Clinical trial NCT01622868
Conditions: HER2-Positive Breast Carcinoma Invasive Breast Carcinoma Metastatic Malignant Neoplasm in the Brain Recurrent Breast Carcinoma Stage IV Breast Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)
Start date: 2012-12-06; Completion date: 2022-05-20
Enrollment: 143 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well whole-brain radiation therapy or stereotactic radiosurgery with or without lapatinib ditosylate works in treating patients with breast cancer that has too many of a protein called human epidermal growth factor receptor 2 (HER2) on its cells and has spread to the brain. Radiation therapy uses high energy x rays to kill tumor cells and shrink tumors. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may kill more tumor cells and cause less damage to normal tissue. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether whole-brain radiation therapy or stereotactic radiosurgery together with lapatinib ditosylate is an effective treatment for brain metastasis from breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine if there is a signal for an increase in complete response (CR) rate in the measurable brain metastases at 12 weeks post radiation therapy (RT) (whole brain or stereotactic radiosurgery \[SRS\]) as determined by magnetic-resonance imaging (MRI) scan of the brain, with the addition of lapatinib (lapatinib ditosylate) to whole-brain radiation therapy (WBRT)/SRS compared to WBRT/SRS alone.

SECONDARY OBJECTIVES:

I. To evaluate CR rate of the measurable brain metastases at 4 weeks post RT (WBRT/SRS) as determined by MRI scan of the brain, with the addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

II. To evaluate objective response rate of measurable brain metastases at 4 and 12 weeks post RT (WBRT/SRS) as determined by MRI scan of the brain, with the addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

III. To evaluate targeted lesion-specific objective response rate (CR + partial response \[PR\]) at 4 and 12 weeks post WBRT/SRS.

IV. To evaluate central nervous system (CNS) progressive disease outside the targeted measurable disease with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

V. To evaluate targeted lesion-specific progression at 4 and 12 weeks post WBRT/SRS.

VI. To evaluate treatment related adverse events when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

VII. To evaluate overall CNS complete response: disappearance of all CNS target lesions sustained for at least 4 weeks; with no new lesions, no use of corticosteroids, and patient is stable or improved clinically, when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

VIII. To evaluate overall CNS progressive disease (within or outside targeted measurable disease) with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

IX. To evaluate overall survival when adding lapatinib to WBRT/SRS compared to WBRT/SRS alone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments or SRS for 1 treatment.

ARM B: Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate orally (PO) once daily (QD) for 6 weeks.

After completion of study treatment, patients are followed up at 4 and 12 weeks and then every 12 weeks thereafter.

Arms: arm 1: Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments, or SRS for 1 treatment. arm 2: Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate PO QD for 6 weeks.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Lapatinib Ditosylate intervention 3: Stereotactic Radiosurgery intervention 4: Whole-Brain Radiotherapy
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Undergo SRS intervention 4: Undergo WBRT

Protocol documents:
Prot_SAP_000.pdf: 
For Protocol Amendment 10 of RTOG 1119, Phase II Randomized Study of Whole Brain 
Radiotherapy/Stereotactic Radiosurgery in Combination With Concurrent Lapatinib In Patients With Brain 
Metastasis From HER2-Positive Breast Cancer- A COLLABORATIVE STUDY OF NRG Oncology AND KROG. 
 
NCI/Local Protocol #: RTOG-1119/RTOG 1119 
NCI Protocol Version Date:  April 2, 2019 
 
 
Section 
Change 
Document 
Footer  
The protocol version date was updated. 
Document 
History table 
This amendment was added. 
Title Pages 
 
Dr. Daniel Boulter’s contact information has been updated. 
Dr. Jennifer De Los Santos’s contact information has been updated 
CTSU Contact 
Information 
table 
 
Updated per current NCTN/CTSU standard text. 
7.2 
 
Due to a Request for Amendment (RA) from CTEP for studies using Lapatinib the 
Comprehensive Adverse Events and Potential Risks (CAEPR) list for lapatinib was 
updated.  As part of the implementation of version 5.0 of the Common Terminology 
Criteria for Adverse Events (CTCAE), the CAEPR list for lapatinib, which was 
previously in CTCAE 4.0 language (version 2.7), has been migrated to CTCAE 5.0 
language (version 2.8).  There is no new or modified risk information for Lapatinib. 
7.6 
The last two paragraphs were removed due to redundancy with Section 7.7 and to 
adhere to current NRG Oncology standard language. 
10.3 
This section is deleted as the reimbursement information is posted on the CTSU 
website; the remainder of this section was renumbered accordingly. 
 
 


1 
RTOG 1119, version date April 2, 2019 
NRG ONCOLOGY 
 
RTOG 1119 
 
PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY/STEREOTACTIC 
RADIOSURGERY IN COMBINATION WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN 
METASTASIS FROM HER2-POSITIVE BREAST CANCER - A COLLABORATIVE STUDY OF NRG 
ONCOLOGY AND KROG 
 
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 (02-APR- 2019) 
 
 
Protocol Agent  
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Lapatinib 
NCI/PMB 
727989 
70252 
NCI/DCTD 
 
 
Principal Investigator/Radiation Oncology  
In Ah Kim, MD, PhD 
Department of Radiation Oncology 
Seoul National University Bundang Hospital 
173 Gumiro, 
Seongnamsi, Kyeonggido, South Korea, 13620 
Phone: 82-31-787-7651/Fax: 82-31-787-4019 
Email: inah228@snu.ac.kr 
 
Radiation Oncology Co-Chairs 
Jennifer De Los Santos, MD 
3670 Grandview Parkway 
Suite 100 
Birmingham, Al 35243 
Phone: 205-971-1804/Fax: 205-978-3928 
E-mail: jdelossantos@grandviewhealth.com 
 
Paul Sperduto, MD, MPP 
Ridgeview Regional Radiation Oncology 
560 S. Maple Street, Suite 10 
Waconia, MN 55387 
Phone: 952-442-6000/Fax: 952-442-7851 
E-mail: psperduto@mropa.com 
 
Medical Oncology Co-Chair 
David Peereboom, MD 
Cleveland Clinic Main Campus 
Mail Code CA5  
9500 Euclid Avenue 
Cleveland, OH 44195 
Phone: 216-445-6068/Fax: 216-444-9464  
E-mail: peerebd@ccf.org 
 
 
 
Medical Physics Co-Chair 
Tomi Ogunleye, MS, DABR 
Northside Hospital Cancer Institute Department 
of Radiation Oncology 
1000 Johnson Ferry Rd NE Atlanta, GA 30342 
Phone: 770-292-7065/Fax: 770-292-7002 
E-mail: tomi.ogunleye@northside.com 
 
Neuroradiology Co-Chair 
Daniel Boulter, MD 
The Ohio State University Wexner Medical 
Center 
395 W. 12th Avenue, Room 489 
Columbus, OH 43210 
Phone: 614-293-8315/Fax: 614-293-6935 
Email: daniel.boulter@osumc.edu 
 
Senior Statistician 
Kathryn Winter, MS 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
Phone:215-574-3198/Fax: 215-928-0153 
Email: winterk@nrgoncology.org 


2 
RTOG 1119, version date April 2, 2019 
 
 
 
PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY/STEREOTACTIC 
RADIOSURGERY IN COMBINATION WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN 
METASTASIS FROM HER2-POSITIVE BREAST CANCER - A COLLABORATIVE STUDY OF NRG 
ONCOLOGY AND KROG 
 
 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 10 
April 2, 2019 
N/A 
Amendment 9 
February 14, 2018 
N/A 
Amendment 8 
February 8, 2018 
N/A 
Amendment 7 
October 10, 2016 
October 17, 2016 
Amendment 6 
September 7, 2016 
October 17, 2016 
Amendment 5 
July 22, 2016 
October 17, 2016 
Amendment 4 
March 23, 2016 
April 6, 2016 
Amendment 3 
October 22, 2014 
November 10, 2014 
Amendment 2 
September 2, 2014 
November 10, 2014 
Update 
April 17, 2014 
April 17, 2014 
Amendment 1 
November 26, 2013 
December 12, 2013 
Update 
October 8, 2012 
October 8, 2012 
Update 
July 26, 2012 
July 26, 2012 
Activation 
July 19, 2012 
July 26, 2012 
 
 
 
    
NRG Oncology 
1-800-227-5463, ext. 4189 
  
  
NRG ONCOLOGY 
 
RTOG 1119 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 


3 
RTOG 1119, version date April 2, 2019 
PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY/STEREOTACTIC 
RADIOSURGERY IN COMBINATION WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN 
METASTASIS FROM HER2-POSITIVE BREAST CANCER - A COLLABORATIVE STUDY OF NRG 
ONCOLOGY AND KROG 
 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION (02-APR- 2019) 
To submit registration 
documents:   
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact  the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
 
 
 
 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com 
Submit study data to: 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA  19103 
 
Submit data electronically via 
the NRG Oncology/RTOG web 
site, www.rtog.org 
 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
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 patient eligibility or treatment-related questions 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.  
The CTSU Website is located at https://www.ctsu.org. 
 


4 
RTOG 1119, version date April 2, 2019 
 
TABLE OF CONTENTS 
 
 
 
SCHEMA ....................................................................................................................................................... 6 
ELIGIBILITY CHECKLIST ............................................................................................................................. 7 
1.0 
INTRODUCTION ............................................................................................................................. 11 
1.1  
Central Nervous System (CNS) Disease in Patients With HER2-overexpressing Breast  ......... 11 
1.2.  
Standard Treatment for Brain Metastases .................................................................................. 11 
1.3 
Lapatinib ...................................................................................................................................... 12 
1.4 
Rationale for the Use of Lapatinib in the Treatment of Brain Metastasis.................................... 12 
1.5  
Rationale for Concurrent Use of Lapatinib and Radiation .......................................................... 14 
1.6 
Summary ..................................................................................................................................... 20 
1.7 
Rationale for Collaborative Studies in the US and Korea ........................................................... 20 
1.8 
Rationale for Allowing Prior Use of Lapatinib  ............................................................................. 20 
2.0 
OBJECTIVES .................................................................................................................................. 20 
2.1 
Primary Objective ........................................................................................................................ 20 
2.2 
Secondary Objectives ................................................................................................................. 21 
3.0 
PATIENT SELECTION .................................................................................................................... 21 
3.1 
Conditions for Patient Eligibility ................................................................................................... 21 
3.2 
Conditions for Patient Ineligibility ................................................................................................ 22 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT...................................................................... 23 
4.1 
Required Evaluations/Management ............................................................................................ 23 
5.0 
REGISTRATION PROCEDURES ................................................................................................... 23 
5.1  
Regulatory Pre-Registration Requirements ................................................................................ 24 
5.2  
OPEN Registration  ..................................................................................................................... 26 
5.3 
Digital RT Data Submission to NRG Oncology Using TRIAD  .................................................... 26 
5.4 
In order to utilize Stereotactic Radiosurgery (SRS) with a Gamma Knife .................................. 27 
6.0 
RADIATION THERAPY SRS/WBRT (ARMS A AND B)  ................................................................ 28 
6.1 
Radiation Therapy Schema  ........................................................................................................ 28 
6.2 
Treatment Technology  ............................................................................................................... 28 
6.3 
Immobilization and Simulation  ................................................................................................... 28 
6.4 
Imaging for Structure Definition, Image Registration/Fusion and Follow-up  ............................. 29 
6.5 
Definition of Target Volumes and Margins  ................................................................................. 29 
6.6 
Definition of Critical Structures and Margins  .............................................................................. 30 
6.7 
Dose Prescription  ....................................................................................................................... 31 
6.8 
Compliance criteria  .................................................................................................................... 32 
6.9       Treatment Planning Priorities and Instructions  .......................................................................... 33 
6.10 
Patient specific QA  ..................................................................................................................... 33 
6.11     Daily Treatment Localization/IGRT  ............................................................................................ 34 
6.12 
Case Review  .............................................................................................................................. 34 
6.13 
Radiation Therapy Adverse Events ............................................................................................ 34 
6.14 
Radiation Therapy Adverse Event Reporting .............................................................................. 34 
7.0 
DRUG THERAPY ............................................................................................................................ 34 
7.1 
Treatment With Lapatinib (Arm B patients only) ......................................................................... 35 
7.2 
Lapatinib Agent Information (NSC # 727989, IND # 70252)  ...................................................... 35 
7.3 
Clinical Trials Agreement ............................................................................................................ 41 
7.4 
Dose Modifications  ..................................................................................................................... 42 
7.5 
Modality Review .......................................................................................................................... 44 
7.6 
Adverse Events  .......................................................................................................................... 44 
7.7 
CTEP-AERS Expedited Reporting Requirements ...................................................................... 45 
8.0 
SURGERY ....................................................................................................................................... 47 
9.0 
OTHER THERAPY .......................................................................................................................... 48 
9.1 
Permitted Therapy ....................................................................................................................... 48 
9.2 
Non-Permitted Therapy  .............................................................................................................. 49 


5 
RTOG 1119, version date April 2, 2019 
10.0 
TISSUE/SPECIMEN SUBMISSION ................................................................................................ 49 
10.1 
Tissue/Specimen Submission  .................................................................................................... 50 
10.2 
Specimen Collection for Banking for Future Research  .............................................................. 50 
10.3 
Confidentiality/Storage ................................................................................................................ 51 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 52 
11.1 
Study Parameters: See Appendix I for a summary of time frames and assessments ................ 52 
11.2 
Measurement of Response  ........................................................................................................ 52 
11.3 
Central Review  ........................................................................................................................... 53 
11.4 
Criteria for Discontinuation of Protocol Treatment ...................................................................... 53 
12.0 
DATA COLLECTION ....................................................................................................................... 53 
12.1 
Summary of Data Submission .................................................................................................... 53 
12.2 
Summary of Dosimetry Digital Data Submission for SRS ONLY ................................................ 55 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 55 
13.1 
Endpoints  ................................................................................................................................... 55 
13.2 
Stratification ................................................................................................................................ 56 
13.3 
Sample Size and Power Justification  ......................................................................................... 56 
13.4 
Analysis Plan  .............................................................................................................................. 57 
13.5 
Gender and Minorities ................................................................................................................. 59 
REFERENCES ............................................................................................................................................ 61 
APPENDIX I  ............................................................................................................................................... 65 
APPENDIX II ............................................................................................................................................... 67 
APPENDIX III .............................................................................................................................................. 68 
APPENDIX IV .............................................................................................................................................. 74 
APPENDIX V  .............................................................................................................................................. 75 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
6 
RTOG 1119, version date April 2, 2019 
NRG ONCOLOGY 
 
 
RTOG 1119 
 
PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY/STEREOTACTIC 
RADIOSURGERY IN COMBINATION WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN 
METASTASIS FROM HER2-POSITIVE BREAST CANCER – A COLLABORATIVE STUDY OF NRG 
Oncology AND KROG 
 
SCHEMA (7/22/16) 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
Graded Prognostic 
Assessment (GPA) 
Score:  
1.5-2 vs. 2.5-3 vs. 3.5-4 
 
 
Use of Non-CNS–
Penetrating HER2 
Blockade at Study Entry: 
No vs. Yes: trastuzumab 
± pertuzumab 
 
RT to Be Used: 
WBRT vs SRS 
 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm A 
Radiation (WBRT or SRS) 
 
Versus 
 
Arm B 
Radiation (WBRT or SRS) 
Plus 
Lapatinib 
 
 
 
See Section 6.0 for details of radiation therapy and Section 7.0 for details of drug therapy. 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility) (08-FEB-2018) 
Pathologically (histologically or cytologically) proven diagnosis of invasive HER2-overexpressing breast 
cancer (3+ staining by immunohistochemistry or HER2 gene amplification by FISH or SISH ≥ 2.0). At 
least one measurable, , unirradiated parenchymal brain lesion (See Section 3.1 for details). 
 
Required Sample Size: 143 


 
7 
RTOG 1119, version date April 2, 2019 
 
 
ELIGIBILITY CHECKLIST (08-FEB-2018) 
 
 
 
 
 
 
(page 1 of 4) 
NRG Oncology Institution #   
 
RTOG 1119 
 
 
 
 
 
 
 
 
     
        
Case # 
 
 
(Y) 
1. Does the patient have pathologically (histologically or cytologically) proven 
diagnosis of invasive breast cancer? 
 
 
(Y) 
2. Is the breast cancer HER2 overexpressing (3+ staining by immunohistochemistry 
or HER2 gene amplification by FISH or SISH ≥ 2.0)? 
 
 
(Y) 
3. Does the patient have at least 1 measurable, , unirradiated parenchymal brain 
metastasis per section 3.1.3. (For a single solitary lesion the size must be ≥ 10 
mm; for 2 or more lesions, the size of at least 2 lesions must be ≥ 5mm) within 21 
days prior to study entry? 
 
