated Data. Springer; 
2003. 
 
Kwak EL, Bang Y-J, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase 
inhibition in non-small-cell lung cancer. NEJM. 2010 Oct. 28;363(18):1693–1703 
 
Langer CJ, Wakelee H, Schiller J, et al. Cooperative group portfolio in locally advanced non-small-cell 
lung cancer: are we making progress? Clin Lung Cancer. 2008; 9:85-91. 
 
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. 
NEJM.  2009; 361: 947-57. 
 
Morgensztern D, Goodgame B, Baggstrom MQ, Gao F, Govindan R. The effect of FDG-PET on the stage 
distribution of non-small cell lung cancer. J Thorac Oncol. 2008; 3:135-9. 
 
Movsas B, Scott C, Langer C, et al. Randomized trial of amifostine in locally advanced non-small-cell lung 
cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology 
group trial 98-01. J Clin Oncol. 2005; 23(10): 2145-54. 
 
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to 
gefitinib therapy. Science. 2004;304:1497-500. 
 
Ready N, Janne PA, Bogart J, et al. Chemoradiotherapy and gefitinib in stage III non-small cell lung 
cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B 
(CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol. 2010; 5: 1382-90. 
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-
Positive Breast Cancer. NEJM. 2005; 353: 1673-84. 
 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell 
lung cancer. NEJM. 2006; 355: 2542-50. 
 
 


 
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REFERENCES (Continued) 
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with 
cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung 
cancer. J Clin Oncol. 2008; 26: 3543-51. 
 
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung 
cancer. NEJM. 2005; 353: 123-32. 
 
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-
small-cell lung cancer. Nature. 2007; 448: 561-6. 
 
Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung 
cancer treated with chemoradiation and bevacizumab. J Clin Oncol. 2010; 28:43-8. 
 
Vokes EE, Senan S, Treat JA, Iscoe NA. PROCLAIM: A phase III study of pemetrexed, cisplatin, and 
radiation therapy followed by consolidation pemetrexed versus etoposide, cisplatin, and radiation therapy 
followed by consolidation cytotoxic chemotherapy of choice in locally advanced stage III non-small-cell 
lung cancer of other than predominantly squamous cell histology. Clin Lung Cancer. 2009; 10: 193-8. 
 
Wheatley-Price P, Ding K, Seymour L, Clark GM, Shepherd FA. Erlotinib for advanced non-small-cell lung 
cancer in the elderly: an analysis of the National Cancer Institute of Canada Clinical Trials Group Study 
BR.21. J Clin Oncol. 2008; 26: 2350-7. 
 
Wieand S, Schroeder G, O'Fallon JR. Stopping when the experimental regimen does not appear to help. 
Stat Med. 1994; 13(13-14):1453-8. 
 
 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (6/26/15) 
*See Section 11.2 for details and exceptions 
 
 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to Treatment 
(calendar days) 
Institution’s biomarker screening 
and documentation of mutation 
X 
 
Mediastinal staging (by 
mediastinoscopy, 
mediastinotomy, EBUS-TBNS, 
EUS, or VATS) 
X 
 
Tissue submission for 
retrospective central review of 
biomarker screening 
42 
 
*Tumor measurements 
42  
 
*History/Physical exam 
45 
 
Performance status 
14 
 
Whole body FDG-PET/CT 
30 
 
*CT scan with contrast of the 
chest and upper abdomen to 
include liver and adrenals 
30 
 
*MRI of brain with contrast or CT 
scan with contrast 
30 
 
CBC/differential; ANC, platelets; 
hemoglobin 
14 
 
Creatinine clearance 
14 
 
AST/ALT, bilirubin 
14 
 
Serum pregnancy (if applicable) 
14 
 
Pulmonary consultation and 
pulmonary function testing 
 
Recommended: 56 
EKG and/or echo 
 
Recommended: 56 
Lung ventilation/perfusion scan 
+/- CT scan 
 
Recommended: 56 
*Nutritional assessment 
 
Recommended: 56 
†Tissue submission for banking 
Recommended at pre-treatment 
†Serum, plasma, & whole blood 
submission for banking 
Recommended at pre-treatment 
†For patients who consent to participate in this component of the study 
 
 
 


 
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RTOG 1306, Version Date July 25, 2017 
 
APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT (6/26/15) 
*See Section 11.2 for details and exceptions 
 
 
Assessments 
During Treatment 
 
Arms 1 and 3: q3 
weeks during 
erlotinib or 
crizotinib 
All Arms: q3 weeks during 
chemoradiation  
 
*History/Physical exam 
X 
X 
Performance Status 
X 
X 
*Tumor measurements by CT scan with 
contrast of chest & upper abdomen to 
include liver and adrenals 
After 6 weeks of 
oral induction 
therapy and at the 
completion of oral 
induction therapy 
Patients receiving paclitaxel and 
carboplatin: 4-6 weeks after 
completion of chemoradiation (see 
Section 11.2.2) 
CBC, platelets, serum creatinine, 
bilirubin, AST/AST, alk phos 
X 
 
