Conditions: Non-HPV Locally Advanced Head and Neck Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 142
Healthy volunteers: no

Brief summary:
PURPOSE: This trial is studying if and how well lapatinib adds to the effectiveness of radiation therapy plus cisplatin in patients who have head and neck cancer that is not related to the human papillomavirus (HPV).

Detailed description:

Arms:
arm 1: Intensity Modulated Radiation Therapy (IMRT) with cisplatin and placebo arm 2: IMRT with cisplatin and lapatinib

Interventions: intervention 1: IMRT intervention 2: Cisplatin intervention 3: placebo intervention 4: Lapatinib
Intervention descriptions: intervention 1: Intensity modulated radiation therapy (IMRT), 35 fractions over 6 weeks, 6 fractions per week for 5 weeks and 5 fractions per week for 1 week, 2 Gy per fraction to total dose of 70 Gy intervention 2: 100 mg/m\^2 administered intravenously on days 8 and 29 intervention 3: 1500 mg placebo daily by mouth or by feeding tube starting 7 days before IMRT for 7 weeks prior to and during IMRT and 3 months after completion of IMRT intervention 4: 1500 mg lapatinib by mouth or by feeding tube daily starting 7 days before IMRT for 7 weeks prior to and during IMRT and 3 months after completion of IMRT

Protocol document:
Prot_SAP_000.pdf: 
RTOG FOUNDATION 
 
 
RTOG 3501 
 
(ClinicalTrials.gov NCT #: 01711658) 
 
 
TRYHARD: A PHASE II, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY OF LAPATINIB (TYKERB®) FOR NON-HPV 
LOCALLY ADVANCED HEAD AND NECK CANCER WITH 
CONCURRENT CHEMORADIATION 
 
 
Amendment 8:  September 27, 2016 


 
 
RTOG Foundation Collaboration with Novartis 
 
RTOG Foundation Study 3501 
 
A Limited Participation Study 
 
TRYHARD: A PHASE II, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED STUDY OF LAPATINIB 
(TYKERB®) FOR NON-HPV LOCALLY ADVANCED HEAD AND NECK CANCER WITH CONCURRENT 
CHEMORADIATION 
Closure Date: April 18, 2017 
Protocol Version Date: September 27, 2016 
Amendment Number 8 
Sponsor: RTOG Foundation 
 
Principal Investigator/ Medical Oncology 
Stuart Wong, MD 
 
 
Study Co-Chairs 
 
Medical Oncology 
Nabil F. Saba, MD 
Radiation Oncology 
George Shenouda, MD 
Surgical Oncology 
Jeffrey M. Bumpous, MD 
Medical Physics 
Robert E. Wallace, PhD, DABR 
Translational Research 
Christine Chung, MD 
Translational Research 
Quynh-Thu Le, MD 
Pathology 
Adel El-Naggar, MD, PhD 
Quality of Life 
Clement K. Gwede, PhD, RN 
Senior Statistician 
Qiang Zhang, PhD 
Protocol Acceptance 
On behalf of the RTOG Foundation, Inc. 
 
Walter J. Curran, Jr., MD 
RTOG Foundation Chairman  
 
April 18, 2017 


1                                              RTOG 3501 version date: 9/27/16 
 
RTOG FOUNDATION STUDY 3501 
 
TRYHARD: A PHASE II, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED 
STUDY OF LAPATINIB (TYKERB®) FOR NON-HPV LOCALLY ADVANCED HEAD AND 
NECK CANCER WITH CONCURRENT CHEMORADIATION 
 
Limited Participation Study 
 
Study Chairs (8/13/15) 
 
Principal Investigator/Medical Oncology 
Translational Research Co-Chair 
Stuart Wong, MD 
Christine Chung, MD 
Medical College of Wisconsin 
Moffitt Cancer Center 
9200 W. Wisconsin Avenue 
12902 USF Magnolia Drive 
Milwaukee, WI 53226 
Tampa, FL 33612 
414-805-4603/FAX 414-805-4606 
813-745-4673/FAX 813-449-8210 
swong@mcw.edu 
Christine.Chung@Moffitt.Org 
 
 
Medical Oncology Co-Chair 
Translational Research Co-Chair 
Nabil F. Saba, MD 
Quynh-Thu Le, MD 
Emory University/Winship Cancer Institute 
Stanford University 
1365 Clifton Road, C2110 
875 Blake Wilbur Drive, MC 5847 
Atlanta, GA 30322 
650-498-5032/FAX 650-725-8231 
404-778-3126/FAX 404-778-5676 
qle@stanford.edu 
NFSABA@emory.edu 
 
 
 
Radiation Oncology Co-Chair 
Pathology Co-Chair 
George Shenouda, MD 
Adel El-Naggar, MD, PhD 
McGill University Health Center 
MD Anderson Cancer Center 
Montreal General Hospital 
1515 Holcombe Blvd., Unit 085 
1650 Cedar Avenue, D5-400 
Houston, TX 77030 
Montreal, CA H3G 1A4 
713-792-3109/ FAX 713-792-5532 
514-934-8040/FAX 514-934-8450 
anaggar@mdanderson.org 
george.shenouda@muhc.mcgill.ca 
 
 
Quality of Life Co-Chair 
Surgical Oncology Co-Chair 
Clement K. Gwede, PhD, RN 
Jeffrey M. Bumpous, MD 
H. Lee Moffitt Cancer Center 
Univ. of Louisville School of Medicine 
12902 Magnolia Drive MRC-CANCONT 
James Graham Brown Cancer Center, U of L HSC 
Tampa, FL 33612 
529 South Jackson Street 
813-745-3052/FAX 813-745-6525 
Louisville, KY 40202 
clement.gwede@moffitt.org 
502-583-8303/FAX 502-561-7280 
 
Jeffrey.bumpous@louisville.edu 
 
 
 
Medical Physics Co-Chair 
Senior Statistician 
Robert E. Wallace, PhD, DABR 
Qiang Zhang, PhD 
Samuel Oschin Cancer Center/Cedars-Sinai Health System 
RTOG Foundation 
8700 Beverly Blvd. 
1818 Market Street, Suite 1720 
Los Angeles, CA 90048 
Philadelphia, PA 19103 
310-423-0648/FAX 310-659-3332 
215-574-3197/FAX 215-928-0153 
robert.wallace@cshs.org 
ezhang@acr.org 


2                                              RTOG 3501 version date: 9/27/16 
 
TRYHARD: A PHASE II, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED STUDY  
OF LAPATINIB (TYKERB®) FOR NON-HPV LOCALLY ADVANCED HEAD AND NECK CANCER  
WITH CONCURRENT CHEMORADIATION 
 
 
 
RTOG Headquarters Contact Information (9/27/16) 
 
Data Managers:   
For questions concerning eligibility or data submission 
Vanita Patel, 215-574-3170, vpatel@acr.org 
or 
Janelle Robinson, 215-717-0837, jrobinson@acr.org 
 
ACR Core Laboratory/RTQA:  
For questions concerning RT data submission 
Nancy Linnemann, 215-717-0853, 
nlinnemann@acr.org 
 
Marsha Radden, 215-717-2757, 
mradden@acr.org  
 
 
 
ACR Core Laboratory/RTQA:   
For questions concerning data submission to Triad 
Triad-Support@acr.org 
 
 
Serious Adverse Event Coordinator 
For questions concerning serious adverse event reporting 
procedures, timelines, and queries 
Sara McCartney, 267-940-9404, 
smccartney@acr.org 
 
 
Project Manager:  
For questions concerning regulatory documentation, HPV 
testing status and notification of testing results, drug 
supply, and/or drug shipment issues. 
Treena Davis-Trotman, 215-574-3205,  
ttrotman@acr.org 
 
Clinical Trials Administration:  
For questions concerning contracts and reimbursement 
Sharon Hartson Stine, shartson@acr.org 
 
For Code Breaks, 8:30 a.m. to 5 p.m. ET 
215-574-3150, ask for the Supporting Statistician 
 
For Code Breaks after business hours or on weekends or 
holidays 
215-459-3576 
 
 
 
Protocol Agents  
Agent 
Supply 
IND # 
Lapatinib 
Novartis 
115409 
Cisplatin 
Commercial 
N/A 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Closure 
September 27, 2016 
April 18, 2017 
Amendment 8 
September 27, 2016 
November 30, 2016 
Amendment 7 
March 22, 2016 
March 31, 2016 
Amendment 6 
February 2, 2016 
March 31, 2016 
Amendment 5 
August 13, 2015 
August 19, 2015 
Amendment 4 
August 5, 2014 
September 22, 2014 
Amendment 3 
January 16, 2014 
February 4, 2014 
Amendment 2 
October 3, 2013 
October 23, 2013 
Activation 
September 27, 2012 
October 18, 2012 
Amendment 1 
September 27, 2012 
October 3, 2012 


3                                              RTOG 3501 version date: 9/27/16 
 
INDEX 
 
 
 
Schema  
 
Eligibility Checklist  
 1.0 
Introduction 
 2.0 
Objectives 
 3.0 
Patient Selection  
 4.0 
Pretreatment Evaluations/Management 
 5.0 
Registration Procedures 
 6.0 
Radiation Therapy  
 7.0 
Drug Therapy 
 8.0 
Surgery 
 9.0 
Other Therapy 
10.0 
Tissue/Specimen Submission 
11.0 
Patient Assessments 
12.0 
Data Collection 
13.0 
Statistical Considerations 
 
References 
 
 
 
 
Appendix I 
- Study Parameters 
 
Appendix II 
- Performance Status Scoring 
 
Appendix III 
- Staging System 
 
Appendix IV 
- Biospecimen Collection Instructions 
 
Appendix V 
- Diarrhea Management 
Appendix VI 
- Prohibited Medications 
Appendix VII 
- Dental Management 
 
 
 
  


4                                              RTOG 3501 version date: 9/27/16 
 
  
 
RTOG FOUNDATION STUDY 3501 
 
TryHard: A Phase II, Randomized, Double Blind, Placebo-Controlled Study of Lapatinib (Tykerb®) 
for Non-HPV Locally Advanced Head and Neck Cancer with Concurrent Chemoradiation 
 
 
SCHEMA (9/27/16) 
 
 
 
 
 
 
 
 
 
 
Age 
 
 
R 
 
S 
1. ≤ 65 
R 
Week 1: lapatinib/placebo 
E 
*For 
T 
2. > 65 
A 
 
G 
oropharyngeal 
R 
 
N 
Weeks 2-7: AFX RT + cisplatin 
I 
cancer 
A 
T Stage 
D 
+ lapatinib/placebo 
S 
patients: 
T 
1. T1-3 
O 
 
T 
Mandatory 
I 
2. T4 
M 
Followed by maintenance lapatinib/placebo 
E 
analysis for 
F 
 
I 
for 3 months 
R 
p16 status 
Y 
Nodal Status 
Z 
 
 
 
 
1. N0-N2a 
E 
 
 
 
 
2. N2b-N3 
 
 
 
 
 
 
 
 
*Oropharyngeal cancer patients must be negative for p16, prior to Step 2 registration (randomization); these 
patients must consent to use of the submitted tissue for required HPV analysis. Analysis results are expected in 
approximately 7-10 business days. At that time, patients with oropharyngeal carcinoma can be randomized. See 
Section 5.3 for details. Note: If a specimen was previously submitted to the Biospecimen Bank at UCSF for 
determination of HPV status for another RTOG trial  and found to be p16 negative, investigators can forward a 
Specimen Transmittal (ST) Form to the Biospecimen Bank at UCSF requesting that the specimen be sent to Dr. 
El-Naggar for central lab confirmation of p16 negativity. 
 
Intensity Modulated Radiation Therapy (IMRT) is mandatory for this study. Image-Guided radiation therapy 
(IGRT) is mandatory when using a PTV margin of < 5 mm.  
 
Patient Population:  (See Section 3.0 for Eligibility)  
Pathologically (histologically or cytologically) proven (from primary lesion and/or lymph nodes) diagnosis of Stage 
III or IV squamous cell carcinoma of the oropharynx, hypopharynx, or larynx; for patients with an oropharynx 
primary site, the tumor must be negative for p16 by immunohistochemistry. 
 
 
Required Sample Size: 142 
  


5                                              RTOG 3501 version date: 9/27/16 
 
Institution #  
 
 
RTOG Foundation 3501  
  
ELIGIBILITY CHECKLIST– STEP 1 (9/27/16)     
Case #  
 
 
 
     (page 1 of 5) 
 
 
                 (Y) 1. 
Does the patient have pathologically (histologically or cytologically) proven diagnosis (from 
primary lesion and/or lymph nodes) of squamous cell carcinoma of the oropharynx, 
hypopharynx, or larynx? (Note: Patients with oral cavity, nasopharynx, sinuses and salivary 
gland primary tumors are excluded.) 
 
             (Y/N) 2. 
Does this patient have oropharynx primary? If yes, the patient must agree to consent for 
mandatory submission of tissue required for central review. 
 
                (Y) 3. 
Does the patient have selected stage III or IV disease: any anatomic site T2 N2-3 M0, T3-4 
any N M0; p16 negative oropharynx cancer with T1 N2b, N2c, or N3; or hypopharynx T1-2 
any N+?  
 
                (Y) 4.  
Was a history and physical examination done within 28 calendar days prior to registration, 
including assessment of patient’s weight? 
 
                (Y) 5. 
Was the patient examined by a Medical Oncologist and a Radiation Oncologist within 28 
calendar days prior to registration? 
 
               (Y) 6.  
Was the patient examined by an ENT or Head and Neck Surgeon (including 
laryngopharyngoscopy) within 42 days prior to registration? 
 
               (Y) 7.  
Was a Chest CT scan or PET/CT done within 42 calendar days prior to registration ? 
 
               (Y) 8. 
Was a contrast enhanced CT scan or MRI or PET/CT scan of the tumor site and neck nodes 
done within 42 calendar days prior to registration?  
 
              (N) 9.  
Does the patient have distant metastases? 
 
              (Y) 10. 
Was an EKG and ECHO or MUGA scan done within 84 calendar days prior to registration?  
 
             (Y) 11.  
Was the Zubrod Performance Status 0-1 within 14 calendar days prior to registration? 
 
             (Y) 12. 
Is the patient ≥ 18 years of age? 
 
            (Y) 13. 
Does the patient have adequate bone marrow, hepatic and renal function as specified in 
Section 3.1? 
 
            (Y) 14.  
Were magnesium, calcium, glucose, potassium and sodium done within 14 calendar days  
prior to registration with results within the parameters required in Section 3.1? 
 
      (Y/NA) 15.  
For women of child bearing potential, was a serum pregnancy test completed within 14 
calendar days prior to registration? 
 
 _______(Y) 
 
If yes, was the pregnancy test negative? 
 
      (Y/NA) 16.  
If the patient is a woman of child bearing potential or a sexually active male, is the patient 
willing to use effective contraception during treatment and for at least 60 calendar days 
following the last study treatment? 
 
          (Y) 17. 
Will the patient be compliant with treatment plan and follow-up schedule?  
 
 
 
 
 
 
 
 
 
 
Continued on next page 


6                                              RTOG 3501 version date: 9/27/16 
 
 
Institution #  
 
 
RTOG Foundation 3501  
 
ELIGIBILITY CHECKLIST– STEP 1 (10/3/13) 
Case #  
 
 
 
     (page 2 of 5)  
 
__           (Y) 18. 
Did the patient provide specific informed consent prior to study entry? 
 
               (N) 19.   Does the patient have T1N1 or T1N2a oropharynx cancer or T1N1, T1N2a or T2 N1 non-
hypopharynx tumors?  
 
                (N) 20.    Does the patient have simultaneous primary or bilateral tumors? 
 
               (N) 21. 
Has the patient had initial surgical treatment (excluding diagnostic biopsy of the primary        
site or nodal sampling of neck disease); radical or modified neck dissection or gross total 
excision of the primary site (e.g. by tonsillectomy)? 
 
   _____(N/Y) 22.     Did the patient have a prior invasive malignancy? 
 
    _____(Y)              
If yes, is the prior malignancy within the parameters specified in Section 3.2? 
 
 
              (N) 23. 
Has the patient had any prior systemic chemotherapy for the study cancer? 
 
              (N) 24. 
Has the patient had any prior radiotherapy to the region of the study cancer that would result 
in overlap of radiation therapy fields? 
 
              (N) 25. 
Is the primary site of tumor oral cavity, nasopharynx, sinuses or salivary gland? 
 
              (N) 26. 
Does the patient have prior allergic reaction to the study drugs involved in this trial? 
 
              (N) 27. 
Has the patient had any prior therapy that specifically and directly targets the EGFR/HER2 
pathway? 
 
              (N) 28. 
Does the patient have current active hepatic or biliary disease (with exception of patients with 
Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator 
assessment)? 
 
              (N) 29. 
Does the patient have severe, active co-morbidity, as defined in section 3.2? 
 
 
The following questions will be asked at Study Registration:  
 CREDENTIALING for IMRT (and IGRT if using reduced margins) IS REQUIRED BEFORE REGISTRATION. 
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials (First Middle Last) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page 


7                                              RTOG 3501 version date: 9/27/16 
 
Institution #  
 
 
RTOG Foundation 3501  
 
ELIGIBILITY CHECKLIST– STEP 1 (10/18/12)     
Case #  
 
 
 
     (page 3 of 5)  
 
 
 
         
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 a VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date 
 
 
         
18. 
Medical Oncologist’s name  
 
              (Y/N) 19. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 20.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, Alzheimer's 
disease, and heart disease)?   
 
              (Y/N) 22. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's disease, or 
heart disease).  
 
              (Y/N) 23. 
Have you obtained the patient's consent to allow someone from this institution to contact  
him or her in the future to take part in more research?  
 
              (Y/N) 24. 
Did the patient agree to participate in the quality of life component?” 
 
                     
 
If no, please specify the reason from the following: 
 
 
 
 
1. Patient refused due to illness 
 
 
 
 
2. Patient refused for other reason: specify _____________ 
 
 
 
 
3. Not approved by institutional IRB 
 
 
 
 
4. Tool not available in patient’s language 
 
 
 
 
5. Other reason: specify_________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page 


8                                              RTOG 3501 version date: 9/27/16 
 
Institution #  
 
 
RTOG Foundation 3501  
  
ELIGIBILITY CHECKLIST– STEP 1 (10/3/13)     
Case #  
 
 
 
     (page 4 of 5)  
 
 
 
                       
25. 
Specify the patient’s age (≤ 65 vs. > 65) 
 
                       
26. 
Specify T stage (T1-3 vs. T4) 
 
                       
27. 
Specify nodal status (N0-N2a vs. N2b-N3) 
 
                       
28. 
Specify primary site (hypopharynx, larynx, oropharynx) 
 
               (Y/N) 29.  
Will IGRT be used for patient positioning (< 5mm PTV expansion)?  
 
               (Y/N) 30.  
Will IGRT be used for patient positioning and margin reduction? 
 
                   (Y)  
 
If yes, is the institution credentialed for head and neck IGRT? 
 
 
 
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 RTOG audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 


9                                              RTOG 3501 version date: 9/27/16 
 
Institution #  
 
 
RTOG Foundation 3501  
  
ELIGIBILITY CHECKLIST– STEP 2 (2/2/16)     
Case #  
 
 
 
     (page 5 of 5)  
(assigned for Step 1) 
 
 
Note: Sites will complete Step 2 for all patients. For patients with hypopharyngeal and laryngeal cancer, the site 
can proceed to Step 2 (randomization) immediately after completing Step 1 (registration). Patients with 
oropharyngeal cancer must have a mandatory p16 analysis prior to the site completing Step 2.  
 
 
 
 
 
1. Institutional person randomizing case 
 
 
(Y/N) 
2. Is the patient able to continue protocol treatment? 
 
 
  
3. If no, specify the reason the patient cannot continue to Step 2:  
1) progression of disease;  
2) patient is p16 positive; 
3) patient refusal;  
4) physician preference;  
5) failure to submit tissue assay; 
6) other 
 
 
 
 
If response is “6) Other”, specify the reason the patient cannot continue to Step 2. 
 
 
 
4. Patient’s Initials 
 
 
 
5. Verifying Physician 
 
 
 
6. Patient’s ID number 
 
 
 
 
7. Calendar Base Date (for Step 2) 
 
 
 
 
8. Registration/randomization date: (for Step 2) 
 
 
(Y/N) 
9.  If the primary site is oropharynx, is the patient negative for p16 (determined by Dr. El-
Naggar’s lab)? 
 
_______________ 
10. Patient height 
 
_______________ 
11. Patient weight 
 
_______________ 
12. BSA 
 
 
 
 
 


 
 
 
 
 
10 
 
 
RTOG 3501 version date: 9/27/16 
 
1.0 
INTRODUCTION 
 
1.1 
Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) 
 
Over 40,000 new cases of HNSCC are diagnosed each year in the United States (American 
Cancer Society 2010) The majority of these patients present with locally advanced, non-
metastatic disease in which multi-modality therapy may be appropriate. An accepted standard of 
care treatment for locally advanced squamous cell cancer of the head and neck (LA-HNSCC) is 
concurrent cisplatin-based chemotherapy with radiation (chemoRT). The updated MACH-NC 
meta-analysis, demonstrated that concomitant chemotherapy plus radiation was associated with 
significant reduction in risk of death compared to radiation alone (Pignon 2009). Several phase III 
studies comparing radiation alone versus concurrent chemoRT for LA-HNSCC also demonstrated 
this effect (Adelstein 2003; Al-Sarraf 1998; Forastiere 2003; Denis 2004). 
 
Altered fractionated radiation has been studied as a way to enhance the efficacy of the 
concurrent chemoRT.  RTOG 90-03 was a phase III study that showed improved disease free 
survival with accelerated fractionated radiation with concomitant boost compared to standard 
fractionated radiation (Fu 2000). RTOG 0129 was launched to compare 2 concurrent cisplatin 
chemoradiation regimens comprised of accelerated fractionated radiation versus standard 
fractionated radiation. The analysis of the phase III randomized RTOG 0129 trial showed that 
patients randomized to receive either accelerated fractionation radiotherapy (70 Gy in 35 fractions 
over 6 weeks) with 2 cycles of high-dose cisplatin or standard fractionation radiotherapy (70 Gy in 
35 fractions over 7 weeks) with 3 cycles of high-dose cisplatin had similar overall and 
progression-free survival. In the standard fractionation schedule, 31% of the patients were unable 
to receive the last and 3rd dose of cisplatin during the 7th week of conventional radiotherapy 
because of toxicity. On the other hand, 88% of patients treated with the accelerated fractionation 
schedule received the 2 planned cisplatin cycles. Although there were no differences in overall 
high-grade acute or late toxicities, the cisplatin-related toxicities were significantly lower in the 
accelerated fractionation arm patients. Based on these results of RTOG 0129, current RTOG 
head and neck protocols have adopted the accelerated fractionation schedule as the standard 
treatment. 
 
Based upon evidence that EGFR inhibition enhances the cellular response of radiation and 
cytotoxic chemotherapy, RTOG 0522 tested whether the anti-EGFR antibody, cetuximab, 
improves disease-free survival over radiation plus concurrent cisplatin. Initial  report of the results 
of this study showed that the addition of cetuximab to radiation-cisplatin did not improve 
progression-free survival (PFS) or overall survival (OS) (Ang 2011). Failure of cetuximab to 
improved outcome may be due to insufficient synergistic effect of cetuximab or possibly due to 
inadequate duration of anti-EGFR therapy. No differential effect was observed based upon p16 
status; however, testing was not possible for nearly half of oropharynx patients.   
  
While the importance of EGFR in HNSCC has been well established, a direct role of HER2 in 
tumorigenesis and treatment resistance of HNSCC is not clear and poorly understood. HER2 is 
expressed in the range of 0-47% in HNSCC depending on the antibodies used, staining 
conditions, and scoring systems of immunohistochemistry (IHC) [Kearsley 1991; Beckhardt 1995; 
Field 1992; Craven 1992; Ibrahim 1997; Khan 200;Cavalot 2007]. Hou, et al. has shown that 
HER2 expression progressively increased as oral disease progresses from normal mucosa, pre-
malignant lesions to invasive oral SCC (Hou 1992); however, its association with tumor stage, 
locoregional control, and survival as a prognostic marker varies depending on the sample size 
and evaluation methods (Craven 1992; Ibrahim 1997; Khan 2002; Cavalot 2007). In a recent 
study by Cavalot, et al. (2007), a high membranous HER2 protein expression was an 
independent prognostic factor for disease free survival. To date, HER2 expression has never 
been evaluated as a predictive biomarker of HER2-specific inhibitor therapy in HNSCC. 
 
In addition, there is a strong rationale of dual-targeting of EGFR and HER2. There is evidence 
that heterodimers containing HER2 as a partner is the most potent combination for the receptor 
activity compared to other dimers formed by 4 family members of HER receptors (Arteaga 2003). 
Inhibitory effects of one receptor have shown to be negated by heterodimers formed by the rest of 
uninhibited HER receptor family members (Diermeier 2005; Motoyama 2002). The extent of 
EGFR-HER2 and HER2-HER3 heterodimerization in HNSCC is not known; however, potentially 


 
 
 
 
 
11 
 
 
RTOG 3501 version date: 9/27/16 
 
heterodimerization may occur and contribute to resistance given EGFR-specific tyrosine kinase 
inhibitors. Therefore, a dual inhibition using lapatinib warrants further investigation.       
 
The current proposed trial is a randomized study to examine whether the inhibitory effect of 
lapatinib upon the EGFR and HER2 signaling pathways enhances the cytotoxicity of a concurrent 
cisplatin-radiation regimen as determined by improvement in PFS.  Selection of the experimental 
arm of the present study builds upon the RTOG experience, summarized above, and will utilize a 
backbone of accelerated fractionated radiation with 2 concurrent cycles of cisplatin. 
 
1.2 
Importance of a Non-HPV-Specific LA-HNSCC Trial 
A recently published retrospective analysis of oropharyngeal cancer patients from RTOG 0129 
identified factors associated with prognosis (survival outcome) [Ang 2010]. Tumor HPV status, as 
determined by expression of p16, was a strong independent predictor of survival. p16 positive 
patients had the most favorable survival outcome (3-year OS rates of 82.4%), while p16 negative 
patients had the worse outcome (3-year survival rates of 57.1%). An intermediate prognostic 
group also was identified that was p16 positive but had a significant smoking history. Implicit from 
this analysis is that p16 negative (non-HPV) oropharyngeal cancer patients behave much like the 
p16 negative, non-oropharyngeal, head and neck cancer population. Epidemiologic studies 
indicate that HPV positive population is a growing subset of HNSCC (Sturgis 2007). Nonetheless, 
the non-HPV population still represents the majority of HNSCC cases.  It can be estimated that 
roughly 75% of non-HPV HNSCC cases will have aberrant p16, and therefore, carry a poor 
prognosis (Reed 1996; Gruttgen 2001; Bova 1999). 
 
A clinical trial specifically designed for this poor prognostic population has not been conducted in 
the cooperative oncology group setting but is appropriate for several reasons.  First, the 
molecular pathogenesis of disease of this group is quite distinct from the HPV population.  In 
HPV-related oropharyngeal HNSCC, expression of viral E6 and E7 oncoproteins that inactivate 
p53 and pRb is the known mechanism of carcinogenesis (Rampias 2009). In contrast, non-HPV 
HNSCC is thought to occur as a result of a cumulative multistep process of genetic and 
epigenetic events due to chronic exposure to environmental carcinogens. Second, cooperative 
group oncology clinical trials specifically designed for HPV oropharyngeal cancer are active. 
Finally, the prognosis is unacceptably poor for this non-HPV HNSCC population; significant effort 
is necessary in order to improve their outcome. For all these reasons, a specific study for HPV 
negative patients is necessary in order to make overall progress in the treatment of HNSCC. 
 
As discussed in the following section, lapatinib appears to enhance the effects of chemoradiation. 
Pilot data suggests that this effect may be more pronounced in p16 negative HNSCC patients.  
This study will, therefore, test a proof of biologic principle that a potent inhibitor of the EGFR and 
HER2 signaling pathways can enhance the efficacy of a chemoradiation regimen. In addition, 
there has never been a study evaluating the HER2 status as a predictive marker of HER2 
inhibitors in HNSCC; the proposed study will allow us to evaluate this question, which can only be 
answered in a clinical trial setting with a control arm. The results of this study also are pertinent to 
the design of a future phase III clinical trial and development of novel therapeutic regimens and 
biomarkers. 
 
1.3 
EGFR Expression 
EGFR expression by tumor cells has been linked with aggressive tumor growth, disease 
progression, poor survival, and poor response to therapy. Over-expression of EGFR has been 
reported in a number of epithelium-derived carcinomas including head and neck, colorectal, lung, 
esophageal, gastric, and breast carcinoma. Ang, et al. have demonstrated the prognostic value of 
epidermal growth factor receptor (EGFR) expression in predicting survival and patterns of relapse 
for LA-HNSCC patients treated with radiation therapy (2002). Recently, Chung, et al. have 
published a validation of EGFR as a predictive biomarker using an IHC quantitative image 
analysis assay (2010). These observations confirm a body of preclinical tumor biology studies 
that have examined the role of EGFR in modulating radiation response.  
 
