rtog foundation
untitled h2

RTOG 3501
(ClinicalTrials.gov NCT \#: *01711658)*
TRYHARD: A PHASE II, RANDOMIZED, DOUBLE BLIND, PLACEBOCONTROLLED 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
rtog foundation study 3501 tryhard
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
tryhard a phase ii randomized
limited participation study

| RTOG Headquarters Contact Information (9/27/16)                                                                                                                                  |                                                                 |                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|--------------------|
| Data Managers:                                                                                                                                                                   | Vanita Patel, 215-574-3170, vpatel@acr.org                      |                    |
| For questions concerning eligibility or data submission                                                                                                                          | or                                                              |                    |
| Janelle Robinson, 215-717-0837, jrobinson@acr.org                                                                                                                                |                                                                 |                    |
| ACR Core Laboratory/RTQA:                                                                                                                                                        | Nancy Linnemann, 215-717-0853,                                  |                    |
| For questions concerning RT data submission                                                                                                                                      | nlinnemann@acr.org Marsha Radden, 215-717-2757, mradden@acr.org |                    |
| ACR Core Laboratory/RTQA:                                                                                                                                                        | Triad-Support@acr.org                                           |                    |
| For questions concerning data submission to Triad 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:                                                                                                                                                  | Sharon Hartson Stine, shartson@acr.org                          |                    |
| For questions concerning contracts and reimbursement 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                                                                                                                           | 215-459-3576                                                    |                    |
| holidays                                                                                                                                                                         | 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    |  
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
rtog foundation study 3501
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  
| 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 |               |         |              |                               |                                           |  
*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
rtog foundation study 3501
institution # rtog foundation 3501

(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) 17. Will the patient be compliant with treatment plan and follow-up schedule?
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continued on next page

|            | (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) 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) 12. Is the patient ≥ 18 years of age?
rtog foundation study 3501
institution # rtog foundation 3501

__ (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 nonhypopharynx 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?
rtog foundation study 3501
the following questions will be

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?   |
|----------|----------------------------------------------------------------|
| 5.       | Patient's Initials (First Middle Last)                         |  
4. Date informed consent signed  
6. Verifying Physician 7. Patient ID
institution # rtog foundation 3501
the following questions will be

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?   |                                                                                                                                                                                                       |
|-------|------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (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?"                                                                                                                               |  
16. Calendar Base Date  
17. Randomization date  
18. Medical Oncologist's name  
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
institution # rtog foundation 3501
the following questions will be

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) (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  
| 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?   |
|-------------|-------------------------------------------------------------------|
institution # rtog foundation 3501
institution # rtog foundation 3501

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. ElNaggar's lab)?
_______________ 10. Patient height  
 _______________ 11. Patient weight _______________ 12. BSA
1.0 INTRODUCTION
institution # rtog foundation 3501
1.1 treatment of locally advanced

Cancer Society 2010) The majority of these patients present with locally advanced, nonmetastatic 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, premalignant 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 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.
institution # rtog foundation 3501
1.2 importance of a non-hpv-specific

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 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 radiationcisplatin regimen will enhance the cytotoxic effect, resulting in an improvement of PFS in highrisk (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).  
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).
institution # rtog foundation 3501
1.5 quality of life and

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 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 nonclastogenic.  
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, premalignant 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 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 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. |  
| 3.1     | 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;                                                                                                                                                                                                                                       |  
16 RTOG 3501 version date: 9/27/16  
| 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:                                                                                                                                                                                                                                                    |                                 |
|         | 17                                                                                                                                                                                                                                                                                                  | RTOG 3501 version date: 9/27/16 |  
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.
institution # rtog foundation 3501
4.0 pretreatment evaluations/management note this

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
institution # rtog foundation 3501
5.0 registration procedures (8/13/15) note

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.
institution # rtog foundation 3501
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;  
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.
institution # rtog foundation 3501
5.2 pre-registration requirement central pathology

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.)
institution # rtog foundation 3501
5.3 registration (9/27/16) 5.3.1 summary

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 ElNaggar for HPV analysis. The results of the HPV analysis are expected in approximately 710 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.  
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.
institution # rtog foundation 3501
6.0 radiation therapy note all

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.  
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.  
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.
institution # rtog foundation 3501
6.2 technical factors 6.2.1 treatment

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; 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.  
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, reimaging 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 kVsystems. 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.
institution # rtog foundation 3501
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 suprasternal 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.  
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                                                     |
|               | CTV-PTV 5mm margin without IGRT; 3mm with                                     |
| PTV_7000      | daily IGRT Required                                                           |
| CTV_5600      | CTV 7000 + 1cm margin and nodal regions Required when applicable              |
|               | CTV-PTV 5mm margin without IGRT; 3mm with                                     |
| PTV_5600      | 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                 |
|               | CTV-PTV 5mm margin without IGRT;3mm with                                      |
| PTV_5950      | 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 Planning Risk Volume of 5mm                              |
| SpinalCord_05 | Required                                                                      |
| BrainStem     | Brain Stem Required Planning Risk Volume of 5mm                               |
| BrainStem_05  | Required                                                                      |
| Parotid_L     | Left Parotid Required                                                         |
| Parotid_R     | Right Parotid Required                                                        |
| OralCavity    | Oral Cavity Required                                                          |
| Lips          | Lips Required                                                                 |
| Mandible      | Mandible Required                                                             |
|               | Uninvolved posterior pharyngeal wall plus                                     |
| Pharynx       | adjacent constrictor muscles Required Cervical Esophagus                      |
| Esophagus_Up  | Required                                                                      |
| LarynxGSL     | Glottic/Supraglottic (GSL) Required                                           |  
| 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 Minimum dose(cold spot within PTV_7000 not |
| PTV_7000_m08     | 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  
| 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                                                                                                                                                                                                                                                                                                                                                                                                      |  
| 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                                                                                            |                       |
institution # rtog foundation 3501
6.6 documentation requirements for imrt

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.
institution # rtog foundation 3501
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.  
| Per Protocol                                                                                                                                                                              | Variation            | Deviation                                                           |                                                                     |        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|---------------------------------------------------------------------|---------------------------------------------------------------------|--------|
| Acceptable                                                                                                                                                                                | Unacceptable         |                                                                     |                                                                     |        |
| Total RT dose to PTV_7000 (to 95%                                                                                                                                                         | 70 Gy                | 66.5Gy - 73.5Gy                                                     | Outside range of                                                    |        |
| of the PTV)                                                                                                                                                                               | Variation Acceptable |                                                                     |                                                                     |        |
| < 66.5 but > 63 Gy                                                                                                                                                                        | ≤ 63 Gy              |                                                                     |                                                                     |        |
| 66.5 Gy (equals 95% of  prescribed dose)                                                                                                                                                  |                      |                                                                     |                                                                     |        |
| 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) Maximum dose ("hot spot" > 1cc) | ≤ 77 Gy              | > 77 but ≤ 82 Gy                                                    | > 82 Gy                                                             |        |
| within PTV_7000 NonPTV Maximum dose ("hot spot" > 1cc                                                                                                                                     | < 74 Gy              | 74-77 Gy                                                            | > 77 Gy                                                             |        |
| outside the PTVs)  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                                                                                                                                                         | 56 Gy                | < 50.4 Gy                                                           |                                                                     |        |
| the PTV)                                                                                                                                                                                  | <56 Gy but >50.4 Gy  |                                                                     |                                                                     |        |
| ≤ 50 Gy                                                                                                                                                                                   | ≥ 50 but ≤ 52 Gy     | > 52 Gy                                                             |                                                                     |        |
| Total RT dose to SpinalCord_05  (0.03 cc) Total RT dose to BrainStem_05                                                                                                                   |                      | ≤ 52 Gy                                                             | >52Gy but ≤54 Gy                                                    | >54 Gy |
| (0.03cc) 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                                                                                                                                                         | 0-2                  | 2-4                                                                 | > 4                                                                 |        |
| Interruptions                                                                                                                                                                             |                      |                                                                     |                                                                     |        |  
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                              |  
| 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).
institution # rtog foundation 3501
7.0 drug therapy institutional participation

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 215459-3576.
institution # rtog foundation 3501
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 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 prehydration 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 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;    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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |  
| 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.  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. StevensJohnson's Syndrome etc) lapatinib must be permanently discontinued. See Section 7.7.4 for  management guidelines.  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 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 | Order received |
| by Biologics                   | at site                       |                                                 |               |                |
| Monday                         | Monday                        | Monday by 2PM                                   | Monday        | Tuesday        |
| ET                             |                               |                                                 |               |                |
| 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               | Monday                        | Tuesday                                         |               |                |
| ET                             |                               |                                                 |               |                |  
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:
institution # rtog foundation 3501
elliott lee program manager biologics

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).
institution # rtog foundation 3501
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* |  
> 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.  
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                                                                                                                      | Continue lapatinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | therapy at full dose prescribed. |      |           |     |
| (Not attributable to cisplatin or radiation)                                                                                                         | 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                                                                                                                      | Apply maximum supportive care recommendations.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                  |      |           |     |
| (Not attributable to cisplatin or radiation)                                                                                                         | 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*                                                                                                                                             | 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                  |      |           |     |
| *Severity                                                                                                                                            | corresponding                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | to                               | NYHA | criteria; | see |
| Appendix II.                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                  |      |           |     |  
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.  
| 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.
institution # rtog foundation 3501
7.7 management of lapatinib/placebo adverse

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; 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, 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.
institution # rtog foundation 3501
7.9 adverse events (3/22/17) all

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).  
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).
institution # rtog foundation 3501
note if the event is

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.