 
 
(Y/N) 
4. Does the patient have progressive parenchymal brain metastases following 
stereotactic radiosurgery for 1-3 brain metastases, with at least 1 new 
measurable brain lesion? 
 
 
(Y/N) 
5. Does the patient have progressive parenchymal brain metastases following 
surgical resection of 1-3 brain metastases, with at least 1 measurable brain 
lesion? 
 
 
(Y) 
6. Has the patient had a history/physical examination within 21 days prior to study 
entry? 
 
 
(Y) 
7. Is the patient’s Karnofsky performance status ≥60 within 21 days prior to study 
entry? 
 
 
(Y) 
8. Is the patient’s age ≥ 18? 
 
 
(Y) 
9. Is the patient able to swallow and retain oral medication? 
 
 
(Y) 
10. Does the patient have adequate hematologic, renal, hepatic function within 21 
days prior to study entry, as defined in section 3.1.9? 
 
 
(Y/N) 
11. Is the patient a woman of childbearing potential? 
 
 (Y) 
If yes, was there a negative serum pregnancy test within 21 days prior to study 
entry? 
 
 (Y) 
If yes, is the patient, if sexually active, willing to practice adequate contraception 
during therapy and for 12 months after protocol treatment completion? 
 
 
(Y/N) 
12. Is the patient male? 
 
(Y) 
If yes, is the patient, if sexually active, willing to practice adequate contraception 
during therapy and for 12 months after protocol treatment completion? 
 
 
(N) 
13. Has the patient had prior WBRT? 
 
 
(Y/N) 
14. Has the patient had prior lapatinib therapy? 
 
 
 
If yes, does the patient meet the prior lapatinib requirements in section 3.1? 
 
 
 


 
8 
RTOG 1119, version date April 2, 2019 
 
 
ELIGIBILITY CHECKLIST (10/22/14) 
 
 
 
 
 
 
(page 2 of 4) 
NRG Oncology Institution #   
 
RTOG 1119 
 
 
 
 
 
 
 
 
     
        
Case # 
 
 
 
 
(N) 
15. Does the patient have uncontrolled intercurrent illness including, but not limited 
to, ongoing or active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements? 
 
 
(Y/N) 
16. Has the patient had a prior invasive malignancy (except non-melanomatous skin 
cancer, curatively resected thyroid papillary carcinoma, and invasive and non-
invasive cancers related to the breast cancer)? 
 
(Y) 
If yes, has the patient been disease free for a minimum of 3 years? 
 
 
(N) 
17. Does the patient have leptomeningeal disease? 
 
 
(N) 
18. Has the patient had prior radiotherapy to the region of the study cancer that 
would result in overlap of radiation therapy fields except patients who have 
progressed following stereotactic radiosurgery for 1-3 brain metastases, with at 
least 1 new lesion? 
 
 
(N) 
19. Has the patient ever received prior RT(any site) with concurrent lapatinib per 
section 3.2? 
 
 
(N) 
20. Does the patient have any comorbidities described in section 3.2.6? 
 
 
(N) 
21. Does the patient have ≥ grade 2 rash of any cause at the time of study entry? 
 
 
(N) 
22. Does the patient have ≥ grade 2 diarrhea of any cause at the time of study entry? 


 
9 
RTOG 1119, version date April 2, 2019 
 
 
NRG Oncology Institution #   
 
RTOG 1119 
 
 
 
ELIGIBILITY CHECKLIST (10/22/14) 
Case #  
 
 
 
 
     (page 3 of 4) 
 
 
The following questions will be asked at Study 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 Initials (First Middle Last)  
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date 
 
 
         
18. 
Medical oncologist’s name  


 
10 
RTOG 1119, version date April 2, 2019 
 
NRG Oncology Institution #   
 
RTOG 1119 
 
 
 
 
ELIGIBILITY CHECKLIST  (08-FEB-2018) 
Case #  
 
 
 
 
     (page 4 of 4) 
 
 
              (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? 
  
               
24. 
Graded prognostic factor (GPA)? (1.5-2 or 2.5-3 or 3.5-4)  
(See Appendix IV for scoring)  
 
              (Y/N) 25. 
Use of non-CNS–penetrating HER2 blockade at study Entry (Yes = trastuzumab  
 
 
 
± pertuzumab; No = None) 
 
               
26. 
RT to be used (WBRT or SRS) 
 
 
 
(1/2) 
(Credentialing Required for SRS) 
1. WBRT (no limit on number of metastases) 
2. SRS? (no more than 10 metastases permitted) 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
11 
RTOG 1119, version date April 2, 2019 
1.0 INTRODUCTION 
 
 
1.1  
Central Nervous System (CNS) Disease in Patients With HER2-overexpressing Breast 
Cancer 
Human epidermal growth factor receptor 2 (HER2)–positive breast cancer is a disease 
with distinct clinicopathological features and accounts for 25% to 30% of all invasive 
breast cancer. HER2-positive breast cancer is characterized by a particularly aggressive 
course whose natural history (Slamon 1987), however, has been dramatically improved 
since the introduction of trastuzumab, an anti-HER2 monoclonal antibody (Dawood 2010). 
 
HER2 overexpression is known to be associated with an increased risk of brain 
metastasis both as the site of first relapse (4.3% vs. 0.4%) (Kallioniemi 1991) and of 
eventual relapse. Autopsy data show that the incidence for CNS metastasis in HER2-
positive breast cancer is higher (up to 50%) than that in HER2-negative breast cancer 
patients (Aragon-Ching 2007). On the other hand, a retrospective study on 9524 patients 
with early breast cancer identified HER-2 positivity as a clear risk factor for development 
of CNS relapse (Pestalozzi 2006). However, the precise biologic mechanism for the 
tendency of HER2-positive cancer cells to metastasize to the CNS has not been 
completely elucidated. 
 
The advent of trastuzumab has radically altered outcomes, such that patients are 
surviving longer and the pattern of relapse is changing (Piccart-Gebhart, 2005). 
Trastuzumab levels in cerebrospinal fluid are 300-fold lower than those in plasma 
(Pestalozzi 2000, Rusnak 2001), indicating that trastuzumab cannot cross the blood-brain 
barrier due to its high molecular weight (145,531 Da). The limited penetration of 
trastuzumab into the blood-brain barrier may contribute to the increased incidence of 
brain metastasis in patients with HER-2 positive breast cancer and CNS progression and 
is now emerging as a major clinical issue. An analysis of 523 metastatic breast cancer 
patients who enrolled in 2 clinical trials of first-line trastuzumab demonstrated a 10% 
incidence of isolated CNS progression, with a higher incidence of brain metastasis 
among the patients with HER2-positive breast cancer (Burstein 2004). As many as one-
third of patients with HER2-positive metastatic breast cancer are now developing CNS 
disease despite receiving trastuzumab-based therapy (Bendell 2003, Clayton 2004, Lai 
2004, Stemmler 2007, Gori 2007, Kennecke 2010). In contrast, the incidence of CNS 
metastasis in historical series was only 10% to 16% (Hagemeister 1980, Tsukada 1983, 
Patanaphan 1988). These increased incidences of CNS events reflect not only the 
inherent behavior of HER2-positive tumors but also improved survival in these patients, 
which allowed more CNS events to become clinically evident before death (Clayton 2004). 
In a recent 400-patient multi-institutional analysis (Sperduto 2011; Sperduto in press), 
57% of newly diagnosed breast cancer patients with brain metastases (225/400) were 
HER-2 positive. Half of these patients died of intracranial disease progression rather than 
extracranial disease following initial standard therapy with WBRT or stereotactic 
radiosurgery (Bendell 2006). Therefore, in these patients, if CNS control can be 
enhanced by more effective treatment, survival could putatively be improved. 
 
 
1.2.  
Standard Treatment for Brain Metastases  
The selection of initial treatment for brain metastasis depends on the number and size of 
metastases and the status of systemic disease. For patients presenting with a single 
brain metastasis with no or stable systemic disease, surgical resection showed improved 
survival in 2 of 3 randomized clinical trials (Patchell 1990, Vecht 1993, Noordijk 1994). 
Stereotactic radiosurgery (SRS) could be a reasonable alternative to surgical resection 
for patients with single, small (<3 cm), asymptomatic lesions (Shaw 2000, O’Neill 2003, 
Varlotto 2003). In randomized trials of WBRT plus SRS versus WBRT alone, significant 
survival benefit was observed for patients with a single brain metastasis when SRS was 
added to WBRT; a clear survival benefit has not been demonstrated among patients with 


 
12 
RTOG 1119, version date April 2, 2019 
2 or more brain metastases, although addition of SRS resulted in improved local tumor 
control, symptoms, and performance status (Andrews 2004, Kondziolka 1999).  
 
For patients who presented with greater than 3 brain metastases or who have limited 
brain metastases associated with disseminated disease with poor systemic options, 
WBRT is the standard treatment option, although, in practice, SRS alone is also used for 
these patients by some physicians at some centers. WBRT has shown improvement in 
survival (median survival of 4-5 months) and quality of life compared to corticosteroid use 
alone (Lagerwaard 1999, Fokstuen 2000, Mahmoud-Ahmed 2002). In 2 series, median 
survival of unselected patients with HER2-positive breast cancer was 13 to 16 months, a 
rate comparable to the survival reported in selected patient groups who underwent 
resection for solitary brain metastasis. Suh et al also observed a higher overall response 
rate in the HER2-positive subgroup compared to that of the entire cohort of 183 patients 
following WBRT (37% vs. 27% at 3 months) (ASTRO proceeding 2008).   
 
As patients with HER2-positive breast cancer live longer, CNS progression after radiation 
therapy is an emerging issue. Therefore, more effective treatment approaches for this 
group of patients is needed. 
 
1.3 
Lapatinib 
Lapatinib ditosylate (GW572016/Tykerb®; GlaxoSmithKline, Research Triangle Park, 
NC) is a small molecule reversible inhibitor of the intracellular tyrosine kinase domain of 2 
members of the HER family, HER1 (also known as epidermal growth factor receptor 
[EGFR]) and HER2. It has been shown to be a potent and selective inhibitor of EGFR 
and HER2 tyrosine kinase activity, with IC50 values of 10.2 and 9.8 nM, respectively. It 
has demonstrated selective growth inhibition of human cell lines, and inhibition of cell 
growth was correlated with inhibition of phosphorylation of Akt by lapatinib. Inhibition of 
EGFR by lapatinib resulted preferentially in cell growth arrest, while inhibition of HER2 
led to cell growth arrest and apoptosis (Rusnak 2001). Lapatinib showed potent growth 
inhibition of human breast (BT474) as well as head and neck (HN5) tumor xenografts in 
mice. Dose response inhibition was observed, and complete inhibition of tumor growth 
was observed at a dose of 100 mg/kg (Xia 2002).   
 
 
 
Figure 1. Chemical structure of lapatinib   
 
1.4 
Rationale for the Use of Lapatinib in the Treatment of Brain Metastasis 
1.4.1 
Preclinical and Translation Studies 
 
Lapatinib has a very low molecular weight (581 Da), and its theoretical ability to cross 
the blood-brain barrier makes it an ideal candidate for testing against brain metastases 
(Nelson 2006). Preclinical evidence supports the activity of lapatinib against CNS 
disease. Lapatinib is the first HER2-targeting drug to be validated in a preclinical model 
for activity against brain metastasis from HER2-positive breast cancer (Gril 2008). 


 
13 
RTOG 1119, version date April 2, 2019 
 
Figure 2A  Lapatinib-inhibited metastatic colonization of brain-seeking HER2-positive 
breast carcinoma cells (231-BR-HER2) in mouse brain by 50% to 53% (Gril 2008). 
 
In animal studies, concentrations of lapatinib were low in healthy normal brain; however, 
concentrations in tumor were substantially higher than the IC90 values of HER2 in 
BT474 xenograft models and EGFR IC50 values. In patients with glioblastoma exposed 
to lapatinib prior to surgery, therapeutic concentrations in tumor were observed (Kuhn 
2008). 
 
 
Figure 2B. Tumor concentration of lapatinib in surgical specimen of human 
glioblastoma in relation to IC90 inhibition in HER positive xenograft model. The 2 
horizontal bars represent the IC90 range. (Kuhn 2008).   
 
1.4.2 
Clinical Studies 
 
In an unplanned exploratory analysis of the phase III study of lapatinib plus 
capecitabine versus capecitabine alone, fewer CNS relapses as the site of first 
progression were associated with combination therapy (25% vs. 6%) (Cameron 2008). 
However, a recent multicenter phase II trial for patients with established CNS 
metastasis did not reach the predicted efficacy endpoint for lapatinib in recurrent brain 
metastases, although it did demonstrate modest CNS antitumor activity of lapatinib in 
patients who had progressive brain metastases derived from HER2-positive breast 
cancer despite having received prior trastuzumab and cranial radiotherapy (Lin 2008).  
 
In a second international phase II trial, a cohort of 50 patients whose CNS disease had 
progressed on lapatinib monotherapy entered an extension phase involving treatment 


 
14 
RTOG 1119, version date April 2, 2019 
with both lapatinib and capecitabine, obtaining an overall response rate in the brain of 
20%. The study enrolled 242 patients. CNS objective responses (defined as 50% or 
greater volumetric regression) to lapatinib were observed in 6% of patients, and 21% of 
patients experienced a ≥ 20% volumetric reduction in their CNS lesions. An association 
was observed between volumetric reduction and improvement in progression-free 
survival and neurologic signs and symptoms (Lin 2009). 
 
1.5  
Rationale for Concurrent Use of Lapatinib and Radiation (7/22/16) 
 
Lapatinib alone as therapy for CNS disease demonstrated limited potential (Lin 2009) 
following prior radiotherapy; however, lapatinib has been shown to have a 
radiosensitizing effect in vivo in a preclinical breast cancer model (Sambade 2010). At the 
2010 American Society of Clinical Oncology (ASCO) annual meeting, Lin et al (2010) 
presented the results of a phase I study of lapatinib plus whole brain radiotherapy in 
patients with newly diagnosed brain metastases stemming from HER2-positive breast 
cancer. 
1.5.1 
Preclinical Evidence 
 
HER2 Signaling and Radiosensitivity  
HER2 overexpression is associated with relative radioresistance in human breast 
cancer cell lines (Ma 2003).  No et al (2009) showed that specific inhibition of HER2 
via RNA interference increased radiosensitivity of SKBR-3 breast cancer cells 
having HER2 overexpression; sensitizer enhancement at surviving fraction 0.5 was 
1.8. 
 
Figure 3. Specific inhibition of HER-2 using RNA interference increases 
radiosensitivity of SKBR3 breast carcinoma cells with activated HER-2 signaling. 
Specific inhibition of HER-2 using RNAi increases radiosensitivity of breast 
carcinoma cells with activated HER-2 signaling. SKBR3 breast carcinoma cells 
possessing HER-2/neu amplification were transfected with either HER-2 or 
nonspecific control siRNA. Specific inhibition of HER2mRNA expression using 
siRNA led to noticeable downregulation of HER-2 protein expression and attenuated 
the expression of p-AKT and p-ERK, respectively. This was associated with 
increased radiosensitivity of SKBR3 cells (No 2009).  
 
 


 
15 
RTOG 1119, version date April 2, 2019 
 
In Vitro Radiosensitizing Effect of Lapatinib 
Lapatinib led to inhibition of cell proliferation and enhanced the radiation-induced 
cell killing effect in a panel of human breast cancer cell lines that overexpress HER2 
(Zhou 2004).  
 
Figure 4. Radiation response of HER2 overexpressing cells with and without 
lapatinib (Zhou 2004) 
 
Kim et al recently observed pretreatment of lapatinib-led downregulation of p-HER2, 
p-EGFR, p-AKT and p-ERK, and radiosensitized SKBR3 breast cancer cells having 
activated HER2 signaling (Figure 5. Kim, unpublished data).  
 
Figure 5. Lapatinib attenuated the expression of p-HER2, p-EGFR, p-AKT and p-
ERK and radiosensitized SKBR3 human breast cancer cells overexpressing HER2  
 
Lapatinib hindered the repair process of DNA double-strand breaks as measured by 
the γH2AX foci assay and was associated with attenuation of p-DNAPKcs, which is 


 
16 
RTOG 1119, version date April 2, 2019 
known to be involved in nonhomologous end-joining repair (Figure 6A. Kim, 
unpublished data). 
 
 
Figure 6A. Pretreatment of lapatinib-led prolongation of γH2AX foci formation 3 
hours following 6 Gy of radiation and downregulated the expression of p-DNA-PKcs. 
(Kim, unpublished data) 
 
Lapatinib potentiated radiation-induced apoptosis (Figure 6B) and senescence 
(Figure 6C).  
 
Figure 6B. Apoptosis (Kim, unpublished data) 
 


 
17 
RTOG 1119, version date April 2, 2019 
 
Figure 6C. Senescence (Kim, unpublished data) 
 
In terms of the potential toxicity to the normal cell, lapatinib did not potentiate 
radiation-induced cell killing effect on the normal human astrocytes (Figure 7). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                           
                      
 
Figure 7. Lapatinib did not radiosensitize the normal human astrocytes (unpublished 
data). 
 
 
In Vivo Radiosensitizing Effect of Lapatinib 
Sambade et al (2010) showed that lapatinib potentiated tumor growth delay by 
radiation in human breast tumor xenografts providing the rationale for use of 
lapatinib as a radiosensitizer in HER2-positive breast cancer. Lapatinib and 
fractionated radiotherapy were given to mice with xenografts of HER2-positive 
SUM225 breast cancer cells. Immunohistochemical analysis confirmed that the 
inhibition of tumor growth was associated with alterations in ERK1 and AKT 
activation. The treatment with lapatinib alone to HER2-positive SUM225 breast 
0.01
0.1
1
0
2
4
6
8
Control
Lapatinib
Surviving Fraction
Radiation dose(Gy)


 
18 
RTOG 1119, version date April 2, 2019 
cancer tumors was very effective, and the treatment with both lapatinib and 
radiotherapy resulted in an average enhancement ratio of 1.25. The combination of 
lapatinib and radiotherapy was shown to be more effective in controlling the durable 
tumor in the HER2-positive SUM225 model compared to the treatment with either 
lapatinib or radiotherapy alone.  
 
Figure 8A. Lapatinib-mediated radiosensitization of SUM225 HER2+ breast cancer 
xenografts. (Sambade 2010) (A) tumor volume changes normalized to baseline (Day 
10) and plotted over time for each treatment group.  C = vehicle control; L = 
lapatinib; R = radiotherapy; L+R = lapatinib plus radiotherapy. (B) Tumor growth 
rates = the slopes of growth curves for study duration for each treatment group 
 
The radiosensitizing effect of lapatinib was correlated with inhibition of p-AKT in 
HER2+ breast cancer xenograft model (Sambade 2010). 
 


 
19 
RTOG 1119, version date April 2, 2019 
 
Figure 8B. The immunohistochemical study confirmed that the radiosensitization  
by lapatinib was relevant to AKT inhibition in the HER2+ SUM225 model (C, D).  
  
1.5.2 
Clinical Evidence  
A phase I study of lapatinib in combination with WBRT in patients with brain metastases 
from HER2-positive breast cancer was recently reported (Lin 2010). Lapatinib 750 mg 
twice per day was given to patients on the first day, then 1000 mg, 1250 mg, or 1500 mg 
once daily was given during the first 8 days prior to WBRT (37.5 Gy in 15 fractions). The 
drug was given continuously throughout radiation therapy. After the WBRT treatment, 2 
mg/kg of trastuzumab was given to patients every week with 1000 mg of lapatinib daily. 
The determination of the maximum tolerated dose (MTD), defined as the dose at which 
dose-limiting toxicities (DLTs) occurred in 7 days during WBRT, was the primary endpoint. 
Planned accrual was 27 patients at the MTD to fully evaluate the feasibility. If 3 or fewer 
of 27 patients had a DLT, the regimen was considered beneficial. Objective response, 
quality of life, and survival were used as secondary endpoints.  Thirty-five patients of 35 
planned patients were enrolled in the study. Of 3 patients who received lapatinib 1000 mg 
and 5 patients who received lapatinib 1250 mg, none had a DLT. Two patients had DLTs 
with grade 3 diarrhea and grade 3 rash, each associated with a lapatinib dose hold of 16 
days during the first cycle at lapatinib 1500 mg. Twenty-two additional patients 
participated in the MTD (1250 mg) dose phase. Among them, 5 patients had a DLT with ≥ 
8 weeks data (21%, 95% CI 7%-42%): 2 patients with pulmonary embolus, 1 patient with 
grade 3 herpes simplex rash, 1 patient with grade 3 hypoxia, and 1 patient with grade 3 
hyponatremia/hypokalemia. There was no grade 3/4 neurologic toxicity. Among the 24 
patients who had measurable disease with at least 8 weeks of follow-up, 20 (83%, 95% 
CI 63%-95%) experienced an objective CNS response by 1 month after receipt of WBRT. 
 
Based upon the preclinical data and the results of the previous phase I study, we 
hypothesize that lapatinib plus WBRT can improve the intracranial disease control rate 


 
20 
RTOG 1119, version date April 2, 2019 
compared to WBRT alone (according to historical data for WBRT). We therefore propose 
a randomized phase II trial of WBRT plus or minus concurrent lapatinib treatment in 
patients presenting with brain metastasis stemming from HER2-positive breast cancer. 
 
For purposes of sample size calculation and statistical analyses in this trial, we consider 
the complete response (CR) rate for WBRT and SRS to be 5 and 14%, respectively.  The 
WBRT CR rate is based on Suh et al (J Clin Oncol 2006, 24:106-114).  The SRS CR rate 
is based on a computerized search of the medical literature in which the CR varied but 
the median CR rate was 14%. (Bruni 2015, Fokas 2012, Gaudy-Marqueste 2006, 
Hasagawa 2003, Hauswald 2015, Jani 2015, Kocher 2000,Narayana 2007, Serna 2015) 
The response criteria are based on the Response Assessment in Neuro-Oncology 
(RANO) group recommendations for standard response and progression criteria for the 
assessment of brain metastases in clinical trials. (Linn 2015). 
 
 
1.6 
Summary 
Together, recent clinical results of lapatinib treatment for progressive brain metastases 
derived from HER2-positive breast cancer, the evidence of its in vivo radiosensitizing 
effect in a preclinical tumor model, and the results of the phase I study of lapatinib and 
WBRT suggest that lapatinib can be safely combined with WBRT and that this approach 
may provide promising clinical benefit of improved survival and quality of life by 
increasing intracranial tumor control in HER2-positive patients with brain metastasis.  
 
1.7 
Rationale for Collaborative Studies in the US and Korea 
Breast cancer is the second most common cancer in Korean women and its incidence is 
increasing rapidly. The median age at diagnosis in Korean women is 45 years, which is 
approximately 15 years younger than that for women in the US. According to the 2003-
2007 annual report of the Korean Central Cancer Registry (Ministry of Health and 
Welfare 2008) and the National Cancer Institute’s Surveillance Epidemiology and End 
Results Cancer Statistics Review (Altekruse 2009), breast cancers that develop before 
age 35 comprised 7% of Korean cases but only 1.9% of cases in the US. According to a 
collaborative cDNA microarray study of Stanford University and Seoul National University 
using 72 samples of breast cancer and normal breast tissue, Korean breast cancer 
patients exhibit a high percentage of HER-2 expression and hormone receptor negativity 
(Han 2010). Choi et al (2003) compared the expression of HER-2 between 60 Caucasian 
women in the US and 60 native Korean women with early-onset (age 45 years or 
younger) breast carcinoma. Positive HER-2 status was observed in 47.5% of Korean 
women, compared with only 15.8% of Caucasian women (p<0.001). The high proportion 
of early-onset, HER2-positive cases in Korean breast cancer patients will increase the 
value of this collaborative trial. With the reorganization of the US Cooperative Groups, the 
NSABP, GOG and RTOG will be uniting into a single group, which collectively will have 
access to a large population of women with breast cancer, and further, both the NSABP 
and RTOG already have Korean member sites approved, or in process. 
 
1.8         Rationale for Allowing Prior Use of Lapatinib (09/02/2014) 
Because this trial is testing the utility of lapatinib as a radiation sensitizing agent, its use 
as an agent (without concurrent radiation) against the patient’s systemic cancer is not 
expected to have an impact on its ability to act as a radiation sensitizer. We will not, 
however, allow patients who have received lapatinib as treatment for the patient’s CNS 
metastases. This will be defined as the use of lapatinib at any time after the diagnosis of 
brain metastasis. 
 
2.0 OBJECTIVES 
2.1 
Primary Objective (7/22/16) 
 


 
21 
RTOG 1119, version date April 2, 2019 
To determine if there is a signal for an increase in complete response (CR) rate in the 
measurable brain metastases at 12 weeks post RT (whole brain or SRS) as determined 
by MRI scan of the brain, with the addition of lapatinib to WBRT/SRS compared to 
WBRT/SRS alone.  
 
2.2 
Secondary Objectives (7/22/16) 
2.2.1     To evaluate CR rate  of the measurable brain metastases at 4 weeks post RT (WBRT/ 
SRS) as determined by MRI scan of the brain, with the addition of lapatinib to 
WBRT/SRS compared to WBRT/SRS alone. 
2.2.2     To evaluate objective response rate  of measurable brain metastases at 4 and 12 weeks 
post  RT (WBRT/SRS) as determined by MRI scan of the brain, with the addition of 
lapatinib to WBRT/SRS compared to WBRT/SRS alone.  
2.2.3     To evaluate targeted lesion-specific objective response rate (CR + PR) at 4 and 12 
weeks post WBRT/SRS.  
2.2.4     To evaluate CNS progressive disease outside the targeted measurable disease with 
addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone. 
2.2.5       To evaluate targeted lesion-specific progression at 4 and 12 weeks post WBRT/SRS 
2.2.6     To evaluate treatment related adverse events when adding lapatinib to WBRT/SRS 
compared to WBRT/SRS alone. 
2.2.7       To evaluate Overall CNS complete response:  Disappearance of all CNS target lesions 
sustained for at least 4 weeks; with no new lesions, no use of corticosteroids, and patient 
is stable or improved clinically, when adding lapatinib to WBRT/SRS compared to 
WBRT/SRS alone. 
2.2.8 
  To evaluate overall CNS progressive disease (within or outside targeted measurable 
disease) with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.  
2.2.9 
  To evaluate overall survival when adding lapatinib to WBRT/SRS compared to 
WBRT/SRS alone. 
 
 
3.0 PATIENT SELECTION  
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
 
3.1 
Conditions for Patient Eligibility (08-FEB-2018) 
 
For questions concerning eligibility, please contact study data manager 
3.1.1 
Pathologically (histologically or cytologically) proven diagnosis of invasive breast 
cancer  
3.1.2 
HER2 overexpressing breast cancer (3+ staining by immunohistochemistry or HER2 
gene amplification by FISH or SISH ≥ 2.0) 
3.1.3 
At least 1 measurable unirradiated parenchymal brain metastasis within 21 days prior 
to study entry. Patients who are to undergo SRS must have no more than 10 brain 
metastases.  There is no limit on number of brain metastases for WBRT.  The minimum 
size as measured on T1-weighted gadolinium-enhanced MRI must be as follows 
according to the number of brain metastases: 
• 
For a single solitary lesion the size must be ≥10 mm; 
• 
For 2 or more lesions, the size of at least 2 of the lesions must be ≥ 5 mm 
Patients may also have the following provided the size requirements above are met: 
• 
Progressive parenchymal brain metastasis following stereotactic radiosurgery for 
1-3 brain metastases, with at least 1 new measurable brain lesion 
• 
Progressive parenchymal brain metastasis following surgical resection of 1-3 
brain metastases, with at least 1 measurable brain lesion 
3.1.4 
History/physical examination within 21 days prior to study entry 
3.1.5 
Karnofsky performance status ≥ 60 within 21 days prior to study entry  
3.1.6 
Age ≥ 18 
3.1.7 
Able to swallow and retain oral medication (Note, for patients unable to swallow 
tablets, an oral suspension preparation is acceptable, per Section 7.2.10) 


 
22 
RTOG 1119, version date April 2, 2019 
3.1.8 
Adequate hematologic, renal, hepatic function within 21 days prior to study entry, as 
defined by the following: 
• 
Absolute neutrophil count (ANC) ≥ 1,200 cells/mm3 
• 
Platelets ≥ 70,000 cells/mm3 
• 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 8.0 g/dl is acceptable) 
• 
Creatinine < 1.5 times institutional upper limit of normal 
• 
Bilirubin < 1.5 times institutional upper limit of normal 
• 
AST and ALT ≤ 3.0 times institutional upper limit of normal with or without liver 
metastasis 
3.1.9 
Patient must provide study specific informed consent prior to study entry 
3.1.10 
Women of childbearing potential must have a negative serum pregnancy test within 21 
days prior to study entry 
3.1.11 
Sexually active women of childbearing potential and sexually active men must practice 
adequate contraception during therapy and for 12 months after protocol treatment 
completion 
3.1.13 
Prior lapatinib is allowed as long as the last dose received was > 21 days prior to study 
entry and provided the patient has not received it at any time after the diagnosis of 
brain metastasis 
 
 
3.2 
Conditions for Patient Ineligibility (09/02/2014) 
3.2.1 
Prior WBRT  
3.2.2 
Prior RT (any site) with concurrent lapatinib defined as 1 or more days on which the 
patient received both radiation therapy and lapatinib on the same day. 
3.2.3 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements 
3.2.4 
Prior invasive malignancy (except non-melanomatous skin cancer, curatively resected 
thyroid papillary carcinoma, and invasive and non-invasive cancers related to the 
breast cancer) unless disease free for a minimum of 3 years 
3.2.5 
Leptomeningeal disease 
3.2.6 
Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields except patients who have progressed following stereotactic 
radiosurgery for 1-3 brain metastases, with at least one new lesion 
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 
study entry 
• 
Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of study entry 
• 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; 
hepatic or biliary disease that is acute or currently active or that requires antiviral 
therapy (with the exception of patients with Gilbert's syndrome, asymptomatic 
gallstones, liver metastases, or stable chronic liver disease per investigator 
assessment) 
• 
History of LVEF below institutional normal unless repeated and within institutional 
normal range within 90 days of study entry 
3.2.8 
Grade 2 or greater rash of any cause at time of study entry 
3.2.9 
Grade 2 or greater diarrhea of any cause at time of study entry 
 


 
23 
RTOG 1119, version date April 2, 2019 
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 
Required Evaluations/Management (09/02/2014) 
Note that failure to perform any required evaluations/management may result in assessment of a 
protocol violation. 
4.1.1 
Women of childbearing potential must have a negative serum or urine pregnancy test 
within 7 days prior to treatment start. (Note: Only one pregnancy test is necessary if the 
negative serum pregnancy test obtained as part of Section 3.1.11 is also obtained 
within 7 days prior to treatment start.) 
4.1.2 
There must be at least 14 days between FINAL dose of prior chemotherapy and 1st day 
of protocol treatment with recovery of toxicities to grade 0 or 1. 
 
5.0 REGISTRATION PROCEDURES (14-FEB-2018) 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified investigators.  
NCI policy requires all persons participating in any NCI-sponsored clinical trial to register and renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  
In addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), 
or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 
1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
 


 
24 
RTOG 1119, version date April 2, 2019 
Additional information can be found on the CTEP website 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
 
 
5.1  
Regulatory Pre-Registration Requirements  (02-APR-2019) 
5.1.1 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
IRB Approval: 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria including but not limited 
to the following:  
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization  
• 
A valid IRB approval  
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
Requirements for RTOG 1119 site registration: 
• IRB approval letter (local IRB documentation, an IRB-signed CTSU IRB Certification 
Form, 
Protocol 
of 
Human 
Subjects 
Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
• For applicable NCTN studies with a radiation and/or imaging (RTI) component, the 
enrolling site must be aligned to a RTI provider.  To manage provider associations 
access 
the 
Provider 
Association 
tab 
on 
the 
CTSU 
website 
at 
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated 
providers.  Sites must be linked to at least one IROC credentialed provider to 
participate on trials with an RT component. Enrolling sites are responsible for ensuring 
that the appropriate agreements are in place with their RTI provider, and that 
appropriate IRB approvals are in place.   
• IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC to 
begin the modality credentialing process.   
o 
.   
• Credentialing documentation received from IROC Houston for this trial- See Section 
5.4 for details. 
• IRB/REB approved consent (Non-North American and Canadian sites only: English 
and native language versions*)  
• *Note: International and Canadian Institutions (Non-North American sites must 
provide certification/verification of IRB/REB consent translation to NRG Oncology 
(described below).  
 
 
Non-English Speaking Canadian and Non-North American Institutions 
Translation of documents is critical. The institution is responsible for all translation costs. All 
regulatory documents, including the IRB/REB approved consent, must be provided in English and 
in the native language. Certification of the translation is optimal but due to the prohibitive costs 
involved NRG Oncology will accept, at a minimum, a verified translation. A verified translation 
consists of the actual REB approved consent document in English and in the native language, 
along with a cover letter on organizational/letterhead stationery that includes the professional title, 


 
25 
RTOG 1119, version date April 2, 2019 
credentials, and signature of the translator as well as signed documentation of the review and 
verification of the translation by a neutral third party. The professional title and credentials of the 
neutral third party translator must be specified as well. 
 
5.1.2    Downloading Site Registration Documents:   
Site registration forms may be downloaded from the RTOG 1119 protocol page located 
on the CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the NRG Oncology link to expand, then select trial protocol # RTOG 
1119 
• 
Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.   
 
 
5.1.3 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website.   
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
5.1.4  
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
Prior to clinical trial commencement, Canadian institutions must complete the 
following documents and submit them to the CTSU Regulatory Office (see Section 
5.1.3).  
o 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site 
Information Form,  
o 
Qualified Investigator Undertaking Form,  
o 
Research Ethics Board Attestation Form.  


 
26 
RTOG 1119, version date April 2, 2019 
5.1.5 
Pre-Registration 
Requirements 
FOR 
APPROVED 
KOREAN 
AND 
ISRAELI 
INSTITUTIONS 
Please see the Regulatory Resources tab under the RTOG 1119 protocol-specific page 
for a list of requirements to be fulfilled prior to enrolling patients to the study. 
 
5.2  
OPEN Registration (08-FEB-2018) 
5.2.1  
Online Registration 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To 
access OPEN, the site user must have an active CTEP-IAM account (check at < 
https://ctepcore.nci.nih.gov/iam >) and a 'Registrar' role on either the LPO or 
participating organization roster.  Registrars must hold a minimum of an AP registration 
type.   
 
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. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org.  To assign an IVR or NPIVR as the treating, crediting, 
consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, the 
IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on the 
site’s IRB approval.   
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your records.  
 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
In the event that the OPEN system is not accessible, participating sites can contact 
NRG web support for assistance with web registration at websupport@acr.org or call 
the NRG Registration Desk at 215-571-3191, 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.  
 
 
5.3 
Digital RT Data Submission to NRG Oncology Using TRIAD (08-FEB-2018) 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a secure method 
to transmit DICOM RT and other objects. TRIAD anonymizes and validates the 
images as they are transferred. 
 
TRIAD Access Requirements: 
• 
Site 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, and be registered as an AP, 


 
27 
RTOG 1119, version date April 2, 2019 
NPIVR or IVR.  Please refer to the CTEP Registration Procedures section for 
instructions on how to request a CTEP-IAM account and complete registration in 
RCR. 
• 
To submit images, the site physics user must be on the site’s affiliated rosters and be 
assigned the 'TRIAD site user' role on the CTSU roster.  Users should contact the 
site’s CTSU Administrator or Data Administrator to request assignment of the TRIAD 
site user role.  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 the proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to be 
able to submit images. TRIAD installation documentation can be found by 
following this link https://www.irocqa.org/Resources/TRIAD 
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password and RCR registration. 
 
If you have any questions regarding this information, please send an e-mail to 
the TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
5.4 
In order to utilize Stereotactic Radiosurgery (SRS) with a Gamma Knife or Linear Accelerator on 
this study, the institution must have met specific technology requirements and have provided 
baseline physics information. Instructions for completing these requirements are available on the 
IROC Houston QA Center (IROC H) web site at http://irochouston.mdanderson.org/rpc/; select 
“Credentialing” and “RTOG” To determine if these requirements have already been met by your 
institution, select “Credentialing Status Inquiry.”  (7/22/16) 
 
5.4.1   The IROC Houston electronic facility questionnaire (FQ) should be completed or 
updated with the most recent information about your institution. The questionnaire is 
available on the IROC H web site, http://irochouston.mdanderson.org , under “Facility 
Questionnaire” at the top of the homepage.  
 
 
5.4.2   An SRS phantom study with IROC Houston must be successfully completed. If an 
institution has previously successfully irradiated an IROC-Houston SRS phantom and 
their treatment equipment has not changed since the initial credentialing, the institution 
is not required to perform the phantom irradiation study again. However, if the 
institutions treatment equipment has changed significantly then they will be required to 
re-credential by performing the phantom irradiation study again. Instructions for 
requesting and irradiating the phantom are available on the IROC Houston web site at 
http://irochouston.mdanderson.org; select “Credentialing” and “RTOG”. Upon review 
and successful completion of the phantom irradiation, IROC Houston will notify both the 
registering institution, CTSU and NRG Operations Office of your approved 
credentialing.    
 
5.4.3 
Institutions utilizing frameless SRS methods must complete IGRT credentialing for 
boney-anatomy in addition to the SRS phantom study. The institution must complete an 
IGRT questionnaire found on the IROC-Houston website under “Credentialing” and 
must submit a set of treatment day position verification images via TRIAD.  Instructions 
can be found on the IROC-Houston website (http://irochouston.mdanderson.org) or 
data along with a spreadsheet of IGRT data from two anonymized SRS patients. This 
must include pre-treatment images which include three-dimensional (3D) volumetric 
images (either fan- or cone-beam CT with Megavoltage (MV) or kilovoltage (kV) x-ray) 


 
28 
RTOG 1119, version date April 2, 2019 
or Orthogonal (MV or kV) 2D images. These data are submitted via TRIAD. The 
spreadsheet can also be uploaded to TRIAD. The spreadsheet can be found on the 
IROC Houston QA Center website at http://irochouston.mdanderson.org. Once the data 
has been submitted via TRIAD, please complete the DDSI found at 
http://www.rtog.org/CoreLab/RTQASubmissionInformation.aspx.  If the institution has 
already been approved for boney-anatomy IGRT, no further IGRT credentialing is 
required. 
 
 
6.0 RADIATION THERAPY SRS/WBRT (ARMS A AND B) (08-FEB-2018) 
 
NOTE 1: For patients being treated by WBRT and SRS, protocol treatment must begin within 21 days 
after the diagnosis of brain metastasis was made by MRI. 
 
NOTE 2: For institutions desiring to use SRS as a treatment modality, patients can only be enrolled by 
treating physicians and institutions that have irradiated and passed the IROC SRS Head Phantom.  
 
NOTE 3: Institutions using frameless SRS methods or planning to use IGRT for SRS treatment will need 
to complete an IGRT verification study. 
 
NOTE 4: The patient must have at least 1 unirradiated metastases as described in section 3.1.3.  
• 
Patients who are to undergo SRS: there must be no more than 10 brain metastases. 
• 
Patients who are to undergo WBRT: there is no limit on the number of brain metastases. 
 
 
 
6.1 
Radiation Therapy Schema (7/22/16) 
 
Schema at the beginning of the protocol should be followed. 
 
6.2 
Treatment Technology (7/22/16) 
This protocol requires photon treatment with nominal energies between 4 and 10MV except when Co-60 
treatment units are used.  
 
WBRT 
Opposed lateral helmet fields will typically be used for this treatment modality.  Individually fabricated 
compensators, wedges and field-within-field techniques can be used to adjust for missing tissue at the 
discretion of the treating physician. Inverse planned IMRT is not allowed for patients getting WBRT.  
 
SRS 
3DCRT, IMRT, VMAT, Gamma Knife, Cyberknife, and Tomotherapy are allowed for patients getting SRS.  
 
All participating sites must have calibrations verified by OSLDs through the IROC Houston Quality 
Assurance Center as well as credentialing for IMRT/VMAT if those technologies are being used. . Gantry 
mounted linac treatments should be performed with a minimum source-axis distance of 80cm.  
 
6.3 
Immobilization and Simulation (7/22/16) 
 
WBRT 
Immobilization: 
 
Proper immobilization is critical for this protocol.  Patient setup reproducibility must be achieved using 
appropriate clinical devices. Patients receiving WBRT should be treated in the supine position. A head-
holding device must ensure adequate immobilization during therapy and ensure reproducibility 
 
Simulation Imaging: 


 
29 
RTOG 1119, version date April 2, 2019 
A non-contrast treatment-planning CT scan of the entire head region using an axial slice thickness not 
exceeding 2.5mm is required. The field shape should include the entire cranial contents, with flashing 
beyond skin and a minimum margin of 0.75 cm on the skull base as visualized on the simulator images or 
portal films to account for beam penumbra and day-to-day set-up variation. The treatment-planning CT 
scan must be acquired with the patient in the same position and immobilization device as for treatment. A 
planning MRI is not required for WBRT treatment.  
 
SRS 
Immobilization: 
Patient setup reproducibility must be achieved using appropriate clinical devices. Multiple isocenter 
techniques are permitted and should be used when the separation between the isocenter and the most 
distant lesion exceeds 10 cm. Framed and frameless SRS delivery methods are allowed for this protocol. 
IGRT is required. 
 
Simulation Imaging: 
A gadolinium contrast-enhanced spoiled gradient or axial T1-weighted and T2-weighted MRI with axial 
thickness not exceeding 1.5mm should be used for the planning MRI. The images should be obtained 
with the patient in the supine position. Immobilization devices used for CT treatment planning simulation 
and treatment need not be used when obtaining the MRI imaging sequences, but the patient should be 
positioned as close to the same orientation as the CT simulation if possible.  
For SRS planning with CT images, a treatment-planning CT scan of the entire head region using an axial 
slice thickness not exceeding 1.5mm is required. The planning CT should be fused with the planning MRI 
for structure definition.  
 
6.4 
Imaging for Structure Definition, Image Registration/Fusion and Follow-up (7/22/16) 
 
A planning MRI is not required for WBRT volume delineation or treatment planning. 
MRI imaging will be required to assist in volume delineation in all patients treated with SRS 
 
6.5 
Definition of Target Volumes and Margins (7/22/16) 
Note: All structures must be named for digital RT data submission as listed in the table below.  The 
structures marked as “Required” in the table must be contoured and submitted with the treatment plan. 
Structures marked as “Required when applicable” must be contoured and submitted when applicable. 
Resubmission of data may be required if labeling of structures does not conform to the standard DICOM 
name listed.  Capital letters, spacing and use of underscores must be applied exactly as indicated. 
 
WBRT 
There are no required dose target volumes for patients being treated with WBRT.  
 
SRS 
For patients treated with SRS, target names should follow the naming convention detailed in the table 
below. Each target will be named anatomically for the lobe of the brain along with “Left (L) or Right (R)” 
denoting which hemisphere the target is located. Following the name will be a number representing the 
order in which the target appears on the MRI as one moves from patient superior to inferior. 
The GTV is defined as the enhancing metastasis on a gadolinium enhanced T1 weighted MRI scan. The 
PTV is defined as the defined GTV plus a symmetrical 1.0mm margin. Each GTV and PTV should have 
“GTV#_” and “PTV#_” respectively preceding the target name. Example names are: GTV1_Frontal_L, 
GTV2_Occipital_R, and GTV3_Occipital_R. 
 
 
Targets 
Anatomical Region or Lobe 
 
Possible Descriptors 
GTV(1-10)_ 
CTV(1-10)_ 
PTV(1-10)_ 
Frontal 
Parietal 
Cerebellum 
Temporal 
_L/R 


 
30 
RTOG 1119, version date April 2, 2019 
Occipital 
Brainstem 
 
 
Detailed Specifications  
6.6 
Definition of Critical Structures and Margins (7/22/16) 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” under the heading of Validation in the table below must be 
contoured and submitted with the treatment plan. Structures marked as “Required when 
applicable” must be contoured and submitted when applicable.   
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
For WBRT patients, critical structure contouring is recommended but not required.  
 
Standard Name 
 
Description 
 
Validation (WBRT) 
 
Validation (SRS) 
 
Brain 
Brain 
 
Optional 
Optional 
BrainStem 
Brain Stem 
Optional 
Required 
OpticNerve_L 
Left Optic Nerve 
Optional 
Required 
OpticNerve_R 
Right Optic Nerve 
Optional 
Required 
Orbit_L 
Left Orbit 
 
Optional 
Required 
Orbit_R 
Right Orbit 
 
Optional 
Required 


 
31 
RTOG 1119, version date April 2, 2019 
OpticChiasm 
Optic Chiasm 
 
Optional 
Required 
Lens_L 
Left lens 
Optional 
Required 
Lens_R 
Right Lens 
Optional 
Required 
MotorStrip 
Defined as 2cm 
anterior and posterior 
to the central gyrus 
Optional 
Required 
 
Detailed Specifications 
6.7 
Dose Prescription (7/22/16) 
 
Note: The information provided in this section can be used for adjusting the dose constraints for treatment 
planning purposes.  This table together with the planning priority table should be used during dose 
optimization.  It is important to remember that ideal plans might not be achievable in all cases.  Thus, the 
Compliance Criteria table could be different than the information given here.  Cases will be scored using 
the Compliance Criteria table. 
 
WBRT: 
One treatment of 2.5Gy will be given daily 5 days per week (15 fractions) for a total of 37.5Gy over 3 
weeks. Doses are specified as the target dose to a point, which shall be the dose on the central ray at 
mid-separation for 2 opposed coaxial equally weighted beams. All portals should be treated during each 
treatment session. 
 
Target Standard Name 
Dose (Gy) 
Fraction Size (Gy) 
# of fractions  
Brain 
37.5 
2.5 
15 
 
SRS: 
For patients with > 1 brain metastasis, the maximum SRS dose for any lesion is  
18 Gy  
 
All doses will be delivered in a single fraction.  The dose will be prescribed to the isodose surface (50%-
90% [maximum = 100%]), which encompasses the margin of the metastasis, as defined by the imaging 
studies.  The maximum dose to a point that is at least 0.03 cc within each PTV will be recorded for each 
patient.  The reported prescription dose is defined as the dose to the periphery (defined as 99% of the 
volume) of the PTV as established by the SRS treatment planning software, generated dose-volume 
histogram (DVH). The maximum point dose would be 40 Gy when a lesion that is less than 4 cc is treated 
to a 20Gy dose prescribed to the 50% isodose line. 
 
SRS Target Volume 
Dose (Gy) 
# of fractions  


 
32 
RTOG 1119, version date April 2, 2019 
<4.0cc 
20 
1 
4.0-14.0cc 
18 
1 
14.1-33.0cc 
15 
1 
>33cc 
Ineligible 
for SRS 
 
 
6.8 
Compliance criteria (7/22/16) 
The compliance criteria listed here will be used to score each case.  Given the limitations inherent in the 
treatment planning process, the numbers given in this section can be different than the prescription table.  
Both the Per Protocol and Variation Acceptable categories are considered to be acceptable.  The Per 
Protocol cases can be viewed as ideal plans, and the Variation Acceptable category can include more 
challenging plans that do not fall at or near the ideal results.  A final category, called Deviation 
Unacceptable, results when cases do not meet the requirements for either Per Protocol or Variation 
Acceptable. Plans falling in this category are considered to be suboptimal and additional treatment 
planning optimization is recommended. 
 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not met 
 
Target Volume Constraints and Compliance Criteria for Composite Plans 
 
The prescription dose should be specified as the dose to the periphery of the target. Deviations from the 
target volume dosing table listed in section 6.7 should only be made in order to comply with dose 
constraints to critical structures as detailed below.  
 
Name of Structure 
Dosimetric parameter* 
Per Protocol 
Variation Acceptable 
All SRS Targets 
 
D99%(Gy) 
≥Rx dose 
95% of Rx dose 
Dmin(Gy) 
≥90%  of Rx Dose 
for a volume of 0.03 
cc 
≥40% of Rx Dose for 
volume of 0.03 cc 
 
 
Normal Structure Constraints and Compliance Criteria 
 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
BrainStem 
Dmax(Gy) 
≤10 
None 
OpticNerve_L 
Dmax(Gy) 
≤8 
None 
OpticNerve_R 
Dmax(Gy) 
≤8 
None 
OpticChiasm 
Dmax(Gy) 
≤8 
None 
Orbit_L 
Dmax(Gy) 
≤8 
None 
Orbit_R 
Dmax(Gy) 
≤8 
None 
MotorStrip 
Dmax(Gy) 
≤15 
None 
 
Recommended dose acceptance criteria for other normal tissue, but not to be used for plan score: 
 
Lens_L 
Dmax(Gy) 
≤2 
Lens_R 
Dmax(Gy) 
≤2 
 
 
Delivery Compliance criteria 
For SRS and WBRT care should be taken to minimize the dose to the lens and orbits.  
For WBRT, the radiotherapy treatment course will be continued without interruption if possible. If the sum 
total of treatment interruptions exceeds 2 normally scheduled treatment days, the treatment will be 
considered a protocol deviation unacceptable 


 
33 
RTOG 1119, version date April 2, 2019 
 
 
Per Protocol 
Variation Acceptable 
Start date  
Within 21 day period after 
the diagnosis of brain 
metastasis was made by 
MRI 
 
Interruptions (WBRT) 
0 break days 
1-2 break days 
 
 
 
6.9 Treatment Planning Priorities and Instructions (7/22/16) 
 
WBRT: 
Three-dimensional approaches to radiotherapy planning will be used for patients treated with WBRT. 
There are no treatment-planning priorities.  
 
SRS:  
Three-dimensional or intensity-modulated radiotherapy approaches to radiotherapy planning can be used 
for patients treated with SRS. In creating and optimizing a plan priority should be placed on achieving the 
highest possible prescription dose to the target while keeping critical structures under their maximum 
dose limits.  
Conformity index (CI) is defined as the ratio of the prescription isodose volume to the target volume.  
 
 
 
Gradient index (GI) gives a measure of the rate of dose fall-off outside of the target. It is defined as the 
ratio between the half-prescription isodose volume to the prescription isodose volume. 
 
 
 
 
RTOG Conformity and Gradient Indexes should be kept to ≤2.0 and ≤4.0 respectively if possible.  
 
 
- Primary dataset for dose calculation 
For WBRT, the primary dataset for calculation should be a non-contrast treatment planning CT. In the 
case in which contrast is present during the treatment planning CT, the density of the contrast should be 
overridden to a representative background electron density. 
For SRS, the primary dataset for calculation can either be a non-contrast treatment planning CT or 
planning MRI. In the case in which contrast is present during the treatment planning CT, the density of the 
contrast should be overridden to a representative background electron density. 
 
-Dose matrix resolution 
Dose grid size should be ≤ 3 mm in all directions. 
 
 
6.10 
Patient specific QA (7/22/16) 
 
Any patient-specific QA that needs to be acquired should follow institutional guidelines. 
 
For photon IMRT plans, patient specific QA is highly recommended. QA is performed by delivering the 
plan onto a phantom and measuring the dose using an ion chamber array or other 2D/3D device. 
Measured dose distribution will be compared to planned dose distribution using a Gamma criterion of 4% 


 
34 
RTOG 1119, version date April 2, 2019 
dose difference and 3 mm distance to agreement. The pass rate should be at least 90% measured for the 
entire plan. 
 
6.11 Daily Treatment Localization/IGRT (7/22/16) 
WBRT 
Acquisition of verification orthogonal films or images is required. This data will not be collected but should 
be held by the institution and available for review if requested. 
 
SRS 
For all forms of SRS except for Gamma Knife and CyberKnife dose delivery that use their own unique 
built-in imaging systems, IGRT verification systems must be used.  Checking the agreement of the 
treatment beam reference point and the IGRT imaging reference point on each day of SRS treatment is 
required. 
 
IGRT credentialing is required for any facilities utilizing frameless SRS methods. NRG Oncology defines 
IGRT as a computer assisted process that uses imaging devices that generate a series of coordinates for 
shifting the patient support system in three orthogonal directions (sometimes including rotational 
changes) to position the treatment beams relative to target regions. The allowed technologies are as 
follows: cone-beam CT (CBCT) using either a specially mounted kV imaging head or the MV treatment 
beam with an opposed electronic imaging panel, dual fixed-position in-room kV imaging systems that are 
orthogonal or near orthogonal, an in-room standard diagnostic CT scanner that is geometrically linked to 
the treatment unit, and the Tomotherapy approach. 
 
 
6.12 
Case Review (7/22/16) 
WBRT 
There will be no case reviews 
SRS 
The first two cases submitted by each institution will undergo pre-treatment review except for Gamma 
Knife. Three business days are required to complete a pre-treatment review.  The 3 days start once 
complete data is received.  All other cases will be reviewed post treatment. The digital data should be 
sent within a week of treatment completion. One of the Principal Investigators and the Medical Physics 
Co-chair will perform ongoing remote RT Quality Assurance Review after cases enrolled have been 
received at IROC Philadelphia-RT.  
 
6.13 
Radiation Therapy Adverse Events (7/22/16)  
Adverse events related to WBRT include both short-term and long-term side effects.  
Short-term side effects include fatigue, hair loss, scalp erythema/irritation, and muffled 
hearing.  These events usually resolve 2-4 weeks after WBRT, although hair loss may be 
permanent.  Long-term side effects may include difficulty with short-term memory.  All of 
the above are common. 
Adverse events related to SRS include both short and long-term side effects.  Short term 
side effects may include pin-site soreness for frame-based SRS and headache which 
resolve within 1-2 days.  Long-term side effects include radiation necrosis which may 
cause brain swelling months after SRS.  That swelling may be subclinical (seen only on 
MRI), transient (bloom and wilt) or persistent.  If symptomatic, steroids may be needed 
but should be used in the lowest dose needed to control symptoms. 
 
 
6.14 
Radiation Therapy Adverse Event Reporting (7/22/16) 
 
See Section 7.6 for Adverse Event Reporting 
 
7.0 DRUG THERAPY  
 
 
 
 
Protocol treatment must begin within 21 days after the diagnosis of brain metastasis was 
made by MRI.  


 
35 
RTOG 1119, version date April 2, 2019 
 
7.1 
Treatment With Lapatinib (Arm B patients only) (7/22/16) 
7.1.1 
Dose Definition  
Lapatinib 1000 mg orally once daily  
7.1.2 
Technique of Administration 
Patients should be advised to take lapatinib on an empty stomach (ie, the dose must be 
taken at least 2 hours after the last meal and the patient must wait at least 1 hour after 
the dose before eating again). If doses are held or missed, they should be continued at 
the end of the course of lapatinib therapy. If the patient misses more than 14 
continuous days of lapatinib for any reason, protocol treatment will be discontinued. 
Before starting treatment, the patient will be provided with and instructed in the proper 
use of a pill diary (see “Non-Study Specific Forms” on the NRG Oncology/RTOG 
website, or http://www.rtog.org/LinkClick.aspx?fileticket=CrZv7t2tB1w%3d&tabid=308, 
for a pill diary template) to record their daily pill consumption. The investigator will 
check this record for compliance. The diary will be retained in the patient’s record for 
submission to RTOG ONLY upon request (ie, diaries are not to be submitted but will be 
retained at the site as source documents). Patients who are non- compliant must be re-
instructed in the use of the pill diary. 
7.1.3 
Timing of Administration 
SRS patients: Lapatinib dosing will start up to 1 day before SRS and should be timed to 
occur approximately 3-6 hours prior to SRS. 
 
WBRT patients: On days when patients are receiving radiation treatments, lapatinib 
dosing should be timed to occur approximately 3-6 hours prior to WBRT. 
7.1.4 
Duration of Treatment 
All patients randomized to receive lapatinib will take drug for 6 weeks. 
 
SRS patients: Lapatinib will start up to 1 day before SRS and should be taken 
continuously for 6 weeks.  
 
WBRT patients: Lapatinib will start up to 1 day before the first day of WBRT and 
continue throughout WBRT and 21 days after the final day of WBRT without drug 
holiday (i.e., Saturdays and Sundays included). Drug should be taken continuously 
including days on which WBRT is not given. 
 
7.2 
Lapatinib Agent Information (NSC # 727989, IND # 70252) (02-APR-2019) 
 
To supplement the toxicity information contained in this document, investigators must 
obtain the current version of the investigator brochure for comprehensive pharmacologic 
and safety information 
7.2.1 
Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account 
status, a “current” password and active person registration status.  Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
7.2.2 
Chemical Name 
 
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-
(methylsulfonyl)ethyl]amino}methyl)-2 furyl]-4-quinazolinamine 
7.2.3 
Other Names 
 
GW572016F, lapatinib ditosylate, Tykerb® 
7.2.4 
Molecular Formula 
 
C29H26ClFN4O4S (C7H8O3S)2H2O 
7.2.5 
Molecular Weight 
 
943.48 
7.2.6 
Approximate solubility 
 
0.007 mg/mL in water and 0.001 mg/mL in 0.1 N HCl at 25°C.   


 
36 
RTOG 1119, version date April 2, 2019 
7.2.7 
How supplied  
 
GlaxoSmithKline supplies and the NCI/DCTD distributes lapatinib as 250 mg oval, 
biconvex, orange film-coated tablets with one side plain and the opposite side 
debossed with FG HLS. The tablets contain 405 mg of lapatinib ditosylate 
monohydrate, equivalent to 250 mg lapatinib free base per tablet. The tablets are 
packaged into HDPE bottles with child-resistant closures containing 90 tablets per 
container. 
 
 
Excipients present in the tablet include: Microcrystalline cellulose, povidone, sodium 
starch glycolate, and magnesium stearate. 
 
The film-coat contains:  Hypromellose methylcellulose, titanium dioxide, macrogol/PEG 
400, Polysorbate 80, FD&C Yellow No. 6, and FCF aluminum lake. 
 
Drug provided free of charge as part of a research protocol must be used only for the 
intended study. It is the responsibility of the Investigator to ensure the 
provided/investigational product is only dispensed to eligible study patients 
7.2.8 
Storage 
 
Store intact bottles at controlled room temperature (15°C-30°C) 
7.2.9 
Stability 
 
Shelf life surveillance studies of the intact bottle are on-going 
7.2.10 
Route of Administration 
Oral on an empty stomach (ie, the dose must be taken at least 2 hours after the last 
meal and the patient must wait at least 1 hour after the dose before eating again)  
7.2.11 
Method of Administration 
 
Whenever possible, administer whole tablets. Lapatinib tablets have not been 
deliberately formulated to be dispersible tablets; however, in circumstances where 
dosing of whole tablets is not possible, see procedure below. Tablet crushing is not 
recommended 
 
 
For patients unable to swallow tablets, a suspension preparation in water or Kool-Aid 
can be made using the following procedure: 
 
1. 
Prepare Lemonade or Tropical Punch Kool-Aid as directed on package. 
2. 
Place 2 or 4 ounces of water or Kool-Aid in a glass container, then add the 
required number of lapatinib tablets for dose (up to 4 tablets per 2 to 4 ounces) to 
the container.  
3. 
Cover the container, let it stand for 5 minutes, and then stir the mixture 
intermittently for 15 minutes or until it is fully dispersed. 
4. 
Stir the container for 5 seconds then administer. 
5. 
Rinse the container with 2 ounces of water or Kool-Aid and repeat the 
administration process.  
 
(The lemonade mixture appears somewhat like orange juice whereas the tropical 
punch mixture appears like carrot juice) 
7.2.12 Possible Drug Interactions 
Lapatinib is extensively metabolized by CYP3A4/5 with minor contributions from CYP 
2C8 and 2C19.  Co-administration of lapatinib with strong or moderate CYP3A4/5 
inhibitors (including grapefruit juice) and all CYP3A4/5 inducers is prohibited.  Assess 
risk/benefit before co-administering lapatinib with weak CYP3A4/5 inhibitors.  CYP3A4/5 
inhibitors may decrease lapatinib metabolism (increasing levels); while CYP3A4/5 
inducers may increase lapatinib metabolism (decreasing levels).   
 
In vitro, lapatinib inhibited CYP3A4 and CYP2C8 at clinically relevant concentrations. 
Avoid co-administration of lapatinib with drugs that are substrates of CYP3A4 or CYP2C8 


 
37 
RTOG 1119, version date April 2, 2019 
and have narrow therapeutic windows.    
Lapatinib is a substrate for P-glycoprotein (Pgp) and Breast Cancer Resistance Protein 
(BCRP) transport proteins. Inhibitors and inducers of these transporters may affect 
lapatinib exposure in patients. Lapatinib is an inhibitor of Pgp, BCRP and OATP1B1 
transport proteins. Use caution when dosing lapatinib concurrently with narrow-
therapeutic drugs that are substrates for these transport proteins, such as digoxin or 
statins.  
Lapatinib is highly protein bound (> 99%) to albumin and alpha-1 acid glycoprotein; 
therefore, use other highly protein bound concomitant medications with caution and 
monitor for toxicity. 
 Use of proton pump inhibitors prior to lapatinib administration decreased lapatinib 
exposure by 27% on average. Use caution when lapatinib is administered concomitantly 
with PPIs. 
 
For a list of Prohibited Drug Medications, see Section 9.2 
 
 
 
7.2.13   Adverse Events 
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.pd
f  for further clarification. Frequency is provided based on 6120 patients. Below is the 
CAEPR for Lapatinib (GW572016). 
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 2.8, February 4, 20191  
 
 Adverse Events with Possible  
 Relationship to Lapatinib (GW572016) 
 (CTCAE 5.0 Term) 
[n= 6120] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
 Left ventricular systolic 
dysfunction (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 


 
38 
RTOG 1119, version date April 2, 2019 
 
 Adverse Events with Possible  
 Relationship to Lapatinib (GW572016) 
 (CTCAE 5.0 Term) 
[n= 6120] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
 
Nausea 
 
 Nausea (Gr 2) 
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Flu like symptoms 
 
 Flu like symptoms (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
 Hepatic failure (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
 
Ejection fraction decreased 
  
 
 
Electrocardiogram QT corrected 
interval prolonged 
 Electrocardiogram QT corrected 
interval prolonged (Gr 2) 
 
Neutrophil count decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Myalgia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Epistaxis 
 
  
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
 
Pneumonitis 
  
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  


 
39 
RTOG 1119, version date April 2, 2019 
 
 Adverse Events with Possible  
 Relationship to Lapatinib (GW572016) 
 (CTCAE 5.0 Term) 
[n= 6120] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Dry skin 
 
  
 
 
Erythema multiforme 
  
 
Nail changes 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2)  
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
Hot flashes 
 
  
 
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. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
 
Adverse events reported on lapatinib (GW572016)) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that lapatinib (GW572016) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Pericarditis; Sinus tachycardia 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dysphagia; Gastritis; Hemorrhoids; Ileus; 
Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever; Non-
cardiac chest pain; Pain 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; GGT increased; INR 
increased; Lymphocyte count decreased; Platelet count decreased; Weight loss; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperphosphatemia; 
Hypoalbuminemia; Hypoglycemia; Hypokalemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Flank pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage 
NERVOUS SYSTEM DISORDERS - Cerebrospinal fluid leakage; Depressed level of consciousness; 
Dizziness; Intracranial hemorrhage; Nervous system disorders - Other (altered dream pattern); Nervous 
system disorders - Other (sleep walking); Paresthesia; Peripheral motor neuropathy; Peripheral sensory 
neuropathy; Syncope 
PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS - Pregnancy loss 
PSYCHIATRIC DISORDERS - Insomnia 


 
40 
RTOG 1119, version date April 2, 2019 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Oropharyngeal 
pain; Pleural effusion; Pulmonary edema; Pulmonary fibrosis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Nail loss; Pain of skin; Skin and subcutaneous 
tissue disorders - Other (onychocryptosis); Skin and subcutaneous tissue disorders - Other (seborrheic 
dermatitis); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hypertension; Hypotension; Thromboembolic event; Vascular 
disorders - Other (hypovolemia) 
 
 
Note: Lapatinib (GW572016) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.2.14 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution. 
 
Sites may order agent when a patient is in screening. Expedited orders may be 
processed overnight Monday-Thursday when a site provides expedited courier 
information in OAOP. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account status, 
a “current” password, and active person registration status.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management.   
 
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 Drug Accountability Record Form (DARF).  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
All 
forms 
can 
be 
accessed 
on 
the 
NCI 
web 
site 
http://ctep.cancer.gov/forms/index.html.  
 
Non-Canadian International Institutions: 
 
Please refer to your LOI Approval Notification. Your institution will be responsible for 
acquiring any drug noted in the protocol as commercially available and not provided 
for the study.  
 
Before drug can be provided your institution must comply with all pre-registration 
requirements and certifications and provide all necessary documentation listed in 
your LOI Approval Notification document.  
 
7.2.15 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  


 
41 
RTOG 1119, version date April 2, 2019 
https://ctepcore.nci.nih.gov/OAOP 
• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• 
IB Coordinator:  IBCoordinator@mail.nih.gov  
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
7.3 
Clinical Trials Agreement  
The agent supplied by CTEP, DCTD, NCI used in this protocol is provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company (hereinafter referred to as a Collaborator and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
Intellectual 
Property 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent in this study: 
 
1. 
The Agent may not be used for any purpose outside the scope of this protocol, 
nor can the Agents be transferred or licensed to any party not participating in the 
clinical study.  The Collaborator’s data for the Agent are confidential and 
proprietary to the Collaborator and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational Agents 
contain confidential information and should not be shared or distributed without 
the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in 
combination with another investigational Agents, 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 NIH, 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 investigational Agent. 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator, 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. 


 
42 
RTOG 1119, version date April 2, 2019 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
5. 
Any data provided to the Collaborator 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 the 
Collaborator for advisory review and comment prior to submission for publication.  
The Collaborator will have 30 days from the date of receipt for review.  The 
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to the Collaborator’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to the 
Collaborator 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: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator=s 
confidential/ proprietary information. 
 
7.4 
Dose Modifications (7/22/16) 
 
Grading of toxicity will be according to Common Terminology Criteria for Adverse Events 
v (CTCAE) v 4. Toxicity that requires holding lapatinib should be re-evaluated at intervals 
of no more than 7 days. If patient meets criteria for restarting lapatinib, this may be 
restarted at the discretion of the investigator. If drug cannot be restarted within 14 days, 
the drug will be discontinued permanently. Patient, however, will stay on study. The 
administration of RT will not be altered for toxicities that are related to drug. Once the 
drug dose is reduced it will not be increased. 
7.4.1 
Lapatinib Dose Modification for LVEF Events 
▪ 
Any patient who develops clinical signs or symptoms of cardiac failure should 
undergo an LVEF assessment and an ECG 
▪ 
Lapatinib therapy must be discontinued permanently in case of symptomatic 
cardiac failure or decrease in LVEF to below the institutional normal range 
7.4.2 
Lapatinib Dose Modification for Non-Cardiac Events 
▪ The maximum treatment delay for any reason is 14 days 
7.4.3  
Severe Cutaneous Reactions 
▪ 
Severe cutaneous reactions have been reported with lapatinib. If life-threatening 
reactions such as erythema multiforme, Stevens-Johnson syndrome, or toxic 
epidermal necrolysis (e.g., progressive skin rash often with blisters or mucosal 
lesions) are suspected, discontinue treatment with lapatinib. 
 
 
INTERSTITIAL PNEUMONITIS 
Any grade 
Patients who developed pulmonary infiltrates or 
pneumonitis must have lapatinib held while workup is 
ongoing.  If interstitial pneumonitis is confirmed, 
lapatinib must be discontinued permanently. 


 
43 
RTOG 1119, version date April 2, 2019 
SKIN REACTIONS 
Grade 4 rash or toxic epidermal 
necrolysis (eg, Stevens-Johnson 
Syndrome, etc.)  
Permanently discontinue lapatinib 
 
ABNORMAL LIVER FUNCTION TESTS 
Grade 2 ALT OR grade 2 bilirubin 
1st Occurrence: Hold lapatinib until grade ≤ 1 (up to 14 
days). If resumed, reduce the dose to 750 mg. 
 
2nd Occurrence: If toxicity recurs hold lapatinib until 
grade ≤ 1 (up to 14 days). If resumed, reduce the 
dose to 500 mg. 
 
3rd Occurrence If toxicity recurs again, discontinue 
lapatinib permanently. 
Grade 2 ALT AND grade 2 
bilirubin 
Discontinue lapatinib permanently. 
 
Grade 2 ALT AND INR > 1.5 if in 
the opinion of treating physician 
are both related to liver injury 
caused by lapatinib 
Discontinue lapatinib permanently. 
Grade 2 ALT OR grade 2 bilirubin 
with signs/symptoms that in the 
opinion of treating physician are 
related to liver injury caused by 
lapatinib 
Discontinue lapatinib permanently (such signs and 
symptoms may include abdominal pain, fever, 
jaundice, rash, eosinophilia or a Karnofsky 
performance status drop of ≥ 20 points from baseline). 
Grade 3 or 4 ALT and/or bilirubin 
Discontinue lapatinib permanently. 
DIARRHEA 
Grade 1 
Continue lapatinib, but start loperamide (initial dose 4 
mg followed by 2 mg every 4 hours or after every 
unformed stool).  It is suggested to continue 
loperamide until the subject is free from diarrhoea for 
12 hours. See Supportive care for diarrhea in Section 
9.0. 
Grades 2-4 
1st Occurrence: Hold lapatinib until grade ≤ 1 (up to 14 
days).  Start loperamide, as above, and other 
measures. See supportive care for diarrhea in Section 
9.0. Resume at reduced dose of 750 mg 
 
2nd Occurrence: Repeat above dose delay. Resume at 
reduced dose of 500 mg. 
 
3rd Occurrence: If toxicity recurs again, discontinue 
lapatinib permanently. 
 
OTHER AES DUE TO LAPATINIB 
≥ Grade 3 or intolerable grade 2 
1st Occurrence: Hold lapatinib therapy until recovery to 
grade ≤ 1 (up to 14 days). Resume at reduced dose of 
750 mg.  
 
2nd Occurrence: Repeat above dose delay and 
resume at reduced dose of 500 mg. 
 
3rd Occurrence: Discontinue lapatinib permanently. 


 
44 
RTOG 1119, version date April 2, 2019 
 
If 2 different toxicities call for different degrees of dose reduction (eg, 2nd occurrence of elevated ALT 
[mandating dose reduction to 500 mg/d] and 1st occurrence of diarrhea [mandating dose reduction to 
750 mg/d] the lower of the 2 doses will be used (eg, 500 mg/d in the example). 
 
See Section 9.0 for medical management of other potential events. 
 
7.5 
Modality Review 
 
The Medical Oncology Chair, David M. Peereboom, 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 with respect to drug dosing and 
protocol-directed dose modifications. The review process is contingent on timely 
submission of chemotherapy treatment data as specified in 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. 
 
 
This Chemotherapy Assurance Review will be performed on an ongoing basis (for 
example, the first review after NRG Oncology receives complete data for 20 cases and 
the next review after NRG Oncology receives complete data for 20 more cases). The final 
cases will be reviewed within 3 months after this study has reached the target accrual or 
as soon as NRG Oncology receives complete data for all cases, whichever occurs first. 
 
7.6 
Adverse Events (02-APR-2019) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for 
all AE reporting, CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized 
for CTEP-AERS reporting beginning April 1, 2018; all study case report forms will 
continue to use CTCAE version 4.0. All appropriate treatment areas should have access 
to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
7.6.1 
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/adverse_events.ht
m 
 
 
7.6.2 
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited 
reporting criteria defined in the table in section 7.7 will be reported via CTEP-AERS.  
SAEs that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table in section 7.7.  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; 


 
45 
RTOG 1119, version date April 2, 2019 
▪ 
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. 
7.6.3 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to 
treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the 
CTEP-AERS system 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.  
 
7.7 
CTEP-AERS Expedited Reporting Requirements (08-FEB-2018) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via CTEP-AERS, the Adverse Event Expedited 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 RTOG and satisfies RTOG 
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 RTOG 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. 
 


 
46 
RTOG 1119, version date April 2, 2019 
• 
CTEP-AERS-24 Hour Notification requires that a 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 a 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 an 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 240-276-6575 and the RTOG dedicated SAE 
FAX, 215-717-0990. 
• 
A serious adverse event that meets expedited reporting criteria outlined in the 
following table but is assessed by the CTEP-AERS System as “expedited 
reporting NOT required” must still be reported to fulfill RTOG safety reporting 
obligations. Sites must bypass the “NOT Required” assessment; the CTEP-
AERS System allows submission of all reports regardless of the results of the 
assessment.  
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described 
in 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 under an IND/IDE 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 


 
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RTOG 1119, version date April 2, 2019 
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. 
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 
 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements  
**The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for 
all AE reporting, CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized 
for CTEP-AERS reporting beginning April 1, 2018; all study case report forms will 
continue to use CTCAE version 4.0. 
• 
The following are SAEs and should be reported expeditiously via CTEP-
AERS: Cardiac dysfunction will be reported as an SAE and will be defined as 
any signs or symptoms of deterioration in left ventricular cardiac function that 
are grade 3 (**CTCAE, v. 4) or a ≥ 20% decrease in left ventricular cardiac 
ejection fraction (LVEF) relative to baseline which is below the institution's 
lower limit of normal. 
• 
Hepatobiliary events have been seen in subjects taking lapatinib and other 
tyrosine kinase inhibitors.  As a precaution, the following will be reported as 
an SAE: • 
ALT > 3×ULN and total bilirubin > 2.0×ULN (>35% direct; 
bilirubin fractionation required). Note:  If bilirubin fractionation testing is 
unavailable and a subject meets the criterion of total bilirubin > 2.0 × ULN, 
then the event should still be reported as an SAE. Other hepatic events 
should be documented as an AE or an SAE as appropriate. 
• 
Neurologic dysfunction should be reported as a 24h notification/5 day report. 
Neurologic dysfunction is defined as any grade 3 (**CTCAE v.4) signs or 
symptoms concerning for radionecrosis (including headache, nausea, 
vomiting) or neurologic deficit.  
 
8.0 SURGERY 
Not applicable to this study. 
 


 
48 
RTOG 1119, version date April 2, 2019 
9.0 OTHER THERAPY    
9.1 
Permitted 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.  
9.1.1 
Dexamethasone can potentially induce CYP3A4 and therefore could theoretically 
decrease circulating levels of the study drug, lapatinib. On the other hand, the data 
supporting dexamethasone as a CYP3A4-inducing agent are not strong, and clinical 
need in this group of patients may be significant. Therefore, the use of dexamethasone is 
permitted in this study.  However, because of the potential interaction, the dose should be 
minimized if possible. The use and dose of dexamethasone should be assessed at each 
study visit and documented on the case report forms.  
9.1.2 
Anticonvulsants 
 
Anticonvulsant usage and dosage should be noted at the time of study entry, at each 
follow-up evaluation, and at any changes in medication use. Phenytoin, carbamazepine, 
and barbiturates are CYP3A4 inducers. If a patient requires an anticonvulsant, non-
enzyme-inducing anticonvulsants are preferred (e.g., levetiracetam (Keppra) valproic acid 
and should be substituted if possible, under the direction of her treating physician and/or 
neurologist. 
9.1.3 
Antiemetics 
Antiemetics may be used as needed. It is recommended that dexamethasone be avoided 
if possible. 
9.1.4 
Antidiarrheals 
 
Diarrhea 
Early diarrhea management for patients taking lapatinib must be initiated as soon as 
the first episode of diarrhea has occurred.  Close monitoring and proactive 
management of diarrhea is essential.  At the time of starting lapatinib, all patients 
should be given a prescription for loperamide or analogue, and be advised to keep 
the prescription/medication with them at all times.  The patient should be clearly 
instructed to start loperamide promptly at the first signs of diarrhea.  A dose of 4 mg 
loperamide must be given after first episode of diarrhea, and 2 mg every 4 hours or 
after every episode of unformed stool, until the patient is free from diarrhea for 12 
hours.  The maximum allowed daily dose of loperamide is 16 mg.  The patient must 
contact the Investigator as soon as possible after diarrhea starts. 
 
For Grade 3 or 4 diarrhea or Grade 1 or 2 with complicating features (severe 
cramping, severe nausea/vomiting, decreased performance status, fever, sepsis, 
Grade 3 or 4 neutropenia, frank bleeding, dehydration):  use intravenous fluids as 
appropriate, consider hospital admission and use prophylactic antibiotics as needed 
(example fluoroquinolones) especially if diarrhoea is persistent beyond 24 hours or 
there is a fever or Grade 3-4 neutropenia. 
9.1.5 
Trastuzumab 
 
Patients on trastuzumab at the time of study entry may continue to receive this agent 
throughout the study at the discretion of the treating physician. The dose and schedule 
will be at the discretion of the treating physician. Patients not on trastuzumab at study 
entry will NOT be permitted to begin this therapy while on protocol treatment. 
9.1.6 
Pertuzumab 
 
Based on the encouraging results of the CLEOPATRA study (Baselga 2012), patients on 
pertuzumab at the time of study entry may continue to receive this agent throughout the 
study at the discretion of the treating physician. The dose and schedule will be at the 
discretion of the treating physician. Patients not on pertuzumab at study entry will NOT 
be permitted to begin this therapy while on protocol treatment. 
9.1.7 
Prior Chemotherapy (09/02/2014) 
 
There must be at least 14 days between FINAL dose of prior chemotherapy and 1st day 
of protocol treatment with recovery of toxicities to grade 0 or 1. 
 


 
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RTOG 1119, version date April 2, 2019 
9.2 
Non-Permitted Therapy (9/7/16) 
 
Patients not on trastuzumab, pertuzumab or any other breast cancer therapy at study 
entry will not be permitted to begin this therapy while on protocol treatment (ie, 6 weeks 
of lapatinib [SRS patients: during 6 weeks of lapatinib; WBRT patients: 3 weeks during 
WBRT/lapatinib + 3 weeks during post-WBRT lapatinib]). Patients may begin other drug 
therapy 24 hours after the completion of all protocol treatment. 
 
 
 
Co-administration of lapatinib with strong or moderate CYP3A4/5 inhibitors (including 
grapefruit juice) and all CYP3A4/5 inducers is prohibited.  Assess risk/benefit before co-
administering lapatinib with weak CYP3A4/5 inhibitors.  CYP3A4/5 inhibitors may 
decrease lapatinib metabolism (increasing levels); while CYP3A4/5 inducers may 
increase lapatinib metabolism (decreasing levels). All efforts should be made to avoid the 
use of therapies that induce CYP3A4 enzymes, as described in the table below  
   
Avoid co-administration of lapatinib with drugs that are substrates of CYP3A4 or CYP2C8 
and have narrow therapeutic windows.   
 
(For Arm B DURING treatment; may be initiated immediately after treatment completion) 
 
Drug Class 
Agent 
Wash-Out 
Prior to 
Protocol 
Treatment 
CYP3A4 Inducers 
 
Antibiotics 
All rifamycin class agents (e.g. rifampicin, rifabutin, 
rifapentine) 
14 days 
Anticonvulsants 
Phenytoin, carbamazepine, barbiturates (e.g. 
phenobarbital) 
Antiretroviral 
Efavirenz, nevirapine 
Other 
St. John’s Wort, modafinil 
CYP3A4 Inhibitors 
Antibiotics 
Clarithromycin, erythromycin, troleandomycin 
7 days 
Antifungals 
Itraconazole, ketoconazole, fluconazole (>150 mg daily),  
Voriconazole 
Antiretrovirals, 
protease inhibitors 
Delavirdine, nelfinavir, amprenavir, ritonavir, indinavir,  
saquinavir, lopinavir 
Calcium channel  
Blockers 
Verapamil, diltiazem 
Antidepressants 
Nefazodone, fluvoxamine 
GI agents 
Cimetidine, aprepitant 
Other 
Grapefruit, grapefruit juice 
Other 
Amiodarone 
6 months 
 
 
10.0 
TISSUE/SPECIMEN SUBMISSION  
NOTE: Patients must be offered the opportunity to participate in the tissue/specimen 
submission component of this study 
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. 
 


 
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RTOG 1119, version date April 2, 2019 
10.1 
Tissue/Specimen Submission (09/02/2014) 
 
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 storage and processing. NRG Oncology  
encourages participants in protocol studies to consent to the banking of their tissue. The 
NRG Oncology Biospecimen Bank 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. The 
NRG Oncology Biospecimen Bank also collects tissue for Central Review of pathology. 
Central Review of tissue can be for eligibility and/or analysis.  
 
 
In this study, tissue will be submitted to the NRG Oncology Biospecimen Bank for the 
purpose of tissue and whole blood banking for future research (recommended). For 
patients who have consented to participate in the tissue/blood component of the study. 
(See the sample consent). 
 
10.2 
Specimen Collection for Banking for Future Research (08-FEB-2018) 
10.2.1 
Tissue Submission 
The following must be provided in order for the case to be evaluable for the 
Biospecimen Bank: 
• 
One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic 
slide (block); it does not have to be the diagnostic slide itself). 
• 
A corresponding paraffin-embedded tissue block of the tumor (the block must match 
the H&E being submitted) or a 5 mm diameter core of tumor tissue, punched from the 
tissue block containing the tumor with a punch tool and submitted in a plastic tube 
labeled with the surgical pathology number. Note: A kit with the punch, tube, and 
instructions can be obtained free of charge from the NRG Oncology Biospecimen 
Bank. Block or core must be clearly labeled with the pathology identification number 
and block number that corresponds to the Pathology Report and H&E slide. 
• 
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. 
• 
A Specimen Transmittal (ST) Form clearly stating that tissue is being submitted for 
the NRG Oncology Biospecimen Bank; 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.  
10.2.2 
Whole Blood and Plasma Submission 
 
See Appendix II 
10.2.3 
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; Canada: Monday-
Tuesday). 
OR: 
• Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
• Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and 
time stored. 


 
51 
RTOG 1119, version date April 2, 2019 
 
10.2.4 
Specimen Collection Summary  
 
 
Specimens for Banking for Future Research 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E 
stained slides of the 
primary (breast) tumor  
Pre-treatment 
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
A corresponding paraffin-
embedded tissue block 
of the primary (primary) 
tumor taken before 
initiation of treatment or a 
5 mm diameter core of 
tissue, punched from the 
tissue block with a punch 
tool  
Pre-treatment 
Paraffin-embedded 
tissue block or punch 
biopsy (must match 
the H&E slide being 
submitted)   
 
Block or punch shipped 
ambient 
 
PLASMA: 5-10 mL of 
anticoagulated whole 
blood in EDTA tube #1 
(purple/ lavender top) 
and centrifuge 
Pre-treatment, at 4 wks 
after WBRT/SRS 
completion, and at 12 
wks after WBRT/SRS 
completion 
Frozen plasma 
samples containing a 
minimum of 0.5 mL 
per aliquot in 1 mL 
cryovials (five) 
Plasma sent frozen on 
dry ice via overnight 
carrier 
Whole blood for DNA: 5-
10 mL of anticoagulated 
whole blood in EDTA 
tube #2 (purple/ lavender 
top) and mix 
Pre-treatment. Note if 
site missed the 
collection site may 
collect this specimen at 
any timepoint or follow-
up but this must be 
noted on the STF. 
Frozen whole blood 
samples containing  
1-1.5 ml per aliquot 
in 2ml cryovials 
(three) 
Whole blood sent frozen 
on dry ice via overnight 
carrier 
 
10.2.5 
Submit materials for banking as follows: 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank- San Francisco  
University of California San Francisco- box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143- 
 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen 
Specimens 
NRG Oncology Biospecimen Bank- San Francisco 
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 
 
 
 
10.3 
Confidentiality/Storage (02-APR-2019) 
10.3.1 
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. 


 
52 
RTOG 1119, version date April 2, 2019 
10.3.2 
Specimens for banking will be stored for an indefinite period of time. If at any time the 
patient withdraws consent to store and use specimens, the material will be returned to 
the institution that submitted it upon request. 
 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters: See Appendix I for a summary of time frames and assessments 
 
11.2 
Measurement of Response (7/22/16) 
11.2.1 
Gadolinium-enhanced brain MRI will be checked at baseline, 4 weeks after 
WBRT/SRS, 12 weeks after WBRT/SRS, and every 12 weeks thereafter until 
progression. MRI will be obtained on a 1.5T or 3Tesla scanner according to 
standardized imaging protocols outlined in Appendix V. MR imaging will be collected 
electronically for ad hoc central review of responses. 
11.2.2 
Response and progression in the brain is the primary endpoint of the study and will be 
evaluated separately from the rest of the body using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) (Eisenhauer 2009). Response in the brain also will be measured 
using bidimensional measurements (WHO/modified McDonald’s criteria). Changes in 
the largest diameter (unidimensional measurement) of the tumor lesions are used in 
the RECIST criteria.  
11.2.3 
Response Definitions 
The case report forms for this study will collect response as measured by both RECIST 
1.1 and the WHO/modified McDonald Criteria separately per the definitions in the table 
below: 
 
 
 
Response 
RECIST 1.1 Criteria 
WHO/modified McDonald Criteria 
CR 
(complete 
response) 
Complete disappearance of all 
enhancing disease and off all steroids 
complete disappearance of all 
enhancing disease and off all steroids 
PR 
(partial response) 
≥ 30% reduction in the sum of 
diameters of up to 2 target lesions* 
≥ 50% reduction in the sum of 
products of the perpendicular 
diameters of up to 2 target lesions* 
plus no new lesion, no progression of 
non-measurable CNS lesion, no 
increasing steroid requirements, and 
no worsening of neurologic symptoms 
Stable disease 
Any assessment that falls between PR 
and PD 
Any assessment that falls between PR 
and PD 
PDT 
(progressive 
disease) 
• 
≥ 20% increase of up to 2 
target CNS lesions relative to 
nadir 
• 
New CNS lesions 
• 
Unequivocal progression 
(defined below‡)  
• 
Tumor-related increase in 
steroid dose  
• 
New or worsening tumor-
related neurologic symptoms 
• 
≥ 25% increase of up to 2 
target CNS lesions relative to 
nadir 
• 
New CNS lesions 
• 
unequivocal progression 
(defined below‡)  
• 
Tumor-related increase in 
steroid dose 
• 
New or worsening tumor-
related neurologic symptoms 
* Target lesions are defined as reliably measurable lesions and should consist of the 2 
largest such lesions. Lesions with prior local treatment (e.g., SRS) are not considered 
measurable unless there has been demonstrated progression in the lesion (Eisenhauer 
2009). 


 
53 
RTOG 1119, version date April 2, 2019 
† It is encouraged that lesions previously treated with SRS be assessed with ancillary 
imaging (eg, PET scan). 
‡ Unequivocal progression: overall level of substantial worsening in non-target lesions 
such that, even in presence of SD or PR in target lesions, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. 
 
11.3 
Central Review (7/22/16) 
The study neuroradiology co-chair, Daniel Boulter, will perform a retrospective central 
review of the pre-study, 4-week post-WBRT/SRS, 12-week post-WBRT/SRS, and 
progression scans on all cases. Results from this central review will be reported, in 
addition to the results based on the data reported by the institutions. 
 
11.4 
Criteria for Discontinuation of Protocol Treatment 
▪ 
Progression of disease; 
▪ 
A delay in protocol treatment, as specified in Section 7.0.  
If protocol treatment is discontinued, follow-up and data collection will continue as 
specified in the protocol. 
 
 
 
 
 
 
 
 
 
 
12.0 
DATA COLLECTION (08-FEB-2018) 
Data should be submitted to: 
NRG Oncology* 
1818 Market Street, Suite 1720 
Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
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. 
 
12.1 
Summary of Data Submission (7/22/16) 
 
Item 
Due 
Demographic Form (A5) 
Within 2 weeks of study entry 
Initial Evaluation Form (I1) 
 
Surgical Pathology Report (S5) 
 
HER2 Status Documentation (pathology) 
 
 
 
Concurrent Treatment Form (TF) 
1 week after concurrent treatment completion 
(Arm B only) 
 
 
Maintenance Treatment Form (SF) 
1 week after maintenance treatment 
completion (Arm B only) 
 
 
Follow-up Form (F1) 
4 weeks post-RT completion, 12 weeks post-
RT completion, every 3 months to year 3, and 
then annually 
Dosimetry Data (for Whole Brain Radiation 
 


 
54 
RTOG 1119, version date April 2, 2019 
Therapy Only) 
▪ 
Previous SRS treatment information 
form (F4)  
Within 1 week of study entry 
▪ 
Previous SRS treatment planning (TM) 
(See Section 6.5 for specific details of 
data needed)  
Within 1 week of study entry 
▪ 
Radiotherapy Form (T1) 
Within 1 week of RT end 
▪ 
Daily Treatment Chart (T5) 
Within 1 week of RT end 
NOTE: ALL SIMULATION, PORTAL FILMS, IGRT AND/OR DIGITAL FILM IMAGES WILL BE 
KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED. 
 
Scan Submission 
 
▪ 
Pre-study MRI scan and report (MR, 
ME) 
Within 1 week of study entry 
▪ 
4-wk post-RT MRI scan and report 
(MR,ME) 
Within 2 weeks of scan date 
▪ 
12-wk post-RT MRI scan and report 
(MR,ME) 
Within 2 weeks of scan date 
▪ 
Progression MRI scan and report 
Within 2 weeks of scan date 
▪ 
Radiology review form (SR) 
At 4 and 12 weeks post-RT, then every 12 
weeks and at progression 
12.1.1 Methods of Scan Submission 
 
The MRI scans will be archived by Imaging and Radiation Core (IROC) using the latest 
version of TRIAD image submission software. 
 
Information or questions about the MRI submission can be directed to: 
 
Email:   imagearchive@acr.org in Subject Line enter: RTOG 1119 MRI for IROC DI. 
You can expect a response within 1 business day 
 
TRIAD Digital Image Submission: 
TRIAD is the secure electronic image upload application utilized for IROC Services of this trial. TRIAD de-
identifies and validates the images as they are transferred. 
 
1. TRIAD Access Requirements: 
 
TRIAD will be the sole means of image transfer to the IROC Philadelphia DI. TRIAD should be installed 
prior to study participant enrollment to ensure prompt secure, electronic submission of imaging. 
• Site staff who submits images through TRIAD will need to be registered with the Cancer 
Therapy Evaluation Program (CTEP) and have a valid and active CTEP-IAM account.(https://eapps-
ctep.nci.nih.give/iam/index.jsp) 
• To submit images, the site user must be on the site’s affiliating rosters and be assigned the 
'TRIAD site user' role on the CTSU roster. Users should contact the site’s CTSU Administrator or Data 
Administrator to request assignment of the TRIAD site user role. 
 
 
2. TRIAD Installations: 
 
After a user receives a CTEP-IAM account with the proper user role, he/she will need to have the TRIAD 
application installed on his/her workstation to be able to submit images.  
 
TRIAD installation. Documentation can be found by following this link: 
 


 
55 
RTOG 1119, version date April 2, 2019 
https://triadinstall.acr.org/triadclient/ 
Questions regarding image submissions should be directed to: 
IROCPHILA-DI@acr.org.  
 
Questions about TRIAD should be directed to: 
http://triadhelp.acr.org/ClinicalTrials.aspx 
 
Tech Support is available from Monday to Friday between 8am - 5pm EST. 
Contact By Phone:  
703.390.9858 
Contact By Email: 
Triad-Support@acr.org 
 
12.2 
Summary of Dosimetry Digital Data Submission for SRS ONLY (Submit to TRIAD; See 
Section 5.2) (08-FEB-2018 
NOTE: ALL DIGITAL RT DATA REQUIRED IN DICOM FORMAT VIA TRIAD.  ALL REQUIRED 
STRUCTURES MUST BE LABELED PER DICOM STANDARD NAME AS LISTED IN SECTION 
6. 
 
Preliminary Dosimetry Information (DD)  
Within 1 week of RT start 
Digital Data Submission – Treatment Plan submitted to TRIAD by 
Physicist  
 
Digital data submission includes the following:  
 
 CT data, critical normal structures, all GTV, CTV, and PTV 
contours   
 
 Digital beam geometry for  beam sets  
 
 Doses for  concurrently treated beams  
 
 Digital DVH data for all required critical normal structures, GTV, 
CTV, and PTVs for total dose plan  All required structures MUST 
be labeled per the table in Section 6 
Submit via TRIAD with the digital data listed above.  
 
Upon submission of the digital data via TRIAD, complete an 
online digital data transmission form (DDSI) located in the 
CORE LAB section on the NRG Oncology/RTOG web site at 
https:    www.irocqa.org/Resources/TRIAD-for-RT-QA 
 
Note: All simulation and portal films and/or digital film images will 
be kept by the institution and only submitted if requested.  
 
 
 
 
Final Dosimetry Information 
Within I week of RT end 
Radiotherapy Form (T1) 
 
Daily Treatment Record (T5) 
 
 
 
 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Endpoints (7/22/16) 
13.1.1 
Primary Endpoint 


 
56 
RTOG 1119, version date April 2, 2019 
Complete response (CR) rate in the measurable brain metastases at 12-weeks post 
whole brain irradiation (WBRT) or stereotactic radiosurgery (SRS) (measured using 
revise RECIST version 1.1 based on MRI scan of the brain – see Section 13.4 for 
details) 
13.1.2 
Secondary Endpoints 
▪ 
Complete response (CR) rate of measurable brain metastases at 4 weeks 
post WBRT/SRS 
▪ 
Objective response rate (CR + PR) of measurable brain metastases at 4 
and 12 weeks post WBRT/SRS 
▪ 
Targeted lesion-specific objective response rate (CR + PR) at 4 and 12 
weeks post WBRT/SRS  
▪ 
CNS progressive disease out the targeted measurable disease 
▪ 
Targeted lesion-specific progression at 4 and 12 weeks post WBRT/SRS 
 
▪ 
Treatment-related adverse events as measured by CTCAE v 4 
▪ 
Overall CNS complete response as defined in Section 2.2.7 
▪ 
Over CNS progressive disease (within or outside measurable disease) 
▪ 
Overall survival (OS) (failure: death due to any cause) 
 
13.2 
Stratification (7/22/16) 
Patients will be stratified before randomization with respect to graded prognostic 
assessment (GPA) score (1.5-2 vs 2.5-3 vs 3.5-4); use of non-CNS–penetrating HER2 
blockade at time of study entry (No vs. Yes: trastuzumab ± pertuzumab); and RT to be 
used (WBRT vs. SRS). The treatment allocation scheme described by Zelen (1974) will 
be used because it balances patient factors other than institution. 
 
13.3 
Sample Size and Power Justification (7/22/16) 
13.3.1 
The study will be a randomized phase II screening trial as proposed by Rubinstein et al 
(2005).  Specifically, this randomized phase II trial will evaluate if there is a sufficient 
enough signal in improved 12-week (post WBRT/SRS) CR rate with the addition of 
lapatinib to WBRT/SRS in patients with brain metastasis from HER-2 positive breast 
cancer to warrant a future phase III trial.  The null hypothesis is that the 12-week post 
WBRT/SRS CR rate is ≤ 5% for both WBRT/SRS (control arm, Suh, ENRICH study, 
personal communication) and WBRT/SRS + lapatinib (experimental arm). The 
alternative hypothesis is that the addition of lapatinib to WBRT/SRS will result in a 12-
week post WBRT/SRS CR rate of at least 20%.  The randomization of experimental 
and control arms is set as 1:1. With 114 eligible subjects there will be 86% power to 
detect a 15% absolute increase in CR rate at a significance level of 0.10, using a 1-
sided Z-test for 2 proportions. Guarding against up to 5% of ineligibility rate and 15% 
patients not evaluable for the primary endpoint due to death, patient withdrawal, or 
other reasons, the final targeted accrual for this study component will be 143 cases. In 
the event that the WBRT/SRS CR rate is ≤ 10% for WBRT/SRS (control arm), 114 
eligible patients provides 80% power to detect a 15% absolute increase to at least 25% 
in CR rate with the addition of lapatinib at a significance level of 0.10, using a 1-sided 
Z-test for 2 proportions.  
 
 
No Sample Size Change with SRS Amendment  
The amendment to allow RT delivery with SRS will not change the planned sample 
size, as described below.  The current sample size provides 86% statistical power to 
detect an increase in the 12-week CR rate from 0.05 to 0.20.  The current statistical 
section of the protocol also already states that in the event that the control arm rate is 
up to 0.10, the sample size provides 80% power to detect the hypothesized 15% 
absolute increase.   
 
Under the assumption that patients treated with SRS have a 12-week CR rate of 0.14, 
the overall control arm 12-week CR rate will be higher than 0.05, but how much higher 
will depend on the proportion of SRS treated patients entered onto the trial.  As the 


 
57 
RTOG 1119, version date April 2, 2019 
planned accrual is already halfway completed and assuming a 0.14 CR rate for patients 
treated with SRS, the table below shows what the overall control arm rates would be for 
the proportion of patients receiving SRS ranging from 10-50%.    
 
 
 
 
 
 
 
 
 
% of WBRT Patients 
(Assuming 12 wk CR 
rate of 0.05) 
% of SRS Patients 
(Assuming 12 wk CR 
rate of 0.14) 
Overall CR rate for  
control arm  
 
 
100% - original design 
0% 
0.05 
 
 
90% 
10% 
0.059 
 
 
80% 
20% 
0.068 
 
 
70% 
30% 
0.077 
 
 
60% 
40% 
0.086 
 
 
50% 
50% 
0.095 
 
 
As shown in the table above, even if all of the rest of the patients receive RT via SRS, 
the control arm 12-week CR rate would not exceed 0.10, and therefore the original 
planned sample size provides sufficient power to address the primary hypothesis.    
 
 
13.3.2 
Patient Accrual (09/02/2014) 
Patient accrual is projected to be 6 cases per month.  With a 6-month ramp-up period 
with little to no accrual while the study is approved by institutional IRBs, accrual is 
projected to be completed in 30 months. The study will officially be reviewed for accrual 
by the NRG Oncology Data Monitoring Committee at the NRG Oncology semi-annual 
meetings.  Eighteen months post activation, if the average monthly accrual rate in 
months 13 to 18 is less than 3 patients, the study will be re-evaluated with respect to 
feasibility. If this occurs, considerations will be given to revising the eligibility to 
increase accrual. 
 
13.4 
Analysis Plan (7/22/16) 
All analyses will be done based on the assigned treatment arm for all eligible patients 
entered. 
13.4.1 
Statistical Methods 
 
Complete Response (CR) Rate 
Response in the brain is the primary endpoint of the study and will be evaluated 
separately from the rest of the body using the new international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer 2009). Response in the brain also will be measured using 
bidimensional measurements (WHO/modified McDonald’s criteria). Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. Non-CNS lesions are considered non-target lesions. Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 
3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) 
early death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data). 
 


 
58 
RTOG 1119, version date April 2, 2019 
For patients who received prior SRS, response will be based on the new (protocol-
treated) lesion(s).  
 
For a given treatment arm, the CR rate will be calculated by dividing the number of 
patients classified as CR by the number of analyzable patients.  A Z-test will be 
used to compare the CR rates between the treatment arms. 
 
Response Definitions 
▪ 
Objective response (CR + PR) will be based on up to 2 target lesions and 
will evaluated based on responses reported by the institution and also 
evaluated based on a central review of MRIs. 
▪ 
Lesion-specific response will be performed for up to 2 target lesions based 
on responses reported by the institution and also evaluated based on a 
central review of MRIs. Lesion-specific response for up to 8 additional non-
target lesions will based on a central review of MRIs. 
Overall response will be defined per the following table: 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = inevaluable PD = progressive disease; PR = partial 
response; SD = stable disease. 
 
  
 
Overall Survival (OS) 
OS will be estimated by the Kaplan-Meier method (Kaplan 1958). The distribution of 
OS estimates between the two arms will be compared using the log rank test 
(Mantel 1966).  OS time will be measured from the date of randomization to the date 
of first failure or last follow-up.  The Cox proportional hazard regression model will 
be used to analyze the effects of factors, in addition to treatment, that may be 
associated with OS (Cox 1972).  
13.4.2 
Interim Analysis to Monitor the Study Progress 
Interim reports with statistical analyses will be prepared twice per year until the initial 
treatment results have been presented/published.  In general, the interim reports will 
contain the following information: 
 
▪ 
patient accrual rate with a 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, and 
▪ 
compliance rates of treatment delivery. 
 
The interim reports will not contain the results from the treatment comparisons with 
respect to the primary endpoint, 12-week post WBRT/SRS CR rate, or any secondary 
endpoints, with the exception of reporting of adverse events. 
 


 
59 
RTOG 1119, version date April 2, 2019 
13.4.3 
Data and Safety Monitoring 
This study will be reviewed by the RTOG Data Monitoring Committee (DMC) on a 
semiannual basis for accrual (while applicable) and adverse events.    
 
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. 
13.4.4 
Analysis for Reporting the Initial Treatment Results  
The primary hypothesis of this study is that the addition of lapatinib to WBRT/SRS will 
increase the 12-week post WBRT/SRS CR rate from 10% to 25%, for patients with 
brain metastasis from HER-2+ breast cancer.  This analysis will occur after the last 
patient has been followed for a minimum of 12 weeks after WBRT/SRS. It will include: 
 
▪ 
tabulation of all cases entered and those excluded from the analyses with the 
reasons for exclusion given, 
▪ 
distributions of important prognostic baseline variables,  
▪ 
the frequencies and severity of adverse events by treatment arm, 
▪ 
compliance rate of treatment delivery, and 
▪ 
observed results with respect to the primary and secondary endpoints 
 
All eligible patients randomized will be included in the comparison and will be grouped 
by assigned treatment in the analysis.  The primary hypothesis of treatment benefit will 
be tested using the Z-test comparing 1 proportions with a significance level of 0.10.  
Additional analyses of treatment effect will be performed using the logistic regression 
model with the stratification factor included as a fixed covariate, as well as any factors 
that show an imbalance between the arms. 
 
13.5 
Gender and Minorities 
Both men and women of all races and ethnic groups are eligible for this study.  In 
conformance with the national Institutes of Health (NIH) Revitalization Act of 1993 with 
regard to inclusion of women and minorities in clinical research, possible interaction 
between race/ethnicity and treatment have been considered. A statistical analysis will 
be performed to examine the possible difference between among the races, as accrual 
across classes of race permits. Based on previous RTOG studies, it is projected that: 
4% will be of Hispanic or Latino ethnicity and 96% will not; racial distribution will be 
58% white, 30% Asian, 11% black or African American, and 1% American Indian or 
Alaskan Native: The following table lists the projected accrual by ethnic and racial 
categories.   
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
6 
0 
6 
Not Hispanic or Latino 
137 
0 
137 
Ethnic Category: Total of all subjects 
143 
0 
143  
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
2 
0 
2 
Asian 
43 
0 
43 
Black or African American 
15 
0 
15 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
83 
0 
83 


 
60 
RTOG 1119, version date April 2, 2019 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Racial Category: Total of all subjects 
143 
0 
143  
 


 
61 
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APPENDIX I (7/22/16) 
 
 
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS 
 
Assessments 
Time Point 
 
Prior to registration 
≤ 21 days prior 
to registration 
≤ 7 days prior to treatment start 
Histo/cyto eval 
X 
 
 
T1-weighted 
gadolinium-
enhanced MRI of 
brain 
 
X 
 
History/physical 
 
X 
 
Performance status 
 
X 
 
ANC, platelets, 
Hgb 
 
X 
 
Creatinine, AST 
 
X 
 
Bilirubin 
 
X 
 
ALT 
 
X 
 
Serum pregnancy 
test (if applicable) 
 
X 
 
Serum or urine 
pregnancy test (if 
applicable) 
 
 
See Section 4.1 
Tissue for banking 
(for consenting pts) 
Prior to start of treatment 
Plasma for banking 
(for consenting pts) 
Prior to start of treatment  
Whole blood for 
banking (for 
consenting pts) 
Prior to start of treatment  
 (if site misses pretreatment time point, collection may occur at any other time 
point or follow-up visit) 
 


 
66 
RTOG 1119, version date April 2, 2019 
 
APPENDIX I (cont’d) 
 
STUDY PARAMETER TABLE: DURING TREATMENT ASSESSMENTS  
 
Assessments 
Time Point 
 
After 7 days of 
WBRT (for SRS 
patients: 7 days 
after SRS) 
After 14 days of 
WBRT (for SRS 
patients: 14 
days after SRS) 
At end of WBRT 
 
 
 
 
 
Bilirubin 
 
 
Arm B only; repeat wkly if 1st sample 
triggers dose modification or hold; 
otherwise repeat not needed 
ALT 
 
 
Arm B only repeat wkly if 1st sample 
triggers dose modification or hold; 
otherwise repeat not needed 
Adverse Event eval 
X 
X 
X 
 
 
 
STUDY PARAMETER TABLE: FOLLOW-UP ASSESSMENTS 
 
Assessments 
Time Point 
 
28 days after 
WBRT/SRS 
completion  
 
12 weeks after 
WBRT/SRS 
completion  
 
Then every 12 weeks 
T1-weighted 
gadolinium-
enhanced MRI of 
brain 
X 
X 
X (until progression) 
Performance status 
X 
X 
X 
Adverse event 
eval. 
X 
X 
 
Plasma for banking 
(for consenting pts) 
X 
X 
 
 
 
 
 
 


 
67 
RTOG 1119, version date April 2, 2019 
APPENDIX II 
 
KARNOFSKY PERFORMANCE SCALE 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
20 
Very sick; hospitalization necessary; active support treatment is 
necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
 


 
68 
RTOG 1119, version date April 2, 2019 
  
APPENDIX III (08-FEB-2018) 
NRG Oncology FFPE Specimen Plug Kit Collection 
NRG Oncology Blood Collection Kit Instructions 
 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For Formalin fixed paraffin embedded 
(FFPE) or Non-frozen Specimens Only 
 
NRG Oncology Biospecimen Resource 
University of California San Francisco 
Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143- 
Courier Address (FedEx, UPS, etc.): For  ALL Frozen or Trackable Specimens 
NRG Oncology Biospecimen Resource 
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 Form (ST) 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 block shaking it might  l 
break during shipping.   
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States 
Postal Service (USPS) to the USPS address (94143) or 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. If possible keep Serum, Plasma, and Whole Blood specimens in 
separate bags. 
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 on dry ice via overnight courier to the address above. Specimens 
should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) 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 Bankby e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-
5271. 


 
69 
RTOG 1119, version date April 2, 2019 
 
NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen 
Resource. 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. 
 
 
 
Step 2 
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. 
 
*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  Bankand 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. 
Ship 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: RTOGNRGBB@ucsf.edu or call 415-476-7864/Fax 
415-476-5271. 
 
 
 
 
 
 
 
 
 


 
70 
RTOG 1119, version date April 2, 2019 
 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank- San Francisco  
University of California San Francisco 
Campus Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens or Trackable 
shipments 
NRG Oncology Biospecimen Bank- San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
71 
RTOG 1119, version date April 2, 2019 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS 
 
This Kit is for collection, processing, storage, and shipping of plasma or whole blood (as 
specified by the protocol): 
 
Kit contents:Sites are responsible for providing their blood draw tubes 
• 
Fifteen (15) 1 ml cryovials for plasma 
• 
Three (3) 2ml cyrovials for whole blood 
• 
Biohazard bags (4) and Absorbent shipping material (4 
• 
One Styrofoam container (inner) and Cardboard shipping (outer) box per case 
• 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
• 
Specimen Transmittal Form (ST) and Kit Instructions 
 
PREPARATION AND PROCESSING OF PLASMA AND WHOLE BLOOD: 
(A) Plasma (If requested): Purple Top EDTA tube #1 
❑ 
Label five1ml cryovials (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 STForm. 
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 a minimum of 0.5 ml plasma into  fivecryovials as are necessary 
for the plasma collected () labeled with RTOG 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 tubes upright at -70 to -90C. 
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form. 
 
(continued on next page) 


 
72 
RTOG 1119, version date April 2, 2019 
 
 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
(B) 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 1.0-1.5 ml blood into  three cryovials as are necessary for the 
blood collected 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 tubes upright 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 
STForm. 
 
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; Canada: Monday-
Tuesday 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; Canada: Monday-Tuesday only). 
OR: 
▪ 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday only). 
❑ 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
❑ 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) 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. 


 
73 
RTOG 1119, version date April 2, 2019 
❑ 
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 RTOGNRGBB@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Resource 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-RTOG (7864) or e-mail: RTOGNRGBB@ucsf.edu  


 
74 
RTOG 1119, version date April 2, 2019 
APPENDIX IV 
 
GRADED PROGNOSTIC ASSESSMENT FOR BREAST CANCER (BREAST-GPA) 
 
Prognostic Factor 
0 
0.5 
1.0 
1.5 
2.0 
 
Score 
Karnofsky 
Performance 
Status 
< 50 
60 
70-80 
90-100 
n/a 
 
____ 
Subtype 
Basal 
n/a 
LumA 
HER2 
LumB 
 
____ 
Age 
> 60 
< 60 
n/a 
n/a 
n/a 
 
____ 
 
 
 
 
 
 
Sum Total 
____ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subtype: 
Basal = 
Triple Negative (ER/PR/HER2-neg) 
 
LumA = 
Luminal A (ER/PR-pos, HER2-neg) 
 
LumB = 
Luminal B (Triple Positive, ER/PR/HER2-pos) 
 
HER2 = 
HER2-pos, ER/PR-neg 
 
 
MST (mo) by GPA: 0-1.0 = 3.4, 1.5-2.0 = 7.7, 2.5-3.0 = 15.1, 3.5-4.0 = 25.3 
 
Sperduto PW, Kased N, Roberge D, et al.  Effect of tumor subtype on survival and the Graded Prognostic 
Assessment (GPA) for patients with breast cancer and brain metastases.  Int J Radiat Oncol Biol Phys. 
2011;Apr14 (Epub ahead of print). 
 
 
Sperduto PW, Kased N, Roberge D, et al.  Summary report on the Graded Prognostic Assessment 
(GPA): an accurate and facile diagnosis-specific tool to estimate survival for patients with brain 
metastasis.  J Clin Oncol. 2012;30:419-25. 
 
 
 


 
75 
RTOG 1119, version date April 2, 2019 
Appendix V (7/22/16) 
Consensus Recommendations for a Standardized Brain Tumor Imaging Protocol in Clinical Trials 
 
 
Minimum standard 1.5 T & 3 T MRI protocol1 
 
3D T1w Preb 
Ax 2D 
FLAIRj 
Ax 2D DWI 
 
Ax 2D 
T2wh,i 
(Contrast 
Injectiona) 
3D T1w Postb 
(Contrast 
Injectiona) 
 
Sequence 
 
IR-GREe,f 
 
TSEc 
 
SS-EPIg 
 
TSEc 
 
IR-GREe,f 
 
Plane 
 
Sagittal/axial 
 
Axial 
 
Axial 
 
Axial 
 
Sagittal/axial 
 
Mode 
 
3D 
 
2D 
 
2D 
 
2D 
 
3D 
 
TR [ms] 
 
2100m 
 
>6000 
 
>5000 
 
>2500 
 
2100m 
 
TE [ms] 
 
Min 
 
100–140 
 
Min 
 
80–120 
 
Min 
 
TI [ms] 
 
1100n 
 
2000–2500k 
 
1100n 
 
Flip angle 
 
10°–15° 
 
90°/≥160° 
 
90°/180° 
 
90°/≥160° 
 
10°–15° 
 
Frequency 
 
≥172 
 
≥256 
 
≥128 
 
≥256 
 
≥172 
 
Phase 
 
≥172 
 
≥256 
 
≥128 
 
≥256 
 
≥172 
 
NEX 
 
≥1 
 
≥1 
 
≥1 
 
≥1 
 
≥1 
 
FOV 
 
256 mm 
 
240 mm 
 
240 mm 
 
240 mm 
 
256 mm 
 
Slice thickness 
 
≤1.5 mm 
 
≤4 mml 
 
≤4 mml 
 
≤4 mml 
 
≤1.5 mm 
 
Gap/spacing 
 
0 
 
0 
 
0 
 
0 
 
0 
 
Diffusion optionsp 
b = 0, 500, 1000 
s/mm2 ≥3 
directions  
 
Parallel imaging 
 
Up to 2x 
 
Up to 2x 
 
Up to 2x 
 
Up to 2x 
 
Up to 2x 
 
Scan time (approx) 
[benchmarked on 3 
T Skyra] 
 
5–10 min [5:49 
for 1 mm 
isotropic] 
 
4–8 min 
[3:22 for 2D 
FLAIR] 
 
2–4 min [1:22 
for 3 direction 
DWI and 3 b-
values] 
 
4–8 min 
[5:10 for 
dual echo] 
 
5–10 min [5:49 
for 1 mm 
isotropic] 
  
  
 Abbreviations: 2DFL, 2-dimensional FLASH (fast low angle shot) gradient recalled echo; 3D, 2-
dimensional; A/P, anterior to posterior; ADC, apparent diffusion coefficient; Ax, Axial; DSC, dynamic 
susceptibility contrast; DWI, diffusion-weighted imaging; EPI, echo-planar imaging; FLAIR, fluid-


 
76 
RTOG 1119, version date April 2, 2019 
attenuated inversion recovery; FOV, field of view; GE-EPI, gradient-echo echo-planar imaging; IR-
GRE, inversion-recovery gradient-recalled echo. MPRAGE, magnetization prepared rapid gradient-
echo; NEX, number of excitations or averages; PD, proton density; R/L, right to left; SS-EPI, single-
shot echo-planar imaging; TE, echo time; TI, inversion time; TR, repetition time; TSE, turbo spin-echo.  
 
a0.1 mmol/kg dose injection with a gadolinium-chelated contrast agent. Use of a power injector is 
desirable at an injection rate of 3–5 cc/s.  
 
bPostcontrast 3D T1-weighted images should be collected with equivalent parameters to precontrast 
3D T1-weighted images.  
 
cTSE = turbo spin-echo (Siemens & Philips) is equivalent to FSE (fast spin-echo; GE, Hitachi, Toshiba).  
 
dFL2D = 2-dimensional fast low angle shot (FLASH; Siemens) is equivalent to the spoil gradient 
recalled echo (SPGR; GE) or T1-fast field echo (FFE; Philips), fast field echo (FastFE; Toshiba), or the 
radiofrequency spoiled steady state acquisition rewound gradient echo (RSSG; Hitachi). A fast gradient 
echo sequence without inversion preparation is desired.  
 
eIR-GRE = inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = 
magnetization prepared rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled 
gradient-echo (IR-SPGR or Fast SPGR with inversion activated or BRAVO; GE), 3D turbo field echo 
(TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba).  
 
fA 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE 
or another IR-prepped 3D T1-weighted sequences and therefore should be avoided.  
 
gIn the event of significant patient motion, a radial acquisition scheme may be used (eg, BLADE 
[Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, this 
acquisition scheme can cause significant differences in ADC quantification and therefore should be 
used only if EPI is not an option. Further, this type of acquisition takes considerably more time.  
 
hDual echo PD/T2 TSE is optional for possible quantification of tissue T2. For this sequence, the PD 
echo is recommended to have a TE < 25 ms.  
 
iAdvanced sequences can be substituted into this time slot, so long as 3D postcontrast T1-weighted 
images are collected between 4 and 8 minutes after contrast injection.  
 
j3D FLAIR is an optional alternative to 2D FLAIR, with sequence parameters as follows per EORTC 
guidelines: 3D TSE/FSE acquisition; TE = 90–140 ms; TR = 6000–10 000 ms; TI = 2000–2500 ms 
(chosen based on vendor recommendations for optimized protocol and field strength); GRAPPA ≤ 2; fat 
saturation; slice thickness ≤1.5 mm; orientation sagittal or axial; FOV ≤ 250 mm × 250 mm; matrix ≥244 
× 244.  
 
kChoice of TI should be chosen based on the magnetic field strength of the system (eg, TI ≈ 2000 
milliseconds for 1.5 T and TI ≈ 2500 milliseconds for 3 T).  
 
lIn order to ensure comparable SNR, older 1.5 T MR systems can use contiguous (no interslice gap) 
images with 5 mm slice thickness or increase NEX for slice thickness ≤4 mm.  
 
nFor Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400–450 
milliseconds for similar contrast.  
 
mFor Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5–15 
milliseconds for similar contrast.  
 
pOlder model MR scanners that are not capable of >2 b values should use b = 0 and 1000 s/mm2.  
  
 1. 
Ellingson BM, Bendszus M, Boxerman J, et al. Consensus recommendations for a standardized 
Brain Tumor Imaging Protocol in clinical trials. Neuro-oncology 2015; 17(9): 1188-98.