CBC, platelets, serum creatinine, and 
bilirubin 
 
Weekly for patients receiving 
paclitaxel and carboplatin 
 
CBC, platelets, serum creatinine 
 
Weeks 1, 2, 5, and 6 for patients 
receiving cisplatin and etoposide 
Adverse event evaluation 
 Weekly; may be 
done over the 
phone by study 
nurse/CRA 
Weekly 


 
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APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP (6/26/15) 
*See Section 11.2 for details and exceptions 
 
 
Assessments 
Follow Up 
At 1 month Post-
Treatment 
At 2 mos. Post-
Treatment 
q3 mos. x 2 yrs; 
q6 mos. x 3 
years; then 
annually 
*History/Physical exam 
 
 
X 
Performance Status 
 
 
X 
CT scan with contrast of the 
chest and upper abdomen 
to include liver and 
adrenals 
4-6 weeks after completion of 
chemoradiation.  
X 
Adverse event evaluation 
X 
X* 
 
X 
 
 
 
 


 
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APPENDIX II: ZUBROD PERFORMANCE SCALE 
 
 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry work of a light or sedentary nature.  For example, light 
housework, office work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more 
of waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed  
 
5 
Death  
 


 
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APPENDIX III: AJCC STAGING SYSTEM 
 
  
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
LUNG 
 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in 
sputum or bronchial washings but not visualized by imaging or bronchoscopy 
T0 
No evidence of primary tumor.   
Tis 
Carcinoma in situ 
T1 
Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the 
main bronchus)* 
T1a 
Tumor 2 cm or less in greatest dimension 
T1b 
Tumor more than 2 cm but 3 cm or less in greatest dimension 
T2 
 
Tumor more than 3 cm but 7 cm or less with any of the following features (T2 tumors with 
these features are classified T2a if 5 cm or less):  Involves main bronchus, 2 cm or more 
distal to the carina; Invades the visceral pleura PL1 or PL2);  Associated with atelectasis 
or obstructive pneumonitis that extends to the hilar region but does not involve the entire 
lung 
T2a 
Tumor more than 3 cm but 5 cm or less in greatest dimension 
T2b 
Tumor more than 5 but 7 cm or less in greatest dimension 
T3 
Tumor more than 7 cm or one that directly invades any of the following:  parietal (PL3), 
chest wall (including superior sulcus tumors),  diaphragm, phrenic nerve, mediastinal 
pleura, parietal pericardium; or tumor in the main bronchus (less than 2 cm distal to the 
carina* but without involvement of the carina; or associated atelectasis or obstructive 
pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe 
T4 
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, 
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor 
nodules in a different ipsilateral lobe 
*The uncommon superficial spreading tumor of any size with its invasive component limited to the 
bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a. 
 
Regional Lymph Nodes (N) 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph nodes metastasis 
N1 
Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and 
intrapulmonary nodes including involvement by direct extension 
N2 
Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) 
N3 
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s) 
 
 
 


 
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APPENDIX III (Continued) 
 
AJCC STAGING SYSTEM 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
LUNG 
 
Distant Metastasis   (M) 
M0 
 
No distant metastasis 
M1 
 
Distant metastasis  
M1a 
Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant 
pleural (or pericardial) effusion* 
M1b 
Distant metastasis 
* Most pleural (and pericardial effusions with lung cancer are due to tumor. In a few patients, however, 
multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is 
nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is 
not related to the tumor, the effusion should be excluded as a staging element, and the patient should be 
classified as M0. 
 
 
STAGE GROUPING  
Occult Carcinoma 
TX, N0, M0 
Stage 0 
Tis, N0, M0 
Stage IA 
T1a-b, N0, M0 
Stage IB 
T2a, N0, M0 
Stage IIA 
T2b, N0, M0 
 
T1a-b, N1, M0 
 
T2a, N1, M0 
Stage IIB 
 
T2b, N1, M0 
 
T3, N0, M0 
Stage IIIA 
T1a-b, N2, M0 
 
T2a-b, N2, M0 
 
T3, N1-2, M0 
 
T4, N0-1, M0 
Stage IIIB 
T1a-b, N3, M0 
 
T2a-b, N3, M0 
 
T3, N3, M0 
 
T4, N2-3, M0 
Stage IV 
Any T, Any N, M1a-b 
 
 
  


 
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APPENDIX IV:  BIOSPECIMEN COLLECTION (6/26/15) 
 FFPE Specimen Plug Kit Collection 
 Blood Collection Kit Instructions 
 
Shipping Instructions: 
Courier Address (FedEx, UPS, etc.): For Frozen and Trackable Central Review 
Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341  
San Francisco, CA 94115 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal (ST) Form has the consent boxes checked off.  
 