Other tyrosine kinase receptors in the ErbB family, besides EGFR, may play a role in HNSCC 
tumor progression as well as prognosis--specifically human epidermal growth factor receptor-2 
(HER2/neu) (Khan 2002; Xia 1999; Rait 2003). In a similar manner, ErbB2 has been reported to 


 
 
 
 
 
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be over-expressed in 15-30% of invasive ductal breast cancer and has been associated with 
increased proliferation, poor clinical outcome, and altered responsiveness to various adjuvant 
therapies (Nahta 2003). Activation of either EGFR or ErbB2 initiates a series of signaling 
cascades that includes mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase 
(PI3K), Akt, and p70S6K. Dual inhibition of EGFR and HER2/neu may be attractive strategy to 
examine for treatment of LA-HNSCC. 
 
1.4 
Lapatinib 
. 
Lapatinib acts as a dual inhibitor of both EGFR and ErbB2 tyrosine kinase activity. As a member 
of the 4-anilinoquinazoline class of kinase inhibitors, lapatinib is thought to react with the ATP 
binding site of EGFR/ErbB2, resulting in inhibition of autophosphorylation and subsequent 
proliferative signaling (Rusnak 2001). The ErbB family consists of 4 closely related growth factor 
receptor tyrosine kinases: ErbB1 (EGFR/HER), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 
(HER4).  All members of the ErbB family share a common extracellular ligand-binding domain, a 
single membrane-spanning region, and a cytoplasmic tyrosine kinase domain (Yarden 2001; 
Atalay 2003). A ligand for ErbB2 has not been identified, while ErbB3 lacks tyrosine kinase 
activity. Ligand binding to EGFR, ErbB3 or ErbB4 induces these inactive monomers to undergo 
an array of homo- or heterodimerization with other members of the ErbB family.  ErbB2 is the 
preferred heterodimeric partner for all ErbB receptors, resulting in a complex that is endocytosed 
at one half to one third the rate of other EGFR dimers (Alroy 2000; Hendriks 2003).  ErbB 
dimerization leads to receptor autophosphorylation and subsequent activation of the tyrosine 
kinase domain. The signaling characteristics of the ErbB family are thought to be strongly 
interdependent. 
1.4.1 
Lapatinib in Combination Chemoradiotherapy for LA-HNSCC 
By virtue of its dual pathway inhibition of EGFR and HER2 signaling, lapatinib may have a 
greater inhibitory effect on downstream signaling and on cell growth than an anti-EGFR 
monoclonal antibody. A large randomized, placebo- controlled multicenter trial of post-operative 
lapatinib or placebo and chemoRT for high risk HNSCC is active and currently accruing patients 
(NCT00424255).  Harrington, et al. recently reported the results of a multi-center randomized 
phase II study that examined concurrent chemoRT with or without concurrent and maintenance 
lapatinib for LA-HNSCC (2010). Complete clinical response at 6 months appeared to favor the 
lapatinib arm compared to the placebo arm (53% vs. 36%, odds ratio =2.2 (0.7, 7,0); p value= 
0.1858).  Although also not statistically significant, PFS and OS aligned similarly to demonstrate 
a trend towards favoring the lapatinib arm. Thus, a positive signal that lapatinib enhances the 
effects of chemoRT was observed in this pilot study. A retrospective analysis of patients on this 
study for whom p16 status could be determined (n=46), demonstrated that among p16 negative 
patients (n=33), those who received lapatinib plus chemoRT appeared to have improved PFS 
compared to those who received chemoRT alone (HR=0.626 (0.261, 1.506); log rank p value 
0.2963). Unfortunately, definitive conclusions cannot be drawn from this analysis due to the 
small size of the subgroup in addition to the retrospective nature of the analysis. However, 
these findings are sufficiently compelling to warrant further examination of this question using a 
larger sampling of this high-risk patient population. Based upon these observations, we 
hypothesize that, due to the disruptive effect of lapatinib upon EGFR and HER2 signaling 
pathways, the addition of concurrent and maintenance lapatinib to a concurrent radiation-
cisplatin regimen will enhance the cytotoxic effect, resulting in an improvement of PFS in high-
risk (non-HPV) LA-HNSCC patients. 
1.4.2 
Mechanism of Action 
Lapatinib has been shown to be a potent and selective dual inhibitor of EGFR and ErbB2 
tyrosine kinase activity with IC50 values of 10.2 and 9.8 nM, respectively (Rusnak 2001). 
Lapatinib has demonstrated selective growth inhibition of human cell lines (head and neck, 
breast, and gastric) in vitro (IC90 values <2.26 µM or 1313 ng/mL) with no outgrowth observed 
up to 18 days following cessation of treatment. Growth inhibition corresponded with the ability 
of lapatinib to inhibit phosphorylation of Akt. These studies suggested that inhibition of EGFR 
by lapatinib resulted preferentially in cell growth arrest, while inhibition of ErbB2 led to cell 
growth arrest and apoptosis after 72 hours. Treatment with lapatinib leads to arrest of tumor cell 
growth and/or apoptosis, even in the presence of saturating concentrations of epidermal growth 
factor (EGF).  Treatment of tumor xenografts resulted in inhibition of activation of EGFR, erbB2, 
Erk1/2, and Akt (Xia 2002). 
 


 
 
 
 
 
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1.4.3 
Antitumor Activity 
 
The ability of lapatinib to inhibit the growth of EGFR-over-expressing cell lines (IC50 <0.16 µM) 
was observed to be equal to that of other EGFR inhibitors being tested in clinical trials (e.g. 
gefitinib/IressaTM or erlotinib/TarcevaTM). With the exception of ErbB4, lapatinib was >300-fold 
more selective towards ErbB2 and EGFR kinase inhibition than to other kinases tested.  
Lapatinib demonstrated potent growth inhibition of human breast ductal (BT474) and head and 
neck (HN5) tumor xenografts in mice.  A dose response inhibition was observed in both models 
receiving lapatinib (30 or 100 mg/kg twice daily orally for 21 days).  Complete inhibition of tumor 
growth was seen in mice receiving 100 mg/kg (Rusnak 2001). 
1.4.4 
Signal Transduction 
 
Lapatinib has been shown to inhibit Erk1/2 and Akt phosphorylation (pErk and pAkt) in both 
EGFR and erbB2-expressing cell lines (BT474 and HN5). The ability of lapatinib to inhibit pAkt 
was associated with a 23-fold increase in the percentage of cells undergoing apoptosis 
compared to control cells.  Similarly, lapatinib treatment of BT474 and HN5 xenografts in mice 
also resulted in inhibition of Erk1/2 and Akt phosphorylation. These results suggested that 
lapatinib treatment of EGFR/erbB2 expressing tumors could lead to inhibition of downstream 
signaling events (Xia 2002). 
 
 
A study of human breast cancer cell lines that over-express EGFR or erbB2 (SUM102, 
SUM149, SUM185, and SUM225) reported that treatment with lapatinib resulted in inhibition of 
cell proliferation that was associated with inhibition of Erk phosphorylation. Inhibition of Erk 
phosphorylation also correlated with radiosensitization of cell lines pretreated with lapatinib 
(Zhou 2003). 
1.4.5 
Toxicology 
 
A range of toxicology studies has been conducted to support the oral administration of lapatinib 
to humans.  Repeat oral dose toxicity studies have been completed in rats and dogs for up to 6 
and 9 months, respectively. The effects of lapatinib on fertility in the rat and embryofetal 
development in the rat and rabbit have been investigated. A range of genetic toxicity studies 
has been performed in vitro and in vivo.  The significant findings from the toxicology studies are 
summarized below. 
 
Following single oral administration, lapatinib was well-tolerated by both CD-1 mice and 
Wistar Han rats at doses up to 2000 mg/kg. Treatment-related findings consisted of 
reversible changes in body weight and body weight gain as well as reversible GI effects. 
 
A 13-week oral dose ranging pilot carcinogenicity study in mice showed that treatment 
with lapatinib at doses up to 200 mg/kg/day was generally well tolerated. Microscopic 
changes attributable to treatment with lapatinib were noted in the liver and preputial gland 
of males and large intestines (cecum and colon) of males and females. 
 
Administration of lapatinib to rats and dogs for up to 6 months or 9 months resulted 
primarily in exaggerated pharmacologic effects and organ toxicities generally associated 
with degenerative and/or inflammatory epithelial changes (GI tract and accessory 
digestive organs, skin, mammary gland, liver and prostate). Other treatment-related 
effects included clinical signs, decreased body weight and food consumption, organ 
weight changes and alterations in clinical pathology parameters.  Following the recovery 
period, treatment-related changes were either significantly improved or completely 
reversed. 
 
There were no effects on male or female rat gonadal function, mating, fertility or 
pregnancy nor were there any increases in the number or incidence of any malformations 
when rats or rabbits were given lapatinib during the period of major organogenesis. At 
maternally toxic doses (≥ 60 mg/kg/day in rats and rabbits), lapatinib treatment was 
associated with growth retardation and developmental variations. 
 
In genetic toxicity studies, lapatinib was demonstrated to be non-mutagenic and non-
clastogenic. 
 
1.5 
Quality of Life and Patient-Reported Outcomes  
This study affords another unique opportunity: to prospectively explore quality of life (QOL) and 
patient-reported outcomes (PROs) in this disease. Most curative intent, multimodality treatment 
regimens in locally advanced head and neck cancer are associated with significant acute and late 
toxicities. Standard validated QOL measurements used in patients treated for squamous cell 


 
 
 
 
 
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carcinomas of the head and neck have demonstrated that a considerable proportion of patients 
report debilitating functional compromise and psychosocial morbidity (Bjordal 2000; Weymuller 
2000; Ringash 2005; Martino 2008; Logemann 2008). There also is a growing body of literature 
supporting a relationship between better QOL with superior treatment outcomes (Siddiqui 2008; 
Karvonen-Gutierrez 2008). To our knowledge, data of this nature is nonexistent among patients 
treated with lapatinib with chemoradiation for non-HPV locally advanced head and neck cancer, 
and this trial would be an ideal mechanism to collect and analyze this subjective, patient-reported 
longitudinal data. Therefore, we will explore the impact of treatment assignment on QOL/PROs 
after initial therapy and during maintenance therapy using validated instruments:  the Functional 
Assessment of Cancer Therapy (FACT) H&N subscale (12 items); the 15-item University of 
Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) and the Performance Status Scale 
for Head and Neck Cancer (PSS-HN) [Ringash 2007; Ringash 2008; Murphy 2007; Henson 2001; 
Rodgers 2009; List 1996; 1999]. These outcomes will be assessed at baseline (pretreatment) and 
at 3, 12, and 24 months from completion of radiation treatment. 
 
In this phase II trial, preliminary data will be obtained for assessing the extent to which quality of 
life, swallowing, and xerostomia are adversely affected by the addition of lapatinib in this setting. 
It is hypothesized that the above indicators, as measured by the FACT-H&N subscale, PSS-HN, 
and XeQOLS instruments, will be less favorable for patients undergoing chemoradiation with 
lapatinib relative to chemoradiation and placebo, at 3 months after completion of radiation 
treatment. The current investigation is exploratory, but allows us to explore the relative 
importance of these QOL/PROs in this setting.  The goal of including an exploratory QOL/PROs 
correlative component is to generate estimates of effect sizes (means, standard deviations) that 
will guide the statistical power and effect size estimates for a subsequent phase III trial. 
1.5.1 
QOL and PRO Assessments 
1.5.1.1 
The FACT-HN is a multidimensional, patient self-report QOL instrument specifically 
designed and validated for use with head and neck cancer patients. The FACT-HN module 
consists of a 12-item head and neck subscale targeting head and neck related symptoms 
and side effects (Cella 2000; Ringash 2004; Ringash 2005; Ringash 2007; Ringash 2008), 
and can be administered independently from the general FACT-G instrument. High scores 
indicate better QOL and functioning. This tool takes approximately 5-10 minutes to 
complete. 
1.5.1.2 
The PSS-HN is a clinician/interviewer administered assessment that focuses on three 
functional areas: Normalcy of Diet, Eating in Public, and Understandability of Speech. The 
score on each of the three subscales ranges from 0-100, with higher scores indicating better 
performance (List 1996; List 1999; List 2000). 
1.5.1.3 
The XeQOLS instrument is patient self-report measure that consists of 15 items on a 5-point 
Likert-type scale covering mouth/throat dryness and its impact on four major domains of oral 
health-related quality of life: physical functioning, personal/psychological functioning, social 
functioning, and pain/discomfort issues [Murphy 2007; Henson 2001; Rodgers 2009]. The 
XeQOLS takes the patient approximately 5 minutes to complete. 
 
1.6 
Correlative Studies 
While the importance of EGFR in HNSCC has been well established, a direct role of HER2 in 
tumorigenesis and treatment resistance of HNSCC is not clear and is poorly understood. HER2 is 
expressed in the range of 0-47% in HNSCC depending on the antibodies used, staining 
conditions and scoring systems of immunohistochemistry (IHC). Hou, et al. have shown that 
HER2 expression progressively increased as oral disease progresses from normal mucosa, pre-
malignant lesions to invasive oral SCC; however, its association with tumor stage, locoregional 
control, and survival as a prognostic marker varies depending on the sample size and evaluation 
methods. In a recent study by Cavalot, et al., a high membranous HER2 protein expression was 
an independent prognostic factor for disease-free survival. To date, HER2 expression has never 
been evaluated as a predictive biomarker of HER2-specific inhibitor therapy in HNSCC. Biologic 
correlative studies of the TryHard study will address these important scientific questions as 
permitted by the study design that includes a randomized control arm.   
 
Dual-targeting of EGFR and HER2 also provides a strong rationale for the use of lapatinib with 
chemoRT for LA-HNSCC. There is evidence that heterodimers containing HER2 as a partner is 
the most potent combination for the receptor activity compared to other dimers formed by 4 family 


 
 
 
 
 
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members of HER receptors. Inhibitory effects of 1 receptor have shown to be negated by 
heterodimers formed by the rest of uninhibited HER receptor family members. The extent of 
EGFR-HER2 and HER2- HER3 heterodimerization in HNSCC is not known; however, potentially 
heterodimerization may occur and contribute to resistance given EGFR-specific tyrosine kinase 
inhibitors. Therefore, a dual inhibition using lapatinib warrants further investigation and will be 
examined in the correlative studies. 
1.6.1 
HER2 Expression as a Predictive Biomarker of Lapatinib Response 
Since lapatinib is a dual inhibitor of both EGFR and HER2, it is logical to evaluate HER2 protein 
expression and gene amplification in addition to the EGFR analysis and HPV assay (for 
oropharynx only). For this aim, we propose the following: 
 
HER2 protein expression determined by image-guided quantification of IHC staining 
(Cavalot 2007); 
 
HER2 gene amplification determined by FISH (Khan 2002). 
1.6.2 
EGFR-HER2 Heterodimer Expression as a Predictive Biomarker of Lapatinib Response 
Activation of EGFR involves either homodimerization or heterodimerization between EGFR and 
HER2.The in situ proximity ligation assay (PLA) was developed to enable detection of individual 
proteins and protein–protein interactions in cell lines and tissues, specifically paraffin 
embedded tissues (Söderberg 2006; Weibrecht 2010). The approach uses oligonucleotides 
attached to the antibodies against the 2 target proteins, in this case, pEGFR and pHer2. The 
oligonucleotides on the proximity probes when brought into close proximity by protein 
dimerization, serve as templates for the circularization, which can then be amplified and 
visualized as bright fluorescent RCPs or colometric RCP dots (depending on the type of 
detection). Since each detected protein demierization gives rise to one RCP, the detected 
complexes can be easily enumerated and counted. Tissue PLA has been used to assay for 
HER-family dimerization in tissue samples using the Duolink Kit from Olink Bioscience 
(Uppsala, Sweden). We have also evaluated pEGFR dimerization in head and neck squamous 
cell carcinoma and found that this approach can be readily applied to tissue microarray of 
formalin-fixed, paraffin-embedded tumor tissues. We propose to use this assay to evaluate 
EGFR homodimerization and EGFR-HER2 heterodimerization on pretreatment tumor samples 
as a potential predictor for lapatinib efficacy. 
1.6.3 
EGFR Ligand Expression Levels in Tissue and Blood as a Predictive Biomarker of Lapatinib 
Response 
mRNA expression of EGFR ligands such as TGFA, AREG, EREG, and HB-EGF have been 
shown to correlate with prognosis in HNSCC (Grandis 1998) and predict for efficacy of EGFR 
targeting, specifically cetuximab in colorectal cancer (Khambata-Ford 2007; Hatakeyama 
2010). Based on this information, we propose to evaluate the following EGFR ligand expression 
levels as a biomarker predictor of lapatinib response: TGFA, AREG, EREG and HB-EGF 
mRNA levels determined by RT-PCR (Grandis 1998; Khambata-Ford 2007; Hatakeyama 
2010). In addition, we will measure HB-EGF (one of the EGFR ligands) protein levels in plasma 
samples collected at pre-, end-of-radiation, and post-treatment (Hatakeyama 2010). 
1.6.4 
Variant EGFR 497 Arg Allele and EGFR Intron 1<20 CA Repeats as a Prognostic Biomarker of 
Poor Relapse-Free Survival and a Predictive Biomarker of Lapatinib Sensitivity 
Variant EGFR 497 Arg allele and EGFR introl 1<20 CA repeats have been shown to be a 
prognostic biomarker of poor relapse-free survival (RFS) in HNSCC. However, its role in 
predicting lapatinib sensitivity in unknown in these patients. Since these polymorphisms can be 
readily measured from circulating WBC, we propose to evaluate these allelic variants in 
patients enrolled on this study, both to validate their prognostic significance as well as to 
determine their predictive effect of lapatinib response. The following assays will be performed: 
 
Assess EGFR gene polymorphism 497 arginine-to-lysine determined by PCR-RFLP using 
germline DNA collected from pre-treatment PBMC (Zhang 2005); 
 
Assess EGFR intron 1 CA repeat polymorphisms determined by PCR-RFLP using germline 
DNA collected from pre-treatment PBMC (Amador 2004). 
1.6.5 
Validation of Lysyl Oxidase (LOX) and Gli Family Zinc Finger (Gli1) as Biomarkers of Distant 
Metastasis 
We have previously identified LOX and Gli1 as biomarkers for distant metastasis in HNSCC 
treated with radiation alone on RTOG 90-03 (Le 2009, Chung 2010). The role of these markers 
in HPV negative patients treated with chemoradiation has not been evaluated. We propose to 
validate the role of these biomarkers as predictors for distant metastasis by quantifying the level 


 
 
 
 
 
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of these proteins in pre-treatment tumor samples (as previously described in Le 2009 and 
Chung 2010). 
1.6.6 
Epithelial-to-Mesenchymal Transition (EMT) as a Prognostic Biomarker of Poor RFS and a 
Predictive Biomarker of Lapatinib Resistance 
EMT is a well known process governing invasion and metastasis in epithelial cell tumors. 
Although several biomarkers have been suggested to reflect the EMT process, one common 
hallmark of EMT is increased vimentin expression in the tumor (Frederick 2007). Recently, 
certain microRNAs, including miR-212, miR-103 and miR-200 have been linked to the EMT 
process, and their expression levels have been correlated with poor outcomes (Hatakeyama 
2010; Martello 2010). In this exploratory study, we proposed to measure EMT by the following 2 
approaches and determine whether the levels of these EMT biomarkers correlate with poor 
RFS and/or lapatinib resistance in the treated patient population. 
 
Vimentin expression in pre-treatment tumors determined by automated quantitative 
analysis (AQUA) (Frederick 2007); 
 
miR-212, miR-103 and miR-200 expression in serum/plasma samples collected at pre-, 
end-of-radiation, and post-treatment (Hatakeyama 2010; Martello 2010). 
 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
2.1.1 
To evaluate if the addition of lapatinib to concurrent cisplatin and radiation in this patient 
population sufficiently improves progression-free survival (PFS) to warrant a phase III trial  
 
2.2 
Secondary Objectives  
2.2.1 
To evaluate if the addition of lapatinib to concurrent cisplatin and radiation in this patient 
population improves overall survival (OS); 
2.2.2 
To evaluate if the addition of lapatinib to concurrent cisplatin and radiation in this patient 
population improves control of distant metastasis; 
2.2.3 
To evaluate toxicity and tolerability between treatment arms; 
2.2.4 
To evaluate if the addition of lapatinib to concurrent cisplatin and radiation in this patient 
population improves local regional control; 
2.2.5 
To investigate quality of life and patient-reported outcomes between treatment arms; 
2.2.6 
To explore HER2 expression, amplification and heterodimerization, EGFR ligand expression, 
EGFR polymorphisms, hypoxia, and EMT characteristics as biomarkers of lapatinib response, 
sensitivity, and resistance, PFS, and metastasis. 
 
 
3.0 
PATIENT SELECTION (10/3/13) 
For questions concerning eligibility, contact the study Data Managers (see the title pages for contact 
information). 
3.1 
Conditions for Patient Eligibility (9/27/16) 
3.1.1 
Pathologically (histologically or cytologically) proven diagnosis (from primary lesion and/or 
lymph nodes) diagnosis of squamous cell carcinoma of the oropharynx, hypopharynx, or larynx; 
3.1.2 
For patients with an oropharynx primary, the tumor must be negative for p16 by 
immunohistochemistry;  
3.1.3 
Selected stage III or IV disease: patients with T2 N2-3 M0, T3-4 any N M0 are eligible; in 
addition, p16 negative oropharynx cancer T1 N2b, N2c, or N3; and hypopharynx cancer 
patients with T1-2 any N+ are eligible, including no distant metastases, based upon the 
following minimum diagnostic workup: 
3.1.3.1 
History/physical examination within 28 calendar days prior to registration, including an 
examination by a Medical Oncologist and Radiation Oncologist and documentation of the 
patient’s weight;  
3.1.3.2 
Examination by an ENT or Head & Neck Surgeon, including laryngopharyngoscopy (mirror 
and/or fiberoptic and/or direct procedure) within 42 days prior to registration; 
3.1.3.3 
Chest CT scan, or PET/CT scan within 42 calendar days prior to registration to rule out 
metastatic disease;  
3.1.3.4 
Contrast enhanced CT scan or MRI or PET/CT scan of the tumor site and neck nodes within 
42 calendar days prior to registration;  
3.1.3.5 
EKG and ECHO or MUGA scan within 84 calendar days prior to registration; 


 
 
 
 
 
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3.1.4 
Zubrod Performance Status 0-1 within 14 calendar days prior to registration;  
3.1.5 
Age ≥ 18; 
3.1.6 
CBC/differential obtained within 14 calendar days prior to registration, with adequate bone 
marrow function defined as follows: 
3.1.6.1 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;  
3.1.6.2 
Platelets ≥ 100,000 cells/mm3;  
3.1.6.3 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 
8.0 g/dl is acceptable.); 
3.1.7 
Adequate renal and hepatic function within 14 calendar days prior to registration, defined as 
follows: 
3.1.7.1 
Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min within 14 calendar 
days prior to registration, determined by 24-hour collection or estimated by Cockcroft-Gault 
formula: 
CCr male = [(140 – age) x (wt in kg)] 
[(Serum Cr mg/dl) x (72)] 
CCr female = 0.85 x (CrCl male) 
3.1.7.2 
Total bilirubin < 2 x the institutional ULN; 
3.1.7.3 
AST or ALT ≤  3 x the institutional ULN;  
3.1.8 
Magnesium, calcium, glucose, potassium, and sodium within 14 calendar days prior to 
registration, with the following required parameters: 
3.1.8.1 
Magnesium: > 0.9 mg/dl or < 3 mg/dl; 
3.1.8.2 
Calcium: > 7 mg/dl or < 12.5 mg/dl; 
3.1.8.3 
Glucose: > 40 mg/dl or < 250 mg/dl; 
3.1.8.4 
Potassium: > 3 mmol/L or < 6 mmol/L; 
3.1.8.5 
Sodium: > 130 mmol/L or < 155 mmol/L. 
3.1.9 
Negative serum pregnancy test within 14 calendar days prior to registration for women of 
childbearing potential; 
3.1.10 
Women of childbearing potential and men who are sexually active must practice adequate 
contraception during treatment and for at least 60 calendar days following treatment.  
3.1.11 
Patients must be deemed able to comply with the treatment plan and follow-up schedule. 
3.1.12 
Patients must provide study specific informed consent prior to study entry, including, for 
oropharyngeal cancer patients, consent for mandatory submission of tissue for required, central 
p16 review. 
 
3.2 
Conditions for Patient Ineligibility (9/27/16)  
3.2.1 
Patients with T1 any N or with T2 N1 are ineligible except for specific oropharynx or 
hypopharynx patients as described in Section 3.1.3; 
3.2.2 
Patients with simultaneous primaries or bilateral tumors; 
3.2.3 
Gross total excision (e.g., by tonsillectomy) of the primary tumor; however, partial removal of 
the tumor to alleviate an impending airway obstruction does not make the patient ineligible. 
3.2.4 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a 
minimum of 3 years; noninvasive cancers (for example, carcinoma in situ of the breast, oral 
cavity, or cervix are all permissible) are permitted even if diagnosed and treated < 3 years ago; 
3.2.5 
Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different 
cancer is allowable; 
3.2.6 
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields; 
3.2.7 
Primary site of tumor of oral cavity, nasopharynx, sinuses, or salivary glands; 
3.2.8 
Initial surgical treatment, excluding diagnostic biopsy of the primary site or nodal sampling of 
neck disease; radical or modified neck dissection is not permitted. 
3.2.9 
Prior allergic reaction to the study drugs; 
3.2.10 
Prior therapy that specifically and directly targets the EGFR/HER2 pathway; 
3.2.11 
Patients who have current active hepatic or biliary disease (with exception of patients with 
Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator 
assessment); 
3.2.12 
Pregnant women or women of childbearing potential and men who are sexually active and not 
willing or able to use medically acceptable forms of contraception; this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic. 
3.2.13 
Severe, active co-morbidity, defined as follows: 


 
 
 
 
 
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3.2.13.1 
Uncontrolled cardiac disease, such as uncontrolled hypertension or unstable angina; 
3.2.13.2 
Transmural myocardial infarction within the last 6 months; 
3.2.13.3 
History of congestive heart failure and/or history of left ventricular ejection fraction < 50%; 
3.2.13.4 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 
3.2.13.5 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy within 30 calendar days prior to registration;  
3.2.13.6 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, 
that laboratory tests for liver function and coagulation parameters are not required for entry 
into this protocol. 
3.2.13.7 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, 
however, that HIV testing is not required for entry into this protocol. The need to exclude 
patients with AIDS from this protocol is necessary because the treatments involved in this 
protocol may be significantly immunosuppressive.  Protocol-specific requirements may also 
exclude immuno-compromised patients. 
 
 
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 
4.1.1 
If the patient consents to participate in the quality of life (QOL) component of the study, sites 
are required to administer the baseline QOL and PRO assessments prior to the start of protocol 
treatment: the PSS-HN, FACT-HN, and XeQOLS. 
 
4.2 
Highly Recommended Evaluations/Management 
The following pre-treatment evaluations/interventions are not required but are highly recommended. 
4.2.1 
Dental evaluation and if applicable, prophylaxis, within 84 calendar days prior to the start of 
treatment (see Appendix VII, Dental Management); 
4.2.2 
Whole body PET/CT scan within 42 calendar days prior to the start of treatment; 
4.2.3 
Baseline audiogram within 84 calendar days prior to the start of treatment; 
4.2.4 
Assessment of swallowing (dysphagia) within 28 calendar days prior to the start of treatment; 
4.2.5 
Nutritional evaluation for a prophylactic gastrostomy (PEG) tube placement any time prior to the 
start of treatment; note: In RTOG 99-14, a completed phase II trial assessing the feasibility of 
combining accelerated fractionation by concomitant boost with cisplatin, 79% of patients who 
did not have prophylactic PEG placement prior to treatment required placement of PEG during 
treatment 
 
 
5.0 
REGISTRATION PROCEDURES (8/13/15) 
Note: This is a limited institution study; see participating institutions on the RTOG web site. 
 
IGRT is mandatory when using reduced PTV margins (<5 mm). If the institution is not head and 
neck IGRT credentialed, contact the ACR Core Laboratory/RTQA Credentialing at 215-574-3219. 
 
5.1 
Regulatory Pre-Registration Requirements (10/3/13) 
5.1.1 
Prior to the recruitment of a patient for this study, investigators at participating institutions must 
maintain an “active” investigator registration status through the annual submission of a 
complete investigator registration packet (FDA Form 1572 with original signature, current CV, 
Supplemental Investigator Data Form with signature, and Financial Disclosure Form with 
original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. 
 
Each investigator or group of investigators at a participating site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the RTOG 
Headquarters (FAX 215-940-8919) or e-mail them to RTOG3501Regulatory@acr.org.  The 
following study-related regulatory documentation is required:  
 
Institutional Qualifying Questionnaire with RTOG approval for participation; 
 
RT Credentialing for IMRT and IGRT; 
 
IRB/REB initial approval letter; 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
IRB/REB approved consent (English and native language versions*); *Note: Institutions 
with a large number of patients whose primary language is not English must provide 
certification/verification of IRB/REB consent translation to RTOG Headquarters 
(described below in Section 5.1.1.1); 
 
IRB/REB assurance number including renewal information, as appropriate; 
 
Study Agent Shipment Form (SASF) [available on the RTOG web site, www.rtog.org, 
under protocol-specific materials/regulatory resources]; 
 
All subsequent amendment and annual approvals; 
 
All Regulatory submissions must also include a completed IRB certification Form as a 
cover sheet. 
 
Note: In the event of an amendment of this protocol, sites should submit their amended 
consent form to RTOG Regulatory for approval prior to IRB/REB submission. Sites can submit 
the consent form with tracked changes to RTOG3501Regulatory@acr.org. 
5.1.1.1 
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 RTOG will accept, at a minimum, a verified translation. A verified 
translation consists of the actual REB approved consent document in English and in the 
native language, along with a cover letter on organizational/letterhead stationery that 
includes the professional title, credentials, and signature of the translator as well as signed 
documentation of the review and verification of the translation by a neutral third party. The 
professional title and credentials of the neutral third party translator must be specified as 
well. 
5.1.2 
Pre-Registration Requirements for the Initial Shipment of Lapatinib:  
5.1.2.1 
Participating Institutions: 
All pre-registration requirements must be met before registering the first case. Institutions 
must electronically complete (versus hand write) a Study Agent Shipment Form (SASF), 
which is available on the RTOG web site, www.rtog.org, under protocol-specific 
materials/regulatory resources. Institutions must submit the SASF to RTOG Headquarters by 
FAX 215-940-8919 or e-mail: RTOG3501Regulatory@acr.org as soon as the individual 
responsible for the study agent has been identified.  
 
5.2 
Pre-Registration Requirement: Central Pathology Review 
 
Central pathology review for eligibility is required prior to registration. Pathology materials and a 
pathology report must be submitted to the Central Pathology Reviewer. (See Section 10.2.)  
 
5.3 
Registration (9/27/16) 
5.3.1 
Summary of Procedures 
This study incorporates a two-step registration process for oropharyngeal patients. 
5.3.1.1 
All patients can be registered after completing the Eligibility Checklist, Step 1 via online 
registration. 
 
All patients, except patients with oropharyngeal cancer, then can be randomized after 
completing the Eligibility Checklist, Step 2 via online registration. 
 
See Section 5.3.2 online for registration instructions.  
5.3.1.2  
Oropharyngeal carcinoma patients must consent to submit tissue for HPV analysis; see 
Section 10.2 for details of submission. The  Biospecimen Bank at UCSF will process 4 
unstained slides from the tissue block submitted and will send the slides to Dr. Adel El-
Naggar for HPV analysis. The results of the HPV analysis are expected in approximately 7-
10 business days, and RTOG Headquarters will inform sites by e-mail of the completion of 
the HPV analysis. At this point, oropharyngeal carcinoma patients may be randomized; sites 
must complete the Eligibility Checklist, Step 2 via online registration.  
 
 
 
Note: If a specimen was previously submitted to the Biospecimen Bank at UCSF for 
determination of HPV status for another RTOG trial and found to be p16 negative, 
investigators can forward a Specimen Transmittal (ST) Form to the Biospecimen Bank at 
UCSF requesting that the specimen be sent to Dr. El-Naggar for central lab confirmation of 
p16 negativity. 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
5.3.2 
General Online Registration Instructions 
Patients can be registered only after eligibility criteria are met.   
 
 
Each individual user must have an RTOG user name and password to register patients on the 
RTOG web site. To get a user name and password: 
 
The investigator and research staff must have completed Human Subjects Training and 
been 
issued 
a 
certificate 
(Training 
is 
available 
via 
http://phrp.nihtraining.com/users/login.php). 
 
A representative from the institution must complete the Password Authorization Form  
(http://www.rtog.org/LinkClick.aspx?fileticket=-BXerpBu5AQ%3d&tabid=219) and fax it to 
215-923-1737.  RTOG Headquarters requires 3-4 days to process requests and issue user 
names/passwords to institutions. 
 
 
An institution can register the patient by logging onto the RTOG web site (http://www.rtog.org), 
going to “Data Center Logon" and selecting the link for new patient registrations.  The system 
triggers a program to verify that all regulatory requirements (OHRP assurance, IRB approval) 
have been met by the institution. The registration screens begin by asking for the date on which 
the eligibility checklist was completed, the identification of the person who completed the 
checklist, whether the patient was found to be eligible on the basis of the checklist, and the 
date the study-specific informed consent form was signed. 
 
 
Once the system has verified that the patient is eligible and that the institution has met 
regulatory requirements, it assigns a patient-specific case number. The system then moves to a 
screen that confirms that the patient has been successfully enrolled.  This screen can be 
printed so that the registering site will have a copy of the registration for the patient’s record.  
Two e-mails are generated and sent to the registering site:  the Confirmation of Eligibility and 
the patient-specific calendar. The system creates a case file in the study’s database at the 
DMC (Data Management Center) and generates a data submission calendar listing all data 
forms, images, and reports and the dates on which they are due.  
 
 
If the patient is ineligible or the institution has not met regulatory requirements, the system 
switches to a screen that includes a brief explanation for the failure to register the patient.  This 
screen can be printed. 
 
 
Institutions can contact RTOG web support for assistance with web registration: 
websupport@acr.org. 
 
 
In the event that the RTOG web registration site is not accessible, participating sites can 
contact RTOG web support for assistance with web registration: websupport@acr.org or call 
RTOG Headquarters, at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET.  
  
 
6.0 
RADIATION THERAPY 
Note: All participating institutions will be credentialed for IMRT prior to registering patients to the 
study. Rapid review of cases is not required prior to patient enrollment. 
 
Intensity Modulated Radiation Therapy (IMRT) is mandatory for this study. Image-Guided 
Radiation Therapy (IGRT) is mandatory when using a PTV margin of < 5 mm. Only institutions that 
are credentialed for head and neck IGRT are allowed to use a PTV margin of less than 5 mm. 
 
Protocol treatment must begin within 14 calendar days after randomization.  
 
6.1 
Dose Specifications (8/5/14) 
IMRT will be given in 35 fractions over 42 calendar days, which requires delivery of 6 fractions 
per week during 5 of the 6 treatment weeks. The sixth fraction can be delivered either on 
Saturday or as a second daily fraction, with at least a 6-hour interfraction interval, on one of the 
weekdays.  
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
Treatment must be delivered using one single plan; concomitant boost techniques using a 
separate IMRT plans are not allowed. Sites must have completed pre-registration requirements 
for IMRT (and IGRT, if using reduced margins) credentialing prior to enrolling patients on trial. 
 
Missed treatments due to holidays or logistic reasons can be compensated by delivering 
additional BID fractions, with a minimum inter-fraction interval of 6 hours, or by treating on 
Saturday or Sunday. 
6.1.1 
The primary tumor and involved nodes will be encompassed by the PTV-High Dose 
(PTV_7000) and will receive a dose of 70 Gy in 2 Gy fractions (see Section 6.1.3 for details of 
the prescription for the PTV_7000). 
6.1.1.1 
Regional lymph nodes that are considered to be at high risk of microscopic disease, PTV 
Intermediary (PTV_5950-6300), may be treated to a dose in the range of 59.5 Gy to 63 Gy in 
1.7 Gy to 1.8 Gy per fraction, respectively. 
6.1.1.2 
Lower-risk targets, such as neck nodal levels that are not first echelon nodes and are not 
adjacent to levels containing grossly involved nodes, will be encompassed by PTV-Elective 
Dose (PTV_5600) and will receive a dose of 56 Gy in 1.6 Gy per fraction. 
6.1.2 
Treatment of the Low Neck 
See details in Section 6.5.1. In patients with non-involved low neck nodes, the preferred 
technique is to treat with isocentric matching AP or AP-PA fields with a larynx block, matched to 
the IMRT portals just above the arytenoids. The dose will be 2 Gy per fraction prescribed to 3 
cm depth to a total dose of 50 Gy in 25 daily fractions. Whole-neck IMRT is allowed.  
 
In cases of gross involvement of the vallecula or low neck nodes, whole-neck IMRT should be 
considered. Whole-neck IMRT may also be considered if level VI is considered to be at high 
risk due to gross involvement of level IV nodes. 
6.1.3 
Prescription for the PTV_7000 
All plans must be normalized such that 95% of the volume of the PTV_7000 is covered with 
prescription dose of 70 Gy.  
Additionally: 
 At 1 cc PTV_7000 volume on the DVH curve, the dose should not be >110% of the 
prescribed dose of 70 Gy. 
 No volume > 0.03 cc within the PTV_7000 volume on the DVH curve should receive a 
dose < 95% of the prescribed dose. 
 No more than 1 cc of the tissue outside the PTVs should receive >105% of the prescribed 
dose to PTV_7000. 
 
Dose should be reported with inhomogeneity corrections.  
 
6.2 
Technical Factors  
6.2.1 
Treatment Planning/Delivery 
Megavoltage energy photon beam irradiation with a photon beam of > 4 MV is required. Any 
treatment planning and delivery system that has been credentialed for head and neck IMRT for 
previous RTOG trials is acceptable. 
6.2.2 
Image Guidance for IGRT When Using Reduced Margins 
Daily image guidance of IMRT may be achieved using any one or more of the following 
techniques: 
 
Orthogonal kilovoltage (KV) images, e.g. ExacTrac; 
 
Linear-accelerator mounted kV and MV  conebeam CT images; 
 
Linear-accelerator mounted MV CT images (e.g., Tomotherapy). 
6.2.2.1 
The institution’s procedure for registering daily treatment imaging datasets with a reference 
dataset should comply with the following recommendations: 
 
Region-of-Interest (ROI) or “clip box” for fusion should be set to encompass the high 
dose PTV and adjacent spinal cord; if the supraclavicular region is a part of the target 
volume the ROI should extend to the C6 level; 
 
If the fusion software allows the user to create an irregular ROI (e.g. ExacTrac), 
treatment room objects seen on in-room x-rays should be excluded from the 
registration; 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
Both manual (e.g. based on bony anatomy) and automatic (e.g. based on mutual 
information) types of registration can be used; the result of the fusion must be visually 
checked for the alignment of the bony anatomy, such as vertebral bodies and 
applicable soft tissue structures (e.g. optic nerves and/or optic chiasm). 
 
Following the registration, the translational and (if the appropriate technology is 
available) rotational corrections should be applied to the treatment couch. If all the 
variances are <2.5 mm (this typically corresponds to one half of the usual PRV 
margin), the treatment can proceed without correction (however, the physician/team 
may elect to perform adjustments even for a variance <2.5 mm). If one or more 
corrections are 2.5 to 5 mm, adjustment is necessary prior to treatment; however, re-
imaging is not mandatory. If one or more of the corrections are >5 mm, the imaging 
must be repeated in addition to performing table/positioning adjustments. However, 
the use of numerous repeat IGRT studies should be avoided (see next section). 
6.2.2.2 
Management of Radiation Dose to the Patient from IGRT 
Estimates of patient doses per imaging study for various imaging systems vary considerably. 
The doses are in the range of 1 mGy for Cyberknife’s and BrainLab’s ExacTrac planar kV-
systems. The doses from helical MV CT scan on a Tomotherapy unit were estimated to be in 
range from 1 to 3 cGy for head and neck studies, similar to doses reported for kV cone 
beam CT on the Varian OBITM and Elekta SynergyTM machine. The doses for MV cone beam 
CT are in the range of 10 cGy for a pelvis study to 6 cGy for a head and neck study. Thus, 
the doses for 3D imaging systems are in the range from 1 to 6 cGy for head and neck 
imaging and can contribute from 0.5 to 3% to the daily dose of 2.0 Gy. These are small 
enough dose contributions that if there is only one imaging study done per treatment 
session, the dose is not expected to have any clinical relevance to the patient. However, the 
imaging dose to the patient may become significant if repeated studies are done for patients 
with severe set up problems (e.g., requiring frequent corrections of more than 5 mm). It is 
recommended that patients demonstrating severe set up problems during the first 7 calendar 
days of treatment be moved to a treatment with larger margins. 
 
6.3 
Localization, Simulation, and Immobilization 
6.3.1 
Immobilization 
The use of a thermoplastic head and shoulder mask is mandatory for head and neck IMRT.  
Patients will be planned in the supine position with their arms at their sides. 
6.3.2 
Planning CT scan 
The treatment planning CT scan is mandatory for defining target volumes and normal organ at 
risk. The “planning” CT scan will be done with and without contrast, the one with no contrast is 
intended for use in heterogeneity corrected IMRT planning. The “structuring” scan with contrast 
is fused to the planning scan for the purposes of structure definition and so that the major 
vessels of the neck are easily visualized.  An institution may elect to use the “structuring” scan 
as the “planning” scan. CT scan thickness should be 0.3 cm, and the CT scan should be 
acquired with the patient in the same position and using the same immobilization device as for 
treatment.  All tissues receiving irradiation should be included in the CT scan limits. The 
scanning limits should at least encompass the orbits superiorly, and 1 cm below the supra-
sternal notch inferiorly. For more accurate contouring, diagnostic CT scans and/or MRI may be 
fused with the planning CT scan. 
 
6.4 
Treatment Planning/Target Volumes (8/13/15) 
The primary tumor and involved nodes will be encompassed by the PTV_7000 and will receive 2 
Gy per fractions, while subclinical disease sites will be encompassed by PTV_5600 which will 
receive 1.6 Gy per fraction. The total doses will thus be 70 Gy and 56 Gy in 35 fractions, 
respectively. Regional lymph node areas considered to be at high risk for microscopic disease, 
PTV_5950-6300, may be treated to dose in the range of 59.5 - 63 Gy at 1.7-1.8 Gy per fractions. 
 
The treatment plan used for each patient will be based on an analysis of the volumetric dose,   
including dose-volume histogram (DVH) analyses of the PTV (CTV with a 5 mm margin) and 
critical normal structures. 
 
An “inverse” planning with computerized optimization should be used. 
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
Structures marked “required” in the table below must be contoured and submitted for review. 
Resubmission of data may be required if labeling of structures does not conform to the 
standard DICOM name as listed. 
 
All submitted treatment plans must strictly adhere to the structure names listed below: 
 
GTV 
Primary tumor and involved nodes 
Required 
CTV_7000 
GTV + 1cm margin 
Required 
                
PTV_7000 
CTV-PTV 5mm margin without IGRT; 3mm with 
daily IGRT 
Required 
CTV_5600 
CTV  7000 + 1cm margin and nodal regions 
Required when applicable 
                      
PTV_5600 
CTV-PTV 5mm margin without IGRT; 3mm with 
daily IGRT 
Required when applicable 
CTV_5950 
Volume slightly larger than CTV 7000 
Required when applicable 
CTV_6000 
Volume slightly larger than CTV 7000 
Required when applicable 
CTV_6300 
Volume slightly larger than CTV 7000 
Required when applicable 
                 
PTV_5950 
CTV-PTV 5mm margin without IGRT;3mm with 
daily IGRT 
Required when applicable 
PTV_6000 
CTV-PTV 5mm margin without IGRT;3mm with 
daily IGRT 
Required when applicable 
PTV_6300 
CTV-PTV 5mm margin without IGRT;3mm with 
daily IGRT 
Required when applicable 
SpinalCord 
Spinal Cord 
Required 
 
SpinalCord_05 
Planning Risk Volume of 5mm 
Required 
BrainStem 
Brain Stem 
Required 
 
BrainStem_05 
Planning Risk Volume of 5mm 
Required 
Parotid_L 
Left Parotid 
Required 
Parotid_R 
Right Parotid 
Required 
OralCavity 
Oral Cavity 
Required 
Lips 
Lips 
Required 
Mandible 
Mandible 
Required 
                    
Pharynx 
Uninvolved posterior pharyngeal wall plus 
adjacent constrictor muscles 
Required 
 
Esophagus_Up 
Cervical Esophagus 
Required 
LarynxGSL 
Glottic/Supraglottic (GSL) 
Required 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
Submandibula_L 
Left Submandibular Salivary Gland 
Required 
Submandibula_R 
Right Submandibular Salivary Gland 
Required 
External 
External border of patient used to define 
Unspecified Tissue 
Required 
 
PTV_7000_m08 
Minimum dose(cold spot within PTV_7000 not 
including portion of PTV near (<8mm) skin) 
defined for a point that is 0.03cc in size 
Required 
NonPTV  
External minus PTVs 
Required 
 
6.4.1 
Gross Tumor Volume (GTV) represents the region judged to contain gross primary tumor or 
involved node(s) based on clinical and endoscopic examinations, CT scan, and, when 
applicable, other imaging techniques. Grossly positive lymph nodes are defined as any lymph 
nodes > 1 cm or nodes with a necrotic center. 
6.4.2 
Clinical Target Volume (CTV) is defined as the GTV plus areas considered at risk for containing 
microscopic disease delineated by the treating physician. CTV_7000 represents GTV plus a 
margin of generally 1 cm, and CTV_5600 represents CTV_7000 with a margin of 1 cm and 
nodal regions to receive elective irradiation.  
 
When the tumor is infiltrative (endophytic) or when the border is ill defined, it might be desirable 
to deliver an intermediate dose (e.g. 59.5-63 Gy) to a volume (CTV_5950-6300) that is slightly 
larger than CTV_7000. The CTV margins can be narrower when GTV is in the proximity of the 
spinal cord or critical normal tissues. CTV should be limited by potential anatomical barriers to 
tumor spread such as air cavities and bones, and external body contours.  
 
The guidelines for CT based delineation of lymph node levels for node negative patients can be 
found at the RTOG web site: http://www.rtog.org/CoreLab/ContouringAtlases/HNAtlases.aspx. 
For patients with positive neck nodes, the proposal by Gregoire (2006) for the delineation of the 
nodal CTV in the node-positive neck, may be used. 
6.4.3 
Planning Target Volume (PTV_7000, PTV_5950-6300, and PTV_5600) represents an 
additional margin around CTV_7000, CTV_5950-6300, and CTV_5600 to compensate for the 
variability of treatment set-up and internal organ motion.  A minimum margin of 0.5 cm around 
the CTV is required in all directions to define each respective PTV, except for situations in 
which the CTV is adjacent to spinal cord or other critical normal tissues. In such situations, the 
margin can be reduced judiciously.  
 
For those institutions using daily IGRT and that are credentialed to use IGRT for margin 
reduction, a minimum of 3 mm may be used for the CTV to PTV expansion. If IGRT is used 
without margin reduction, a minimum of 5 mm margin is required for the expansion of CTV to 
PTV. 
 
When expansion of a CTV results in a PTV that extends beyond the patient’s body surface, the 
PTV should be constrained to 5 mm from within the external contour.  A 3 mm constraint of the 
PTV may be used if disease is near the skin surface. The use of tissue equivalent bolus 
material is indicated in situations where the disease is at or just under the skin surface. The 
PTV does not need to be constrained underneath the bolus. 
6.4.4 
The density corrected dose distributions shall be calculated, and the dose prescription is to be 
based on a dose distribution corrected for heterogeneities. 
 
6.5 
Critical Structures (8/5/14) 
6.5.1 
Management of the Low Neck/Supraclavicular Region (Match versus No Match) 
It is recognized that comprehensive head and neck irradiation incorporating IMRT can be done 
in several ways, any of which is permitted for this study. Patient-specific QA measurements are 
required for all IMRT treatments.  When a field “match” technique is used for treating the lower 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
neck, patient-specific measurements should include a verification of the dose coverage in the 
gap region for each patient. 
1. Match: The upper cervical lymphatics and primary tumor bed are treated with IMRT. The 
lower cervical lymphatics and supraclavicular region are treated with a single AP (or 
occasionally APPA for larger patients with posterior neck at high risk) non-IMRT technique. 
The latter non-IMRT field(s) is matched to the upper neck IMRT fields. This technique 
requires comprehensive mid-line spinal cord blocking in the lower neck fields. This 
technique also allows for a simultaneous blocking of portions of the larynx, hypopharynx, 
and cervical esophagus in the lower neck fields. Matching 2 IMRT plans is allowed. 
2. No Match: The entire clinical target volume (CTV) [upper and lower neck and primary tumor 
bed] is irradiated with IMRT. There is no match line between upper and lower portions of 
the regions at risk. In this technique, limiting radiotherapy dose to organs at risk (OARs), 
e.g., the cervical esophagus, is entirely achieved by inverse treatment planning via IMRT 
algorithms. 
6.5.2 
Definitions of Normal Tissues/Organs at Risk (OARs) 
6.5.2.1 
Spinal Cord: The cord begins at the cranial-cervical junction (i.e. the top of the C1 vertebral 
body). Superior to this is brainstem and inferior to this is cord. The inferior border of the 
spinal cord is at approximately T3-4 (i.e., just below the lowest slice level that has PTV on it). 
The spinal cord shall be defined based on the treatment planning CT scan. In addition, 
however, a Planning Risk Volume (PRV) spinal cord shall be defined. The PRV cord = spinal 
cord + 5 mm in each dimension. This is irrespective of the use of IGRT for margin 
reduction. 
6.5.2.2 
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction where 
it meets the spinal cord. For the purposes of this study, the superior most portion of the 
brainstem is approximately at the level of the top of the posterior clinoid process. The 
brainstem shall be defined based on the treatment planning CT scan.  In addition, however, 
a Planning Risk Volume (PRV) brainstem shall be defined. The PRV brainstem = brainstem 
+ 5 mm in each dimension. This is irrespective of the use IGRT for margin reduction. 
6.5.2.3 
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is to 
keep the lip dose much lower than the oral cavity dose. The definition of lips is self 
explanatory. The oral cavity will be defined as a composite structure consisting of the 
anterior one half to two thirds of the oral tongue/floor of mouth, buccal mucosa, and palate. 
6.5.2.4 
Parotid Glands: Parotid glands are defined based on the treatment planning CT scan. 
6.5.2.5 
Pharynx: This is defined as the “uninvolved” posterior pharyngeal wall plus adjacent 
constrictor muscles. This extends from the superior constrictor region (the inferior pterygoid 
plates level) to the cricopharyngeal inlet (posterior cricoid cartilage level). 
6.5.2.6 
Cervical Esophagus: This is defined as a tubular structure that starts at the bottom of 
pharynx and extends to the thoracic inlet. 
6.5.2.7 
Glottic/Supraglottic Larynx (GSL): The GSL begins just inferior to the hyoid bone and 
extends to the cricoid cartilage inferiorly and extends from the anterior commissure to 
include the arytenoids. This includes the infrahyoid but not suprahyoid epiglottis.  
6.5.2.8 
Mandible: The mandible includes the entire bony structure from TMJ through the symphysis. 
6.5.2.9 
Unspecified Tissue Outside the Targets: This tissue is located between the skull base and 
thoracic inlet that is not included in either the target volumes or the normal tissues described 
above.    
6.5.3 
In cases of weight loss >10%, or significant shrinkage of lymphadenopathy during therapy, it is 
recommended that the immobilization mask be adjusted or remade and a new plan be 
performed to assess the dose distributions with the current anatomy. Whether a new IMRT plan 
will be generated is at the discretion of the treating physician. If a new plan is made, the targets 
should be the same as those used for the initial plan. The new CT contour should be used for 
IGRT image registration with the new plan. 
6.5.4 
Doses to Normal Structures 
6.5.4.1 
Spinal Cord: The cord should not exceed 48 Gy to any volume in excess of 0.03 cc 
(approximately 3 mm x 3 mm x 3 mm). The PRV spinal cord should not exceed 50 Gy to any 
volume in excess of 0.03 cc.  In treatment planning, the spinal cord PRV should be given the 
highest priority. 
 6.5.4.2 
Brainstem: The PRV brainstem should not exceed 52 Gy to any volume in excess of 0.03 cc 
(approximately 3 mm x 3 mm x 3 mm). In treatment planning, the PRV brainstem should be 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
given less priority than the PRVcord but more priority than the other critical structures listed 
below.  
6.5.4.3 
Lips: Reduce the dose as much as possible. The mean dose should be <20 Gy.   
6.5.4.4  
Oral Cavity: Reduce the dose as much as possible. The mean dose should be <30 Gy for 
the non-involved oral cavity. Efforts should also be made to avoid hot spots (>60 Gy) within 
the non-involved oral cavity. 
6.5.4.5 
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The 
treatment planning goal will be for this individual parotid gland to receive a mean dose of 
<26 Gy.   
 
Contralateral submandibular gland: If contralateral level I is not a target, aim to reduce mean 
contralateral submandibular gland to <39 Gy.  
6.5.4.6 
Pharynx: Reduce the dose as much as possible. Some recommended (but not mandatory) 
treatment goals include: 1) No more than 33% of the pharynx exceeds 50 Gy; 2) Mean dose 
<45 Gy; 3) No more than 15% of the pharynx exceeds 60 Gy. 
6.5.4.7 
Cervical Esophagus: Reduce the dose as much as possible.  Some recommended (but 
treatment goals include: Mean dose <30 Gy. 
6.5.4.8 
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. The glottic 
larynx mean dose is recommended to be <20 Gy. If whole-neck IMRT is used, under-dosage 
of PTV_5950-6300 and PTV_5600 adjacent to the glottic larynx will be limited to <10% 
receiving <95% prescribed dose.  
6.5.4.9 
Mandible: Reduce the dose as much as possible. Hot spots within the mandible should be 
avoided. It is recommended that maximum dose within the mandible be <66 Gy.  
6.5.4.10 
Unspecified Tissue Outside the Targets: No more than 1cc of unspecified tissue outside the 
targets can receive 74 Gy or more.  
6.5.5 
Prioritization of IMRT Planning 
1. Spinal Cord 
2. Brainstem 
3. PTV_7000 
4. PTV_5950-6300(if applicable) 
5. PTV_5600 (if applicable) 
6. a. Pharynx 
b. Parotid gland contralateral to primary tumor site 
7.   a. GSL  
   b. Esophagus 
8.   a. Lips 
   b. Oral Cavity 
9.   a. Parotid gland ipsilateral to primary tumor site 
 b. Mandible 
10.  Unspecified tissue outside the targets 
 
6.6 
Documentation Requirements for IMRT (9/27/12) 
 
Pre-treatment Radiation therapy planning CT scan (see Section 6.3.2); 
 
If IGRT is not used, then orthogonal images that localize the isocenter placement of 
IMRT are required. This information should be archived by the submitting institution, so it 
can be made available for possible future review. 
 
6.7 
Compliance Criteria (8/13/15) 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Treatment breaks, if necessary, ideally should not exceed 5 treatment 
days at a time and 10 treatment days total. Treatment breaks should be allowed only for 
resolution of severe acute toxicity and/or for intercurrent illness and not for social or logistical 
reasons. Any treatment break(s) exceeding 2 treatment days for reasons other than 
toxicity/illness will be considered a protocol deviation. 
 
All treatment plans are to be normalized to provide exactly 95% volume coverage of the 
PTV_7000 with 70 Gy.  


 
 
 
 
 
27 
 
 
RTOG 3501 version date: 9/27/16 
 
 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Total RT dose to PTV_7000 (to 95% 
of the PTV) 
70 Gy 
66.5Gy – 73.5Gy 
Outside range of 
Variation Acceptable  
 
Minimum dose (“cold spot” within 
PTV_7000, not including portion of 
PTV near (< 8 mm) skin) defined for 
a point that is 0.03 cc in size 
(PTV_7000_m08) 
66.5 Gy (equals 95% of 
prescribed dose) 
< 66.5 but > 63 Gy 
 
 ≤ 63 Gy 
 
Maximum dose (“hot spot” > 1cc) 
within PTV_7000 NonPTV 
≤ 77 Gy 
> 77 but ≤ 82 Gy 
 
> 82 Gy 
Maximum dose (“hot spot” > 1cc 
outside the PTVs)  
< 74 Gy 
74-77 Gy 
> 77 Gy 
Total dose to PTV_5950 or 
PTV_6000, or PTV_6300 (to 95% of 
the PTV_5950 or PTV_6000, or 
PTV_6300)  
≥ 59.5 but < 63 Gy 
------- 
< 59.5 or  ≥ 63 Gy 
Total dose to PTV_5600 (to 95% of 
the PTV)  
56 Gy 
 
<56 Gy but >50.4 Gy 
< 50.4 Gy 
Total RT dose to  SpinalCord_05  
(0.03 cc) 
≤ 50 Gy 
≥ 50 but ≤ 52 Gy 
> 52 Gy 
Total RT dose to BrainStem_05 
(0.03cc) 
               ≤ 52 Gy          
>52 Gy but ≤54 Gy     
>54 Gy 
Overall RT treatment time 
< 45 days 
46-50 days (without a 
medically appropriate 
indication for delay) 
> 50 days (without a 
medically appropriate 
indication for delay). 
Non-Medically Indicated Treatment 
Interruptions 
0-2 
2-4 
> 4 
 
Recommended dose acceptance criteria for other normal tissue, but not to be used for plan score. 
 
Structure 
Recommended dose acceptance criteria 
 SpinalCord 
D0.03cc(Gy) < 48  
 BrainStem 
D0.03cc(Gy) < 50  
Lips 
Dmean(Gy) < 20  
OralCavity  
Dmean(Gy) < 30   
Dmax(Gy) < 60 
Parotid_L 
Dmean(Gy) < 26  
Parotid_R 
Dmean(Gy) < 26  
Submandibula_L 
Dmean(Gy) < 39  
Submandibula_R 
Dmean(Gy) < 39  
Pharynx 
 
V50Gy(%) ≤ 33 
Dmean(Gy) < 45  
V60Gy(%) ≤ 15 
Esophagus_Up 
Dmean(Gy) < 30   


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
LarynxGSL 
 
Dmean(Gy) < 20   
V66.5Gy(%) < 10 
Mandible 
 
Dmax(Gy) < 66  
 
6.8 
R.T. Quality Assurance Reviews (8/13/15) 
 
The Radiation Oncology Co-Chair, George Shenouda, MD, will perform RT Quality Assurance 
Reviews. These reviews will be ongoing and performed remotely. RT Quality Assurance reviews 
will be facilitated by the ACR Core Laboratory/RTQA. 
 
6.9 
Radiation Therapy Adverse Events 
Grade 3-4 (CTCAE, v. 4) therapy-induced mucositis and/or dysphagia, which are enhanced by 
cisplatin, are expected to develop in about two thirds of patients. Other common radiation 
adverse events include: fatigue, weight loss, regional alopecia, xerostomia, hoarseness, transient 
ear discomfort, dysgeusia, and skin erythema and desquamation within the treatment fields. 
 
Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, and 
chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. Much less 
common radiation adverse events include: mandibular osteoradionecrosis (< 5% incidence with 
attention to the dental recommendations provided in Appendix VII), and cervical myelopathy 
(<1% with restriction of spinal cord dose to ≤ 45 Gy). 
 
 
6.10 
Radiation Therapy Adverse Event Reporting  
 
See Section 7.10 for details. 
 
 
7.0 
DRUG THERAPY 
 
Institutional participation in chemotherapy studies must be in accordance with the Medical 
Oncology Quality Control guidelines stated in the RTOG Procedures Manual. 
 
 
Protocol treatment must begin within 14 calendar days after randomization. 
 
7.1 
Code Breaks  
 
The decision to break the code must be based on a life-threatening event or extraordinary clinical 
circumstance for which knowledge of drug assignment will affect clinical judgment. One of these 
criteria must be met for RTOG to consider breaking the treatment code.  
 
 
During business hours (8:30 AM to 5 PM ET), call RTOG Headquarters at 215-574-3150 and ask 
to speak to the Supporting Study Statistician. For after hours, weekends, and holidays, call 215-
459-3576. 
 
7.2 
Treatment (2/2/16) 
7.2.1 
Cisplatin:  
Weeks 2-7 with concurrent radiation therapy and lapatinib/placebo: Patients will receive 
cisplatin, 100 mg/m2, administered intravenously on days 8 and 29 of the treatment course 
(Note: cisplatin given within 24 hours of days 8 and 29, e.g. due to holidays, is acceptable). 
Weekends count as days. Cisplatin can be given before or after the fraction of radiation that is 
given on the same day.  If radiation is held for more than 2 days (for any reason), cisplatin may 
be held as well until radiation therapy resumes. 
 
See Section 7.6.1 for dose modification for weight loss.  Use the actual body weight for all 
patients. Dose modification for obesity is not recommended.  
7.2.1.1 
High dose cisplatin is a highly emetogenic regimen with significant incidence of delayed 
nausea and vomiting. Institutional guidelines for highly emetogenic regimens should be 
followed. In the absence of such guidelines: 
 
For acute nausea and vomiting, premedication should include a 5-HT3 antagonist, 
such as granisetron 1 mg iv.; ondansetron, up to 16 mg iv; or palonosetron, 0.25 mg 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
iv.; plus a corticosteroid, such as dexamethasone, up to 20 mg iv.. Palonosetron has 
a longer half life (40h) than the first generation 5HT3 antagonists. 
 
Breakthrough nausea and vomiting should be managed at the discretion of the 
medical or radiation oncologist. Delayed nausea and vomiting (greater than 24 hours 
after chemotherapy administration) may be managed by the addition of aprepitant 
concurrently or with metoclopramide and dexamethasone. Potential delayed nausea 
regimens include: 
1. The NK-1 antagonist, aprepitant (125 mg p.o.), may be added for prevention of 
delayed emesis on the day of cisplatin administration and for 2 consecutive days 
thereafter (80 mg, 80 mg p.o.), with a corticosteroid, such as dexamethasone on 
days 1, 2, and 3 after cisplatin. Dexamethasone should be reduced on day 1 to 
12 mg and delivered at up to 8 mg total daily for up to 4 days total. 5HT3 
antagonist (e.g. granisetron, ondansetron) may be given for 3 days, only if 
palonosetron was not given prior to chemotherapy.  Fosaprepitant (115 mg iv. x 
1) may be used instead of aprepitant on day 1, 30 minutes before cisplatin; if 
used, fosaprepitant may be used with or without aprepitant day 2 and 3, and 
dexamethasone will be given as described above. 
2. Delayed emesis also may be managed by the addition of dexamethasone 8 mg 
bid x 2 days, followed by dexamethasone 4 mg bid x 2 days, beginning day after 
chemotherapy; oral metoclopramide 0.5 mg/kg (usually 20-40 mg) in addition qid 
x 2-4 days; 5HT3 antagonist (e.g. granisetron, ondansetron) may be given for 3 
days, only if palonosetron was not given prior to chemotherapy. Adjust 
dexamethasone downward if aprepitant was given in the preceding 4 days. 
7.2.1.2 
Patients must receive vigorous hydration and diuresis. A suggested regimen is pre- 
hydration with a 1 liter of D5N S over 2-4 hours and mannitol, 12.5 g iv. bolus immediately 
prior to cisplatin. Then cisplatin, 100 mg/m2, in 500 ml NS is administered over 1-2 hours 
with an additional 1 to 1.5 liters of fluid given post-hydration. Any pre-existing dehydration 
must be corrected prior to cisplatin administration. Should extravasation occur, the treating 
physician should follow institutional guidelines for management. 
 
Overnight hospitalization for hydration after cisplatin is strongly encouraged, if it is allowed 
by the patient's insurance company. Additional iv. hydration and BUN/creatinine check 
should be strongly considered later in the week after cisplatin administration, in order to 
prevent dehydration and severe fluid/electrolyte imbalance. 
7.2.2 
Lapatinib/Placebo: (1/16/14) 
Note: See Section 7.2.2.1 for lapatinib/placebo feeding tube administration. See Section 7.6.2 
for lapatinib/placebo dose modifications. 
 
Week 1: Starting 7 calendar days prior to radiation, patients will take 6 lapatinib/placebo tablets 
(1500 mg) once daily, 7 days a week, by mouth or by feeding tube on an empty stomach (either 
1 hour before or 1 hour after meals). Lapatinib/placebo tablets are not to be crushed. 
 
Weeks 2-7: Concurrent with radiation and cisplatin, patients will take 6 lapatinib/placebo tablets  
(1500 mg) once daily, 7 days a week, by mouth or by feeding tube on an empty stomach (either 
1 hour before or 1 hour after meals). Lapatinib/placebo tablets are not to be crushed. 
 
After Concurrent Treatment (Maintenance): After completion of radiation, patients will continue 
lapatinib/placebo 6 tablets (1500 mg) once daily, 7 days a week, by mouth or by feeding tube 
on an empty stomach (either 1 hour before or 1 hour after meals) for 3 months. 
 
Patient Diary: Patients will be asked to document daily lapatinib/placebo on a pill diary during 
concurrent treatment and maintenance, which will be collected by the institution as source 
documentation. Institutions will submit the DP form to RTOG at the end of concurrent treatment 
and every month during maintenance treatment (see Sections 11.2.3 and 12.1). 
7.2.2.1 
Recommended Dosing Procedure for Slurry Preparation of Lapatinib/Placebo Water 
Suspension 
 
Lapatinib tablets are NOT to be crushed. 
 
Place 120 mL (4 oz) of water in a glass container, then add 6 lapatinib/placebo tablets 
to the container.  Cover the container, let it stand for 5 minutes, and then stir the 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
mixture intermittently for 10 minutes or until it is fully dispersed.  Stir the mixture for 5 
seconds then administer. Rinse the container with a 2 oz aliquot of water and repeat 
the administration process. This completes the administration process (total of 6 oz of 
liquid is dispensed). 
7.2.2.2 
Recommended Dosing Procedure for Slurry Preparation of Lapatinib/Placebo Kool-Aid 
Suspension 
 
Prepare Lemonade or Tropical Punch Kool-Aid as directed on the package. Place 2 or 4 oz 
of Kool-Aid in a glass container, then add 6 lapatinib/placebo tablets to the container. Cover 
the container, let it stand for 5 minutes, and then stir the mixture intermittently for 10 minutes 
or until it is fully dispersed.  Stir the mixture for 5 seconds then administer.  Rinse the 
container with a 2 oz aliquot of water and repeat the administration process. This completes 
the administration process (total of 4-6 oz of liquid is dispensed). 
 
7.3 
Cisplatin (Cis-Diamminedichloroplatinum, DDP) 
Refer to the package insert for additional information 
7.3.1 
Formulation: Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, 
and hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. 
The pH range will be 3.5 to 4.5. Cisplatin injection also is available from the manufacturer in 
aqueous solution, each ml containing 1 mg cisplatin and 9 mg NaCl and HCL or NaOH to 
adjust pH. 
7.3.2 
Mechanism of Action: The mechanism of action of DDP has not been clearly elucidated; 
however, preliminary studies have indicated that the most likely mechanism of antitumor action 
of this drug resides in its ability to inhibit DNA synthesis and to a lesser degree, RNA and 
protein synthesis. It has also been shown that DDP binds to DNA and produces inter-strand 
cross-links. Also DDP is not phase-sensitive and its cytotoxicity is similar in all phases of the 
cell cycle. 
7.3.3 
Administration: Intravenous 
7.3.4 
Storage and Stability: Reconstituted solution of cisplatin is stable for 20 hours when stored at 
27°C and should be protected from light if not used within 6 hours. The vials and injection 
should not be refrigerated. Cisplatin has been shown to react with aluminum needles, 
producing a black precipitate within 30 minutes. 
7.3.5 
Adverse Events: The following adverse events are anticipated:  
 
Hematologic: Myelosuppression, often with delayed erythrosuppression; rarely, acute 
leukemia; 
 
Gastrointestinal: Nausea, vomiting, anorexia, loss of taste;  
 Dermatologic: Alopecia;
 
 
Renal: Elevation of BUN, creatinine and impairment of endogenous creatinine clearance, 
as well as renal tubular damage which appears to be transient); hyperuricemia, much 
more severe and prolonged adverse events have been observed in patients with 
abnormal or obstructed urinary excretory tracts; 
 
Hepatic: Hypomagnesemia, hypokalemia, hypocalcemia; 
 
Neurologic: Restlessness, involuntary movements, loss of coordination, seizures, 
peripheral neuropathy;  
 
Allergic: Flushing, bronchoconstriction, tachycardia, hypotension; 
 
Other: Ototoxicity (with hearing loss which initially is in the high-frequency range, as well 
as tinnitus); muscle cramps; weakness. 
7.3.6 
Supply: Cisplatin is commercially available.  
 
 
7.4 
Lapatinib/Placebo (Tykerb®; GW572016) IND 115409 (8/5/14) 
This study will be conducted under an IND to be held by RTOG and will require FDA submission 
and approval. Lapatinib and placebo will be supplied to patients on study free of charge. 
Participating institutions can access the Lapatinib Investigator Brochure on the RTOG web site 
(password protected).  
7.4.1 
Chemical Name: N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-
(methylsulfonyl)ethyl]amino}methyl)-2 furyl]-4-quinazolinamine 
7.4.2 
Mode of Action: Dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 
tyrosine kinases. 
7.4.3 
How Supplied: Lapatinib and placebo are supplied as 250 mg oval, biconvex, orange film-
coated tablets with one side plain and the opposite side debossed with FG HLS.  The lapatinib 


 
 
 
 
 
31 
 
 
RTOG 3501 version date: 9/27/16 
 
tablets contain 410 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. 
Excipients present in the tablet include: Microcrystalline cellulose, povidone, sodium starch 
glycolate, and magnesium stearate. The film-coat contains: Hydroxypropyl methylcellulose, 
titanium dioxide, triacetin/glycerol triacetate, and yellow iron oxide. Each bottle of lapatinib or 
placebo contains 90 tablets. 
7.4.4 
Administration: Oral on an empty stomach (either 1 hour before or 1 hour after meals). 
7.4.4.1 
Prohibited Medications 
 
See Appendix VI. 
7.4.5 
Storage and Stability: The intact bottles should be stored at controlled room temperature 
(15°C-30°C). Shelf life surveillance studies of the intact bottle are on-going.  Current data 
indicates lapatinib is stable for at least 2 years at controlled room temperature (15°C - 30°C). 
7.4.6 
Lapatinib Adverse Events 
7.4.6.1 
Cardiac: Cardiovascular events have been seen in patients taking other compounds that 
inhibit ErbB2 when used in combination with or following anthracyclines, and interstitial 
pneumonitis has been reported in patients taking compounds that inhibit ErbB1. See 
Sections 7.7.1 and 7.7.2 for management guidelines. 
7.4.6.2 
Hepatotoxicity: Hepatobiliary events have been seen in patients taking lapatinib and other 
tyrosine kinase inhibitors. See Section 7.7.3 for management guidelines. 
7.4.6.3 
Dermatologic 
Significant skin adverse events (Grade 3 or more) resulting from lapatinib are rare (1-3%).  
For CTCAE, v. 4 Grade 4 rash manifested as toxic epidermal necrolysis (i.e. Stevens-
Johnson’s Syndrome etc) lapatinib must be permanently discontinued. See Section 7.7.4 for 
management guidelines. 
7.4.6.4 
Gastrointestinal  
Experience thus far suggests that when lapatinib is used as monotherapy most diarrhea 
presents as uncomplicated CTCAE v. 4 grade 1 or 2 (G1 54%, G2 20%, G3 15%, G4<1%). 
In rare cases, diarrhea can be debilitating, and potentially life threatening if accompanied by 
dehydration, renal insufficiency, and/or electrolyte imbalances. Standardized and universal 
guidelines have been developed by an American Society of Clinical Oncology (ASCO) panel 
for treating chemotherapy-induced diarrhea (Benson, 2004). Early identification and 
intervention is critical for the optimal management of diarrhea.  A patient’s baseline bowel 
patterns should be established so that changes in patterns can be identified while the patient 
is on treatment.  See Section 7.7.5 for management of nausea and/or vomiting and 
Appendix V for diarrhea management guidelines.  
7.4.6.5 
Interstitial Lung Disease 
 
See Section 7.7.6 for management guidelines. 
7.4.7 
Supply: Lapatinib and matching placebo will be provided free of charge by Novartis and 
distributed by a vendor, Biologics, Inc., under contract to RTOG. 
 
 
Each blinded, patient-specific bottle will be labeled with the following: 
 
The study number (i.e. RTOG 3501); 
 
The bottle number (i.e. Bottle 1 of 2 and Bottle 2 of 2); 
 
The number of capsules 
 
The patient ID number (e.g. 3501-YYY, where the study number and sequence number 
represents the unique patient identifier assigned by RTOG at registration); 
 
The patient’s initials (i.e. first, middle, last); 
 
A blank line for the site pharmacist to enter the patient’s name; 
 
Administration instructions (i.e. “Take xx tablets every day for xx days”); 
 
Storage instructions (i.e. “Store at controlled room temperature, xx degrees”); 
 
Emergency contact instructions. 
7.4.8 
Drug Ordering (2/2/16) 
BLINDED (lapatinib or placebo) THERAPY   
 
No blinded starter supplies will be available for this study. Blinded, patient-specific clinical 
supplies will be sent to the registering investigator at the time of randomization.  This 
randomization will be performed by RTOG Headquarters.  The patient ID number assigned by 
RTOG Headquarters must be recorded by the registering institution for proper study medication 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
dispersion. Once a patient has been registered, RTOG Headquarters will electronically transmit 
a clinical drug request for that patient to Biologics, Inc. This request will be entered and 
transmitted by RTOG Headquarters the day the patient is registered.  
 
Upon receipt of patient randomization notification, Biologics will: 1) Check to confirm site has an 
active Study Agent Shipment Form (SASF): 2) Place a call to the study site confirming the order 
was received and arrange day and time of arrival for the study drug; 3) Ship the initial shipment 
of study drug as listed below: 
7.4.8.1 
Initial Shipment: 4 Bottles of study drug to be taken continuously beginning 1 week prior to 
RT (8 weeks at 1500 mg (6 tabs/250mg each) PO QD). Biologics will place a follow-up call 
at week 4 for subsequent shipment of maintenance therapy study drug. Subsequent 
shipments will be made as listed below. 
7.4.8.2 
Subsequent Shipment: 3 months for maintenance treatment (6 bottles: 3 months at 1500 mg 
(6 tabs/250 mg each) PO QD. 
 
Drug requests received by Biologics prior to 2 PM ET Monday through Friday, will be processed 
and shipped that day.  Drug requests received after 2PM ET Monday through Friday will be 
processed and shipped the next business day. See shipment schedule below. 
 
RTOG 3501 Shipment Schedule 
Patient 
registered with 
RTOG 
E-order 
transmitted by 
RTOG 
E-order 
Received by 
Biologics  
Order shipped 
by Biologics 
Order received 
at site 
Monday 
Monday 
Monday by 2PM 
ET 
Monday 
Tuesday 
Tuesday 
Tuesday 
Monday after 
2PM ET until 
Tuesday 2pm ET 
Tuesday 
Wednesday 
Wednesday 
Wednesday 
Tuesday after 
2PM ET until 
Wednesday 2pm 
ET 
Wednesday 
Thursday 
Thursday 
Thursday 
Wednesday after 
2PM ET until 
Thursday 2pm 
ET 
Thursday 
Friday 
Friday 
Friday 
Thursday after 
2PM ET until 
Friday 2pm ET 
Friday 
Monday 
 
 
Friday after 2PM 
ET 
Monday 
Tuesday 
 
The SASF (available on the RTOG web site, www.rtog.org, under protocol-specific 
materials/regulatory resources) for U.S. and Canadian sites must be submitted to RTOG 
Headquarters (FAX 215-940-8919) or e-mail it to RTOG3501Regulatory@acr.org as soon as 
the individual responsible for the study agent has been identified.   
 
All shipments will be sent by FedEx Priority Overnight delivery (delivery by 10:30AM to most US 
addresses. Packages will be tracked by Biologics until confirmed delivered and delivery 
exceptions are managed with the highest level of urgency to ensure therapy start date 
adherence. Packing slips with the shipment tracking number included will be faxed to the 
designated site coordinator for all shipments. 
 
Questions about supply and delivery should be directed to:  
 
Elliott Lee, Program Manager 
Biologics, Inc. 
Clinical Research Services 


 
 
 
 
 
33 
 
 
RTOG 3501 version date: 9/27/16 
 
120 Weston Oaks Court 
Cary, NC  27513-2256 
(800) 693-4906 
FAX (919) 256-0794 
clinicalresearchservices@biologicsinc.com 
 
7.4.9 
Accountability 
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 Novartis. It is the 
responsibility of the Investigator to ensure that the agents are only dispensed to study patients. 
The agents must be dispensed only from official study sites by authorized personnel according 
to local regulations. 
7.4.10 
Drug Destruction  
 
Opened bottles of lapatinib/placebo must be disposed of by incineration at the site as 
chemotherapy or biohazardous waste. At the completion of the study, all unused 
lapatinib/placebo also must be incinerated at the site. If the site is unable to dispose by 
incineration, opened bottles and/or unused lapatinib/placebo should be returned to Biologics, 
Inc. for destruction (see contact information above). It is the responsibility of the Investigator to 
ensure that a current record of agent disposition is maintained at each study site where agents 
are inventoried and disposed, including dates and quantities. Sites should complete the drug 
destruction form located on the RTOG web site, www.rtog.org , 
under 
protocol-specific 
materials/regulatory resources and send the form to Biologics (see above for contact 
information). 
 
7.6 
Dose Modifications (3/22/16) 
7.6.1 
Cisplatin Modifications, Day 29 
7.6.1.1 
Neutropenia: If on the day of scheduled treatment with cisplatin the absolute neutrophil 
count (ANC) is < 1200, hold treatment until ANC ≥ 1200, then treat at 100% dose. 
Neutropenic fever will require permanent 25% dose reduction. Per CTCAE, v. 4, febrile 
neutropenia is described as ANC < 1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥ 38 degrees C (100.4 degrees F) for more 
than 1 hour. 
7.6.1.2 
Thrombocytopenia: If on the day of scheduled treatment with cisplatin the platelet count is < 
75,000, hold treatment until platelets are > 75,000, then treat at 100% dose. 
Thrombocytopenia that results in bleeding will require a 25% dose reduction. 
7.6.1.3 
Neurotoxicity: If any signs of grade 3 or greater neurotoxicity occur, discontinue cisplatin. 
Continue radiation therapy (RT) and lapatinib/placebo. 
7.6.1.4 
Renal Adverse Events: Cisplatin should be administered on the scheduled day of treatment 
using the following guidelines. Note: If creatinine is > 1.3 mg/dl, clearance must be 
calculated (Cockcroft-Gault) in order to make dose adjustment. If the calculated nomogram 
is 50 mL/min or above, a 24-hour urine collection is not needed, but if the calculation is less 
than 50 mL/min, a 24-hour urine collection is mandated and the cisplatin will be determined 
as follows: 
 
Serum Creatinine 
Creatinine Clearance 
Cisplatin Dose 
≤ 1.5 mg/dl       OR 
> 50 ml/min. 
100 mg/m2 
> 1.5 mg/dl       AND 
40-50 ml/min. 
50 mg/m2 
> 1.5 mg/dl       OR 
< 40 ml/min. 
Hold drug* 
 
 
*Cisplatin should be held (but RT continued), and the creatinine measured weekly. If the 
serum creatinine is < 1.5 mg/dl or creatinine clearance is > 50 ml/min, then the second dose 
of cisplatin can be given at the reduced dose of 50 mg/m2. Also see Section 7.6.1.6 below. 
7.6.1.5 
Other Adverse Events 
 
Mucositis: Significant mucositis from radiation and cisplatin is expected and will not be 
an indication for cisplatin dose modification. No cisplatin dose reductions will be made. 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
Ototoxicity: For new clinical hearing loss not requiring a hearing aid or for tinnitus that 
interferes with activities of daily living, treat at 50% dose reduction. For hearing loss 
requiring a hearing aid, discontinue cisplatin. Continue RT and lapatinib/placebo.  
 
If the physician is unsure about the severity of the hearing loss, an audiogram is 
encouraged. 
7.6.1.6 
If the second dose of cisplatin is delayed more than 21 days because of hematologic or 
renal adverse events, that dose will be omitted. 
7.6.2 
Lapatinib/Placebo Modifications 
 
Patients will be treated per protocol as described in Section 7.2.2 or until disease progression 
or withdrawal from treatment due to unacceptable adverse event or treatment consent 
withdrawal. 
 
If lapatinib dose reduction is required the following general rules should be applied: 
 
Lapatinib/placebo dose should be reduced by increments of 250 mg at a time and only 
after all supportive care measures have been exhausted without an improvement of 
patient status. 
 
Lapatinib/placebo should not be used at doses below 1000 mg if given as monotherapy 
or below 750 mg concomitantly with cisplatin. 
 
See the table below for a summary of dose holding/interruptions and dose de-escalation 
recommendations in case of lapatinib-related adverse events (graded according to CTCAE, v. 
4). See Section 7.7 below for management guidelines of lapatinib adverse events. 
 
Adverse Event (CTCAE, v. 4) 
Action 
Non-hematological, grade 1 or 2 
(Not attributable to cisplatin or radiation) 
Continue lapatinib therapy at full dose prescribed.  
Apply maximum supportive care recommendations. If 
prolonged duration of grade 2 adverse event is 
affecting quality of life a one-time decrease of dose by 
250 mg is allowed. 
Non-hematological, grade 3 or 4 
(Not attributable to cisplatin or radiation) 
Apply maximum supportive care recommendations.  
Hold lapatinib therapy until recovery to grade  1 (up to 
14 days). 
 
In patients with symptomatic grade 3 or 4 left 
ventricular cardiac dysfunction, lapatinib must be 
permanently discontinued. For grade 3 or 4 interstitial 
pneumonitis or grade 4 rash manifested as toxic 
epidermal necrolysis (e.g. Stevens-Johnson Syndrome 
etc.), lapatinib must be permanently discontinued. 
 
If recurrence of adverse event after drug hold and/or 
interruptions is observed and maximum supportive care 
measures applied, a dose reduction by 250 mg is 
recommended. Lapatinib should not be used at doses 
below 1000 mg if given as monotherapy or 750 mg in 
combination with chemoRT. NOTE: The 750 mg dose 
should only be used after all supportive measures have 
been exhausted.  
Non-hematological, grade 3 or 4 and adverse events 
NOT resolved to grade  2 within a maximum of 14 
calendar days from last planned administration  
Dose reductions by 250 mg (up to 2 reductions) will be 
considered 
after 
maximum 
supportive 
care 
recommendations are introduced. 
Cardiac*  
 
*Severity 
corresponding 
to 
NYHA 
criteria; 
see 
Appendix II. 
Lapatinib therapy to be discontinued permanently in the 
case of symptomatic NYHA class III and IV congestive 
heart failure OR decrease in LVEF by > 20% relative to 
baseline or less than the institution’s lower limit of 
normal.  


 
 
 
 
 
35 
 
 
RTOG 3501 version date: 9/27/16 
 
 
Abnormal Liver Function Tests 
In the event of grade 3 or 4 abnormal ALT and/or 
bilirubin, lapatinib must be discontinued permanently. 
Refer to Section 7.7.4.  
 
For grade 1 or 2 abnormal ALT/bilirubin, lapatinib must 
be discontinued permanently for patients with: 
 BOTH bilirubin and ALT abnormalities being of 
grade 2  
OR  
 EITHER bilirubin OR ALT abnormality is grade 2 and 
accompanied by signs or symptoms which, in the 
opinion of the treating physician, are related to liver 
injury caused by lapatinib.  
 
Such signs and symptoms may include abdominal pain, 
fever, jaundice, rash, eosinophilia or a PS drop of ≥ 1 
point from baseline. Refer to Section 7.7.4. 
In case of multiple short interruptions of dose due to either adverse events or drug supply or other reasons the 
sum of days without lapatinib treatment should not exceed 21 days in any 90 day treatment period. 
 
 
7.7 
Management of Lapatinib/Placebo Adverse Events (8/5/14) 
 
NOTE: SEE APPENDIX V FOR MANAGEMENT OF DIARRHEA. 
7.7.1 
Management of Non-Hematologic Adverse Events 
If any of the following conditions occur, administration of lapatinib/placebo may be interrupted 
for a maximum of 14 days to allow the adverse event (AE) to resolve or decrease in severity: 
 
CTCAE, v. 4 grade 3 or 4 or unacceptable adverse events, e.g. cosmetic effect of grade 
2 rash; 
 
No consideration and/or corroborative evidence that the AE is due to progressive 
disease;  
 
The AE is consistent with previously described lapatinib/placebo AEs. At a minimum, 
reassessment of AEs should be done weekly and more frequently if clinically indicated. 
When the AE decreases in severity to CTCAE, v. 4 grade 1, the patient may continue to 
take the assigned dose. 
7.7.2 
Management of Asymptomatic Cardiac Adverse Events 
Refer to CTCAE v. 4 grading of left ventricular cardiac function. After the baseline ECHO or 
MUGA, repeat LVEF assessment is required at week 12.  If a patient is found to have a ≥ 20% 
decrease in LVEF relative to baseline, or the ejection fraction is below the institution's lower 
limit of normal, then lapatinib/placebo should be permanently discontinued, and the patient 
should have a repeat evaluation of ejection fraction 28 calendar days later to confirm recovery.  
7.7.3 
Management of Symptomatic Cardiac Adverse Events 
Study medication must be withdrawn if a patient develops symptoms of heart failure or test 
results indicating abnormal LVEF (see Section 7.7.2). 
7.7.4 
Management of Hepatoxicity 
Liver chemistry stopping and follow up criteria have been designed to assure patient safety and 
evaluate liver event etiology.  All patients who meet liver chemistry criteria requiring permanent 
discontinuation of investigational product must continue to be followed per the Liver Chemistry 
Follow-up Criteria below. 
7.7.4.1 
Permanent Discontinuation Criteria 
If a patient experiences ALT > 3 × ULN and total bilirubin > 2.0 × ULN (> 35% direct; bilirubin 
fractionation required), then the following actions must be taken: 
 
Immediately and permanently discontinue investigational product;  
 
In addition to the liver event follow up assessments, the following are suggested:  
specialist or hepatology consultation; anti-nuclear antibody, anti-smooth muscle 
antibody, and Type 1 anti-liver kidney microsomal antibodies; and liver imaging 
and/or liver biopsy to evaluate liver disease; 
 
Promptly report the event to Novartis within 24 hours of learning its occurrence; 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
Monitor every 7 calendar days until liver chemistries resolve, stabilize or return to 
within baseline values; 
 
Do not re-challenge with investigational product. 
NOTE:  If bilirubin fractionation testing is unavailable and a patient meets the criterion of 
total bilirubin >2.0 × ULN, then the management of hepatotoxicity actions above must still be 
performed. 
7.7.4.2 
Interruption Criteria 
If a patient experiences: 
 
ALT >8 × ULN or 
 
ALT >5 × ULN persisting for > 14 calendar days: retest within 3 days from the first 
occurrence and then every 7 calendar days to determine if ALT elevation persists 
or 
 
ALT >3 × ULN with signs or symptoms of hepatitis or hypersensitivity (the 
appearance or worsening of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia) 
then hold investigational product for 14 calendar days, repeat liver chemistry testing in 14 
calendar days, and then contact the Principal Investigator, Dr. Wong, to discuss the 
possibility of re-starting lapatinib. Liver chemistries and aforementioned signs and symptoms 
should be monitored at a minimum of every 14 calendar days until resolution, stabilization, 
or a return to baseline values, at which point monitoring should be continued per protocol. 
7.7.4.3 
Continuation Criteria 
If a patient experiences ALT >3 × ULN but <5 × ULN and total bilirubin ≤2 × ULN, without 
signs or symptoms of hepatitis or hypersensitivity, and who can be monitored every 7 
calendar days, then the following actions should be taken: 
 
Continue investigational product; 
 
Monitor every 7 calendar days until liver chemistries resolve, stabilize, or return to 
within baseline, then monitor liver chemistries as per protocol assessment 
schedule; 
 
If ALT >3 and < 5 × ULN persists for > 28 calendar days, discontinue  treatment 
7.7.4.4 
Liver Chemistry Follow-up Criteria 
For all patients who meet any of the liver chemistry criteria described above, make every 
attempt to carry out the liver event follow up assessments described below: 
 
Viral hepatitis serology including: 
 
Hepatitis A IgM antibody; 
 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
 
Hepatitis C RNA; 
 
Cytomegalovirus IgM antibody; 
 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); 
 
Hepatitis E IgM antibody (if patient resides or has traveled outside USA or Canada 
in past 3 months). 
 
 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH): 
 
Complete blood count with differential to assess eosinophilia; 
 
Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever, or rash as relevant on an AE report form; 
 
Record use of concomitant medications, acetaminophen, herbal remedies, other 
over-the-counter medications, other putative hepatotoxins, and/or alcohol use. 
7.7.5 
Management of Dermatologic Adverse Events 
Patients with poorly tolerated skin adverse events may be successfully managed by providing a 
brief (up to 14 days) therapy interruption; the daily dose of lapatinib should then be reinstated. 
However, the rash may improve without the need for interrupting therapy with lapatinib. Of note 
in current studies, many patients were able to resume lapatinib therapy at the same dose after 
resolution of rash, and they then had less extensive and/or severe rashes. A variety of agents 
can be used to manage skin rashes. These include mild-to-moderate strength steroid creams, 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
topical or systemic antibiotics, topical or systemic antihistamines, and occasionally, retinoid 
creams. 
 
There is no standard, known, or established treatment proven effective for drug-related skin 
rashes or changes due to lapatinib. If the rash is severe (1-3%) then most commonly, a 
papular/pustular rash has been observed, which frequently improves even though the same 
dose of lapatinib therapy is continued uninterrupted. The need for oral or topical antibiotics is a 
clinical decision of the investigator and should be preceded by a culture of affected areas and, 
if indicated, a dermatology consultation. Oral retinoids should not be given because of 
theoretical concerns about negatively affecting the lapatinib mechanism of action. Oral steroids 
are also strongly discouraged. Other options for treatment of significant rashes may be 
determined upon consultation with dermatologist. 
7.7.6 
Management of Nausea and/or Vomiting 
 
In patients who have emesis and are unable to retain lapatinib, every attempt should be made 
to obtain control of nausea and vomiting. A dose may be repeated if tablets can be visually 
found after the vomiting episode. 
7.7.7 
Management of Interstitial Lung Disease 
If a patient develops symptoms suggestive of interstitial pneumonitis, adult respiratory distress 
syndrome (ARDS), or non-cardiogenic pulmonary edema, lapatinib therapy should be 
interrupted and a thorough evaluation performed. If CTCAE v. 4 grade 3 or 4 
pneumonitis/fibrosis or pulmonary infiltrate is confirmed (and the relationship to lapatinib  
cannot be excluded), lapatinib must be permanently discontinued. All incidences of interstitial 
lung disease/ interstitial pneumonitis regardless of grade must be reported as serious adverse 
events (SAEs). 
7.7.8 
Management of Other Adverse Events 
For any other CTCAE v. 4 grade 3 or 4 adverse events or any clinically significant, lower-grade 
adverse event, treatment with lapatinib should be interrupted for a maximum of 14 days until 
the patient recovers completely or the adverse event reverts to CTCAE v. 4 grade 1 or to 
baseline grade. If recurrence of an adverse event after drug holiday/interruptions is observed, 
then a dose reduction by 250 mg is recommended. Dose reduction should only be implemented 
when all supportive care measures have been exhausted without an improvement of patient 
status. 
 
7.8 
Modality Review 
The Principal Investigator, Stuart Wong, MD, will perform a Chemotherapy Assurance Review of 
all patients who receive or are to receive chemotherapy in this trial.  The goal of the review is to 
evaluate protocol compliance. The review process is contingent on timely submission of 
chemotherapy treatment data as specified in 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. 
   
 
The Principal Investigator, Stuart Wong, MD, will perform a Quality Assurance Review after 
complete data for the first 20 cases enrolled has been received at RTOG Headquarters. Dr. 
Wong will perform the next review after complete data for the next 20 cases enrolled has been 
received at RTOG Headquarters. The final cases will be reviewed within 3 months after this study 
has reached the target accrual or as soon as complete data for all cases enrolled has been 
received at RTOG Headquarters, whichever occurs first. 
 
 
7.9 
Adverse Events (3/22/17) 
 
All AE reporting on the study case report forms (CRFs) should follow grading criteria 
instructions on the specific CRF.  
7.9.1 
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).  


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
AEs, as defined above, experienced by patients accrued to this protocol should be reported on 
the AE section of the appropriate case report form (see Section 12.1).  
 
NOTE: If the event is a Serious Adverse Event (SAE) [see next section], further reporting 
will be required. Reporting AEs only fulfills Data Management reporting requirements.  
7.9.2 
Serious Adverse Events (SAEs)  
 
Definition of an SAE: An undesirable sign, symptom or medical condition which: 
 
is fatal or life-threatening; 
 
results in persistent or significant disability/incapacity; 
 
constitutes a congenital anomaly/birth defect; 
 
requires inpatient hospitalization or prolongation of existing hospitalization; 
Note: Hospitalization for the following reasons does not require expedited reporting: 
      routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition; 
      elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug; 
      treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission; 
      social reasons and respite care in the absence of any deterioration in the patient’s 
general condition. 
 
is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
 
Any pregnancy, including a male patient’s impregnation of his partner, occurring on study must 
be reported as a medically significant event. 
 
SAE reporting is safety related and separate and in addition to the Data Management reporting 
requirements as outlined in the previous AE reporting section.  
7.9.2.1 
Additions to SAE Definition 
 
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. 
 
 
7.10 
Serious Adverse Event (SAE) Reporting Requirements (9/27/16) 
The treating investigator has the obligation to report all serious adverse events to RTOG and per 
the local IRB per institutional policy. This study will utilize the RTOG SAE Report Form for 
reporting of SAEs. The SAE Report Form, SAE Reporting Guidelines, and SAE Report Form 
Instructions are available on the RTOG web site, www.RTOG.org. 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after protocol-
specified procedures begin and 30 days after the patient has stopped study treatment must be 
reported to RTOG within the timeframe detailed in the reporting table below.  Information about all 
SAEs is collected and recorded on a Serious Adverse Event Report Form; all applicable sections 
of the form must be completed in order to provide a clinically thorough report. The investigator 
must assess and record the relationship of each SAE to each specific study treatment (if there is 
more than one study treatment), complete the SAE Report Form, and e-mail the completed  
form to RTOG at RTOG3501AE@acr.org. RTOG will report applicable SAEs to Novartis within 
24 hours of awareness.  
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
It is the responsibility of the investigator to document all adverse events which occur during the 
study. It is the responsibility of the IND holder to comply with IND safety reporting of SAEs as set 
forth in the Code of Federal Regulations, Section 312.32 and as IND holder, RTOG will report 
applicable SAEs to FDA and Novartis within the requirement timeframe 
7.10.1 
Reporting SAEs  
Any SAE regardless of relationship to protocol treatment must be reported by the investigator. 
All deaths during treatment or within 30 days following completion of protocol treatment must be 
reported within 5 working days. 
 
Any SAEs experienced after this 30 days period should only be reported to RTOG if the 
investigator suspects a causal relationship to protocol treatment; see the reporting table below 
for timeframes. Recurrent episodes, complications, or progression of the initial SAE must be 
reported as follow up to the original episode.  
 
The SAE report should comprise a full written summary, detailing relevant aspects of the SAE 
in question. The SAE summary also must include the investigator’s assessment of 
expectedness and relatedness to specific protocol treatment (e.g., radiation, cisplatin, or 
lapatinib). When applicable, information from relevant hospital case records and autopsy 
reports should be included. Initial and follow-up information, when it becomes available, should 
be e-mailed to RTOG3501AE@acr.org. In the rare event when Internet connectivity is 
disrupted, a 24-hour notification must be made to the RTOG Operations Office by phone, (1-
4189215-574-3191).  An electronic report must be submitted immediately upon re-establish of 
the Internet connection. RTOG will report the SAE to the FDA and to Novartis. 
 
SAEs brought to the attention of the investigator at any time after cessation of protocol 
treatment and considered by the investigator to be related or possibly related to protocol 
treatment also must be reported via the SAE Report Form, using the SAE Form instructions.  
 
All SAEs must be e-mailed to RTOG3501AE@acr.org within the designated timeframe 
outlined in the table below as well as the SAE Form Instructions.  RTOG will complete a 
preliminary review of the SAE details and may contact the site with queries.  RTOG then 
will report the SAE to the FDA and Novartis. Note: The individual completing the SAE 
Report Form should remain vigilant for RTOG’s review and be prepared to respond to 
queries expeditiously in order to ensure timely reporting to the FDA and Novartis. 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND within 30 Days of the Last Administration of 
the Investigational Agent/Intervention1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization  
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 within the timeframes 
detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
Resulting in 
Hospitalization  
 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported within 24 hours; 5 Calendar Days; the 
AE must initially be reported within 24 hours of learning of the AE, followed by a complete expedited 
report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of protocol treatment and 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 
 
7.10.1.1 
Pregnancy (2/2/16) 
Patients who become pregnant during the study should discontinue the study immediately.  
Investigators should report any pregnancy, including a male patient’s impregnation of his 
partner, as a grade 3 SAE and submit an SAE report to RTOG at RTOG3501AE@acr.org. 
Investigators should submit the pregnancy report form within 14 days of notification. RTOG 
will report the pregnancy to Novartis within 24 hours of awareness. Patients should be 
instructed to notify the investigator if it is determined after completion of the study that they 
become pregnant either during the treatment phase of the study or within five calendar days 
after the treatment period. Whenever possible a pregnancy should be followed to term, any 
premature termination reported, and the status of the mother and child should be reported 
after delivery to RTOG Headquarters. RTOG will report the status to Novartis. 
7.10.2 
Assessment of Causality and Expectedness 
Every effort should be made by the investigator to explain each SAE and assess its 
expectedness and relationship, if any, to study drug treatment.  Causality should be assessed 
using the following categories: no (not related), or yes (reasonable possibility). 
 
The determination of expectedness and the degree of certainty with which a SAE is attributed 
to drug treatment (or alternative causes, e.g. natural history of the underlying diseases, 
concomitant therapy, etc.) will be determined by how well the experience can be understood in 
terms of the following: 
 
Known pharmacology of the drug 
 
Reaction of similar nature being previously observed with this drug or class of drug 
 
The event having often been reported in literature for similar drugs as drug related (e.g. 
skin rashes, blood dyscrasia) 
 
The event being related by time to drug administration terminating with drug withdrawal 
(dechallenge) or reproduced on rechallenge. 
 
The investigator may change his/her opinion of expectedness and/or causality in light of follow-
up information, by amending the SAE Report Form. The expectedness and causality 
assessment is one of the criteria used when determining regulatory reporting requirements to 
the FDA. 
 
8.0 
SURGERY 
8.1 
Neck Dissection (8/13/15) 
All patients will be assessed 3 months post-treatment with CT scan or MRI or PET/CT.  
 
A neck dissection is required for patients with persistent nodal disease, any stage, if a palpable 
abnormality or worrisome radiographic abnormality persists in the neck 8-9 weeks after 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
completion of therapy. A neck dissection is optional for patients with multiple positive lymph 
nodes or with lymph nodes exceeding 3 cm in diameter at pre-treatment (N2a, N2b, N3) who 
achieve a complete clinical and radiographic response in the neck. Surgery will be performed 
within 2 weeks once the decision for neck dissection is made. The status of the primary tumor 
should be assessed thoroughly at the beginning of the surgical procedure before undertaking 
nodal dissection. Presence of persistent disease at the primary site, confirmed by frozen section, 
will be considered a failure of protocol treatment. Further treatment of such a patient will depend 
on the clinical situation and are at the discretion of the treating physicians. 
8.1.1 
For Patients Undergoing a Neck Dissection 
Cervical lymphadenectomy will encompass the original levels of lymph node involvement, 
which should be removed en bloc. Preservation of the accessory nerve, jugular vein, and 
sternomastoid muscle is encouraged if consistent with complete removal of all residual nodal 
disease; however, the extent of the neck dissection will be at the discretion of the surgeon. A 
selective neck dissection should be performed when feasible. At no time will synchronous 
bilateral radical neck dissections be performed. If bilateral radical neck dissections are 
necessary the neck procedure must be staged at an interval of 6 weeks between 
lymphadenectomies. 
 
The neck dissection specimens must be divided and oriented into discrete anatomic levels in 
the operating room by the supervising surgeon, and submitted for pathologic review in separate 
containers. Discrete groups of nodes that are matted or spaced too closely to be resolved as 
separate nodes under the microscope or by FDG-PET/CT (< 0.5 cm intervening distance) will 
be categorized as “nodal clusters.” These clusters will be considered equivalent to solitary 
nodes to allow for simpler and more accurate categorization of all sampled tissue. An attending 
pathologist should oversee evaluation of all neck dissection specimens according to Appendix 
IV. 
8.1.2 
Institutions must submit a Surgery Form (S1), a Surgical Operative Report (S2), and a Surgical 
Pathology Report (S5) for patients who have surgery to the primary site and/or to regional 
nodes post-treatment (see Section 12.1). 
 
8.2 
Surgical Removal (Salvage) of the Primary Tumor 
Directed biopsies at the site of the index lesions will not be performed in the absence of suspicion 
for relapse. Criteria for biopsy after chemoradiation include a persistent mucosal abnormality or 
imaging studies that are suspicious for persistent or recurrent disease at 8-9 weeks after 
completion of therapy. Options for salvage therapy will depend upon the clinical situation and are 
at the discretion of the treating physicians. Surgical removal (salvage resection) of the primary 
tumor will be performed, if possible, when biopsy-proven cancer remains more than three months 
after completion of therapy. The nature of the surgical resection will be dictated by the extent of 
tumor at the initial evaluation. The operation will be conducted using accepted criteria for primary 
surgical treatment of the cancer. 
 
Tissues for pathologic evaluation of margins must be taken from the patient (rather than the 
surgical specimen itself). However, the specimen itself should be marked at sites corresponding 
to the evaluated margins in order to assess sampling error in obtaining clear margins. If gross 
tumor remains or when no effort to remove tumor has been made, the patient will be considered 
to have "gross residual disease." In the absence of residual disease, if the cancer extends to 
within 5 mm of a surgical margin, the patient would be considered to have "close" margins. 
 
 
9.0 
OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication.  
 
9.2 
Non-permitted Supportive Therapy 
9.2.1  
Hematopoietic Growth Factors 
The routine use of erythropoietic growth factors (e.g. darbepoetin, erythropoietin) is strongly 
discouraged. Granulocytic growth factors (e.g. filgrastim) should not be used concurrently 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
during radiation therapy, unless radiation therapy has been stopped to allow for recovery of 
neutropenia and fever. Radiation therapy, lapatinib/placebo, and/or cisplatin should not be 
resumed within 48 hours of the last dose of filgrastim. 
 
10.0 
TISSUE/SPECIMEN SUBMISSION (8/13/15) 
NOTE: Patients must be offered the opportunity to participate in the correlative 
components of the study, such as tissue/specimen submission. 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. Sites are not permitted to delete 
the tissue/specimen component from the protocol or from the sample consent. 
10.1 
Tissue/Specimen Submission  
 
The  Biospecimen Bank at the University of California San Francisco acquires and maintains high 
quality specimens from RTOG trials. Tissue from each block is preserved through careful block 
storage and processing. The RTOG encourages participants in protocol studies to consent to the 
banking of their tissue. The Biospecimen Bank at UCSF 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  
Biospecimen Bank at UCSF also collects tissue for central pathology review. Central review of 
tissue can be for eligibility and/or analysis.  
 
 
In this study, pre-treatment tissue will be submitted to the Biospecimen Bank at UCSF for the 
purpose of central review of pathology (mandatory for eligibility for oropharyngeal patients), for 
banking, and for translational research (highly recommended but optional). In addition, blood will 
be submitted pre-treatment, at the end of radiation treatment, and at 6 months from the end of 
treatment for translational research (highly recommended but optional).  
 
 
If the patient consents to submission of tissue and blood for translational research, pre-treatment 
tissue will be used to test for predictive biomarkers of lapatinib response, lapatinib resistance, 
poor RFS, and metastasis. Blood will be used to test for prognostic biomarkers of poor RFS and 
predictive biomarkers of lapatinib sensitivity and resistance (see Section 1.6 for further details).  
 
 
10.2 
Specimen Collection For Central Review For Eligibility: Mandatory for Oropharyngeal 
Patients (9/27/16) 
Patients with oropharyngeal carcinoma must consent to participate in use of submitted 
tissue for HPV analysis by p16 immunohistochemistry. 
 
 
For patients with oropharyngeal carcinoma, the Biospecimen Bank at UCSF will process 2 
unstained sections from the tissue block and will send the sections to Dr. Adel El-Naggar who will 
determine HPV status by p16 immunohistochemistry within 7-10 business days. Note: If a 
specimen was previously submitted to the Biospecimen Bank at UCSF for determination of HPV 
status for another RTOG trial and found to be p16 negative, investigators can forward a 
Specimen Transmittal (ST) Form to the Biospecimen Bank requesting that the specimen be sent 
to Dr. El-Naggar for central lab confirmation of p16 negativity. 
 
The following material must be provided to the Biospecimen Bank at UCSF for Central Review: 
10.2.1 
One H & E stained slide per positive biopsy site (slide can be duplicate cut stained H&E; it does 
not have to be the diagnostic slide);  
10.2.2 
A corresponding paraffin-embedded tissue block of the tumor or three paraffin-embedded 2mm 
punches from the same block (with an H&E of the embedded punches); Institutions that are 
unable to submit a tissue block for the required HPV analysis of oropharyngeal cases may 
instead take 4 unstained sections from the block then obtain three 2 mm core punches of the 
block and re-embed the core punches into a recipient paraffin block for submission (or sites can 
send the punches to the Biospecimen Bank to be embedded). Institutions can request an FFPE 
specimen plug kit (see Appendix IV) from the  Biospecimen Bank at UCSF free of charge for 
this purpose: 415-476-7864 (7864)/FAX 415-476-5271; RTOG@ucsf.edu. 
 
If an institution is uncomfortable with obtaining the unstained sections and punches and wants 
to retain the tissue block, the site can send the entire block to the  Biospecimen Bank at UCSF, 
and the Bank will obtain the unstained sections and the core punches from the block and return 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
the remaining block to the site.  Please indicate this request (to obtain the sections, perform the 
core punch procedure, and return the block) on the submission form.  Note: For oropharyngeal 
carcinoma patients, there is a 10-day turnaround needed for HPV assays, so institutions should 
send the block (or punches/slides) by overnight courier to the Biospecimen Bank as soon as 
possible with their request. 
 
If an institution is not allowed to submit a tissue block or take punch biopsy cores from the 
paraffin block, the site may submit 15 unstained slides, but this is considered as an exception. 
10.2.3 
A Pathology Report documenting that the submitted block, core, or slides contain tumor; the 
report must include the RTOG 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. 
 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol violation. 
The block, unstained, or punches must all be from the same block as the H&E being submitted. 
10.2.4 
A Specimen Transmittal (ST) Form stating that the tissue is being submitted for Central Review.  
The Form must include the RTOG protocol number and the patient’s case number. 
10.2.5 
Central Review will be performed for every oropharyngeal case by Adel El-Naggar, MD, PhD. 
 
10.3 
Specimen 
Collection 
for 
Tissue 
Banking 
and 
Translational 
Research: 
Highly 
Recommended but Optional  (8/13/15) 
 
For patients who have consented to participate in the tissue/blood component of the study 
 
The following must be provided in order for the case to be evaluable for the Biospecimen Bank 
(Note: For patients with oropharyngeal cancer, the H&E slides and block must be submitted for 
required central review as described above in Section 10.2 and would not be submitted again as 
described below.):  
10.3.1 
One H&E stained slide (slide can be a duplicate cut stained H&E; it does not have to be the 
diagnostic slide.) 
10.3.2 
A corresponding paraffin-embedded tissue block (the block must match the H&E being 
submitted) of the tumor or three 2 mm diameter core of tumor tissue, punched from the tissue 
block containing the tumor with a punch tool and embedded in paraffin along with a 
corresponding H&E slide. The new block made from the punches must be labeled with the 
surgical pathology number. Note: A kit with the punch, tube, and instructions can be obtained 
free of charge from the Biospecimen Bank. Block or core must be clearly labeled with the 
pathology identification number and block ID that corresponds to the Pathology Report. If sites 
are unable to submit tissue blocks, then an exception can be made to accept 15 unstained 
slides. The block, unstained, or punches must all be from the same block as the H&E being 
submitted (in Section 10.3.1). 
10.3.3 
A Pathology Report documenting that the submitted block or core contains tumor. The report 
must include the RTOG 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. 
 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol violation. 
10.3.4 
Plasma and whole blood will be collected and stored for future translational studies. See 
Appendix IV for specimen processing and shipping information. Blood collection kits can be 
requested from the Biospecimen Bank free of charge at rtog@ucsf.edu or 415-476-7864. 
10.3.5 
A Specimen Transmittal (ST) Form clearly stating that tissue/plasma/blood is being submitted 
for the  Biospecimen Bank at UCSF; if for translational research, this should be stated on the 
form. The form must include the RTOG protocol number and patient’s case number.  
 
 
The following materials must be provided to the  Biospecimen Bank at UCSF with all 
specimens: A Specimen Transmittal (ST) Form documenting the date of collection of the 
biospecimen; the RTOG protocol number, the patient’s case number, time point of study, and 
method of storage, for example, stored at -80 C, must be included.] 
10.3.6 
Storage Conditions 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
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 refrigerator preferred) 
for up to 7 calendar days (please ship out Monday-Wednesday only; Canada: Monday-
Tuesday). 
OR: 
 Samples can be stored in plenty of dry ice for up to 7 calendar days, 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 ST Form the storage conditions used and time stored. 
 
10.3.7 Specimen Collection Summary (8/13/15) 
 
Specimens for Central Review (mandatory for patients with oropharyngeal cancer)  
and  Tissue Banking (highly recommended) 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E stained 
slides of the primary tumor 
Pre-treatment 
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
A corresponding paraffin-
embedded tissue block of the 
primary tumor taken before 
initiation of treatment or three 
2 mm diameter cores of 
tissue, punched from the 
tissue block with a punch tool 
and embedded in paraffin with 
4 unstained slides 
Pre-treatment 
Paraffin-embedded tissue 
block or block with 3 punch 
biopsies with 4 unstained 
slides  
Note: If site is not allowed 
to send blocks or punches, 
then 15 unstained slides 
will be allowed, but this is 
an exception. 
Block or punch block shipped 
ambient; include a cold pack 
during warm weather. 
 
 
Specimens for Banking and Translational Research (highly recommended) 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
PLASMA: 5-10 mL of 
anticoagulated whole blood in 
EDTA tube #1 (purple/ 
lavender top) and centrifuge 
Pre-treatment, end of 
radiation therapy (or within 2 
weeks of end of radiation 
therapy), and at 6 mos. from 
the end of treatment. 
Frozen plasma samples 
containing 0.5 mL per 
aliquot in 1 mL cryovials 
(five to eight) 
Plasma sent frozen on dry 
ice via overnight carrier 
DNA: 5-10 mL of 
anticoagulated whole blood in 
EDTA tube #2 (purple/ 
lavender top) and mix 
Pre-treatment (If site missed 
this collection they can collect 
this specimen at any time 
point or at follow up but this 
must be noted on the ST) 
Frozen whole blood 
samples containing  1 ml 
per aliquot in 1ml cryovials 
(three to five) 
Whole blood sent frozen on 
dry ice via overnight carrier 
 
10.3.8 
(8/13/15) Submit materials for Tissue Banking, Central Review, Translational Research as 
follows:  
 
U. S. Postal Service Mailing Address: For Non-urgent, Non-frozen Specimens Only 
Biospecimen Bank at UCSF 
University of California San Francisco 
Campus Box 1800 
 2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS): For Frozen Specimens and Urgent FFPE Samples 
 Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341 (Box 1800) 
San Francisco, CA 94115 


 
 
 
 
 
45 
 
 
RTOG 3501 version date: 9/27/16 
 
 
Questions: 415-476-7864/FAX 415-476-5271; RTOG@ucsf.edu 
 
10.4 
Reimbursement 
 
The RTOG Foundation will reimburse institutions for submission of protocol-specified 
biospecimen materials sent to the Biospecimen Bank at UCSF. After confirmation from the 
Biospecimen Bank that appropriate materials have been received, ACR Clinical Trials 
Administration will authorize payment according to the schedule detailed in the study-specific 
contract.   
 
10.5 
Confidentiality/Storage  
 
(See 
the 
RTOG 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further details.) 
10.5.1 
Upon receipt, the specimen is labeled with the RTOG protocol number and the patient’s case 
number only. The Biospecimen Bank at USCF database only includes the following information: 
the number of specimens received, the date the specimens were received, documentation of 
material sent to a qualified investigator, type of material sent, and the date the specimens were 
sent to the investigator. No clinical information is kept in the database. 
10.5.2 
Specimens for tissue banking will be stored for an indefinite period of time. Specimens for 
central review will be retained until the study is terminated. Specimens for the translational 
research component of this protocol will be retained until the study is terminated, unless the 
patient has consented to storage for future studies. If at any time the patient withdraws consent 
to store and use specimens, the material will be returned to the institution that submitted it. 
 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters: See Appendix I for a summary of assessments. See Section 11.2 below for 
details of assessments and exceptions. 
 
11.2 
Details of Assessments (8/13/15) 
11.2.1 
It is necessary to repeat the ECHO or MUGA at week 12 (4 weeks post-completion of radiation 
therapy); see Section 7.7.2. 
11.2.2 
A chest CT scan, or a PET/CT scan must be done within 42 calendar days prior to registration 
to rule out metastatic disease. In addition, a contrast enhanced CT scan or MRI or PET/CT 
scan of the tumor site and neck nodes must be done within 42 calendar days prior to 
registration. Note: The CT scan of the neck and/or PET/CT performed for radiation planning 
may serve as both staging and planning tools. 
11.2.3 
If the patient consents to submission of tissue and blood for translational research, primary 
tumor tissue will be submitted pre-treatment, and peripheral blood will be submitted pre-
treatment, at the end of radiation therapy, and at 6 months from end of treatment. 
11.2.4 
Patients will be asked to document daily lapatinib/placebo on a pill diary during concurrent 
treatment and maintenance treatment, which will be collected by the institution as source 
documentation. Institutions will submit the DP form to RTOG at the end of concurrent treatment 
and every month during maintenance treatment (see Section 12.1). 
11.2.5 
Evaluation During Radiotherapy 
 
A brief history and physical by a Radiation Oncologist and/or Medical Oncologist must be 
done weekly. 
 
Bilirubin and AST/ALT must be done 4 weeks after start of lapatinib/placebo. 
11.2.6 
Evaluation in Follow Up 
 
Patients will be seen in long-term follow up every 3 months for years 1 and 2, every 6 
months for years 3-5 and then annually until publication of study results. 
 
A brief history and physical by a Radiation Oncologist and/or Medical Oncologist and/or 
ENT or Head & Neck Surgeon must be done at 4 weeks and 3 months from the end of 
radiation treatment, then every 3 months through year 2, every 6 months for years 3-5, then 
annually. A laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is 
recommended at these time points but is not required. 
 
Post-radiation imaging evaluation of the primary tumor and neck at 3 months from the end 
of radiotherapy is required. The post-radiation imaging can be contrast enhanced CT, MRI, 
or PET/CT of the head and neck or “whole body” PET/CT (minimum neck and chest), 


 
 
 
 
 
46 
 
 
RTOG 3501 version date: 9/27/16 
 
based on the preference of the treating clinician. However, if a pre-treatment PET/CT was 
performed, it is highly recommended that a post-radiation PET/CT be used as the post-
radiation imaging modality. 
 
 
Post-radiation imaging evaluation (CT scan or MRI) of the primary tumor and neck also 
must be done at 6 and 12 months from end of treatment, then annually until year 5.  
 
 A chest CT scan must be done at 6 and 12 months from end of treatment, then annually 
until year 5. 
 
11.3 
Measurement of Response/Progression  
11.3.1 
Response versus “Tumor Clearance” versus Cancer Progression 
Response and confirmation of local (primary site) or regional (neck) “tumor clearance” are not 
endpoints in this study. Clinical or radiographic evidence of progressive local-regional disease 
beyond 20 weeks should be documented in the clinical record and ideally confirmed by local or 
regional biopsy, neck dissection, or salvage surgery. CT or MRI (of head and neck region, with  
Chest CT), or PET/CT (including chest anatomy) may be used as radiographic evaluation of 
overall cancer status. The primary, neck and chest portions of the scans should be evaluated 
and reported separately. The CT portion of a PET/CT may serve as sufficient radiographic 
evaluation of the chest. If CT or MRI is used for evaluation of the head and neck region, CT of 
chest will be needed to rule out distant disease or second primaries at the designated 
evaluation intervals as outlined above in Section 11.2.6 and Appendix I. 
11.3.2 
Local or Regional Progression 
Local (primary site) or regional (neck) progression is defined as palpable residual disease or 
CT/MRI evidence of persistent disease at the primary site or neck. The location of progressive 
disease should be separately distinguished (local vs. neck) to document the precise pattern of 
failure if possible. Progression of local or regional disease should be confirmed by biopsy when 
possible but may be clinically assessed and documented in the clinical record at the judgment 
of the treating clinicians. 
11.3.3 
Distant Metastasis 
Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where 
possible. A solitary, spiculated lung mass/nodule is considered a second primary neoplasm 
unless proven otherwise.  
11.3.4 
Second Primary Neoplasm 
Tumor reappearing with the initial and immediate adjoining anatomical region of the primary will 
be considered local recurrence. Multiple lung nodules/masses are considered distant 
metastases from the index cancer unless proven otherwise.  
 
11.4 
Criteria for Discontinuation of Protocol Treatment 
 
Progression of disease; 
 
Unacceptable adverse events per the judgment of the treating physician(s); 
 
Patient refusal. 
 
 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
 
11.5 
Quality of Life/Patient-Reported Outcomes Instruments 
Note: Patients must be offered the opportunity to participate in the correlative components of the 
study, such as quality of life assessment. If the patient consents to participate in the quality of life 
(QOL) component of the study, sites are required to administer the baseline QOL and PRO 
assessments prior to the start of protocol treatment: the PSS-HN, FACT-HN, and XeQOLS. 
Outcomes will be assessed at baseline (pretreatment) and at 3, 12, and 24 months from 
completion of radiation treatment. 
11.5.1 
The Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N) is a 
multidimensional, patient-self report quality of life (QOL) instrument specifically designed and 
validated for use with head and neck patients. The patient can complete the 12-item head and 
neck subscale in 5-10 minutes. The site research nurse or CRA is encouraged to be sensitive 
to each patient's demeanor. If patients appear particularly uncomfortable answering a question, 
they will be informed that they can skip that question.  Similarly, interviewers will give patients a 
short break if the patient appears fatigued or otherwise in need of a few minutes break. 


 
 
 
 
 
47 
 
 
RTOG 3501 version date: 9/27/16 
 
11.5.2 
The University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) consists of 15 
items covering 4 major domains of oral health-related quality of life: physical functioning, 
personal/psychological functioning, social functioning, and pain/discomfort issues. The patient 
can respond to the 15 items in the scale in approximately 5 minutes. The Scale is only available 
in English.  
11.5.3 
The Performance Status Scale for Head and Neck Cancer (PSS-HN) consists of assessment of 
3 functional areas (subscales): Normalcy of Diet, Eating in Public, and Understandability of 
Speech. The site research nurse or clinical research associate (CRA) will administer the PSS-
HN. Interviewers are encouraged to be sensitive to each patient's demeanor. If patients appear 
particularly uncomfortable answering a question, they will be informed that they can skip that 
question.  Similarly, interviewers will give patients a short break if the patient appears fatigued 
or otherwise in need of a few minutes break. The interviewer rates the patient on each scale 
based on the patient’s responses to targeted questions. The PSS-HN takes approximately 5 
minutes to complete.  
 
12.0 
DATA COLLECTION (9/27/16) 
Data should be submitted to: 
RTOG Headquarters* 
 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 (9/27/16) 
 
 
 
Item 
Due 
Demographic Form (A5) 
Initial Evaluation Form (I1) 
Pathology Report (P1) 
Slides/Blocks (P2)  
PSS-HN (QP) 
FACT-HN (FA) 
Xe-QOL (L4) 
Within 14 calendar days of study entry 
 
 
Treatment Form (TF) 
Within 7 calendar days of end of treatment 
 
 
Pill Diary (DP) 
End of concurrent treatment and every 30 
calendar days during maintenance treatment 
 
 
Surgery Form (S1) 
Surgical Operative Report (S2) 
Surgical Pathology Report (S5) 
Only for patients who have surgery to the primary 
site and/or to regional nodes post-treatment 
 
 
Radiotherapy Form (T1) 
Daily Treatment Record (T5) 
Within 7 calendar days of RT end 
 
 
PSS-HN (QP) 
FACT-HN (FA) 
Xe-QOL (L4) 
At 3, 12, and 24 months from end of RT 
 
 
Follow-up Form (F1) 
q3 mos. for years 1-2, q6 mos. for years 3-5, then 
annually until publication of study results 
 
 
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
 
12.2 
Summary of Dosimetry Digital Data Submission (Submit to RTOG Headquarters; see Section 
12.2.1) 
 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
Digital Data Submission – Treatment Plan submitted 
in DICOM format to RTOG via TRIAD exported from 
treatment planning machine by Physicist 
Within 7 calendar days of start of RT  
Digital data submission includes the following: 
 
 
DICOM CT data (non-contrast CT and CT with 
contrast; see Section 6.3.2)  
 
 
DICOM STRUCTURE 
 
 
DICOM RT PLAN 
 
 
DICOM DOSE 
 
 
 
NOTE: Sites must notify RTOG via e-mail RTOG-
RTQA@acr.org after digital data is submitted. The 
e-mail must include both the study, “Foundation 
3501”, and case numbers. 
 
Digital Data Submission Form (DT) - Web data 
entered 
(form 
is 
located 
on 
RTOG 
website: 
Foundation 3501 under Forms). 
 
 
 
Final Dosimetry Information 
Within 7 calendar days of RT end 
Radiotherapy Form (T1)  
Daily Treatment Record (T5)  
 
 
Modified digital patient data as required by RTOG  will 
be submitted via TRIAD 
 
 
 
12.2.1 
Digital Data Submission to RTOG Headquarters  
Digital data will be submitted to RTOG via the site’s TRIAD account.  
12.2.2 
Method of Plan Submission 
RTOG will provide sites with the American College of Radiology Imaging Network’s image 
acquisition and management software, TRIAD, via electronic installation.  TRIAD offers a web-
based, software solution allowing institutions to submit DICOM data securely through electronic 
transmission. Internal to the site, TRIAD allows the site to “DICOM push” from the site’s 
Treatment Planning System (TPS), thus eliminating the need to burn physical media. Once the 
institution has transferred the RT data onto a TRIAD workstation, the software will anonymize, 
encrypt, and submit the DICOM RT data via secure internet to the RTOG image archive. For 
more information please visit the TRIAD web site at https://triad.acr.org.  
 
Institutions initiate installation of TRIAD by e-mailing the name and e-mail address of the 
person(s) responsible at the site for submitting RT data for the trial (recommend the Physicist 
and/or Dosimetrist) to TRIAD-Support@acr.org. The site will then receive a TRIAD greeting 
letter, which describes how to prepare for the installation.   
 
TRIAD technical assistance may be requested by e-mailing TRIAD-Support@acr.org.  
Please always include the institution name and trial number when requesting TRIAD technical 
assistance.  
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Primary Endpoint 
13.1.1 
Progression-free survival (PFS) 
 
13.2 
Secondary Endpoints 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
13.2.1 
Overall survival; 
13.2.2 
Distant metastasis; 
13.2.3 
Adverse events; 
13.2.4 
Compliance with planned treatment; 
13.2.5 
Local-regional control; 
13.2.6 
Quality of life and patient-reported outcomes; 
13.2.7 
HER2 expression, amplification and heterodimerization, EGFR ligand expression, EGFR 
polymorphisms, hypoxia, and EMT characteristics as biomarkers of lapatinib response, 
sensitivity, and resistance, PFS, and metastasis.  
 
13.3 
Randomization and Stratification (10/3/13) 
Patients will be randomized to 1 of 2 treatment arms. Additionally, patients will be stratified 
according to age (≤ 65 vs. > 65); T stage (T1-3 vs. T4); and N stage (N0-2a vs. N2b-3).  
 
13.4 
Definitions of Failure 
The following table shows how each first event will be counted for progression-free survival, local-
regional failure, and distant metastasis. Anything not explicitly in the table (e.g., second primary 
tumor) is not considered an event, and the patient will continue to be followed for failure. For 
overall survival, death from any cause will be considered a failure. All failure times will be 
measured from randomization to the date of failure, competing risk, or last follow-up. 
 
First event 
Progression-
Free Survival 
Local-Regional 
Failure 
Distant 
Metastasis 
None 
Censored 
Censored 
Censored 
Local-regional progression or recurrence 
Failure 
Failure 
Competing risk 
Distant metastasis 
Failure 
Competing risk 
Failure 
Death due to study cancer or from 
unknown causes 
Failure 
Failure 
Competing risk 
Death to due any other reason 
Failure 
Competing risk 
Competing risk 
Salvage surgery of primary with tumor 
present/unknown 
Failure 
Failure 
Competing risk 
Salvage neck dissection with tumor 
present/unknown, > 20 weeks from end 
of RT  
Failure 
Failure 
Competing risk 
 
13.5  
Sample Size and Patient Accrual (9/27/16) 
This study will be a randomized phase II screening trial as proposed by Rubinstein, et al (2005). 
Based on the accrual to RTOG 0129 in this population, it is expected that the monthly accrual will 
be 12 patients after the first 6 months post-activation (allowing for IRB approvals). In RTOG 0129, 
this group of patients treated on the accelerated fractionation arm had a 2-year progression-free 
survival (PFS) rate of 53.5%. Hazard rates for first and second years are 37% and 15%. Based 
on discussions with the study chair, a 35% reduction in the hazard rate is clinically meaningful. 
With statistical power 0.80 and significance level 0.20 (1-sided) and one interim efficacy and 
futility analysis, the Lan-Demets (OF) spending function boundary for efficacy and rho family 
spending function with parameter of 1.5 for futility were utilized to derive a nonbinding rule. A total 
of 69 PFS events are required. To observe the required number of events, a sample size of 158 
accrued over 1.22 years with an additional 2.6 years of follow-up (total study duration 4.3 years 
including 6 months for IRB approvals) is required. Allowing for up to 10% of patients to be 
ineligible or not evaluable, the total original required sample size is 176. 
 
Following activation of the study little accrual is anticipated initially. The date at which the first 
patient is accrued will be used as the baseline for monitoring accrual. If the total accrual during 
months 18 through 24 is less than 20% of the projected total for 6 months of accrual (15 patients), 
then the study statistician will recommend to the RTOG DMC and the sponsor that the protocol 
will be discontinued. If the total accrual is between 21-49%, then the protocol will continue to 
accrue subjects pending approval to remain open by the RTOG DMC and the study sponsor. 
 
Revised Sample Size and Patient Accrual 


 
 
 
 
 
50 
 
 
RTOG 3501 version date: 9/27/16 
 
As of September 2016, the observed accrual rate in this study is about 30 patients/year 
(2.5/month). To finish accrual within a reasonable timeframe and to maintain the same design 
parameters detailed above, we plan to accrue a total of 142 patients (128 analyzable), with a total 
accrual duration of 4.7 years instead of 5.9 years. According to this plan, we will finish accrual 
around March 2017. 
 
13.6 
Analysis Plan (9/27/16) 
Progression-free and overall survival rates will be estimated using the Kaplan-Meier method 
(1958) and rates of distant metastasis (DM) and local-regional control (LRC) by the cumulative 
incidence method (Kalbfleisch 1980) to account for competing risks (see Section 13.4). The 
distributions of the progression-free and overall survival times will be compared between 
treatment arms with a one sided log rank test (Mantel, 1966). Distant metastasis and local-
regional control will be compared using cause-specific log rank test. If the resulting p-value for 
PFS is < 0.1803, the result will be interpreted as a significant indication of lapatinib  improving 
progression-free survival of these patients to warrant a definitive phase III trial.  
 
Only adverse events (AEs) assessed to be definitely, probably, or possibly related (if the 
relationship is missing, it will be assumed to be definitely, probably, or possibly) to protocol 
treatment will be considered. The rates of adverse events and  treatment compliance will be 
estimated using a binomial distribution along with their associated 95% confidence intervals and 
will be compared using Fisher’s exact test. 
 
Comparison of change from baseline quality of life scores between the 2 arms will be done using 
a 2-sample independent t test. With 158 patients, we will have 87% power to detect an effect size 
of 0.5 with a two-sided type I error rate of 5% and the statistical power will be 79% and 66% to 
detect effect sizes of 0.5 with 126 and 94 patients. Analysis of the covariance model (ANCOVA) 
will be used to adjust for effects from other factors. 
 
For analysis of local-regional control, distant metastasis, PFS, and OS, we will examine whether 
patients with normal baseline levels of biomarkers have a different prognosis than patients with 
abnormal baseline levels by calculating the product-limit estimates of the survival function and 
comparing those estimates using the log-rank statistic. The relationship between local-regional 
control, distant metastasis, PFS, OS, and abnormal baseline marker levels also will be explored 
by fitting Cox proportional hazards regression models, both adjusted for baseline disease and 
patient characteristics and unadjusted. Assuming usable baseline tissue/blood samples can be 
obtained from 118 eligible patients (~75%), this will provide at least modest power (>69%) to 
detect large differences (hazard ratios > 2.0) between patients with normal and abnormal marker 
levels, assuming 50% abnormal prevalence, with a two-sided 5% alpha, for the PFS endpoint. 
13.6.1 
Interim Analysis to Monitor Study Progress 
Interim reports will be prepared twice each year until the final analysis has been accepted for 
presentation or publication. In general, these reports will contain information about the accrual 
rate with projected completion date for the accrual phase, exclusion rates and reasons, 
pretreatment characteristics of patients accrued, compliance rate of treatment delivered with 
respect to the protocol prescription, and the frequency and severity of AEs. The RTOG Data 
Monitoring Committee (DMC) will review this study twice a year in conjunction with the RTOG 
semiannual meetings with respect to patient accrual and morbidity. The DMC also will review 
this study on an “as needed” basis between meetings. 
13.6.2 
Significance Testing for Early Termination and Reporting 
One interim treatment comparison will be performed when 50% (34 PFS failures) of the 69 
required number of PFS failures are observed. Only the primary endpoint will be tested in the 
interim analysis. The efficacy will be tested using boundary of 0.0699 on the p value scale for 
the interim tests and 0.1803 for the final analysis to preserve an overall alpha level of 0.20 for 
the study. A single interim futility analysis will be conducted when one-half (34) of the requisite 
events for definitive analysis have been observed. If the p value is equal to or greater than 
0.5827 favoring the control (i.e. in the wrong direction with respect to demonstrating that the 
lapatinib arm is more favorable), then early stopping will be considered. The results will be 
reported to the RTOG DMC with the treatment blinded. The responsible statistician may 
recommend early reporting of the results and/or stopping accrual (if applicable) of the trial if the 
treatment effect with respect to PFS is highly significant or if it is not likely to be. 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
13.6.3 
Analysis for Reporting the Initial Treatment Results 
The analysis to report the initial results of treatment will be undertaken when each patient has 
finished concurrent therapy, around July 2017. All randomized patients (ITT) will be included in 
the analysis. Eligible patients with both on-study and follow-up information will be considered 
for sensitivity analysis. The emphasis of this analysis will be on treatment compliance and 
adverse events. The usual components of this analysis are: 
 Tabulation of all cases entered, and any excluded from analysis with reasons for 
exclusion; 
 Patient accrual rate; 
 Institutional accrual; 
 Distribution of important baseline prognostic variables; 
 Frequency and severity of adverse events; 
 Compliance rate for treatment delivery with respect to the protocol prescription; 
 Observed results with respect to the endpoints described above. 
 
Only adverse events (AEs) assessed to be definitely, probably, or possibly related (if the 
relationship is missing, it will be assumed to be definitely, probably, or possibly) to protocol 
treatment will be considered. The rates of adverse events, treatment compliance, will be 
estimated using a binomial distribution along with their associated 95% confidence intervals 
and will be compared using Fisher’s exact test. 
13.6.4 
Analysis for Reporting the Final Treatment Results 
The analysis to report the definitive results of treatment will be undertaken when 69 events 
(total from both arms) have been reported for the primary endpoint, PFS, unless the criteria for 
early stopping are met. The time from when accrual is finished to this analysis is projected to be 
approximately 2.7 years based on  the observed accrual rate. All randomized patients (ITT) will 
be included in this analysis. Eligible patients with both on- study and follow-up information will 
be considered for sensitivity analysis. The usual components of this analysis are: 
 Tabulation of all cases entered, and any excluded from analysis with reasons for 
exclusion; 
 Patient accrual rate; 
 Institutional accrual; 
 Distribution of important baseline prognostic variables; 
 Frequency and severity of adverse events; 
 Observed results with respect to the endpoints described above. 
 
The difference in PFS between the control arm and the experimental arm will be tested using 
the one sided log-rank statistic at the significance level of 0.1803 given that the one interim 
analysis is carried out and shows no statistical significance. If the resulting p-value for efficacy 
is <0.1803, this result will be interpreted as an indication of lapatinib in improving progression-
free survival in these patients. 
 
A final analysis report will be prepared and provided for review by the co-investigators. Results 
for dissemination will be developed, and a manuscript drafted for review, approval, and 
submission. After manuscript acceptance, patient follow up will be discontinued and the trial 
terminated. It is anticipated that termination will occur approximately 3.9 years from when the 
accrual is finished. This time-frame may be extended depending on factors such as the 
observed accrual and event rates, in which case a new trial termination date will be 
established. 
  


 
 
 
 
 
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(8/13/15) APPENDIX I:  STUDY PARAMETER TABLE: *See Section 11.2 for details and exceptions 
Assessments 
Prior to 
Registration 
(calendar 
days) 
Prior to Treatment 
(calendar days) 
q7 days 
During 
Treatment 
From End of Radiation Therapy (calendar days) 
q 3 mos. in year 
2;  6 mos. in 
years 3-5;  then 
annually* 
4  
weeks 
3 
mos. 
6  
mos. 
9 mos. 
12 
mos. 
Complete history/physical 
28 days 
 
Brief H&P 
X* 
X* 
X* 
X* 
X* 
X* 
Rad Oncology Exam 
 
 
X* 
X* 
X* 
X* 
X* 
Med Oncology Exam 
28 days 
 
X* 
X* 
X* 
X* 
X* 
Zubrod 
14 days 
 
X 
 
X 
X 
X 
X 
X 
Weight 
28 days 
 
X 
 
X 
X 
X 
X 
X 
Chest CT or PET/CT  
42 days 
 
 
 
 
X* 
 
X* 
Annually until 
year 5 
Contrast enhanced CT or MRI or 
PET/CT of tumor site and neck 
nodes 
42 days 
 
 
 
X* 
X* 
 
X* 
Annually until 
year 5 
EKG  
84 days 
 
 
 
 
 
 
 
 
ECHO or MUGA 
84 days 
 
 
X* 
 
ENT or H&N  Surgeon exam 
42 days 
 
 
See Sec. 
11.2.5 
See Section 11.2.6 
CBC, Diff, Platelets 
14 days 
 
X 
 
X 
X 
X 
X 
 
Na, K, glucose, Ca, Mg 
14 days 
 
 
 
 
 
 
 
 
Na, K, Cl, glucose, Ca, Mg, 
albumin 
 
 
X 
X 
X 
X 
X 
X 
 
Bilirubin, AST/ALT 
14 days 
 
See Sec. 11.2.5 
 
X 
X 
X 
X 
 
Serum creatinine or creatinine 
clearance 
14 days 
 
X 
 
X 
X 
X 
X 
 
Serum pregnancy test, for 
women of childbearing potential 
14 days 
 
 
 
 
 
 
 
 
Adverse Event Eval, including 
mucosal assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
Dental assessment 
 
Recommended at 84 days 
 
 
 
 
 
 
 
Whole body PET scan 
 
Recommended at 42 days 
 
 
 
 
 
 
 
Audiogram  
 
Recommended at 84 days 
 
 
 
 
 
 
 
Swallowing assessment 
 
Recommended at 28 days  
 
 
 
 
 
 
 
Nutritional eval for PEG tube 
 
Recommended prior to tx 
 
 
 
 
 
 
 
*Pill Diary 
 
 
End of tx 
q30 
days. 
for 3 
mos. 
 
 
 
 
 
QOL/PRO assessments, if 
patient consents 
 
X 
 
 
X 
 
 
X 
at 24 mos. from 
end of tx 
Tissue/blood for research, if 
patient consents 
 
Prior to treatment 
 
End of 
RT 
 
X 
 
 
 
 


 
 
 
 
 
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APPENDIX II  
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature.  For example, light housework, office 
work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed  
 
5 
Death  
 
 
 
 
NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC DISEASE 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 


 
 
 
 
 
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APPENDIX III  
 
AJCC STAGING SYSTEM 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
HEAD & NECK  
 
STAGING-PRIMARY TUMOR (T) 
 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
 
 
 
LIP and ORAL CAVITY 
 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
T1 
Tumor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 4 cm in greatest dimension 
T3 
Tumor more than 4 cm in greatest dimension 
T4a 
Moderately advanced local disease* 
 
(lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of 
face (i.e., chin or nose) 
 
(oral cavity) Tumor invades adjacent structures only (e.g., through cortical bone [mandible or 
maxilla] into deep [extrinsic] muscle of tongue [genioglossus, hyoglossus, palatoglossus, and 
styloglossus], maxillary sinus, skin of face) 
T4b 
Very advanced disease 
 
Tumor invades masticator space, pterygoid plates or skull base and/or encases internal 
carotid artery 
*Note: Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as T4. 
 
NASAL CAVITY and PARANASAL SINUSES 
 
 
Maxillary Sinus 
T1 
Tumor limited to maxillary sinus mucosa with no erosion or destruction of bone 
T2 
Tumor causing bone erosion or destruction including extension into the hard palate and/or 
middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates 
T3 
Tumor invades any of the following: bone of the posterior wall of maxillary sinus, 
subcutaneous tissues, floor or medial wall of orbit, pterygoid fossa, ethmoid sinuses 
T4a 
Moderately advanced local disease 
 
Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, 
cribriform plate, sphenoid or frontal sinuses 
T4b 
Very advanced local disease 
 
Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial 
nerves other than maxillary division of trigeminal nerve (V2), nasopharynx or clivus 
 
 
Nasal Cavity and Ethmoid Sinus 
T1 
Tumor restricted to any one subsite, with or without bony invasion 
T2 
Tumor invading two subsites in a single region or extending to involve an adjacent region 


 
 
 
 
 
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within the nasoethmoidal complex, with or without bony invasion 
T3 
Tumor extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or 
cribriform plate 
T4a 
Moderately advanced local disease 
 
Tumor invades any of the following: anterior orbital contents, skin of nose or cheek, minimal 
extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses 
T4b 
Very advanced local disease 
 
Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial 
nerves other than V2, nasopharynx, or clivus 
 
 


 
 
 
 
 
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PHARYNX 
 
 
Nasopharynx 
T1 
Tumor confined to the nasopharynx, or tumor extends to oropharynx and/or nasal cavity with 
out parapharyngeal extension* 
T2 
Tumor with parapharyngeal extension* 
T3 
Tumor involves bony structures of skull base and/or paranasal sinuses 
T4 
Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, or 
with extension to the infratemporal fossa/masticator space 
 
 
*Note: Parapharyngeal extension denotes posterolateral infiltration of tumor. 
 
Oropharynx 
T1 
Tumor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 4 cm in greatest dimension 
T3 
Tumor more than 4 cm in greatest dimension or extension to lingual surface of epiglottis 
T4a 
Moderately advanced local disease 
 
Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or 
mandible* 
T4b 
Very advanced local disease 
 
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or 
encases carotid artery 
 
 
*Note: Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and 
vallecula does not constitute invasion of larynx. 
 
Hypopharynx 
T1 
Tumor limited to one subsite of hypopharynx and/or 2 cm or less in greatest dimension 
T2 
Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures more 
than 2 cm but not more than 4 cm in greatest diameter without fixation of hemilarynx 
T3 
Tumor measures more than 4 cm in greatest dimension or with fixation of hemilarynx or 
extension to esophagus 
T4a 
Moderately advanced local disease 
 
Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus or central 
compartment soft tissue.* 
T4b 
Very advanced local disease 
 
Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures 
*Note: Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat. 
 
 


 
 
 
 
 
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LARYNX 
 
 
Supraglottis 
T1 
Tumor limited to one subsite of supraglottis with normal vocal cord mobility 
T2 
Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region 
outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform 
sinus) without fixation of the larynx 
T3 
Tumor limited to larynx with vocal cord fixation and/or invades any of the following:  postcricoid 
area, pre-epiglottic tissues, paraglottic space, and/or inner cortex of thyroid cartilage 
T4a 
Moderately advanced local disease 
 
Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., 
trachea, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, 
thyroid, or esophagus) 
T4b 
Very advanced local disease 
 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures 
 
 
Glottis 
T1 
Tumor limited to the vocal cord(s) [may involve anterior or posterior commissure] with normal 
mobility 
T1a 
Tumor limited to one vocal cord 
T1b 
Tumor involves both vocal cords 
T2 
Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility 
T3 
Tumor limited to the larynx with vocal cord fixation, and/or invasion of paraglottic space, 
and/or inner cortex of the thyroid cartilage 
T4a 
Moderately advanced local disease 
 
Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond 
the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, 
strap muscles, thyroid, or esophagus) 
T4b 
Very advanced local disease 
 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures. 
Subglottis 
T1 
Tumor limited to the subglottis 
T2 
Tumor extends to vocal cord(s) with normal or impaired mobility 
T3 
Tumor limited to larynx with vocal cord fixation 
T4a 
Moderately advanced local disease 
 
Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., 
trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, 
thyroid, or esophagus) 
T4b 
Very advanced local disease 
 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures. 
 
 
REGIONAL LYMPH NODES (N) Excluding Nasopharynx 
 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral node, 3 cm or less in greatest dimension 
N2 
Metastasis in a single ipsilateral node, more than 3 cm, but not more than 6 cm in greatest 
dimension, or in multiple ipsilateral lymph nodes, none greater than 6 cm in greatest 
dimension, or bilateral or contralateral nodes, none more than 6 cm in greatest dimension 
N2a 
Metastasis in a single ipsilateral node more than 3 cm, but not more than 6 cm in greatest 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
dimension 
N2b 
Metastasis in multiple ipsilateral nodes, none more than 6 cm in greatest dimension 
N2c 
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest 
dimension 
N3 
Metastases in a lymph node, more than 6 cm in greatest dimension 
 
REGIONAL LYMPH NODES (N) Nasopharynx 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Unilateral metastasis in lymph node(s), 3 cm or less in greatest dimension 
N2 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in 
greatest dimension, or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest 
dimension 
N2a 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in 
greatest dimension 
N2b 
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
N2c 
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest 
dimension 
N3 
Metastasis in a lymph node, more than 6 cm in greatest dimension 
   
DISTANT METASTASIS (M) 
 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
 
 
STAGE GROUPING, Excluding Nasopharynx 
STAGE GROUPING Nasopharynx 
Stage 0  
 
Tis, N0, M0 
Stage 0  
Tis, N0, M0 
Stage I 
 
T1, N0, M0 
Stage I 
T1, N0, M0 
Stage II  
 
T2, N0, M0 
Stage II 
T2, N0, M0 
Stage III  
T3, N0, M0  
T1-3, N1, M0  
 
Stage III  
T1-T3, N1, M0 
T3, N0, M0 
Stage IVA 
T4a, N0-1, M0 
Any T, N2, M0 
Stage IVA 
T4a, N0-2, M0 
T1-3, N2, MO 
Stage IVB 
 
 
 
T4b, Any N, MO  
Any T, N3, M0 
Stage IVB 
 
Any T, N3, M0 
T4b, Any N, M0 
Stage IVC 
Any T, Any N, M1 
Stage IVC 
 
Any T, Any N, M1 
 
 
 
 
 
 
  


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX IV (8/13/15) 
 
Biospecimen Bank at UCSF Instructions for 
 FFPE Specimen Plug Kit Collection 
 Blood Collection Kit Instructions 
 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For Non-urgent FFPE or Non-frozen Specimens Only 
Biospecimen Bank at UCSF 
University of California San Francisco 
Campus Box 1800 
 2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS): For Frozen or Urgent FFPE samples and Trackable Specimens 
Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341 (Box 1800) 
San Francisco, CA 94115 
 
 
Include all RTOG paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal Form (STF) has the consent boxes checked off.  
 
Check that all samples are labeled with the RTOG 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 All specimens must be clearly labeled with pathology accession number and block ID. A corresponding 
H&E stained slide must be submitted with all blocks and unstained slides. Incomplete submissions 
without H&E slides will be returned to sites to correct before they can be processed. 
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 shaking, it is likely that they will 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. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs). 
There should be plenty of dry ice under and above the specimens. If the volume of specimens is 
greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any 
Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site 
will be notified.  
o Send frozen specimens via overnight courier to the address above. Specimens should only be shipped 
Monday through Wednesday (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  Biospecimen Bank at UCSF by e-
mail: RTOG@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271. 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX IV (Continued) (8/13/15) 
 FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the Biospecimen Bank at UCSF. 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 (study number, case 
number, pathology accession, and block number).  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 
Embed the punches into one block, and cut an H&E from it.  
For sites unable to embed the punches, 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 Biospecimen Bank at UCSF, and we will sample a plug from the block and return the remaining 
block to your facility.  Please indicate on the submission form the request to perform the plug procedure and 
return of the block and provide a return air bill. 
 
Ship punch block or 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 Biospecimen 
Bank at UCSF by e-mail: RTOG@ucsf.edu or call 415-476-7864/Fax 415-476-5271. 
 
U.S. Postal Service Mailing Address: For Non-urgent, Non-frozen Specimens Only 
 Biospecimen Bank at UCSF 
University of California San Francisco 
Campus Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS): For Frozen Specimens or Urgent, Trackable shipments 
Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341 (Box 1800) 
San Francisco, CA 94115 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX IV (Continued) 
 
 BLOOD COLLECTION KIT INSTRUCTIONS (8/13/15) 
 
This Kit is for collection, processing, storage, and shipping of plasma or whole blood (as specified by the 
protocol): 
 
Kit contents: 
 
Twenty-nine (29) 1 ml cryovials for ALL TIME POINTS 
 
Biohazard bags (4) and Absorbent shipping material (4) 
 
1 Styrofoam container (inner) and Cardboard shipping (outer) box 
 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
 
Specimen Transmittal (ST) Form  and Kit Instructions 
 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
 
(A) Plasma : Purple Top EDTA tube #1 
 
Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with the 
RTOG study and case number, collection date, time, and time point, and clearly mark cryovials 
“plasma”. 
Process: 
1. After collection, into an EDTA blood draw tube (not provided in kit unless requested)  invert tube(s) 
multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM 
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room 
temperature is acceptable if done within 2 hours of draw but must be noted on the ST Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one hour, 
keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the plasma 
collected (5 to 8)  labeled with RTOG study and case numbers, collection date/time, time point collected 
and clearly mark specimen as “plasma”.  Avoid pipetting up the buffy coat layer. If an aliquot has < 0.5 
ml in the tube, please note the volume on the vial and also note it on the ST Form. 
5. Place cryovials into biohazard bag and immediately freeze 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 
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX IV (Continued) 
 BLOOD COLLECTION KIT INSTRUCTIONS (Continued) (8/13/15) 
 
 (B) Whole Blood for DNA : Purple Top EDTA tube 
 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with the 
RTOG study and case number, collection date/time, and time point, and clearly mark cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be 
mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood 
collected (3 to 5) labeled with RTOG study and case numbers, collection date/time, time point 
collected and clearly mark specimen as “blood”. If an aliquot has < 1.0 ml in the tube, please note 
the volume on the vial and also note it on the ST Form. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on ST 
Form. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; 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 RTOG paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box. 
 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard bag.  
Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 
stickers to outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that 
there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail 
RTOG@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS): For all Frozen Specimens 
Biospecimen Bank at UCSF 
University of California San Francisco 
2340 Sutter Street, Room S341 (Box 1800) 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: RTOG@ucsf.edu  


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX V  
 
DIARRHEA MANAGEMENT GUIDELINES 
 
Presented in the sections below are the recommended guidelines for the management of diarrhea in patients 
receiving lapatinib-based therapy; these guidelines were derived from the recommendations published by the 
ASCO panel (Benson, 2004). 
 
Early identification and intervention is critical for the optimal management of diarrhea.  A patient’s baseline bowel 
patterns should be established so that changes in patterns can be identified while patient is on treatment.   
 
It is strongly recommended to give patients receiving lapatinib-based therapy a prescription of 
loperamide with instructions to start loperamide at the onset of diarrhea as per the recommendations 
outlined below.   
 
Patients should be instructed to first notify their physician/healthcare provider at onset of diarrhea of any 
severity. 
 
An assessment of frequency, consistency and duration as well as knowledge of other symptoms such as fever, 
cramping, pain, nausea, vomiting, dizziness and thirst should be taken at baseline. Consequently patients at high 
risk of diarrhea can be identified.  Patients should be educated on signs and symptoms of diarrhea with 
instructions to report any changes in bowel patterns to the physician.  
 
It is recommended that patients keep a diary and record the number of diarrhea episodes and its characteristics. 
They should also include information on any dietary changes or other observations that may be useful in the 
evaluation of their diarrhea history.  
 
If patients present with diarrhea of any Grade, check they are taking lapatinib correctly, i.e. single daily dose, 
rather than splitting it through the day. Obtain information on food (solid and liquid) and over the counter (OTC) 
medication, including herbal supplements, taken during the lapatinib treatment period. 
 
Definitions 
Define diarrhea compared to baseline (Table 1). 
 
Table 1 
Adverse Event 
Grade, CTCAE 
v. 4 
Diarrhea 
1 
Increase of <4 stools/day over baseline; mild increase in ostomy output compared to 
baseline 
2 
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output 
compared to baseline; 
3 
Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; 
severe increase in ostomy output compared to baseline; limiting self care activities of 
daily living (ADL) 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death 
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX V (Continued) 
Uncomplicated diarrhea is considered mild-to-moderate and defined as CTCAE v. 4 grade 1 or 2 with no 
complicating signs or symptoms. 
Complicated diarrhea is severe and defined as any CTCAE v. 4 grade 3 or 4 diarrhea, or grade 1 or 2 with 
one or more of the following signs or symptoms: 
 
Moderate to severe abdominal cramping  
 
Nausea/vomiting ≥Grade2 
 
Decreased performance status 
 
Fever 
 
Sepsis 
 
Neutropenia 
 
Frank bleeding (red blood in stool) 
 
Dehydration 
 
 
Management Guidelines for Patients Receiving Lapatinib Alone or as Combination Therapy 
A) Uncomplicated Diarrhea  
I. 
CTCAE Grade 1   
NOTE:  Patient should be instructed to start supportive care immediately at the first 
episode of diarrhea (i.e., unformed stool) and call their physician.  
 
1. Administer loperamide  
a. Initial dose 4mg followed by 2mg after every unformed stool. Re-evaluate after 24 hours, if: 
i. Diarrhea is resolving: 
 
Continue loperamide treatment at 2mg dose after every unformed stool until diarrhea 
free (i.e., <Grade 1/bowel patterns returned to baseline) for 12 hours. 
 
If diarrhea recurs, re-initiate loperamide treatment as needed to maintain normal 
bowel patterns 
ii. Diarrhea is not resolving: 
 
Administer loperamide at 2mg every 4 hours for the next 24 hour.  Re-evaluate after 
24 hours.  If diarrhea is resolving, administer loperamide at 2mg after every unformed 
stool until diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 12 
hours.  If diarrhea is not resolving continue loperamide treatment at 2mg every 4 
hours and re-evaluate every 24 hours.  
b. If Grade 1 diarrhea persists for more than 1 week with loperamide treatment, consider 
treatment with second-line agents (octreotide, budesonide or tincture of opium).  
 
2. Dietary modifications which are essential in the management of diarrhea  include the following 
recommendations (American Cancer Society; National Cancer Institute):   
a. Stop all lactose containing products and eat small meals 
b. Avoid spicy, fried and fatty foods, raw vegetables and other foods high in fiber 
i. Eat foods low in fiber (i.e., lean meat, rice, skinless chicken or turkey, fish, eggs, canned or 
cooked skinless fruits, cooked/pureed vegetables) 
c. Avoid caffeine and alcohol as they can irritate the bowel and increase motility 
d. Hydration:  Drink 8-10 large glasses of clear liquids a day (e.g., water, electrolyte drink).  
i. Avoid acidic drinks such as tomato juice and fizzy soft drinks  
e. Supplement diet to include foods rich in potassium (e.g., bananas, potatoes, and apricots) , 
evaluate their impact on diarrhea due to the fiber content (e.g., apricots) 


 
 
 
 
 
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APPENDIX V (Continued) 
 
3. Continue with study treatment (i.e. lapatinib-based treatment) 
Continue with supportive care until diarrhea has resolved (diarrhea free for 12 hours/bowel 
pattern return to baseline). Once diarrhea has resolved, the patient can begin to gradually re-
introduce foods from their normal diet.   
 
If diarrhea recurs following stopping of loperamide treatment, resume loperamide treatment at the 
dose and schedule recommended above and re-introduce diet modifications. Continue with study 
treatment.  
 
If grade 1 diarrhea persists for ≥ 2 weeks, refer to the management guidelines for persistent 
grade 2 diarrhea. 
 
II.   CTCAE Grade 2 
NOTE:  Patient should be instructed to call physician at first episode of diarrhea and start 
supportive care immediately 
1. Administer loperamide  
a. Initial dose 4mg followed by 2mg every 4 hours or after every unformed stool. Re-evaluate 
after 24 hours. If: 
i. Diarrhea is resolving, continue loperamide treatment at 2mg dose after every unformed 
stool until diarrhea free (i.e., <Grade 1/bowel patterns returned to baseline) for 12 hours 
 
If diarrhea recurs, re-initiate loperamide treatment as needed to maintain normal bowel 
patterns 
ii. Diarrhea is not resolving, consider loperamide dose of 2mg every 2 hours for 24 hours. If 
Grade 2 diarrhea persists after total of 48 hours of loperamide treatment, start second-line 
agents (octreotide, budesonide or tincture of opium). 
 
Consider performing stool work-up, CBC, electrolytes and other tests as appropriate 
 
2. Dietary modifications which are essential in the management of diarrhea include the following 
recommendations (American Cancer Society; National Cancer Institute):   
a. Stop all lactose containing products and eat small meals 
b. Avoid spicy, fried and fatty foods, bran, raw vegetables and other foods high in fiber 
i. Eat foods low in fiber (i.e., lean meat, rice, skinless chicken or turkey, fish, eggs, canned or 
cooked skinless fruits, cooked/pureed vegetables) 
c. Avoid caffeine and alcohol as they can irritate the bowel and increase motility 
d. Hydration:  Drink 8-10 large glasses of clear liquids a day (e.g., water, electrolyte drink).  
i. 
Avoid acidic drinks such as tomato juice and fizzy soft drinks  
e. Supplement diet to include foods rich in potassium (e.g., bananas, potatoes, and apricots), 
evaluate their impact on diarrhea due to the fiber content (e.g., apricots) 
 
3. Continue with study treatment (i.e., lapatinib-based treatment) 
Continue with supportive care until diarrhea has resolved (diarrhea free for 12 hours/bowel 
pattern return to baseline). Once diarrhea has resolved, the patient can begin to gradually re-
introduce foods from their normal diet.  Refer to Section IV “Recurrent Diarrhea” for study 
treatment guidelines.  
 
If diarrhea recurs following stopping of loperamide treatment, resume loperamide treatment at the 
dose and schedule recommended above and re-introduce diet modifications.   
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX V (Continued) 
 
III. 
Persistent (≥ 3days/72 hours) Grade 2 Diarrhea: hold lapatinib and chemotherapy (if applicable) until 
diarrhea resolves (<Grade 1/return to baseline bowl pattern).  If supportive care measures an 
1. If supportive care measures and the interruption of study treatment (i.e., lapatinib and if 
applicable chemotherapy) are ineffective in treating persistent Grade 1 or Grade 2 diarrhea, 
perform stool work-up, CBC, electrolytes and other tests as appropriate, consider consulting with 
a gastrointestinal (GI) specialist.  
a. After diarrhea resolves (≤Grade 1), resume treatment with lapatinib and chemotherapy (if 
applicable).  
 
IV. 
Recurrent Diarrhea (more than 1 occurrence of Grade 2 diarrhea): once the 2nd occurrence of grade 2 
diarrhea resolves to ≤ grade 1, consider reducing the dose of lapatinib by 250mg or 1 tablet, unless the 
lapatinib dose already had been reduced to 750mg.  No further dose reduction is recommended for 
patients taking lapatinib at 750mg. 
1. Consider a dose reduction for chemotherapy (if applicable) 
B) Complicated Diarrhea 
I. 
CTCAE, v 4 grade 3 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) 
1. Patient must call physician immediately for any complicated severe diarrhea event 
2. If loperamide has not been initiated, initiate loperamide immediately:  Initial dose 4mg followed by 
2mg every 2 hours or after every unformed stool  
3. Refer to the dietary modification recommendations for Grade 1 and Grade 2 uncomplicated diarrhea 
4. For dehydration use intravenous fluids as appropriate, if patient presents with severe dehydration 
administer octreotide 
5. Perform stool work-up, CBC, electrolytes and other tests as appropriate 
6. Administer antibiotics as needed (example fluoroquinolones), especially if diarrhea is persistent 
beyond 24 hours or there is fever or Grade 3-4 neutropenia 
7. Hold lapatinib and chemotherapy (if applicable) until symptoms resolve to ≤Grade 1 and reintroduce 
lapatinib at a reduced dose (unless dose had been reduced to 750mg, contact medical monitor for 
further guidance) 
a. Consider a dose reduction for chemotherapy (if applicable) 
8. Supportive care and other interventions should be continued until diarrhea free (i.e., <Grade 1/bowel 
patterns returned to baseline) for 24 hours 
9. Intervention may require hospitalization for patients most at risk for life threatening complications 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX V (Continued) 
 
II. 
CTCAE v. 4 grade 4  
1. Patient must call physician immediately for any Grade 4 diarrhea event 
2. Discontinue treatment with lapatinib, hold chemotherapy (if applicable) 
3. If loperamide has not been initiated, initiate loperamide immediately:  Initial dose 4mg followed by 
2mg every 2 hours or after every unformed stool 
4. For dehydration use intravenous fluids as appropriate, if patient presents with severe dehydration 
administer octreotide 
5. Perform stool work-up, CBC, electrolyte and other tests as appropriate 
6. Recommend consulting with GI specialist 
7. Administer antibiotics as needed (example fluoroquinolones), especially if diarrhea is persistent 
beyond 24 hours or there is fever or Grade 3/4 neutropenia 
8. Supportive care and other intervention should be continued until diarrhea free (i.e., <Grade 1/bowel 
patterns returned to baseline) for 24 hours 
9. Intervention may require hospitalization for patients most at risk for life threatening complications  
Refer to and follow the recommended supportive care guidelines in the previous sections and as depicted 
in Figure 1 (see next page). 
 


 
 
 
 
 
73 
 
 
RTOG 3501 version date: 9/27/16 
 
Figure 1: Algorithm for the management of diarrhea  
in patients treated with lapatinib-based therapy 
 
1. For Grade 1 diarrhea that persists for 2 weeks or longer, refer to Section III. 
2. For Grade 2 diarrhea that persists longer than 3 days/72 hours, refer to Section III. 
3. For recurrent diarrhea, refer to Section IV for further management guidelines. 
 
RECOMMENDATION 
 Loperamide prescription with instructions on administration for all subjects receiving 
lapatinib 
 Patient diary to record baseline bowel patterns and changes; dietary changes 
EVALUATION 
 Obtain history of onset and duration of diarrhea 
 Describe number of stools and stool composition (Refer to baseline) 
 Assess subject for fever, dizziness, abdominal pain/cramping or weakness 
 Medications (Prescription; OTC; herbal supplements) and dietary profile 
UNCOMPLICATED 
Grade 1 or Grade 2 with no 
complicating signs or symptoms 
ADDED RISK 
FACTORS 
COMPLICATED 
Grade 3 or 4 diarrhea or Grade 1 or 2 
with ≥ 1 of these signs or symptoms: 
• Cramping (moderate/severe) 
• Nausea/vomiting (≥ Grade 2) 
• Decreased performance status 
• Fever 
• Sepsis 
• Neutropenia 
• Frank bleeding 
• Dehydration 
 MANAGEMENT 
• Subjects should be instructed to administer loperamide and notify 
physician 
• Discontinue lactose products  
• Drink 8-10 large glasses of clear liquids per day 
• Eat frequent small meals  
• Eat foods low in fiber  
•
Continue with lapatinib based treatment
Reassess 24 hours later 
Diarrhea Resolving 
• Continue instructions for 
dietary modification 
• Gradually add solid food to 
diet 
• Discontinue standard anti-
diarrheal after 12-hour 
diarrhea-free interval 
• If applicable resume treatment 
Diarrhea Unresolved 
 
Continue  loperamide 
 
Continue dietary 
modifications 
 
Evaluate for  possible 
Reassess 24 hours 
later
Diarrhea unresolved 
 
Continue loperamide (Grade 1) 
 
Start second line anti-diarrheal 
agents (Grade 2) 
 
Start second-line anti-diarrheal 
agents for Grade 1 diarrhea that does 
not improve after 1 week of loperamide 
t
t
t
 MANAGEMENT 
• Subject must call physician immediately 
• Grade 3: hold lapatinib and chemotherapy (if 
applicable) 
• Grade 4:discontinue lapatinib 
• Evaluate for possible infection  
• Consider hospitalization   
SUGGESTED TREATMENT 
• Administer loperamide  
• Hydration (i.v. fluids as needed) 
• Consider need for antibiotics and consider second line 
anti-diarrheals  
Diarrhea Free for 24 hours 
 
Discontinue diarrhea 
intervention 
For Grade 3 
 
Reintroduce lapatinib at a 
reduced dose (if dose was 
>750mg) and chemotherapy (if 
applicable) 
 
Consider dose 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX VI (2/2/16) 
 
PROHIBITED MEDICATIONS 
 
Lapatinib is a substrate for CYP3A4.  Inducers and inhibitors of CYP3A4 may alter the metabolism of lapatinib.  
The following list of CYP3A4 inducers and inhibitors are prohibited from screening through discontinuation from 
study. 
 
 
Drug Class 
Specific Agents 
Wash-out1 
CYP3A4 Inducers 
rifamycin antibiotics 
rifampicin, rifabutin, rifapentine 
 
 
 
 
2 weeks 
anticonvulsants 
phenytoin, carbamezepine, barbiturates (e.g., 
phenobarbital) 
antiretrovirals 
efavirenz, nevirapine, tipranivir, etravirine 
 
glucocortical steroids 
(oral only) 
Note:  Steroids are 
required as an anti-emetic 
for cisplatin.  The short-
term administration of 
steroids for this indication 
poses minimal risk related 
to CYP3A4. 
cortisone (>50 mg), hydrocortisone (>40 mg), 
prednisone 
or 
prednisolone 
(>10 
mg), 
methylprednisolone or triamcinolone (>8 mg), 
betamethasone or dexamethasone (>1.5 
mg)2 
other 
St. John’s Wort, modafinil 
CYP3A4 Inhibitors 
antibiotics 
clarithromycin, erythromycin, troleandomycin, 
flucloxacillin 
 
 
 
 
1 week 
antifungals 
itraconazole, 
ketoconazole, 
fluconazole 
(>150 mg daily), voriconazole 
antiretrovirals 
delaviridine, nelfinavir, amprenavir, ritonavir, 
indinavir, saquinavir, lopinavir, atazanavir 
calcium channel blockers 
verapamil, diltiazem 
antidepressants 
nefazodone, fluvoxamine 
gastrointestinal agents3 
cimetidine 
fruit juices 
grapefruit, star fruit, and papaw 
other 
amiodarone 
6 months 
Miscellaneous 
antacids 
Mylanta, Maalox, Tums, Rennies 
1 hour before and 
after dosing 
herbal supplements4 
ginkgo biloba, kava, grape seed, valerian, 
ginseng, echinacea, evening primrose oil 
2 weeks 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
1. Time period between last dose of listed drug and first dose of lapatinib, required to avoid 
drug-drug interaction potential for toxicity (inhibitors) or loss of efficacy (inducers) that 
could make the patient unevaluable.  Clinically appropriate substitution of drugs not on the 
list is recommended. 
2. A standard 3-5 day course of dexamethasone at a dose following the institutions standard 
of care for the prevention and/or treatment of platinum-induced nausea and vomiting is 
allowed.  Glucocortical steroid oral dose equivalents (in parentheses) to dexamethasone 
1.5 mg (or less) given daily are allowed.  Intravenous dosing should be considered if 
clinically appropriate. 
3. Emetogenic chemotherapy may require 3-4 daily doses of aprepitant.  CYP3A4 inhibition 
by oral (not IV) aprepitant may require a concurrent dose reduction of 1-2 lapatinib tablets. 
4. This list is not all-inclusive; therefore, for herbal supplements not listed, please contact a 
Novartis Medical Monitor or Clinical Scientist. 
NOTE: If future changes are made to the list of prohibited medications, formal documentation 
will be created and stored with the study file.  Any changes will be communicated to the 
investigative sites in the form of a letter. 
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX VII  
 
MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED PATIENTS 
 
Dental Care for Irradiated Patients 
Goals for a dental care program include: 
1. To reduce incidence of bone necrosis. 
2. To reduce incidence of irradiation caries. 
3. To allow proper fitting of dentures following treatment. 
 
Pre-irradiation Care and Procedures 
The patients may be grouped into four groups in accordance with the problems they present prior to irradiation. 
 
Group 1 
Includes edentulous patients.  They may require surgical removal of any symptomatic cysts, infected retained root 
tips, or alveolar hyperplasia.  These patients require hygiene instruction and precautionary instruction about 
trauma with premature use of a prosthesis. 
 
Group 2 
Includes those with poor dental hygiene, including those patients whose teeth are beyond repair by ordinary 
dental procedure, those with generalized oral sepsis, those with generalized periodontal disease, and those with 
chronic periapical abscesses or granulomas. 
 
Procedures performed on this group include removal of all remaining teeth prior to irradiation with primary closure 
and surgical preparation of the alveolar ridges to laterally support a prosthesis.  There should be antibiotic 
coverage during the healing stage and adequate time prior to the start of radiation therapy.  These patients need 
complete hygiene instruction and precautionary instruction about premature use of a prosthesis. 
 
Group 3 
Includes those in whom dental condition is fair, including those patients whose teeth are restored, ordinary dental 
procedures, periodontal pockets are less than 3 mm deep, carious lesions are not in proximity to the pulp, and no 
more than 20 restorable carious lesions are present.  X-ray examinations show at least 1/2 of the bone still 
present around root surfaces.  These patients require removal of any teeth that are non-salvageable in 
accordance with the above and restorations of the remaining teeth as required.  The patients are instructed for 
dental prophylaxis and the patients utilize custom-made fluoride carriers. 
 
Group 4 
Includes those in whom dental hygiene is good.  This includes patients who do not have severe malocclusion in 
whom few carious lesions are present.  Carious lesions are not in close proximity to the pulp and are correctable 
by conventional methods.  These patients require periodontal evaluation and dental prophylaxis training, 
restorations as needed, no extractions prior to radiation therapy, and fitting for custom carriers. 
 
Extraction of Teeth 
If extraction of teeth is necessary prior to radiation therapy, the bone must be contoured so that closure at the 
extraction site is possible.  All loose spicules and sharp projections must be removed.  The approximation of the 
gingival tissue must be such that the closure is neither too loose nor too tight.  At least 10 days are required for 
adequate healing prior to initiation of therapy. 
 
Causative Factors 
The major causative factors appear to be the reduction of the amount of saliva and secondarily, reduced pH in the 
mouth.  This occurs following high dose radiation to the major salivary glands using parallel opposed fields.  The 
decay process usually occurs in the first year following radiation therapy.  It tends to occur more quickly in teeth 
which have a large amount of root cementum exposed to those teeth with large amounts of plaque formation 
present.  Doses of radiation in excess of 20 Gy to salivary tissue place the teeth at risk. 
 


 
 
 
 
 
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RTOG 3501 version date: 9/27/16 
 
APPENDIX VII (Continued) 
Preventive Program 
The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible to the decay 
process.  This is accomplished by a combination of increasing fluoride concentration on the tooth surface and by 
the effect of fluoride on the plaque and flora that are present in the oral cavity.  Adequate results are obtained by:  
1) cleansing the teeth thoroughly, followed by a good home care dental prophylaxis program, 2) construction of  
fluoride carriers, custom-made mouth guards, which provide local application of fluoride solution to the gingiva 
and tooth surfaces.  Fluoride carriers are made individually with the use of casts.  Material used for making a 
mouth guard is "Sta-Guard" plastic used in conjunction with vacutrole unit produced by Jelrus Technical Products, 
Corp., both of which are available through local dental supply.  This material is molded to the cast impression and 
allowed to harden.  A fluoride solution prepared at the M.D. Anderson Hospital is now available from the Emerson 
Laboratories, Inc., Dallas, Texas 75221.  It has been used to coat the plastic carrier for use in the mouth.  The 
patients are instructed to cleanse their teeth prior to placement of the carrier.  It is then worn in place for 5 
minutes each day.  The patients are instructed to rinse their mouths thoroughly following the use of the carrier.  
This will be continued for an indefinite period of time.  Close follow-up is necessary. 
 
Results 
In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 304 patients shows that 
the incidence of necrosis of the jaw was reduced to approximately 21% compared to 37% prior to initiation of the 
study.  Groups 3 and 4 patients randomized with and without fluoride treatment showed reduction in radiation 
carries from 67% to 34% among Group 3 patients, and from 65% to 22% among Group 4 patients. 
 
Failure to Control Decay 
Management of failure to control radiation decay includes silver fillings with continued use of fluoride treatments.  
If the decay process is sufficiently advanced that a filling will no longer stay in place, these teeth are merely 
smoothed so that there will be no sharp, irritating edges.  The mere existence of such a decayed tooth is not 
necessarily reason for extraction, for it must be remembered that extraction could lead to complications such as 
bone necrosis. 
 
Pulp exposure resulting from the decay process can usually be handled by use of antibiotics and/or root-canal 
therapy. 
 
Hypersensitivity of Teeth 
Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished amounts of saliva.  
This has been shown to be reduced in incidence with the fluoride treatments.  Should this problem become 
manifest, increasing the fluoride treatment to 10 to 15 minutes 3 times a day is recommended. 
 
Infections 
Infections occurring in patients under or after radiation therapy are best managed conservatively with good oral 
hygiene, irrigation and flushing procedures, and systemic antibiotics. 
 
Bone Necrosis 
The patients receiving radiation therapy to a high dose to the head and neck region have increased susceptibility 
to bone necrosis for several reasons including:  impairment of normal metabolism, increased susceptibility to 
infection and severely limited repair process.  Bone necrosis occurs most often after dental or oral surgery in 
patients who have been previously radiated.  Conservative management should be tried first, though in more 
aggressive lesions a more radical approach may ultimately be necessary. 
 

ICF_001.pdf: 
RTOG FOUNDATION 
 
 
RTOG 3501 
 
(ClinicalTrials.gov NCT #: 01711658) 
 
 
TRYHARD: A PHASE II, RANDOMIZED, DOUBLE BLIND, PLACEBO-
CONTROLLED STUDY OF LAPATINIB (TYKERB®) FOR NON-HPV 
LOCALLY ADVANCED HEAD AND NECK CANCER WITH 
CONCURRENT CHEMORADIATION 
 
 
Amendment 8:  September 27, 2016 


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
1 
Schulman Use Only: SR#0 
SCHULMAN APPROVED 
IRB #201606280 
Finalized Date: 10/17/2016 
Schulman Version: 1.0 
RTOG FOUNDATION STUDY 3501 
 
TryHard: A Phase II, Randomized, Double Blind, Placebo-Controlled Study  
of Lapatinib (Tykerb®) for Non-HPV Locally Advanced Head and Neck Cancer 
 with Concurrent Chemoradiation 
 
Informed Consent (English Language) 
 
<<PI_FIRST_NAME>> <<PI_LAST_NAME>> 
 
<<PHONE_NUMBER>> 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical 
trial to you.   Clinical trials include only people who choose to take part. Please take 
your time to make your decision about taking part.  You may discuss your decision with 
your friends and family.  You can also discuss it with your health care team.  If you have 
any questions, you can ask your study doctor for more explanation.  
 
You are being asked to take part in this study because you have head and neck cancer. 
 
Why is this study being done? 
 
The combination of radiation and chemotherapy is the standard treatment for head and 
neck cancer. The purpose of this study is to compare the effects, good and/or bad, of 
chemoradiotherapy and lapatinib versus chemoradiotherapy and a non-active tablet (a 
placebo) on you and your head and neck cancer. 
 
Lapatinib was approved in 2007 for use in treatment of breast cancer; however, its use 
for treatment of head and neck cancer is experimental. Lapatinib blocks the action of a 
protein that tells cancer cells to multiply.  
 
The placebo is a tablet that looks the same as lapatinib and is taken like lapatinib, but it 
will have no effect on your cancer. 
How many people will take part in the study? (9/27/16) 
 
About 142 people will take part in this study.  
 
 


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Finalized Date: 10/17/2016 
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What will happen if I take part in this research study? (8/13/15)  
 
For patients with oropharyngeal cancer: Your tumor tissue will be tested for p16, a 
test that shows if the tumor is caused by the Human Papillomavirus (HPV). This tissue 
test is required for this study if your cancer is from the oropharynx. If your tumor is 
caused by HPV, you will not be eligible to take part in this study. 
 
If your cancer was diagnosed by a fine needle aspiration biopsy of a lymph node in your 
neck, it may not be possible to test this sample for p16. If that is the case, a biopsy of 
your tumor may be necessary for p16 testing. The method used and the risks of a tumor 
biopsy will depend upon the size and location of your tumor. Please discuss the risks 
and benefits of tumor biopsy with your doctor. 
  
Eligible participants will be "randomized". Randomization means a computer program will 
choose whether you receive lapatinib or placebo, and neither you nor your study doctor 
can choose or will know which you will receive.  You will have an equal chance of 
receiving lapatinib or placebo. 
 
If you participate in this study, you will receive intensity modulated radiation therapy 
(IMRT). IMRT is a form of radiation in which radiation beams are designed to avoid non-
cancerous parts of your body, such as your salivary glands.  
 
Your doctor also may decide to use a technique called image guided radiation therapy 
(IGRT). The purpose of IGRT is to give radiation treatment more accurately to your tumor 
while decreasing the radiation to normal tissues. Small adjustments in your radiation 
treatment are made each treatment day based on x-ray images taken right before each 
day's treatment to ensure that your radiation treatment is given as accurately as possible.  
 
Week 1: You will take lapatinib or placebo, 6 tablets that you will swallow once a day on 
an empty stomach (either 1 hour before or 1 hour after meals) 7 days/week, for a week. 
These tablets also can be dissolved in liquid and put into a feeding tube. You will not 
receive radiation therapy or chemotherapy during this week. You will be asked to keep a 
record of each dose of lapatinib or placebo you take. 
 
Weeks 2-7: You will receive radiation therapy 6 times a week during 5 of the 6 treatment 
weeks. You will receive the sixth radiation treatment either on Saturday or twice a day on 
Friday of each week. When given twice a day, there will be at least 6 hours between 
radiation treatments. Each treatment may take up to 20 to 25 minutes depending on the 
technique used.  
 
 


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Finalized Date: 10/17/2016 
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You also will receive a chemotherapy drug, cisplatin, through the vein, on days 8 and 29 
(before or after radiation), for a total of 2 treatments. The chemotherapy will take about 
4-6 hours, including administration of medications to prevent nausea and to replace body 
fluids. Your doctor may recommend that you stay in the hospital overnight to receive these 
medications.  
 
You will take lapatinib or placebo, 6 tablets that you will swallow once a day on an empty 
stomach (either 1 hour before or 1 hour after meals) 7 days/week, during radiation 
therapy.  
 
After radiation, you will continue to take lapatinib or placebo, 6 tablets, once a day, 7 
days/week for 3 months. You will be asked to keep a record of each dose of lapatinib or 
placebo you take orally. 
 
Study Plan (1/16/14) 
 
Another way to find out what will happen to you during the study is to read the chart 
below.  Start reading at the top and read down the list, following the lines and arrows.  
 
   
 
 
 
 
                                 
                        
Randomize 
(You will receive lapatinib or placebo) 
 
Lapatinib or Placebo  
 
Week 1: lapatinib or placebo only 
 
Weeks 2-7: lapatinib or placebo and  
Radiation Therapy  
On Days 8 and 29: Cisplatin 
 
Followed by lapatinib or placebo for 3 months 


Sample consent form version: September 27, 2016 
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Before you begin the study: 
 
You will need to have the following exams, tests or procedures to find out if you can be 
in the study.  These exams, tests or procedures are part of regular cancer care and may 
be done even if you do not join the study.  If you have had some of them recently, they 
may not need to be repeated.  This will be up to your study doctor. 
• Physical examination by several doctors and recording of your weight 
• Examination of the back of your throat and voice box (larynx) with a mirror and/or 
a flexible lighted tube inserted through your mouth by an ear, nose and throat 
specialist or by a head and neck surgeon; this examination may be done in an 
office or may need to be done in the hospital under general anesthesia. The 
specialist or surgeon will talk with you about this procedure. 
• Evaluation of your ability to carry out daily activities 
• A CT (Computed Tomography) scan or PET/CT scan of your chest— A CT scan 
is a study using x-rays to look at one part of your body. A PET (Positron 
Emission Tomography) scan is a computerized image that looks at the activity of 
tumor cells in your entire body and that requires injection of a special marker into 
your vein, such as sugar (glucose) combined with a low-dose radioactive 
substance (a tracer). A camera records the tracer’s signal as it travels through 
your body.  
• A CT scan or an MRI (Magnetic Resonance Imaging)  or a PET/CT scan with 
contrast (contrast means that dye is injected into your vein to increase the 
differences between normal and abnormal tissue) of the site of your tumor and 
nodes in your neck — An MRI is imaging using a strong magnetic field to look at 
one part of your body 
• An EKG, a test of your heart function 
• An echocardiogram or MUGA scan — These tests use ultrasound waves 
(ECHO) or a radioactive isotope (MUGA) to make images of the heart chambers, 
valves and surrounding structures.  
• Blood tests (about 2-3 teaspoons of blood will be taken from your vein) 
• For women able to have children, a pregnancy test  
If your study doctor recommends:  
• 
A dental evaluation  
• 
A hearing test 
• 
An evaluation of your ability to chew and swallow 
• 
Placement of a feeding tube to provide food and liquids 
• 
You will be asked about your diet and eating habits. 
• 
A whole body PET /CT scan  
 
During the study: (10/3/13) 
 
If the exams, tests and procedures show that you can be in the study, and you choose 
to take part, then you will need the following tests and procedures.  They are part of 
regular cancer care.  


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Weekly during treatment: 
• A physical examination 
• Evaluation of your ability to carry out daily activities 
• Blood tests (about 2-3 teaspoons of blood will be taken from your vein) 
• Your weight will be recorded 
• Evaluation of any side effects from treatment you may be having 
 
You will need these tests and procedures in follow-up visits: (8/13/15) 
These tests and procedures are being done to see how you and your cancer was 
affected by the treatment you received. These tests and procedures are part of regular 
cancer care. 
 
At 4 weeks from the end of radiation treatment:  
• 
Physical examination by several doctors 
• 
Blood tests (about 2-3 teaspoons of blood will be taken from your vein) 
• 
An echocardiogram or MUGA scan to test your heart function 
• 
Evaluation of any side effects from treatment you may be having 
• 
If your doctor recommends: Examination of the back of your throat and voice box 
(larynx) with a mirror and/or a flexible lighted tube inserted through your mouth by 
an ear, nose and throat specialist or by a head and neck surgeon 
 
At 3 months from the end of treatment:  
• Physical examination by several doctors 
• If your doctor recommends: Examination of the back of your throat and voice box 
(larynx) with a mirror and/or a flexible lighted tube inserted through your mouth by 
an ear, nose and throat specialist or by a head and neck surgeon 
• Your weight will be recorded 
• Evaluation of your ability to carry out daily activities 
• Blood tests (about 2-3 teaspoons of blood will be taken from your vein) 
• A CT scan or an MRI of your tumor and nodes in your neck with contrast (or a 
PET/CT scan if your doctor recommends)  
• Evaluation of any side effects from treatment you may be having 
 
If your cancer is present 3 months from the end of treatment, surgery may be 
necessary. 
 
At  9 months from the end of treatment: You will have the same tests and procedures as 
at 3 months from the end of treatment (above), except the CT scan or MRI. 
 
At 6 and 12 months from the end of treatment: You will have the same tests and 
procedures as at 3 months from the end of treatment (above), with the addition of a CT 
scan of your chest. 
 
 


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Finalized Date: 10/17/2016 
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Once a year until year 5: A CT scan of your chest and a CT scan or MRI with contrast of 
your head and nodes in your neck 
 
Every 3 months for year 2, every 6 months for years 3-5, then yearly 
• 
Physical examination by several doctors 
• 
If your doctor recommends: Examination of the back of your throat and voice box 
(larynx) with a mirror and/or a flexible lighted tube inserted through your mouth by 
an ear, nose and throat specialist or by a head and neck surgeon 
• 
Your weight will be recorded 
• 
Evaluation of your ability to carry out daily activities 
• 
Evaluation of any side effects from treatment you may be having 
 
How long will I be in the study? (1/16/14) 
 
You will receive lapatinib or placebo, radiation therapy, and cisplatin for 7 weeks. After 
treatment, you will take lapatinib or placebo for 3 months.  
 
After you are finished 7 weeks of treatment, the study doctor will ask you to visit the 
office for follow-up exams at the following time points from the end of treatment: 4  
weeks, every 3 months for years 1 and 2, every 6 months for years 3, 4, and 5, and 
then yearly for your lifetime. 
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the treatment can be evaluated by him/her.  Another reason to tell your study doctor that 
you are thinking about stopping is to discuss what follow-up care and testing could be 
most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she 
believes it is in your best interest; if you do not follow the study rules; or if the study is 
stopped. 
 
What side effects or risks can I expect from being in the study? (8/13/15) 
 
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, researchers don’t know all the side 
effects that may happen.  Side effects may be mild or very serious. Your health care 
team may give you medicines to help lessen side effects. Many side effects go away 
soon after you stop treatment. In some cases, side effects can be serious, long lasting, 
or may never go away. There also is a risk of death.  


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Finalized Date: 10/17/2016 
Schulman Version: 1.0 
You should talk to your study doctor about any side effects that you have while 
taking part in the study.    
 
Risks and side effects related to the head and neck radiotherapy include those 
which are: 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving head and neck radiation, more than 20 and up to 100 may 
have: 
• Sores in the mouth and throat which may be painful especially with swallowing 
• Dry mouth, changes in taste, reduced sense of smell—may be permanent 
• Thick saliva 
• Hoarseness 
• Skin changes that may be permanent, swelling and redness of the skin in the 
area of radiation 
• Pain or pressure in the ear 
• Tiredness 
• Weight loss 
• Permanent hair loss in the area of radiation (face, chin, neck) 
• Cavities, tooth decay; loss of teeth; tooth sensitivity 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving head and neck radiation, from 4 to 20 may have: 
• Decrease in function of the thyroid gland that may require you to take thyroid 
replacement medicine  
• Damage to the nerves of the shoulder and arm which may cause decreased 
movement and feeling 
• Ear infection 
• Hearing loss  
• Difficulty swallowing which may require a long term or permanent feeding tube 
 
 
RARE, AND SERIOUS 
In 100 people receiving head and neck radiation, 3 or fewer may have: 
• Breathing and swallowing problems that may require a surgical procedure to 
create an opening through the neck into the windpipe 
• Damage to the nerves in the head and neck that control sensation, expression, 
or other motor functions 
• Damage to the jawbone which may cause jaw pain and loosening of teeth  
• Damage to the voice box or nerves to the voice box which may cause 
hoarseness, shortness of breath, inability to speak 


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Finalized Date: 10/17/2016 
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RARE, AND SERIOUS 
In 100 people receiving head and neck radiation, 3 or fewer may have: 
• Damage to the skin, soft tissues, or other parts of the head and neck that may 
require a major operation to correct and, rarely, can be life threatening  
• Damage to the spinal cord which may cause permanent weakness  
 
Use of image guided radiation therapy (IGRT) to give radiation treatment more accurately 
to your tumor while decreasing the radiation to normal tissues may lead to improved 
accuracy of radiation treatment compared to regular radiation therapy and eventually, 
may be more useful against cancer. At this time, however, there is no proof that using this 
technique is more useful against cancer than regular radiation treatment without this 
technique. The dose from these x-ray images is much smaller than the dose used to treat 
your cancer. However, this dose will cover a somewhat larger region and can spill over 
to healthy tissues and organs that are not affected by your disease.  There is a small risk 
that the dose from these x-ray images can be harmful, and every effort will be made to 
minimize this dose to healthy tissues. In this effort, it is important that we have your full 
cooperation in maintaining your position during treatment. In order to help you stay in 
position, your doctor will use a special device, sometimes called an immobilization mask. 
The mask is plastic mesh formed to the head and shoulder area to help stabilize your 
position during treatment 
 
Risks and side effects related to Lapatinib: (3/22/16) 
 
Like all medicines, lapatinib can cause side effects, although not everybody gets them.  
As of December 2010, lapatinib has been given to over 19,600 patients in clinical trials 
and its benefits have been proved in some circumstances, but further studies are 
underway to prove its benefits in other circumstances.  Not all the side effects of lapatinib 
are known.  You should notify any other healthcare providers you are seeing that you are 
participating in this study, especially if you are about to undergo surgery, dental treatment, 
or any other drug treatment.  You should not donate blood while participating in this study. 
 
Some patients have died while receiving lapatinib. All of these patients suffered from 
cancer and its complications.  It is not known whether lapatinib may have contributed to 
some of the deaths in these patients with cancer and other medical conditions. 
 
 


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Finalized Date: 10/17/2016 
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The following side effects have been seen in cancer patients and healthy volunteers 
who have taken lapatinib: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving lapatinib, more than 20 and up to 100 may have: 
• Diarrhea 
• Rash 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving lapatinib, from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Bloating, heartburn, passing gas, nausea, vomiting 
• Pain 
• Sores in mouth which may cause difficulty swallowing 
• Tiredness 
• Flu-like symptoms including fever, chills, body aches, muscle pain 
• Infection 
• Loss of appetite, dehydration 
• Changes in taste 
• Headache 
• Cough, sore throat 
• Nose bleed 
• Hair loss, itching, acne 
• Dry skin 
• Change in or loss of some or all of the finger or toenails 
• Flushing, hot flashes 
 
 
RARE, AND SERIOUS 
In 100 people receiving lapatinib, 3 or fewer may have: 
• Heart failure which may cause shortness of breath, swelling of ankles, and 
tiredness 
• Liver damage which may cause yellowing of eyes and skin, swelling 
• Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath,  swelling of the face or throat 
• Change in heart function 
• Change in the heart rhythm 
• Swelling of the lungs which may cause shortness of breath 
• Redness, pain or peeling of palms and soles 
• Severe skin rash with blisters and peeling which can involve mouth and 
other parts of the body 


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Risks and side effects related to cisplatin (8/13/15) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, more than 20 and up to 100 may have: 
• Nausea, vomiting,  
• Infection, especially when white blood cell count is low 
• Anemia which may cause tiredness, or may require blood transfusions 
• Bruising, bleeding 
• Kidney damage which may cause swelling, may require dialysis 
• Hearing loss including ringing in ears 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, from 4 to 20 may have: 
• Hair loss 
• Change in taste 
• Diarrhea  
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
• Confusion 
• Difficulty with balance 
• Numbness and tingling of the arms and legs 
• Blurred vision or changes in ability to see colors (especially blue or yellow) 
 
RARE, AND SERIOUS 
In 100 people receiving Cisplatin, 3 or fewer may have: 
• Cancer of bone marrow caused by chemotherapy later in life 
• Seizure 
 
 
Reproductive risks:   
 
The manufacturer of lapatinib has identified a chemical present in lapatinib in very small 
quantities that can cause changes to genes (DNA).  However, many cancer drugs have 
the potential to damage genes including drugs that are being given with lapatinib in this 
trial and/or those you may have previously received in your cancer treatments or might 
receive as alternate treatment. The benefits of these drugs are believed to be greater 
than their risks in patients with cancer. While the risk of harm to you from this chemical 
in lapatinib is thought to be low, the risk to an unborn baby, while unknown, may be 
higher.   
 
 


Sample consent form version: September 27, 2016 
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You should not become pregnant or father a baby while on this study because the drugs 
as well as the radiation therapy in this study can affect an unborn baby. If you are a 
woman of child-bearing potential and choose to participate in this study, part of the blood 
sample taken in the screening process will be used for a pregnancy test. Women should 
not breastfeed a baby while on this study. You will also be asked to use one of the allowed 
contraceptive methods (a way to prevent you from becoming pregnant) from 2 weeks 
before your first study treatment until 60 days after your final study treatment.  Ask your 
study doctor about the choices available and which might be best for you. 
 
Even when you use one of the allowed contraceptive methods, there may be a small risk 
that a woman  of child-bearing potential could become pregnant. If you become pregnant, 
you must tell your study doctor immediately so that he/she may discuss with you the 
possibility of stopping treatment.  Your doctor will need to report this information and the 
outcome of your pregnancy to the manufacturer of lapatinib. The chemotherapy used in 
the study may make you unable to have children in the future.  
 
Risks and side effects related to Radiological Tests 
 
Some of the tests that will be performed (MUGA scans, X-rays, CT scans, and/or bone 
scans) will expose you to controlled amounts of radiation.  The MUGA scan and CT scans 
will involve dyes being injected into one of your veins.  There is a risk of allergic reaction 
to the dye. This reaction may be mild (such as a skin rash or hives) to severe (such as 
breathing difficulties and shock). There also is a risk that the injection of dyes or collection 
of blood samples may cause pain, swelling, bruising, irritation or redness at the site, 
infection at the site of the needle puncture, or feeling faint.  Your study doctor will take 
steps to prevent this from happening, and may recommend medications that may help 
with these particular side effects. 
 
It is very important that you report any side effects to your study doctor as soon as 
possible; you should not wait until your next scheduled visit. 
 
Risks and side effects related to a biopsy 
 
A biopsy is a procedure to remove a small piece of tumor tissue. A numbing medicine 
(also called local anesthetic) is given under the skin and a needle inserted to remove 
tumor tissue or cells. You may feel some pain or irritation where the biopsy needle is put 
in. There is a chance for bruising or bleeding and a slight risk for infection where the 
needle goes into the skin. Your doctor will explain the risks of the biopsy procedure to you 
and answer any questions you may have. 
 
 


Sample consent form version: September 27, 2016 
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For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better.  While researchers 
hope that adding lapatinib to radiation therapy and chemotherapy will be more effective 
in keeping your head and neck cancer from growing as the standard treatment of radiation 
therapy and chemotherapy, there is no proof of this yet. We do know that the information 
from this study will help doctors learn more about these therapies as a treatment for head 
and neck cancer. This information could help future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting no treatment 
 
Talk to your study doctor about your choices before you decide if you will take 
part in this study. 
 
Will my medical information be kept private? (3/22/16) 
 
Data are housed at RTOG Headquarters in a password-protected database.  We will do 
our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Your personal information may 
be given out if required by law.  If information from this study is published or presented 
at scientific meetings, your name and other personal information will not be used.  
 
 
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: 
• RTOG® Foundation, Inc. (RTOG)   
• Novartis, supplier  of the lapatinib and the placebo 
• Biologics, Inc., distributor of lapatinib and the placebo 
• The Institutional Review Boards (IRB) associated with this study. The IRBs are 
groups of people who review the research with the goal of protecting the people 
who take part in the study. 
• The Food and Drug Administration (FDA) and other government agencies, such 
as the Office of Human Research Protections (OHRP),  involved in keeping 
clinical research safe for patients and/or government agencies in other countries 
where the study drug may be considered for approval. 
 
 


Sample consent form version: September 27, 2016 
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What are the costs of taking part in this study? (2/2/16) 
 
Novartis will provide lapatinib and placebo free of charge to patients enrolled on this 
study. 
 
You and/or your health plan/ insurance company will need to pay for some or all of the 
costs of treating your cancer in this study.  Some health plans will not pay these costs 
for people taking part in studies.  Check with your health plan or insurance company to 
find out what they will pay for.  Taking part in this study may or may not cost your 
insurance company more than the cost of getting regular cancer treatment.  
 
You will not be paid for taking part in this study. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s 
name(s)], if you feel that you have been injured because of taking part in this study.  
You can tell the study doctor in person or call him/her at __________________ 
[telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  
You and/or your health plan will be charged for this treatment.   The study will not pay 
for medical treatment.   
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to 
take part in the study.  If you decide to take part in this study, you may leave the study 
at any time.   No matter what decision you make, there will be no penalty to you and you 
will not lose any of your regular benefits.  Leaving the study will not affect your medical 
care.  You can still get your medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study. 
 
A Data Monitoring Committee (DMC) will be regularly meeting to monitor safety and 
other data related to this study. The Committee members may receive confidential 
patient information, but they will not receive your name or other information that would 
allow them to identify you by name. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form.   
 
 


Sample consent form version: September 27, 2016 
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Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have 
about this study.  Contact your study doctor __________________ [name(s)] at 
__________________ [telephone number]. 
 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group 
of people who review the research to protect your rights) at __________________ 
(telephone number).  [Note to Local Investigator: Contact information for patient 
representatives or other individuals in a local institution who are not on the IRB or 
research team but take calls regarding clinical trial questions can be listed here.]    
 
Please note:  This section of the informed consent form is about additional 
research that is being done with people who are taking part in the main study.   
You may take part in this additional research if you want to.  You can still be a 
part of the main study even if you say ‘no’ to taking part in this additional 
research. 
 
You can say “yes” or “no” to each of] the following studies.  Below, please mark 
your choice for each study.   
 
Quality of Life Study 
 
We want to know your view of how your life has been affected by cancer and its 
treatment. This “Quality of life” study looks at how you are feeling physically and 
emotionally during your cancer treatment. It also looks at how you are able to carry out 
your day-to-day activities. 
 
This information will help doctors better understand how patients feel during treatments 
and what effects the medicines are having.  In the future, this information may help 
patients and doctors as they decide which medicines to use to treat cancer. 
 
You will be asked to complete 2 questionnaires and to answer some questions about 
your eating, diet, and speech at the following time points: on your first visit and at 3, 12, 
and 24 months after treatment.  It takes about 5-10 minutes to fill out each 
questionnaire and about 5 minutes to answer the questions.  
 
 If any questions make you feel uncomfortable, you may skip those questions and not 
give an answer. 
 
 


Sample consent form version: September 27, 2016 
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If you decide to take part in this study, the only thing you will be asked to do is fill out the 
2 questionnaires and answer the questions.  You may change your mind about 
completing the questionnaires at any time. 
 
Just like in the main study, we will do our best to make sure that your personal information will 
be kept private. 
 
Please circle your answer. 
 
I choose to take part in the Quality of Life Study.  I agree to fill out the Quality of Life 
Questionnaires. 
 
 
YES  
 
 
 
NO 
 
Consent Form for Use of Tissue and Blood for Research 
 
About Using Tissue and Blood for Research  
 
You are going to have a biopsy (or surgery) to see if you have cancer. Your doctor will 
remove some body tissue to do some tests. The results of these tests will be given to 
you by your doctor and will be used to plan your care.  
 
We would like to keep some of the tissue that is left over for future research. In addition 
to the tumor tissue, we would like to collect 2-3 teaspoons of your blood. Blood for 
research will be collected 3 times: before treatment, at the end of radiation therapy, and 
at 6 months after the end of treatment. Blood for research will be collected  at the same 
time your blood is collected for other tests required in the main part of this study. 
 
If you agree, the tissue and blood will be kept and may be used in research to learn 
more about cancer and other diseases.  
 
Your tissue and blood may be helpful for research whether you do or do not have 
cancer. The research that may be done with your tissue and blood is not designed 
specifically to help you. It might help people who have cancer and other diseases in the 
future.  
 
Reports about research done with your tissue and blood will not be given to you or your 
doctor. These reports will not be put in your health record. The research will not have an 
effect on your care.  
 
 


Sample consent form version: September 27, 2016 
To be attached to protocol version: September 27, 2016 
 
 
 
 
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Things to Think About  
 
The choice to let us keep the left over tissue and blood for future research is up to you. 
No matter what you decide to do, it will not affect your care or your participation in the 
main part of the study.  
 
If you decide now that your tissue and blood can be kept for research, you can change 
your mind at any time. Just contact us and let us know that you do not want us to use 
your tissue and blood. Then any tissue and blood that remains will no longer be used for 
research and will be returned to the institution that submitted it.  
 
In the future, people who do research may need to know more about your health. While 
the doctor/institution may give them reports about your health, it will not give them your 
name, address, phone number, or any other information that will let the researchers 
know who you are.  
 
Sometimes tissue and/or blood is used for genetic research (about diseases that are 
passed on in families). Even if your tissue and/or blood is used for this kind of research, 
the results will not be put in your health records.  
Your tissue and blood will be used only for research and will not be sold. The research 
done with your tissue and blood may help to develop new treatments for cancer in the 
future.  
 
 
Benefits  
 
 
The benefits of research using tissue and blood include learning more about what 
causes cancer and other diseases, how to prevent them, and how to treat them.  
 
Risks (10/3/13) 
 
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
 
Some of your genetic and health information may be placed in central databases that may be 
public, along with information from many other people. Information that could directly identify 
you will not be included. The samples are given a code to protect your privacy before they are 
used. Any related information given to researchers will also be coded.  Researchers will 
receive the code instead of any information that might directly identify you. 
 
 


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There can be a risk in knowing genetic information.  New health information about inherited 
traits that might affect you or your blood relatives could be found during a research study. Even 
though your genes are unique, you share some of the same genes with your blood relatives.   
Although we are not able to know all of the risks from taking part in research on inherited traits, 
we believe that the risks to you and your family are very low, because your samples will be 
coded. Research results will not be returned to you or your doctor. 
 
Very rarely health or genetic information could be misused by employers, insurance 
companies, and others. For example, life insurance companies may charge a higher rate 
based on this information.  
 
Some states have laws to protect against genetic discrimination [list appropriate state 
information if your state has such laws]. A federal law called the Genetic Information Non-
Discrimination Act, or GINA is in effect.  This law does not allow discrimination by insurers or 
employers.  The law does not include other types of misuse by life insurance, disability, or long 
term care insurance. To learn more about the GINA Law, please ask [Note to local 
investigator: List contact information here for patient representatives or other individuals who 
take calls regarding clinical trials but who are not on the site IRB or research team.]   
 
 


Sample consent form version: September 27, 2016 
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Making Your Choice  
Please read each sentence below and think about your choice. After reading each 
sentence, circle "Yes" or "No". If you have any questions, please talk to your doctor or 
nurse, or call our research review board at __________________________ [IRB's 
phone number].  
No matter what you decide to do, it will not affect your care. 
1. My specimens may be kept for use in research to learn about, prevent,  or treat  
cancer, as follows: 
• Tissue Yes  No 
• Blood Yes  No 
 
2. My specimens may be kept for use in research to learn about, prevent or treat 
other health problems (for example: diabetes, Alzheimer's disease, or heart 
disease), as follows:  
• Tissue Yes  No 
• Blood Yes  No 
 
3. Someone may contact me in the future to ask me to take part in more research.  
                    Yes 
 No 
 
You will get a copy of this form.    If you want more information about this study, 
ask your study doctor. 
 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this 
form.  I have read it or it has been read to me.  I understand the information and 
have had my questions answered.  I agree to take part in this study. 
 
Participant ________________________________ 
Date _____________________________________