Check that all samples are labeled with the NRG Oncology study and case number, and include 
date of collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top 
of the container. If you can hear the slides shaking it is likely that they will break during 
shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do 
not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you 
shake the container the blocks are not shaking. If you can hear the blocks or slides shaking it is 
likely that they will break during shipping.   
o 
Slides, Blocks, or Plugs can be shipped ambient or with a cold pack during the warmer 
seasons. For required central review material should only be shipped  by Courier to the 
Street Address (94115). Do NOT ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate 
bag and clearly identified. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at 
least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of 
specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two 
separate boxes. Any Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and 
the site will be notified.  
o Send frozen specimens via overnight courier to the address above. Specimens should only be 
shipped Monday through Wednesday to prevent thawing due to delivery delays. Saturday or 
holiday deliveries cannot be accepted. Samples can be stored frozen at -80 C until ready to 
ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology 
Biospecimen Bank by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-
5271. 


 
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APPENDIX IV (Continued) 
 
FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen 
Bank – San Francisco. The plug kit contains a shipping tube and a punch tool.    
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at 
room temperature. Place the punch tool on the paraffin block over 
the selected tumor area. (Ask a pathologist to select area with 
tumor.) Push the punch into the paraffin block. Twist the punch tool 
once around to separate the plug from the block. Then pull the 
punch tool out of the block. The punch should be filled with tissue 
sample. Site are to embed the punches before shipping and 
include an H&E slide of the new block. Label the new block with 
accession number and block id 
 
 
 
Step 2-3: For sites that are unable to embed the punches: 
Label the punch tool with the proper specimen ID and block id.  
DON’T remove specimen from the punch. 
 
 
Use a separate punch tool for every specimen. Call or e-mail us if 
you have any questions or need additional specimen plug kits. 
 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to 
address below. Please do not mix specimens in the same tube.    
We will remove core specimen from the punch, embed in a paraffin 
block, and label with specimen ID. 
 
 
 
   
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank – San Francisco and we will sample a plug 
from the block and return the remaining block to your facility.  Please indicate on the submission form the 
request to perform the plug procedure and return of the block and include a return label. 
Ship punch block with H&E or specimen plug kit, specimen in punch tool, and all paperwork to the 
address below. For Questions regarding collection/shipping or to order an FFPE Specimen Plug 
Kit, please contact the NRG Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.edu or call 415-
476-7864/Fax 415-476-5271. 
 
Courier Address (FedEx, UPS, etc.): For Central Review and Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 


 
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2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-RTOG (7864) or e-mail: NRGBB@ucsf.edu  
APPENDIX IV (Continued) 
 
 BLOOD COLLECTION KIT INSTRUCTIONS 
 
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as 
specified by the protocol): 
 
Kit contents: Note: Sites must provide their own blood draw tubes. If a site is unable to provide 
the blood draw tubes they must request the tubes be included  when they request the kit. 
• 
Twenty-one (21) 1 ml cryovials 
• 
Biohazard bags (3) and Absorbent shipping material (3) 
• 
1 Styrofoam container (inner) and 1 Cardboard shipping (outer) box 
• 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
• 
Specimen Transmittal (ST) Form  and Kit Instructions 
 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
(A) Serum (if requested): Red Top Tube 
 
Label as many 1ml cryovials (5 to 8) as necessary for the serum collected. Label them with 
the NRG Oncology study and case number, collection date, time, and time point, and clearly 
mark cryovials “serum”. 
Process: 
1. Allow one red top tube to clot for 30 minutes at room temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites 
are unable to process samples at 4C then spinning at room temperature is acceptable if 
done within 2 hours of draw but must be noted on the ST Form. 
3. Aliquot 0.5 ml serum into as many cryovials as are necessary for the serum collected (5 to 8) 
labeled with NRG Oncology study and case numbers, collection date/time, protocol time-point 
collected (e.g. pretreatment, post-treatment), and clearly mark specimen as “serum”. 
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen 
until ready to ship. See below for storage conditions. 
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form. 
 
(B) Plasma (If requested): Purple Top EDTA tube #1 
 
Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with 
the NRG Oncology study and case number, collection date, time, and time point, and clearly 
mark cryovials “plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 
RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted 
on the ST Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one 
hour, keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the 
plasma collected (5 to 8)  labeled with NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “plasma”.  Avoid pipetting up the 
buffy coat layer. 
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C. 


 
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6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 
 
APPENDIX IV (Continued) 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form. 
 
 BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 
 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with 
the NRG Oncology study and case number, collection date/time, and time point, and clearly mark 
cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can 
also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the 
blood collected (3 to 5) labeled with NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
ST Form. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
▪ 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only). 
OR: 
▪ 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(please ship out on Monday-Wednesday only). 
OR: 
▪ 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
 
 


 
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APPENDIX IV (Continued) 
 
 BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday to prevent thawing due to delivery 
delays. Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the 
Styrofoam box. 
 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard 
bag.  Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg 
minimum).  Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 
 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-
mail NRGBB@ucsf.edu or call (415) 476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu