Phase I/II Clinical Trial of Combined Pre-Irradiation With Pemetrexed and Erlotinib Followed by Maintenance Erlotinib for Recurrent and Second Primary Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE1
Conditions: Head and Neck Cancer
Sponsor: Wake Forest University Health Sciences

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 1 
Attn: Please replace the RECIST criteria in the appendix with the newer version.  
 
Study Drug(s):  
Erlotinib (Tarceva tablets) Investigational Supplied by: OSI Pharmaceuticals, Inc. 
Pemetrexed (Alimta) 
 Investigational Supplied by: Eli Lilly 
 
Study Title: Phase I/II Clinical Trial Of Combined Re-irradiation With 
Pemetrexed  And Erlotinib Followed by Maintenance Erlotinib For Recurrent 
And Second Primary Squamous Cell Carcinoma of the Head and Neck 
 
 
Principal Investigator 
 
 
 
 
Co-Principal Investigator 
 
Mercedes Porosnicu, M.D.  
 
 
 
Kathryn Greven, M.D. 
Wake Forest University Baptist Medical Center  
Radiation Oncology 
Section Hematology and Oncology                               Phone: (336) 713-6560 
Medical Center Blvd.                                                     kgreven@wakehealth.edu 
Winston-Salem, NC 27157                                       
Phone: (336) 716-0230 
 
 
 
 
Bhisham Chera, M.D.                                    
Fax: (336) 716-5687 
 
 
 
 
Radiation Oncology (UNC) 
 mporosni@wakehealth.edu                                          Phone: (919) 966-7700       
bchera@med.unc.edu 
Co-Investigators: 
 
Department of Otolaryngology                           
J. Dale Browne, M.D.                                         
 Susan Butler, Ph.D  
Phone: (336) 716-3648                                       
Phone: (336) 716-7272                                  
                                  
Robin Rouchard-Plasser, PA 
Head and Neck Coordinator 
Phone: (336) 716-3850 
 
Section of Hematology and Oncology                 
Public Health Sciences                                  
Gregory Kucera, Ph.D                                         
Ann Geiger, Ph.D..                                        
Phone: (336) 716-6348                                        
Phone: (336) 716-0382 
 
 
 
 
 
 
Biostatistician                                                      
 Molecular Medicine Lab 
Ralph B. D’Agostino, Jr., Ph.D.                            
Christina Furdui, Ph.D  
Phone: (336) 716-9011                                        
Allen Tsang, Ph.D 
Fax: (336) 716-4128                                            
Phone: (336) 716-2697 
 
Protocol Editor                                                     
 
Audrey Bell-Farrow, M.B.A., M.H.A.                     
. 
Phone: (336) 713-6910                                        
 
abellfa@wakehealth.edu 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 2 
 
 
 
Research Nurse                                                    
Regulatory Contact 
Thomas Freeman, II, PA-C                                  
 Megan Brown 
Phone: (336)-713-6914                                                   Phone: (336)-713-6913   
Fax: (336) 713-6772                                              
 Fax: (336) 713-6773 
thfreema@wakehealth.edu  
 
 
 
mebrown@wakehealth.edu 
 
Tissue Procurement Officer 
 
 
 
Clinical Nutrition 
Libby McWilliams 
 
 
 
 
 
Wendy Watson 
Phone:(336)-716-5355 
 
 
 
  
Phone: (336)-713-6919 
Fax: (336)713-6959  
 
 
 
 
  
 
 
 
 
 
 
 
   
Data Coordinator                                                  
Data Assistant 
Claire Kimbrough                                                  
Violet Holladay 
Phone: (336)-713-6920                                         
Phone: (336) 716-7351 
Fax: (336)713-6772 
ckimbro@wakehealth.edu 
 
Drug Monitor  
 
Budget & Contract 
Sharon McFadden  
 
 
 
 
Karen Craver, MT, MHA 
Phone: (336) 713-6931 
 
 
 
 
Phone: (336) 713-4394 
Fax: (336) 713-6772 
 
 
 
 
Fax: (336) 716-5687 
smcfadde@wakehealth.edu 
 
 
           kcraver@wakehealth.edu 
 
Participating Institutions :   
 
Comprehensive Cancer Center of Wake Forest University 
 
 
UNC Lineberger Comprehensive Cancer Center 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 3 
PROTOCOL SYNOPSIS 
 
Phase I/II clinical trial. Patients with recurrent HNSCC or second primary will 
receive re-irradiation and the radiosensitizing drugs Pemetrexed and Erlotinib 
beginning with the first day of RT. Erlotinib dose will be escalated during the 
Phase I portion of the study. Maintenance Erlotinib will be continued until disease 
progression, unacceptable toxicity or to a maximum of 2 years. No randomization 
 
Primary Objective: Phase I: Find MTD for Erlotinib recommended for phase II.  
                                 Phase II: Determine Progression Free Survival at 1 year. 
 
                                                     SCHEMA 
 
 
 
RE-IRRADIATION - IMRT - 6 WEEKS 
 
30 daily fractions that deliver 2.0 Gy  to areas of gross disease (6000 cGy 
total) and 1.8 Gy to the areas felt to be at highest risk of occult involvement 
(5400 cGy). 
                    
                                 + 
  
                                                                          
 
 
                                  
                                                                          
                                  + 
 
 
 
 
 
 
 
 
 
 
 
*Patients will receive premedication as follows: 1. folic acid 350-1000 µg/day starting 5-7 days 
before the first dose of pemetrexed and continued for 3 weeks after the last dose of pemetrexed; 
2. vitamin B12 1000 mcg 1 dose i.m. 1 week before the first dose of pemetrexed; 3. 
dexamethasone 4 mg po bid, days -1, 0 and 1 of each pemetrexed treatment. 
 
**Actively smoking is defined as smoking an average of at least 10 cigarettes daily and smoking 
for at least one year.   
Not actively smoking is defined as either not smoking, smoking an average of less than 10 
cigarettes daily, or smoking for less than 1 year prior to enrollment. 
 
 
Maintenance Erlotinib 
         for 2 years 
 
 
Erlotinib dosed according to 
smoking status at the time of 
maintenance treatment: 
    
**Not actively smoking: 150 mg 
daily 
 
**Actively smoking: 300 mg daily 
 
 
Start : day 1 of  re-irradiation 
 
*Pemetrexed:  500 mg/m2 over 10 min, every 3 weeks x 2   
                       administrations   
 
Start : day 1 of  re-irradiation 
Phase I - Dose 
Escalation 
 
Erlotinib:   100/125/150 mg 
daily, for 6 weeks or until 
mucositis and dermatitis 
reduce to grade I 
Phase II 
 
 
Erlotinib:  established 
dosedaily, for 6 weeks or 
until mucositis and 
dermatitis reduce to grade I 
Follow by  

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 4 
 
TABLE OF CONTENTS 
 
Title Page………………………………………………………………………. 
1 
Protocol Synopsis……………………………………………………………… 3 
Schema…………………………………………………………………………..  3 
Table of Contents………………………………………………………………. 4 
1.0 Introduction…………………………………………………………………. 7 
 
1.1 Disease Background………………………………………………. 7 
 
1.2 Background on Re-irradiation…………………………………….. 8 
 
1.3 Tarceva® Background………………………………………………. 8 
 
1.4 Alimta Background…………………………………………………. 9
 
1.5 Study rationale………………………………………………………. 9 
 
1.6 Other goals of the project…………………………………………… 10 
 
 
1.6.1 Evaluate swallowing impairment & QOL………………. 10 
 
 
1.6.2 Identify tumor biomarkers……………………………….. 13 
2.0 Objectives…………………………………………………………………... 13 
 
2.1 Primary Objectives for Phase I…….………………………. ………13 
 
2.2 Primary Objectives Phase II…………………………………………14 
 
2.3 Secondary Objectives……………………………………………….. 14 
3.0 Trial Population……………………………………………………………... 14 
 
3.1 Inclusion Criteria……………………………………………………. 14 
 
3.2 Exclusion Criteria…………………………………………………… 15 
 
3.3 Inclusion of Women and Minorities……………………………….. 16 
 
3.4 Registration Procedure…………………………………………….. 16 
4.0 Treatment Plan……………………………………………………………… 16 
 
4.1 Re-irradiation……………………………………………..…………   16 
 
 
4.1.1 Dose Fractionation………………………………………… 16 
 
 
4.1.2 Physical Factors…………………………………………… 17 
 
 
4.1.3 Localization Requirements……………………………….. 17 
 
 
4.1.4 Target Volume……………………………………………... 17 
 
 
 
4.1.4.1 Planning………………………………………….. 18 
 
 
4.1.5 Dose Calculation………………………………………….. 18 
 
 
4.1.6 Evaluation Criteria………………………………………… 18 
 
 
4.1.7 Dose Modifications……………………………………….. 19 
 
 
4.1.8 Treatment Verification…………………………………… 19 
 
 
4.1.9 Dosimetry Required……………………………………… 19 
 
4.2 Radiosensitizing Drugs…………………………………………….. 20 
 
 
4.2.1 Tarceva®………………………………………………….. 20 
 
 
 
4.2.1.1 Formulation……………………………………… 20 
 
 
 
4.2.1.2 Packaging and Labeling……………………….. 20 
 
 
 
4.2.1.3 Storage and Handling………………………….. 20 
 
 
 
4.2.1.4 Administration…………………………………… 20 
 
 
4.2.2 Pemetrexed………………………………………………… 21 
 
 
 
4.2.2.1 Description and Handling Instructions………… 21 
 
 
 
4.2.2.2 Dosage………………………………………… 
21 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 5 
 
 
 
4.2.2.3 Administration…………………………………. 22 
 
 
4.2.3 Drug Accountability……………………………………… 22 
 
 
4.2.4 Concomitant Medications………………………………. 23 
 
 
 
4.2.4.1 Potential Drug-Drug Interactions……………. 
23 
 
           4.2.5 Supportive Therapy……………………………….. …… 24 
5.0 Study Design……………………………………………………………… 
25 
6.0 Clinical and Laboratory Evaluations……………………………………… 27 
 
6.1 Mandatory Pre-Treatment Evaluations …………………………. 27 
 
6.2 Mandatory Evaluations During Post Treatment……………….. 
28 
 
6.3 Quality of Life Assessments…………………………………………29 
7.0 Dose Modification / Toxicity Management……………………………… 29 
 
7.1 Radiation adverse events………………………………………….. 29 
 
7.2 Specific drug-related adverse events……………………………… 30 
 
 
7.2.1 Erlotinib…………………………………………………… 30 
 
 
7.2.2 Pemetrexed……………………………………………….. 34 
 
7.3 Phase I portion of the study………………………………………. 36 
 
7.4 Essential protocol-specific adverse events to be collected…… 38 
8.0 Criteria for Study Discontinuation……………………………………….. 
39 
9.0 Reporting of Adverse Events…………………………………………….. 39 
 
9.1 Reporting Definitions……………………………………………… 39 
 
9.2 Reporting Events Associated with Erlotinib……………………. 
40 
 
9.3 Reporting Events Associated with Pemetrexed…………………   41 
10.0 Evaluation of Response…………………………………………………. 42 
 
10.1 Definitions…………………………………………………………. 42 
 
10.2 Response Criteria….................................................................. 43 
 
10.3 Evaluation of Best Overall Response……………………………. 44 
 
10.4 Confirmatory Measurement/Duration of Response…………….. 44 
 
10.5 Efficacy Endpoints…………………………………………………. 44 
 
10.6 Safety Endpoints…………………………………………………… 45 
11.0 Sample Size and Statistical Considerations…………………………… 45 
12.0 Tissue / Specimen submission………………………………………….. 48 
13.0 Retention of Records……………………………………………………… 51 
14.0 Publication Plan………..………………………………………………….. 51 
15.0 Multi-Institutional Monitoring Plan ……………………………………….. 51 
16.0 References…………………………………………………………………. 55 
17.0 Appendices………………………………………………………………… 59 
 
Appendix 1 
 
Blood and Buccal Mucosa Collection Instructions  
Appendix 2 
 
Example of Smoker Status Case Report Form 
Appendix 3 
 
Example of Investigational Product Accountability Log 
Appendix 4 
 
Form 3500A Medwatch 
Appendix 5 
 
Mandatory (STRC) Safety and Toxicity Review   
Committee (Previously CROC) 
Appendix 6 
 
Registration Guidelines 
Appendix 7 
 
RECIST Criteria 
Appendix 8 
 
CTC Criteria version 3 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 6 
Appendix 9 
 
FACT-H&N QOL Survey 
Appendix 10 
 
PSS-HN QOL Survey 
Appendix 11 
 
MD Anderson Dysphagia Inventory (MDADI) 
Appendix 12 
 
ECOG Performance Scale 
Appendix 13                       Master Flow Sheet  
Appendix 14 
 
Tumor Measurement Form 
Appendix 15 
 
CYP3A4 and CYP1A2 Inhibitors/Inducers 
Appendix 16 
 
Swallowing Portion Data Collection Form 
Appendix 17                       Specimen Log 
Appendix 18                       AE Log 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 7 
1. 
INTRODUCTION 
 
1.1 
Disease Background 
 
 
Locoregionally failure remains a serious problem in the treatment of Head 
and Neck Squamous Cell Carcinoma (SCCHN), especially in patients with 
advanced primary stage disease, despite the progress made with definitive or 
adjuvant chemo radiotherapy (CRT) over radiotherapy (RT) alone. For SCCHN 
patients with high risk features after surgery, cumulative estimated 5-year 
incidence of locoregional relapse after postoperative CRT is 29-31% (1). 
Furthermore, second primary tumors in the Head and  Neck develop in up to 30% 
of patients over 10 years due to field cancerization (2).  
 
When recurrence or second primary tumors occur in previously radiated 
fields, there are limited salvage options. When possible and indicated, surgery 
remains the standard of care. Long term salvage is possible in this well-selected 
group, with 5 y survival of 15-35%. However this is feasible for a small subset of 
patients. Many patients are medically unfit for surgery  or have unresectable 
disease because of disease extent or involvement of critical structures. 
 
Inoperable patients are usually offered chemotherapy, with a median 
survival of 8-10 mo, with the most commonly used agents being cisplatinum and 
5-fluorouracil. Newer agents have failed to show survival advantage. The 1y 
survival is less than 35% and overall survival (OS) beyond 2 y is almost never 
realized (1,3).  
 
Long term survival rates of 17% at 5 years have been reported with re-
irradiation in selective patients (3). However, tumor cells persisting through 
radiation are likely radioresistant and adding radiosensitizing drugs offers a 
method to enhance cell killing. Previously published data have demonstrated that 
re-irradiation with concurrent chemotherapy is feasible, however severe toxicity is 
not infrequent.  
 
Two multi-institutional cooperative group trials of re-irradiation combined 
with chemotherapy in inoperable patients have been completed. RTOG 96-10 
examined a split course regimen of radiation with concurrent 5-fluorouracil and 
hydroxyurea: Median survival (MS) was 8.2 mo, 1 y OS was 41.7% and 2 y OS 
was 16.9 %. Severe complications of grad 4 or 5 occurred in 23% of patients (4). 
The succeeding trial RTOG 99-11 used the same radiation schedule, but daily 
cisplatinum and taxol during radiation, with G-CSF during the off weeks.  Median 
survival time was 12.1 mo and median progression free survival was 7.8 mo. 1 yr 
progression free survival was 35% and OS was 50.2% and 2 y OS was 25.9%. 
Acute toxicity grade 4 or 5 occurred in 28%. There were 8 fatal toxicities, 5 during 
treatment and 3 post-treatment (5). Improvement in survival can be observed in 
these 2 consecutive RTOG studies and these results corroborate reports of 
single-institution trials (6,7). 
 
Both these multi-institutional trials as well as almost all single institutional 
reports used split-course RT (1.5 Gy bid, for 5 of 14 days, followed by 7 days 
break to a total of 60 Gy). In an attempt to eliminate RT breaks another schedule 
was investigated at University of Utah, with 2cGy administered daily to a total of 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 8 
50Gy, combined with 5-fluorouracil and hydroxyurea on weeks 1 and 4. MS was 
10.2 mo and 2y survival was 15%. This study demonstrates that it is feasible to 
deliver a continuous course of re-irradiation with minimal treatment breaks (8). 
 
Reported studies of re-irradiation with concurrent chemotherapy 
demonstrate substantial toxicity. Some have questioned whether re-irradiation 
toxicity outweighs the potential benefits because the median survival of re-
irradiated patients marginally exceeds that of chemotherapy alone. However, the 
high rates of loco-regional control and the 2-3 y survival rates appear superior.  
For this reason use of re-irradiation should be limited to the setting of a clinical 
trial. Current studies for head and neck cancers are adding biologic modifiers to 
standard chemotherapy in an attempt to decrease the acute toxicity (1). 
 
1.2 
Background on Re-irradiation 
 
 
Three dimensional radiation simulation of patients using CT or PETCT 
helps to localize tumor precisely. Intensity modulated radiation therapy (IMRT) is 
a way of delivering radiation to specific locations and avoiding normal tissue.  For 
example, IMRT has been demonstrated to help in parotid sparing for patients 
treated de novo. For this population of patients who have received prior radiation, 
re-irradiation of the smallest volume of tumor and normal tissue is desirable. 
Patients will only be eligible for this trial who have gross disease that can be 
adequately contoured and treated while delivering doses to normal tissues within 
the specified constraints.  In this trial patients will be treated with 30 daily 
fractions that deliver 2.0 Gy  to areas of gross disease (6000 cGy total) and 1.8 
Gy to the areas felt to be at highest risk of occult involvement (5400 cGy).  
 
1.3 
Tarceva® Background 
 
 
Tarceva® (erlotinib) is a selective small molecule inhibitor of the 
intracellular tyrosine kinase domain of the epidermal growth factor receptor 
(EGFR).  This drug is approved for the treatment of non-small cell lung cancer 
and pancreatic cancer). In phase I clinical trials, diarrhea and skin rash were the 
main toxicities. Erlotinib has been tested in a phase II study of recurrent 
metastatic SCCHN, for a reported 4% response rate and a median survival of 6 
months. In another phase II study of advanced SCCHN, erlotinib was evaluated 
in 115 patients at a dose of 150 mg/d. Patients had no more than one prior 
therapy for advanced disease. Rash was reported in 79% of patients, and the 
partial response rate was 4.3%, with 38.3% achieving stable disease, suggesting 
activity and tolerability of erlotinib in this group of refractory patients (9).  
 
 
Anti-EGFR therapies are good candidates for combination with other 
treatment modalities, including chemotherapy and radiotherapy, due to their 
tolerable safety profile and non-overlapping toxicities (10). Tumor xenograft 
studies confirm that systemic administration of Erlotinib results in profound tumor 
growth inhibition when combined with radiation. Erlotinib was shown to enhance 
radiation response at several levels, including cell cycle arrest, apoptosis 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 9 
induction, accelerated cellular repopulation, and DNA damage repair. Preliminary 
microarray data suggest additional mechanisms underlying the complex 
interaction between EGFR signaling and radiation response. These data suggest 
that the Erlotinib/radiation combination represents a strategy worthy of further 
examination in clinical trials (11). Moreover, EGFR tyrosine kinase inhibitors 
decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent 
and HIF-1-dependent mechanisms with anti-angiogenic effect expected to further 
add to tumor killing and radiosensitizing efficiency. Tumors with high level of 
VEGF expression and high vessel density are often relatively resistant to 
radiation therapy (12). 
 
 
Smoking status is an important predictor for benefit from Tarceva®.  It has 
recently been found that patients who smoke metabolize the drug rapidly and 
may not achieve adequate drug levels. A phase I clinical trial has been 
completed that found the MTD of Tarceva® for patients who continue to smoke is 
twice that of patients who do not smoke. Thus, it appears that sensitivity to 
Tarceva® is dependent on achieving an adequate dose of the drug.  In the 
maintenance part of the current study will dose Tarceva® according to smoking 
status (13). 
 
1.4 
Alimta® Background 
 
 
Alimta® (Pemetrexed) is a multi-targeted antifolate that inhibits several 
folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The 
principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, 
mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient 
(folate and vitamin B12) patients, and can be ameliorated by the co-
administration of folate and vitamin B12. The use of prophylactic dexamethasone 
is also recommended to reduce the frequency of severe skin rash (14-16). 
Pemetrexed exhibits significant antitumor activity in a broad spectrum of human 
tumors, including mesothelioma, pancreatic, colorectal, lung, head and neck, 
breast and cervix cancers. (17,18). Antifolates have been established in cancer 
treatment for many years and are widely used in combination with radiotherapy. 
The ability of pemetrexed to sensitize cells to ionizing radiation has been reported 
in preclinical studies (19). Laboratory data suggest the potential clinical efficacy of 
combining pemetrexed with radiotherapy for SCC tumors sensitive to 
pemetrexed. (20). Efficacy and safety clinical data of RT and pemetrexed have 
been reported for other types of cancers, such as esophageal cancer (21).  
 
 
1.5 
Study Rationale 
 
 
The main goal of our project is to define a novel combination of 
radiosensitizing drugs which should be able to improve upon the previously 
reported efficacy of combined re-irradiation and chemotherapy, while reducing 
acute and late toxicity. We propose to do this by: 
1) Using continuous RT to increase efficacy. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 10 
2) Using IMRT to improve contouring of tumor and avoid previously irradiated 
normal tissues. 
3) Using radiosensitizing chemotherapy drugs with reduced general toxicity, 
such as pemetrexed. 
4) Adding a radiosensitizing biologic agent, erlotinib which is expected to 
increase efficacy but not toxicity. 
5) Continue administration of erlotinib as single agent maintenance treatment 
after conclusion of re-irradiation to prevent or delay cancer progression.  
This is a very high risk population expected to benefit from maintenance 
strategy. Moreover, erlotinib maintenance treatment is not expected to 
significantly affect quality of life. 
 
1.6 
Other Goals of Our Projects: 
 
1.6.1    Evaluate swallowing impairment and quality of life  
 
 
Evaluate swallowing impairment and quality of life as important 
parameters in weighing the benefits of re-irradiation (such measurements were 
previously reported by just one institution, University of Chicago in re-irradiation 
studies (6). 
 
In HNSCC, both the disease and its treatment have the potential to 
significantly impact key functions, such as eating, speaking, and socializing. 
Although chemoradiotherapy regimens minimize surgery and consequently 
disfigurement, they have other significant immediate, delayed and potentially 
long-term side effects that may profoundly influence quality of life (QOL). 
 
Radiosensitizing chemotherapy given in combination with radiation 
increases the severity of severe mucositis, sticky saliva, pain, dry mouth, 
hoarseness, skin irritation and difficulties in swallowing and tasting, with many of 
these symptoms persisting years after treatment completion.  For example, List 
and colleagues (22) observed that on an intensive chemoradiotherapy regimen 
administered to previously untreated HNSCC patients, up to three-quarters of 
patients reported moderate to severe problems with dry mouth, swallowing, 
tasting, sticky saliva and hoarse voice. While there was some improvement in 
most symptoms over 12 months, there was little change in dry mouth, and over a 
third of patients continued to report difficulties with sticky saliva and swallowing. 
In addition, patients’ diets remained extremely restricted with a half to three-
quarters on a soft food diet at 12 months.   
 
Longer follow-up (2-4 years post-treatment) of these patients suggested 
some continued recovery in ability to eat a full range of foods and comfort in 
eating with others, although a third still had significant restrictions in diet and 
there was little change in other QOL or symptom domains after twelve months. 
There are to date, very few, if any data on the impact of adding novel 
chemotherapeutics, such as pemetrexed and novel biologic agents, such as 
erlotinib, to radiation or re-irradiation. While such agents might be expected to 
add little toxicity, it is important to document short and longer –term QOL and 
performance/function. These evaluations are particularly important in re-

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 11 
irradiation studies, where toxicity might outweigh the possible marginal benefit in 
survival. This study will be one of the first to prospectively assess QOL and 
performance up to 2-3 years post-treatment. The following assessment tools will 
be used: 
 
1  ECOG Performance Status Rating Scale describes global functioning in 
terms of mobility. 
2 The Performance Status Scale for Head and Neck Cancer (PSS-HN) 
(see Appendix 10) The PSS-HN is a clinician rated instrument consisting 
of assessment of three functions (subscales): Normalcy of Diet, Eating in 
Public, and Understandability of Speech. The interviewer rates the patient 
on each scale based on the patient’s responses to targeted questions. 
Scores on each subscale range from 0-100, with higher scores indicating 
better performance. It has been demonstrated to be reliable and valid in 
head and neck cancer patients. The site research nurse will determine the 
score on each of the subscales by performing a clinical evaluation and 
unstructured interview format. The PSS-HN takes approximately 5 
minutes to complete.  
                 a) The Normalcy of Diet subscale assesses the degree to which a 
patient is able to eat a normal diet. Ten food categories are arranged from 
easy-to-eat at the low end to hard-to eat at the high end. Scores range 
from 0-100 with those scores closer to 100 representing a higher level of 
function. Scores are computed by assessing the highest-ranking food the 
patient is able to eat.  
                 b) The Eating in Public subscale was designed to assess comfort 
in socializing, specifically the degree to which the patient eats in the 
presence of others. There are five categories describing the patients’ 
eating patterns. Scores range from 0-100 with those scores closer to 100 
representing a higher level of function. Scores are computed based upon 
patient’s report of with whom he/she eats and in what type of setting. 
 
c) The Understandability of Speech subscale is a five-item scale, 
which assesses how well the patient can be understood by others, 
regardless of voice quality or nature of speech. Scores range from 0-100 
with those scores closer to 100 representing a higher level of function. The 
scores are computed by assessing the degree to which the observer is 
able to understand the patient's speech. In addition, sites will document 
feeding tube status, dentition, and presence or absence of a tracheostomy 
on case report forms. 
3 Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N) 
(see Appendix 9) The FACT-H&N is a multidimensional, self-report QOL 
instrument specifically designed and validated for use with head and neck 
cancer patients. The core scale (FACT-G) consists of 27 core items 
assessing patient well-being in four areas: Physical, Social/Family, 
Emotional, and Functional. Items are rated on a five-point scale: 0-“not at 
all”, 1- “a little bit”, 2-“somewhat”, 3- “quite a bit” and 4-“very much”. This 
core questionnaire is supplemented with a twelve-item head and neck 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 12 
subscale targeting head and neck related symptoms and side effects. 
Overall QOL is the sum of the core items of the FACT-G. The head and 
neck subscale is not included in overall summary score but will be looked 
at separately. 
 
 
Specifically, swallowing function affects quality of life and often decreases 
during and following CRT (23,24). Eisbruch et al (25) studied swallowing in 29 
patients before CRT, early and late post-CRT. They reported decreased base of 
tongue to posterior pharyngeal wall approximation decreased UES opening and 
laryngeal closure which resulted in aspiration after the swallow in approximately 
60% of the patients post-CRT. 
 
 
Although swallowing function has a strong probability to diminish 
throughout CRT, swallowing function in patients in an organ-preservation 
protocol may endure better than patients in a surgical protocol. Fung et al (26) 
investigated swallowing ability in patients who all received chemotherapy 
originally but who received a subsequent laryngectomy for less than a 50% 
response compared to the patient group who did have greater than a 50% 
response who then underwent concurrent Chemoradiation followed by two cycles 
of adjuvant chemotherapy. Eighty-nine percent of the patient group who was able 
to continue the organ-preservation protocol was able to sustain nutrition on oral 
intake alone compared to only 64% of the laryngectomy group. 
 
 
One of the challenges in evaluating swallowing function pre- and post 
CRT is the ability to quantify swallowing pathophysiology. Our institution is 
uniquely positioned to quantify swallowing physiology. We are one of the few 
facilities in the country that offer pharyngeal and upper esophageal sphincter 
manometry which measures pressures and timing of oropharyngeal swallowing 
ability. Furthermore, we will perform Flexible Endoscopic Evaluation of 
Swallowing (FEES) which provides information on swallowing function and 
appropriate diet level. Thus, we will obtain objective and instrumental pre-CRT 
data on swallowing function to objectively measure swallowing change as a 
function of time (i.e. 1-, 6-, and 12-months).  
 
 
Swallowing treatment has recently been demonstrated to benefit patients   
undergoing CRT (27). Kulbersh et al (28) demonstrated improved swallowing 
quality of life in patients who began swallowing exercises prior to XRT and/or 
CRT. Accordingly, patients in the study protocol will be offered instruction in a 
swallowing home therapy program prior to beginning CRT. These exercises will 
be done by the patients twice a day, six days a week throughout the course of 
their CRT and for 6 months following CRT completion. Swallowing quality of life 
will be measured pre-CRT and at 1-, 6- and 12-months post CRT with a validated 
swallowing quality of life survey, M.D. Anderson Dysphagia Inventory (MDADI) 
(29). 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 13 
1.6.2   Identify tumor biomarkers as possible predictors of treatment response 
and prognosis. 
 
 
We have already established collaboration with our Mass Spectrometry/ 
Proteomics laboratory at Wake Forest University and we plan to evaluate the 
level of EGFR phosphorylation using Liquid Chromatography-Tandem Mass 
Spectrometry (LC-MS/MS).  Phosphorylation of specific tyrosine residues within 
the cytoplasmic domain of EGFR is part of the initial activation process that 
occurs upon ligand binding. These phosphotyrosine residues subsequently serve 
as docking sites for intracellular signaling molecules. During the past two 
decades researchers monitored EGFR phosphorylation in response to ligand 
binding and activation as a global immunologic measurement of total 
phosphorylation within intact EGFR. Measuring the accumulative changes in 
overall phosphorylation, rather than dynamic changes at specific sites might 
explain the failure in correlating the level of EGFR phosphorylation and activation 
with the response to EGFR inhibitors.   
 
We plan to measure by nano LC-MS/MS the level of phosphorylation of 
different tyrosine residues within the cytoplasmic domain of EGFR in tumor tissue 
(primary tumor and nodal metastasis whenever tissue available) and compare 
with that in normal tissue from the same patient. Recruited adaptors to the EGFR 
phosporylated sites: Grb2, Shc, NSP1, and NSP2, SCK will be identified and 
measured in the same experiment.  We will measure other molecules considered 
in the literature as markers of activation of different signaling pathways 
downstream of EGFR such as PLC-1, Cbl/Cbl-B, Ras-Raf-MEK-MAPKs, PI3K- 
Akt-ribosomal S6K, STAT 3, c-Src, SAPKs, PAK-JNKK-JNK and PKC and 
corroborate the results with the pattern of EGFR phosphorylation in the C-
terminal region and with the recruited adaptors (30,31). We plan to corroborate 
these findings with P-AKT and P-ERK measured by classic 
immunohistochemistry (IHC) method and with the patients' response to treatment 
and prognosis. 
 
 
We also plan to measure Thymidylate synthase (TS) and p53 levels in 
tumor tissue (as available) and correlate with response to treatment. Specific 
interaction exists between oncogenes and TS, by binding of TS protein to the 
p53 RNA, while wild type p53 can also inhibit TS promotor activity. In some 
preliminary clinical studies evidence was postulated for a combined predictive 
role for TS and p53 for response to antifolates such as Pemetrexed. TS and p53 
will be measured by PCR or IHC, depending on tissue availability. 
 
2. 
OBJECTIVES 
 
2.1 
Primary objective phase I 
  
1)  Evaluate acute toxicity and feasibility of the combined re-irradiation with 
radiosensitizing drugs: Pemetrexed and Erlotinib. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 14 
2)  Determine MTD for Erlotinib, recommended for the phase II portion of the 
study. 
 
2.2 
Primary objective phase II 
1) Determine Progression Free Survival at 1 year defined as the percentage 
of patients who are alive at 1 year after beginning of their concurrent re-
irradiation and chemotherapy without loco-regional progression of their 
disease as measured by CT scan or MRI using RECIST 1.1 criteria (see 
Appendix 7) (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  
 
2.3 
Secondary objectives 
 
1) Median Progression Free Survival, Median Overall Survival and Overall 
survival at 1 year and at 2 years. 
2) Objective tumor response. . 
3) Evaluate acute and chronic toxicity of the combined re-irradiation with 
radiosensitizing drugs: Pemetrexed and Erlotinib. 
4) Measure QOL by standard survey forms: FACT-H&N, PSS-HN, and 
swallowing by direct functional measurements and by SWAL-QOL survey 
at different time points to evaluate the impact of treatment on QOL. 
5) Biomarkers evaluation. Evaluate by nano LC-MS/MS in tumor tissue, 
reported to normal tissue, the level of phosphorylation of different tyrosine 
residues within the cytoplasmic domain of EGFR, bound adaptors, as well 
as markers of downstream pathways activation and corroborate with level 
of P-AKT and P-ERK evaluated by immunohistochemistry and with 
response to treatment. Measure level of TS and P53 and corroborate with 
treatment response. 
 
3. 
TRIAL POPULATION 
 
 
Phase I/II clinical trial. Patients with recurrent HNSCC or second primary 
will receive re-irradiation and the radiosensitizing drugs Pemetrexed and Erlotinib 
beginning with the first day of RT. Erlotinib dose will be escalated during the 
Phase I portion of the study.  Maintenance Erlotinib will be continued until 
disease progression or to a maximum of 2 years. No randomization.  
 
3.1 
Inclusion Criteria 
 
 
Patients must meet all of the following inclusion criteria to be eligible for 
participation in this study: 
 Pathologically (histologically or cytologically) confirmed diagnosis of 
recurrent or second primary squamous cell carcinoma (SCC) of the oral 
cavity, oropharynx, hypopharynx, larynx, or recurrent neck metastases 
with unknown primary.  Exception from pathology confirmation of tumor 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 15 
recurrence is accepted for patients who originally had pathologically 
confirmed SCC of the Head and Neck, the new tumor is located in the 
head and neck area and it is clinically considered as a recurrence of the 
original tumor, and a tumor biopsy is technically difficult and would expose 
the patient to unjustified risk. The treating physicians should agree and 
document the clinical definition of tumor recurrence and should document 
the increased risk for biopsy.    
 Patients will only be eligible for this trial if they have measurable tumor on 
the CTscan/MRI or by direct clinical/endoscopic evaluation.  
 Subjects enrolled in phase II part of the protocol should not have 
metastastatic disease. However, patients with oligometastatic disease that 
can be treated with localized treatment with definitive intent are eligible. 
 Patients should be found unresectable by a preliminary ENT evaluation or 
have refused surgery 
 Prior history of head and neck radiation for Head and Neck Squamous 
Cell Carcinoma to no more than 72 Gy and most (>75%) of the recurrent 
or second primary tumor volume should be in areas previously irradiated 
to > 45 Gy. 
 The entire tumor volume must be included in a treatment field that limits 
the total spinal cord dose to 54Gy (prior plus planned dose). 
 Subjects must have recovered from the acute side effects of prior surgery, 
chemotherapy, or radiation therapy. A minimum time period at least 6 mo 
should have elapsed from prior radiation treatment until enrollment in the 
study. 
 Patients may have received chemotherapy as a component of their 
primary tumor treatment but not for recurrent or metastatic disease. No 
prior treatment with systemic anti-EGFR inhibitors or Pemetrexed is 
permitted. 
 ECOG performance status 0-1. 
 Age ³ 18 years or older. 
 ANC >1500/µl, platelet count > 100,000/µl. Total bilirubin < 1.5 and 
AST/ALT less than 2 times the upper limit of normal. Creatinine< 1.5 and 
creatinine clearance > 45. 
 Subjects should be willing and able to take folic acid and vitamin B12 
supplementation and should interrupt aspirin or other non-steroidal anti-
inflammatory agents for a 5-day period (8-day period for long acting 
agents such as piroxicam) before entering the study.  
 Informed consent must be obtained from all subjects prior to beginning 
therapy. Patients must provide verbal and written informed consent to 
participate in the study. Subjects should have the ability to understand and 
the willingness to give verbal and sign a written informed consent 
document 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 16 
3.2 
Exclusion Criteria 
 
Patients who meet any of the following exclusion criteria are not to be 
enrolled in this study: 
 Patients with Nasopharyngeal Carcinoma. 
 Subjects with uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection or psychiatric illness/social situations that 
would limit compliance with study requirements, significant history of 
uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable 
angina, recent myocardial infarction (within prior 3 months), uncontrolled 
congestive heart failure, and cardiomyopathy with decreased ejection 
fraction.  
 Patients with active Interstitial Lung Disease. 
 Presence of third space fluid which cannot be controlled by drainage. 
 May not be receiving any other investigational agents. 
 Pregnant women are excluded from this. Breastfeeding should be 
discontinued. Prior to study enrollment, women of childbearing potential 
must be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional pregnancy. 
Men enrolled on this study should understand the risks to any sexual 
partner of childbearing potential and should practice an effective method 
of birth control. Subjects who are women of childbearing potential and 
sexually active males must be willing to use effective contraception while 
on study. 
 All WOCBP should be instructed to contact the Investigator immediately if 
they suspect they might be pregnant  
 HIV-positive subjects are excluded from the study. 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all ethnic groups are eligible for this 
trial.  
 
3.4 
Registration Procedure 
 
 
All patients entered on any CCCWFU trial whether treatment, companion or 
cancer control trial must be registered with the CCCWFU Protocol Registrar.  
Patients should be registered prior to the initiation of treatment.  The on study 
form (see Appendix 6) and prestudy flow sheet (see Appendix 13) should be 
completed prior to telephone registration and faxed to the registrar (336-713-
6772). Protocol Registrar can be contact by calling 336-713-6767 between 8:30 
AM and 4:00 PM, Monday – Friday. The form is appendix 6. 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 17 
4. 
TREATMENT PLAN 
 
4.1 
Re-irradiation 
 
 
All patients will receive re-irradiation.  Radiotherapy will consist of 6 weeks 
of daily radiation using intensity modulated radiation 
 
 
4.1.1 Dose Fractionation  
 
RT will be given as one daily fraction for 5 consecutive days every week 
for six weeks. Total dose will be 60 Gy in 30 daily fractions to gross tumor. 
 
Dose to the spinal cord must be limited to 54 Gy total (prior plus current). 
Decay factors are not permitted. Treatment will begin on Mondays, Tuesdays or 
Wednesdays. The exact time and date of each treatment is to be recorded. If the 
patient misses more than two days, i.e., two fractions, missed treatments 
(radiation with chemotherapy) should be made up. 
A boost of an additional 6 Gy (to bring the total dose to 66 Gy) is allowed 
to a small area of gross residual disease assuming that dose to critical structures 
are not exceeded/ 
 
4.1.2 Physical Factors 
 
 
Linear accelerators with appropriate photon and electron energies for 
supplemental boosting. Photon beams of ≥ 1.25 MeV and/or electron beams 
from 4-25 MeV are allowed. Treatment distance must be ≥ 80 cm SSD or 
greater, or ≥ 80 cm SAD for isocentric techniques. 
 
4.1.3 Localization Requirements 
 
 
Simulation of all fields is mandatory. Patients must be reproducibly 
immobilized. Radio-opaque markers should be used whenever possible to 
delineate the extent of nodal disease, skin involvement, and any gross disease. 
The use of customized blocks or multileaf collimation for field shaping is strongly 
recommended. 
 
Treatment planning CT scans are required for IMRT treatment. 
Radioopaque contrast is recommended for better imaging. Beam localization 
films (portal films) should be obtained for all photon and electron fields. 
 
4.1.4 Target Volume 
 
 
The treatment fields should encompass the gross recurrent tumor with .5 
cm margins needed to obtain the CTV. The treatment fields should encompass 
the recurrent tumor defined as the Gross Tumor Volume (GTV), considered all 
known disease defined by clinical radiographic or any other information available. 
Adequate margins should be added whenever possible. Margins less than .5 cm 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 18 
are an acceptable deviation only in instances of spinal cord encroachment. A 
lower risk CTV may be included and will be taken to a lower dose. 
 
A boost volume can be done after the CTV has received 60 Gy, c with 
additional 6 Gy in 3 fractions using electrons, photons, or IMRT planning.  If a 
concomitant boost is desired with IMRT a CTV doses of 66 Gy will be indicated 
on the initial plan.  The dose per fraction will be 2.2 Gy. 
 
 
The Planning Target Volume (PTV) will provide a margin around each 
CTV (i.e. both the primary tumor and the lymph nodes containing clinical or 
radiographic evidence of metastases) to compensate for the variability’s of 
treatment set up and internal organ motion. A minimum of 3 mm around the CTV 
is required in all directions to define each respective PTV. Careful consideration 
should be made when defining the superior and inferior margins in three 
dimensions.  
 
4.1.4.1  Planning  
 
 
The treatment plan used for each patient will be based on an analysis of 
the volumetric dose, including DVH analyses of the PTV and critical normal 
structures. A “forward” iterative planning or “inverse” planning using 
computerized optimization are allowed. The treatment aim will be the delivery of 
radiation to the PTVs and the exclusion of noninvolved tissue as feasible.  
Dose Specification  
 
The prescription dose is the isodose which encompasses at least 95% of 
 
the planning target volume (PTV).  
No more than 20% of any planning target volume (PTV) will receive 
>110% of its prescribed dose.  
No more than 1% of any planning target volume (PTV) will receive <93% 
of its prescribed dose.  
No more than 1% or 1 cc of the tissue outside the PTVs will receive 
>110% of the dose prescribed to the primary PTV.  
 
 
Prescription dose to the PTVs shall be according to the following:  
 
The gross tumor and lymph node will receive 30 fractions of 2.0 
 
Gy/fraction, total 60 Gy.  
 
 
The low risk CTV willreceive 30 fractions of 1.8 Gy/fraction, total 54 Gy. 
 
4.1.5 Dose Calculation  
 
 
Isodose calculations in the axial, sagittal, or coronal planes are 
required. In addition, dose volume histograms for the GTV and the spinal cord 
are required. 
 
Independent of the treatment approach, the maximum dose to the spinal 
cord must be indicated on the daily treatment record. The specification of the 
protocol target dose is in terms of a dose to a point at or near the center of the 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 19 
target volume. The inhomogeneity within the target volume should not exceed ± 
10% of the target dose. 
 
4.1.6 Evaluation Criteria 
 
 
Dose and Fractionation 
 
Total Dose Variation Fractionation Overall Evaluation 
 
≤ 4 % ≤ 2 Days of non HFX Per Protocol 
 
> 4% to ≤ 9% 3-5 Days of non HFX Variation Acceptable 
 
> 9% > 5 Days of non HFX Deviation Unacceptable 
 
 
4.1.7 Dose Modifications  
 
 
Acute local toxicity (skin and mucosa) must be ≤ grade 3 at the beginning 
of each treatment week. If toxicity is > grade 3, treatment may be held up to two 
weeks until ≤ grade 3 is attained. Chemotherapy should be held until RT is 
resumed. Patients who cannot resume treatment within two weeks will be 
removed from study. These patients must be followed for survival. 
 
If a treatment delay for local acute toxicity is required, only the dose of 
chemotherapy will be modified, not the total RT dose. 
Treatment breaks must be clearly indicated in the treatment record. 
If treatment breaks unrelated to toxicity occur, e.g., department schedule, bad 
weather, or patient absence, the missed treatments should be made up. 
 
There is a real, but relatively small risk of carotid rupture in patients whose 
tumors overlap the carotid artery. Most of these events have occurred in 
association with active tumor in this region and may not necessarily be due to 
adverse effects of treatment.  
 
4.1.8 Treatment Verification 
 
 For all forms of IMRT dose delivery, orthogonal films that localize the 
isocenter placement shall be obtained. The length of the treatment field 
shall be indicated on these films. 
 For all delivery techniques, except those that use a source of radiation that 
rotates during treatment, e.g. tomotherapy or IMAT, the intensity pattern 
for each gantry orientation shall be documented on a separate film. These 
films should NOT include the patient’s anatomy. 
 
4.1.9   Dosimetry Required 
 
 For standard treatment approaches, an isodose distribution in a 
transverse plane through the center of the target volume is required 
summating all fields. If the spinal cord is in close proximity to the treatment 
volume, off axis isodose distributions should be performed as well. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 20 
 For 3D-CRT, isodose calculations in the axial, sagittal, or coronal planes 
are required. In addition, dose-volume histograms for the GTV and the 
spinal cord are required. 
 For IMRT, isodose calculations in the axial, sagittal, or coronal planes are 
required. In addition, dose volume histograms for the GTV and the spinal 
cord are required. This documentation must indicate the planning system 
and version, e.g., Corvus, V. 3.1. Please provide a description of the 
treatment delivery system, e.g., IMRT compensating filter, MLC step and 
shoot, or dynamic tomotherapy. 
 
4.2 
Radiosensitizing drugs 
 
 
4.2.1 Erlotinib (Tarceva®) 
 
 
Erlotinib will be administered daily throughout radiotherapy, starting with 
day # 1 of RT.  During Phase I portion of the clinical trial, erlotinib will be dose 
escalated starting with 100, 125 and 150 mg. If DLT is being encountered with 
the first dose level of Erlotinib, both drugs will be reduced by 25% and dose 
escalation restarted. The dose established as MTD or maximum dose of 150 mg 
will be used in the phase II portion of the clinical trial. 
 
At the conclusion of RT the Erlotinib will be continued at the same dose 
until the dermatitis and mucositis reduce to grade I. The maintenance Erlotinb 
dose will then be started. Patients who had the erlotinib dose reduced because of 
erlotinib-related skin rash,during the CRT will continue the same dose of erlotinib 
as maintenance treatment. If this dose is lower than 75 mg daily, the patient will 
be discontinued from the study treatment. For all other patients the maintenance 
Erlotinib will be started at the dose of 150 mg/day for non-smokers or 300 
mg/day for smokers (per smoking status defined at the time of the beginning of 
maintenance). The maintenance treatment will be continued until disease 
progression, unacceptable toxicity (see dose modification chart on section 7) or 
to a maximum duration of 2 years. Erlotinib dose should be adjusted per smoking 
status during maintenance treatment. Smokers are defined as patients smoking 
more than 10 cigarettes per day and for more than 1 year.  
 
 
Tarceva® Tablets 
 
 
Information on the clinical development and use of erlotinib (Tarceva 
tablets) is contained in the Package Insert, Investigator’s Brochure, and 
Guidance for Investigators. The package insert includes the NSCLC and 
pancreatic cancer indications. These documents should be reviewed prior to 
initiating the study. 
 
4.2.1.1           Formulation 
 
 
The pharmaceutical preparations of Tarceva® are formulations containing 
the hydrochloride salt.  Tarceva® is supplied as tablets containing erlotinib 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 21 
hydrochloride equivalent to 150 mg, 100 mg, and 25 mg of erlotinib.  All tablets 
are round, white, film-coated, bi-convex tablets without markings.  Additional 
information regarding Tarceva® can be found in the Package Insert.   
 
4.2.1.2 
Packaging and Labeling 
 
 
Tarceva® tablets are supplied in blue-white, high-density polyethylene 
(HDPE) bottles of 30 tablets each.   
 
4.2.1.3 
Storage and Handling 
 
 
Tarceva® tablets should be stored between 15°C and 30°C (59°F and 
86°F). 
 
4.2.1.4 
Administration 
Tarceva® tablets should be taken at approximately the same time of day.  
Each Tarceva® dose is to be taken with up to 200 mL (~ 1 cup or 8 oz) of water, 
and should be taken 1 hour before or 2 hours after meals or medications, 
including grapefruit juice, vitamins, and iron supplements.  The entire dose must 
be taken at one time.  If the patient vomits after taking the tablet(s), the dose is 
replaced only if the tablet(s) can actually be seen and counted.   
 
Tarceva® will be supplied by OSI Pharmaceuticals 
 
 
4.2.2 Pemetrexed (Alimta®) 
 
 
All patients will receive Pemetrexed starting first day of radiation and 
continued every 21 days through the radiation. Pemetrexed dose will be 500 
mg/m2 for all patients (unless reduced with 25% because of DLT encountered 
with the first dose level of Erlotinib) and will be given as a 10 min infusion.  
           Creatinine clearance will be calculated each time before administration of 
Alimta and the drug will not be administered if the creatinine clearance is < 45. 
           Patients will also receive Folic Acid (350-1000 µg) that must be given daily 
beginning approximately 5-7 days prior to first dose of Pemetrexed and 
continuing daily until 3 weeks after the last dose of study therapy. Patients will 
receive vit B12 1000 µg 1 dose i.m., 1-2 weeks before the first dose of 
Pemetrexed and will also receive Dexamethasone (4 mg of oral or equivalent) 
given twice daily on the day before, the day of, and the day after each dose of 
Pemetrexed, for rash prophylaxis unless medically contraindicated.  
           Because folic acid and vitamin B12 supplementation has significantly 
reduced the number of episodes of Grade 4 hematologic and Grade 3/4 
nonhematologic toxicities associated with Pemetrexed therapy, a need for 
leucovorin as rescue agents is not anticipated. However, this section provides 
information should rescue be necessary. In clinical trials, leucovorin was 
permitted for CTC grade 4 leukopenia lasting > 3 days, CTC Grade 4 
neutropenia lasting > 3 days, and immediately for CTC Grade 4 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 22 
thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or 
Grade 3 or 4 muscositis. The following intravenous doses and schedules of 
leucovorin were recommended for intravenous use: 100mg/m2 once, followed by 
50 mg/m2 intravenously every 6 hours for 8 days. 
 
4.2.2.1  
Description and Handling Instructions 
 
 
Pemetrexed: The freeze-dried drug product is composed of Pemetrexed  
and mannitol in a 1:1 ratio. Sodium hydroxide and/or hydrochloric acid solution 
may be added during processing to adjust the pH. Each 500mg vial contains 
Pemetrexed disodium equivalent to 510 mg of the base compound, Pemetrexed. 
The vial contains 2% excess to facilitate the withdrawal of the label amount the 
500-mg vial. The drug product is stable when stored at room temperature. 
 
4.2.2.2 
Dosage 
All patients will receive Pemetrexed starting first day of radiation and 
continued every 21 days through the radiation. Administration of more than two 
doses of Pemetrexed in the context of prolonged radiation treatment course due 
to interruptions will be at the discretion of the treating physician. Pemetrexed 
dose will be 500 mg/m2 for all patients, unless reduced with 25% because of 
DLT encountered with the first dose level of Erlotinib. 
 
4.2.2.3 
Administration 
Reconstitute each 100 mg vial with 4.2 mL of 0.9% Sodium Chloride 
Injection (preservative free).  Reconstitute each 500 mg vial with 20 ml of 0.9% 
Sodium Chloride Injection (preservative free).  Reconstitution of either size vial 
gives a solution containing 25 mg/mL.  Gently swirl each vial until power is 
completely dissolved.  The resulting solution is clear and ranges in color from 
colorless to yellow or green-yellow without affecting the product quality.  
Parenteral drug products should be inspected visually for particulate matter and 
discoloration.  If particulate matter is observed do not administer.  The 
reconstituted formulation is in the pH range of 6.8 to 7.5 and is not light sensitive.   
 
Further dilution is required for administration.  The appropriate quantity of 
the reconstituted solution must be further diluted in to a solution of 0.9% Sodium 
Chloride Injection (preservative free), so that the total volume is 100 mL.  
Administer intravenously infusion over 10 minutes.   
 
Reconstitution and further dilution prior to intravenous infusion is only 
recommended with 0.9% Sodium Chloride (preservative free).  Physically 
incompatible with diluents containing calcium, including Lactated Ringer’s 
Injection, USP and Ringer’s Injection, USP and therefore should not be used.   
 
Chemically and physical stability of reconstituted and infusion solution 
were demonstrated for up to 24 hours following initial reconstitution, when stored 
at refrigerated or ambient room temperature and lighting.  When prepared as 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 23 
directed, reconstitution and infusion solutions contain no anti-microbial 
preservatives.  Discard any used portions. 
 
           
Pemetrexed will be supplied by Eli Lilly. 
 
4.2.3 Drug Accountability 
 
 
Drug accountability will be maintained by the Drug monitor. These logs will 
record quantities of study drug received and quantities dispensed to patients, 
including lot number, date dispensed, patient identifier number, patient initials, 
protocol number, dose, quantity returned, balance remaining, and the initials of 
the person dispensing the medication. A sample drug accountability form can be 
found in Appendix 3 
 
 
Unused Tarceva® tablets should be destroyed on-site and OSI should be 
provided with documentation when this has occurred. Unused Alimta will be 
handled in accordance to Eli Lilly’s drug accountability guidelines. 
 
 
4.2.4 Concomitant Medications 
 
 
All concomitant medications will be record as part of the patient’s medical 
history and physical. All supportive therapy for optimal medical care will be given 
during the study period at the discretion of the attending physician(s) within the 
parameters of the protocol and documented as concomitant medication.  
 
4.2.4.1 
Potential Drug-Drug Interactions   
 
 
Erlotinib is both protein bound (92% to 95% in humans) and metabolized 
in the liver by CYP3A4 and, to a lesser extent, CYP1A2, and in the lungs by 
CYP1A1.  A potential for drug-drug interaction exists when erlotinib is co-
administered with drugs that are highly protein bound or that are CYP3A4 and 
CYP1A2 inhibitors/inducers (see Appendix 15).   
 
 
For patients who are being concomitantly treated with a potent CYP3A4 
inhibitor, a dose reduction should be considered in the presence of severe 
adverse events (see dose reduction criteria for erlotinib-related toxicities, pg 33).  
For patients who are being concomitantly treated with a potent CYP3A4 inducer, 
alternative treatments that lack potent CYP3A4-inducing properties should be 
considered.  Grapefruit juice is a CYP3A4 inhibitor that interferes with the 
metabolism of Tarceva.  Therefore, consumption of grapefruit or grapefruit juice 
should be avoided during Tarceva treatment. 
 
 
In addition, altered coagulation parameters and bleeding have been 
reported in patients receiving erlotinib alone and in combination with other 
chemotherapeutic agents and concomitant warfarin-derivative anticoagulants.  

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 24 
The mechanism for these alterations is still unknown.  When warfarin is co-
administered with erlotinib (anytime after Day 5), international normalized ratio 
(INR) and prothrombin time should be closely monitored and the anticoagulant 
dose should be adjusted as clinically indicated. 
            
          The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as 
pH increases. Co-administration of erlotinib with omeprazole, a proton pump 
inhibitor, decreased the exposure to erlotinib (AUC) by 46% and the maximum 
concentration (Cmax) by 61%. There was no change to Tmax or half-life. 
Therefore, drugs that alter the pH of the upper GI tract may alter the solubility of 
erlotinib and hence its bioavailability. Concomitant administration of Tarceva with 
300 mg ranitidine, an H2- receptor antagonist, decreased erlotinib exposure 
[AUC] and Cmax by 33% and 54%, respectively. Therefore, co-administration of 
drugs reducing gastric acid production with Tarceva should be avoided where 
possible. Increasing the dose of Tarceva when coadministered with such agents 
is not likely to compensate for this loss of exposure. 
 
 
Ibuprofen (400 mg qid) can be administered with Alimta in patients with 
normal renal function (creatinine clearance > 80 mL/min), caution should be used 
when administering ibuprofen concurrently with Alimta to patients with mild to 
moderate renal insufficiency (CrCl from 45 to 79 mL/min). Patients with mild to 
moderate renal insufficiency should avoid taking NSAIDs with short elimination 
half-lives for a period of 2 days before, the day of, and 2 days following 
administration of Alimta.  
 
In the absence of data regarding potential interaction between Alimta and 
NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt 
dosing for at least 5 days before, the day of, and 2 days following Alimta 
administration. If concomitant administration of an NSAID is necessary, patients 
should be monitored closely for toxicity, especially myelosuppression, renal, and 
gastrointestinal toxicity 
 
4.2.5 Supportive Therapy 
 
 
Folic Acid, Vitamin B12, Dexamethasone, Leucovorin 
 
 
 
 
Folic Acid (350-1000 µg) must be given daily beginning approximately 5-         
7 days prior to first dose of Alimta and continuing daily until 3 weeks after the 
last dose of study therapy.   
 
  
Vitamin B12 (1000 µg) will be administered as an intramuscular injection 
approximately 1 week prior to first dose of Alimta and repeated approximately 
every 9 weeks until 3 weeks after the last dose of study therapy. 
 
Dexamethasone (4 mg of oral or equivalent) given twice daily should be 
taken on the day before, the day of, and the day after each dose of 
pemetrexed, for rash prophylaxis unless medically contraindicated. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 25 
 
 
Because folic acid and vitamin B12 supplementation has significantly 
reduced the number of episodes of Grade 4 hematologic and Grade 3/4 
nonhematologic toxicities associated with Alimta therapy, a need for leucovorin 
as rescue agents is not anticipated. However, this section provides information 
should rescue be necessary. In clinical trials, leucovorin was permitted for CTC 
grade 4 leukopenia lasting > 3 days, CTC Grade 4 neutropenia lasting > 3 
days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated 
with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following 
intravenous doses and schedules of leucovorin were recommended for 
intravenous use: 100mg/m2 once, followed by 50 mg/m2 intravenously every 6 
hours for 8 days.   
 
 
Hematopoietic Growth Factors 
 
 
The routine use of erythropoietic growth factors is strongly discouraged. 
Patients may receive erythropoietin or darbepoetin for anemia with Hb below 
11g%. Granulocytic growth factors (e.g., filgrastim, pegfilgrastim) should be used 
only for neutropenic fever. Prophilactic antibiotic treatment with a quinolone of 
choice, at the discretion of the treating physician, should be administered for 14 
days after second dose of pemetrexed if the patient reaches an ANC nadir of < 
1000 / mm3 with the first dose of chemotherapy. 
 
5.0 
STUDY DESIGN 
 
 
Phase I/II clinical trial. Patients with recurrent HNSCC or second primary 
will receive re-irradiation and the radiosensitizing drugs Pemetrexed and Erlotinib 
beginning with the first day of RT. Erlotinib dose will be escalated during the 
Phase I portion of the study.  The treatment dose of erlotinib given concurrent 
with RT will be maintained until mucositis and dermatitis reduce to grade I. 
Maintenance dose of Erlotinib adjusted per smoking status will then be started 
and will be continued until disease progression, unacceptable toxicity (see dose 
modification chart on section 7) or to a maximum of 2 years. Patients who had 
the erlotinib dose reduced because of erlotinib-related skin rash,during the CRT 
will continue the same dose of erlotinib as maintenance treatment. If this dose is 
lower than 75 mg daily, the patient will be discontinued from the study treatment. 
No randomization.  
 
 
Phase I dosing schedule of Erlotinib to reach MTD refer to safety endpoint 
in section 11.0 regarding DLT’s. 
 
Dose 1 
100 mg 
Dose 2 
125 mg 
Dose 3 
150 mg 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 26 
 
If 2 or 3 of the original 3 patients (or 3+ out of 6) of the first set of patients 
have a DLT at erlotinib (100 mg) then both pemetrexed and erlotinib both will be 
reduced by 25%.   
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 27 
 
Pre-treatment  
0-week1 
Radiotherapy 
6 weeks 
Post  RT 
Week 4 
Post  RT 
Week 8 
Follow up 
Erlotinib 
concomitant 
 
Daily* 
 
 
 
 
 
 
Radiotherapy 
 
daily 
 
 
 
 
 
Pemetrexed 
 
500 mg/m2 q 
21 days** 
 
 
Folic Acid 
350-1000 µg, 
5-7 days prior 
to 1st dose of 
pemetrexed  
Daily and 
continue 3 
weeks after last 
pemetrexed  
 
 
Vitamin B12 
1000 µg i.m. 
single dose, 1 
week prior to 
CRT. 
 
 
Dexamethsone 
 
4 mg bid, days -
1, 0 and 1 of 
pemetrexed 
treatment. 
 
 
Erlotinib 
maintenance 
 
 
*Daily for up to 2 years 
Labs 
X 
X weekly 
X 
X 
q 3 mo first 2 y, q 
6mo 3rd year, 
yearly then. 
ECG, 
ECHO/MUGA 
X 
 
 
 
 
PET/CT  
X 
 
 
X  
q 6 mo for 2 years 
then yearly 
(optional)*** 
CT/MRI tumor 
 
 
X 
X  
q 6 mo for 2 years 
then yearly 
Swallowing 
studies/ 
swallowing 
survey (MDADI) 
X 
 
X 
 
at 5-7 mo and 11-
13 mo 
QOL surveys 
(FACT-H&N and 
PSS-HN)  
X 
 
X 
 
at 5-7 mo 11-13 mo 
and 23-25 mo 
Nutrition 
X 
X - weeks 2,4,6 
X 
 
 at 6 mo and then 
as needed 
* Erlotinb dose given concurrent with RT will be continued after the end of RT until dermatitis and mucositis reduce 
to grade I; Maintenance dose of erlotinb will then be started.   
Patients will receive all necessary supportive care. In particular, we will offer preventive PEG placement before the 
beginning of treatment or later during the treatment for weight loss of more than 10% of initial body weight. 
**Administration of more than two doses of Pemetrexed in the context of prolonged radiation treatment course due to 
interruptions will be at the discretion of the treating physician. 
***PET/CT should be done in the same time with the CT neck with contrast whenever possible and approved by 
Medical Insurance.  
 
Additional pre-treatment evaluations 
1) Dental evaluation and treatment.   
2) Nutritional evaluation for a prophylactic gastrostomy (PEG) tube placement anytime prior to treatment. 
3) Swallow evaluation and instruction in swallowing home therapy. 
4) Quality of life assessment and surveys. 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 28 
6. 
CLINICAL AND LABORATORY EVALUATIONS 
6.1 
Pre-Treatment mandatory evaluations 
 
Investigations 
Timing 
History, Physical Examination and 
Other Evaluations 
 
Medical history 
 
PE 
 
Height 
 
Weight  
 
BSA 
 
ECOG PS 
 
Clinical tumor 
measurements 
 
Prior therapy 
Within 7 days prior to registration 
Vital Signs 
 
Pulse1  
 
BP1 
 
Temperature1 
Within 7 days prior to registration 
Hematology 
 
 
Full blood count with hemoglobin, platelets and 
differential1 
Biochemistry 
 
Na and K 
 
BUN 
 
Creatinine 
 
Total bilirubin 
 
Alkaline 
Phosphatase 
 
Creatinine 
Clearance 
 
AST   
 
ALT 
 
Total protein 
 
Albumin 
 
Magnesium 
 
Pregnancy Test4 
 
Radiology2 
 
CT scan or  MRI 
Within 14 days prior to registration 
 
PET/CT scan  
Within 28 days prior to registration 
Other Investigations 
 
ECHO/MUGA3  
 
 
Within 6 months prior to 
registration 
 
 
ECG3 
Within 14 days prior to registration 
Nutrition  
 
Consult and evaluation for PEG tube placement 
Prior to beginning of CRT 
Dentist  
 
Evaluation and treatment 
Prior to beginning CRT 
Quality of life evaluations 
 
Surveys: FACT-H&N (see Appendix 9), PSS-HN (see 
Appendix 10), MDADI (see Appendix 11) 
Prior to beginning CRT 
Speech pathology 
 
Evaluation of speech and swallowing 
Prior to beginning CRT 
Signs, Symptoms and Toxicities5 
Baseline evaluation should document residual toxicity from 
previous therapy and any current signs and symptoms 
Within 24 hours prior to CRT 
Tissue/specimen submission6 
Tumor and normal tissue biopsy, buccal mucosa scraping  and 
blood collection (see Appendix 1) 
Within 28 days prior to CRT 
Smoker status 
 Complete the sample case report (see Appendix 2)) 
Within 7 days prior to CRT 
1. 
To be repeated 72 hours prior to the start of CRT. 
2. 
To ensure comparability, the baseline radiographs/scans and subsequent radiographs/scans to assess response should be 
performed preferably using identical techniques (eg, scans performed immediately following bolus contrast administration 
using a standard volume of contrast, the identical contrast agent and preferably the same scanner).  The same method, 
radiological or physical, should be employed and assessed by the same individual on each occasion if possible. 
3. 
only if clinically indicated. 
4. 
For women of childbearing potential only. 
5. 
Signs, symptoms and toxicities will be graded according to the NCI CTCAE, v3.0. See Appendix 8 
6. 
If patient consented to participate to tumor/blood component of the study 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 29 
6.2 
Mandatory evaluations during treatment and post-treatment 
 
Pre- 
Study 
entry 
Weekly 
during 
treat. 
From end of CRT 
From start of treatment 
Assessments 
 
 
         Weeks 
6 mos 
9 mos  12 mos  
Follow 
up  
2 
4 
6 
8 
Evaluations 
 
 
 
 
 
 
 
 
 
 
Complete history/physical 
Xa 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xk 
Medical Oncology Exam 
Xa 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xk 
Pulse/ BP/ 
Weight/BSA/Temp/Height  
Xa 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xk 
ECOG Performance Status  
Xa 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xk 
Protocol –specific adverse events-
see 7.4b 
Xa 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xk 
Clinical tumor measurement  
Xa 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xk 
Dentist 
Xp 
 
 
 
 
 
 
 
X 
 
Imaging 
 
 
 
 
 
 
 
 
 
 
PET /CT scan 
Xe 
 
 
 
 
X 
Xo 
Xo 
Xo 
Xo 
ECG 
 
Xc,g 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
ECHO/MUGA 
Xu,g 
 
 
 
 
 
 
 
 
 
CT Scan or MRI of tumor/primary 
site 
Xc 
 
 
X 
     
X 
X 
Xg 
X 
Xk 
Laboratory Studies  
 
 
 
 
 
 
 
 
 
 
CBC, Differential, Platelets  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Creatinine, BUN  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Serum Electrolytes, MG, Ca++, TB, 
AST/ALT,  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Alk Phos, TP/Albumin  
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Creatinine clearence 
Xa 
 Xm 
 
 
 
 
 
 
 
 
Pregnancy test 
Xa,r 
 
 
 
 
 
 
 
 
 
Quality of life assessments 
 
 
 
 
 
 
 
 
 
 
Swallowing studies/ 
swallowing survey (MDADI) 
Xp 
 
 
X 
 
 
Xq 
 
Xq  
 
 QOL and swallowing surveys 
(FACT-H&N, PSS-HN, MDADI ) 
Xp 
 
 
X 
 
 
 
Xq  
 
Xq  
24 mo 
Smoking status 
Xs 
 
 
X 
 
X 
X 
X 
X  
X  
Nutrition evaluation 
Xp 
Xf 
Xg 
X 
Xg 
X 
X 
 
X 
 
 Buccal muc. scraping / blood- 
correlatives  
Xt,l 
 
Xe,l 
Xi,l 
Xi,l  
Xi,l 
Xi,l 
Xi,l 
Xi,l 
Xi,l 
Tissue (normal/tumor) 
Xe,l 
 
 
Xi,l 
Xi,l 
Xi,l 
Xi,l 
Xi,l 
Xi,l 
Xi,l 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 30 
               a    within 7 days prior to registration 
               b    toxicities will be graded according to the NCI CTCAE, v3.0. 
               c    within 14 days prior to registration 
               d    from patients who have consented to participate in the tissue/blood component of the study. 
               e     within 28 days prior to registration 
                f    weeks 2, 4, and 6 of CRT 
               g    if clinically indicated  
               h    last 2 weeks of treatment for FACT-H&N and PSS-HN only. 
                i    if tumor progression or recurrence 
                j   follow up will be performed every 3 mo in year two, every 6 mo in year three and yearly afterwards. 
               k    follow up CT scans or MRI will be performed every 6 mo in year 2 and yearly afterwards. 
                l      if patient has consented to participate in the tissue/blood component of the study. 
               m    before each administration of pemetrexed. 
               o     optional 
               p     prior to beginning CRT                                                                                            
               q     performing the evaluation one month earlier or later is acceptable 
               r     for women of childbearing potential only 
               s     within 7 days prior to CRT 
               t      within 28 days prior to CRT 
               u     within 6 months prior to registration 
 
 
Quality of Life Assessments 
 
 
 
The Performance Status Scale for Head and Neck Cancer (PSS-HN) (see 
Appendix 10) consists of assessment of three functions (subscales): Normalcy of 
Diet, Eating in Public, and Understandability of Speech. The site research nurse 
will administer the PSSHN. Interviewers are encouraged to be sensitive to each 
patient's demeanor. If patients appear particularly uncomfortable answering a 
question, they will be informed that they can skip that question. Similarly, 
interviewers will give patients a short break if the patient appears fatigued or 
otherwise in need of a few minutes break. The interviewer rates the patient on 
each scale based on the patient’s responses to targeted questions. The PSS-HN 
takes approximately 5 minutes to complete. It will be administered by the site 
research nurse initially before the beginning of treatment, then during the last 2 
weeks of treatment and then at 1 mo, 5-7 mo, 23-25 mo.  
 
            Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N) 
(see Appendix 9) is a multidimensional, QOL instrument specifically designed for 
use with HNC patients that the patient can complete in 5-10 minutes. The site 
research nurse is encouraged to be sensitive to each patient's demeanor. If 
patients appear particularly uncomfortable answering a question, they will be 
informed that they can skip that question. Similarly, interviewers will give patients 
a short break if the patient appears fatigued or otherwise in need of a few 
minutes break. It will be administered by the site research nurse initially before 
the beginning of treatment, then during the last 2 weeks of treatment and then at 
1 mo, 5-7 mo, 11-13 mo and 23-25 mo.  
 
            The MD Anderson Dysphagia Inventory (MDADI) (see Appendix 11) is a 
survey specifically designed to assess dysphagia.  It contains 20 questions 
directly addressing the swallowing function and several other general questions. 
It will be applied by the nurse in the Speech and Swallowing Section of the 
Department of ENT, initially once pre-treatment and then post-treatment, at 1 mo, 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 31 
5-7 mo, 11-13 mo (when patients will also have direct functional assessment of 
swallowing by Dr. Susan Butler). 
 
Interviewers are encouraged to be sensitive to each patient's demeanor. If 
patients appear particularly uncomfortable answering a question, they will be 
informed that they can skip that question. Similarly, interviewers will give patients 
a short break if the patient appears fatigued or otherwise in need of a few 
minutes break. It takes approximately 5-10 minutes to complete this survey. 
 
7. 
DOSE MODIFICATION / TOXICITY MANAGEMENT 
 
7.1 
Radiation adverse events 
 
 
This study will utilize the Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0 for grading of all adverse events (appendix 8).  
 
 
Grade 3-4 therapy-induced mucositis and/or dysphagia, which are 
enhanced by radiosensitizing drugs, are expected to develop in majority of 
patients. Nutritional evaluation prior to the initiation of therapy for a prophylactic 
gastrostomy (PEG) tube placement is highly recommended. Placement of a 
feeding tube should be recorded, as should use of a feeding tube during and 
after treatment (e.g., greater than or less than 50% of nutrition by tube).  
 
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, 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, and cervical myelopathy (<1% with restriction of spinal cord 
dose to ≤ 45 Gy). 
 
7.2.     Specific drug-related adverse event 
 
7.2.1 Erlotinib 
 
          Adverse events associated with drug administration 
 
          The most frequently reported undesirable effects in cancer patients 
following administration of oral erlotinib as monotherapy are: dermatosis or rash 
(75%), diarrhea (54%), fatigue (52%), nausea (33%) and vomiting (23%). 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 32 
           Special Warnings and Special Precautions for Use 
 
Interstitial Lung Disease (ILD): The overall incidence of ILD-like events in 
approximately 32,000 erlotinib-treated patients from all studies (including 
uncontrolled studies and studies with concurrent chemotherapy) was 
approximately 1.1%. When cases from a postmarketing surveillance study from 
Japan are excluded, the incidence from rest of world was approximately 0.6% 
 
Gastrointestinal Perforation: Patients receiving erlotinib are at increased risk of 
developing gastrointestinal perforation, which was observed uncommonly. 
Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, 
and/or taxane based chemotherapy, or who have prior history of peptic 
ulceration or diverticular disease are at increased risk.  Erlotinib should be 
permanently discontinued in patients who develop gastrointestinal 
perforation. 
 
Patients with Hepatic Impairment: 
In a pharmacokinetic study (Study OSI-774-104) in patients with 
moderate hepatic impairment (Child-Pugh B) associated with significant 
liver tumor burden, 10 of 15 patients died on treatment or within 30 days 
of the last erlotinib dose.  Six of the 10 patients who died 
had baseline total bilirubin > 3 x ULN suggesting severe hepatic 
impairment. None of the deaths were considered to be related to erlotinib 
treatment by the investigators. However, treatment with erlotinib should 
be used with extra caution in patients with total bilirubin > 3 x ULN. This study will 
not enroll patients with significantly abnormal liver function tests, per inclusion 
criteria. 
 
 Bullous and Exfoliative Skin Disorders: Bullous, blistering and exfoliative skin 
conditions have been reported, including very rare cases suggestive of Stevens-
Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal. 
Erlotinib treatment should be interrupted or discontinued if the patient develops 
severe bullous, blistering, or exfoliating conditions. 
 
Ophthalmologic Disorders: rare cases of corneal perforation or ulceration were 
reported. Erlotinib therapy should be interrupted or discontinued if patients 
present with acute/worsening ocular disorders such as eye pain. 
Infrequent occurrences of keratitis have been observed during erlotinib 
treatment. Isolated reports of uveitis and orbital cellulitis have been reported in 
patients receiving erlotinib therapy. Patients who develop irregular or excessive 
eyelash growth should be monitored for eye symptoms such as eye pain. Careful 
removal of in-growing/abnormal/elongated eyelashes should be considered if 
increased growth leads to scratching and/or irritation of the cornea. Patients with 
a prior history of ocular disorders or additional identifiable risk factors should be 
closely monitored by a physician. Patients with significant ophthalmologic 
abnormalities are excluded from this study. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 33 
 
 
If a patient experiences several toxicities, dose adjustments are to be 
made based on the greatest degree of toxicity (ie, reducing the dose to the 
lowest level).  If significant toxicity is still apparent, the dose may be reduced a 
second time.  Any patient who fails to tolerate treatment of 50 mg/day will be 
withdrawn from the study as indicated in the Table below. 
 
 
Antidiarrheal and antirash medications may be introduced if clinically 
indicated.  Previous Phase I and II studies have demonstrated the frequency and 
severity of diarrhea can be managed with loperamide.  The recommended dose 
of loperamide listed in the Table below is 4 mg at first onset, followed by 2 mg 
every 2 to 4 hours until diarrhea resolves for 12 hours. 
 
 
Skin rash or dermatosis has been observed during the first several days of 
treatment with Tarceva® in many patients and has been noted to diminish in 
severity despite continued treatment.  No controlled clinical trials have been 
conducted to allow definitive recommendations on the treatment of Tarceva®-
related rash. Patients who develop a rash characterized by pustules or raised red 
areas may be treated with oral minocycline (100 mg BID for 7 – 10 days to a 
maximum of 150 mg BID for 7 – 10 days as clinically indicated) at the discretion 
of the Investigator.  Minocycline is known to interfere with anticoagulants and oral 
contraceptives.  Patients treated with minocycline who are taking anticoagulants 
and/or oral contraceptives should be monitored accordingly.  Moreover, 
Minocycline may decrease effectiveness of oral contraceptives with concurrent 
use.  An additional form of birth control, such as barrier protection, is 
recommended.   
 
Tarceva® dosing should be discontinued for any severe toxicity that does 
not respond to treatment or failure to recover within 14 days from hematological 
toxicity attributable to Tarceva® 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 34 
DOSE REDUCTION CRITERIA FOR ERLOTINIB-RELATED TOXICITIES 
Toxicity 
(NCI CTCAE v3.0) 
Dose Modification a 
Diarrhea 
Grade 1 or 2 
None.  Initiate therapy with loperamideb  
Grade 3cor 4c 
Interrupt Erlotinib until resolution to < grade 2 and then restart 1 dose level 
lowere. 
Rash 
Grade 1 
None 
Grade 2 
None.  If rash persists and is interolable or worsens over 10 – 14 days, then 
reduce by 1 dose level and initiate treatment as outlined.d,e  
Grade 3 c 
Reduce by 1 dose lowere.  If rash persists or worsens over 10- 14 days, then 
interrupt erlotinib until resolution to < grade 2 and then restart 1 dose level 
lowere. 
Grade 4 
Permanently discontinue Erlotinib 
Interstitial Lung Disease 
Any Grade 
If ILD is suspected, erlotinib should be interrupted immediately  
pending diagnostic evaluation.  If ILD is diagnosed, Erlotinib should be 
discontinued permanently and appropriate treatment instituted as necessary.  
Other Toxicities 
Grade 1 or 2 
None 
Grade 3c 
Interrupt Erlotinib until resolution to < grade 2 and then restart 1 dose level 
lowere.  
Grade 4 
Permanently discontinue Erlotinib 
a) 
Doses that have been reduced for toxicity may be re-escalated one dose level only if the toxicity abates 
or returns to baseline severity and the investigator believes it is in the best interest of the patient.  
Doses that have been reduced from the highest dose level to the lowest may not be escalated back to 
the highest dose level.  Any patient who fails to tolerate treatment at 50 mg/day will be discontinued 
from the study. 
b) 
The recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every 2 to 4 hours until 
diarrhea-free for 12 hours. 
c) 
If the event does not resolve to < grade 2 within 14 days, Erlotinib will be discontinued  
d) 
Dermatosis has been observed during the first several days of treatment with Erlotinib in many patients 
and has been noted to diminish in severity despite continued treatment.  No controlled clinical trials 
have been conducted to allow definitive recommendations on the treatment of Erlotinib-related rash. 
Patients who develop a rash characterized by pustules or raised red areas may be treated with oral 
minocycline (100 mg BID for 7 – 10 days to a maximum of 150 mg BID for 7 – 10 days as clinically 
indicated) at the discretion of the Investigator.  Minocycline is known to interfere with anticoagulants and 
oral contraceptives.  Patients treated with minocycline who are taking anticoagulants and/or oral 
contraceptives should be monitored accordingly. 
e) 
The erlotinib dose levels for the CRT portion of the treatment are the same as outlined in the dose 
escalation treatment planning (see 4.2.1) and depending on the initial dose, the next dose will be 
lowered with 25 mg. For the maintenance portion of the treatment the dose levels will be dependent on 
the smoking status of the patient at the time of maintenance treatment.: 1) for non- smokers the dose 
levels will be similar with the above (the CRT portion of the treatment) while for smokers the dose 
reduction will be in 50 mg decrements.   
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 35 
7.2.2 Pemetrexed 
In NSCLC where Pemetrexed is FDA approved the most common reported 
adverse events are as follows: 
The most common adverse events with pemetrexed for the treatment of patients 
with NSCLC are (33): 
The most common adverse events (grades 3 and 4) 
Adverse event 
% 
anemia 
8 
leukopenia 
5 
neutropenia 
5 
fatigue 
16 
Thrombosis /embolism 
3 
Cardiac ischemia 
3 
anorexia 
5 
dyspnea 
18 
Chest pain 
7 
The most common clinically relevant adverse events (all grades) 
fatigue 
87 
anorexia 
62 
nausea 
39 
constipation 
30 
vomiting 
25 
diarrhea 
21 
Stomatitis / pharyngitis 
20 
dyspnea 
72 
Chest pain 
38 
Neuropathy /sensory 
29 
Infection without neutropenia 
23 
rash 
17 
For patients who develop or have baseline clinically significant pleural or peritoneal effusions (on 
the basis of symptoms or clinical examination) before or during initiation of Alimta therapy, 
consideration should be given to draining the effusion prior to dosing.  However, if, in the 
investigator's opinion, the effusion represents progression of disease, the patient should be 
discontinued from study therapy. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 36 
Therapy for Diarrhea 
 
            In the event of CTC Grade 3 or 4 diarrhea, the following supportive 
measures are allowed should be used:  hydration, octreotide, and antidiarrheals. 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with 
fever or severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be 
prescribed.  Patients with severe diarrhea or any diarrhea associated with severe 
nausea or vomiting must be hospitalized for intravenous hydration and 
correction of electrolyte imbalances.  
Therapy for Patients with Diarrhea and Febrile Neutropenia 
Patients experiencing febrile neutropenia, especially with diarrhea, should be 
managed in a hospital setting according to standard procedures, with the urgent 
initiation of intravenous antibiotic therapy. 
 
DOSE REDUCTION CRITERIA FOR PEMETREXED-RELATED TOXICITIES 
 
            Pemetrexed therapy should be discontinued if a patient experiences any 
hematologic or nonhematologic grade 3 or 4 toxicity after 2 dose reductions 
(except grade 3 transaminase elevations) or immediately if grade 3 or 4 
neurotoxicity is observed.  
            Patients receiving pemetrexed therapy should be monitored for nadir and 
recovery before each dose and on days 8 and 15 after pemetrexed 
administration with a complete blood count, including a differential and platelet 
count. Periodic blood counts and chemistry tests should be performed to 
evaluate hematologic, renal, and hepatic function.  
            Dose adjustments at the start of a subsequent cycle should be based on 
nadir hematologic counts of maximum nonhematologic toxicity from the 
preceding cycle of therapy. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 37 
 
Toxicity 
(NCI CTCAE v3.0) 
Dose Modification for Pemetrexed  
Hematologic toxicity 
Nadir ANC< 500/mm3 and 
nadir platelets > 50.000/mm3 
 
                       75% of previous dose 
Nadir platelets < 50.000/mm3 
regardless nadir ANC  
  
                       50% of previous dose          
Non-hematologic Toxicities  
Excluding Neurotoxicity 
Grade 1 and 2  
                       100% of previous dose 
Any grade 3 or 4 except 
mucositis and except grade 3 
transaminase elevation 
   
                       75% of previous dose 
Any diarrhea requiring 
hospitalization (irrespective 
of grade) or grade 3 or 4 
diarrhea 
 
                       75% of previous dose 
Grade 4 mucositis lasting at 
least 3 days 
                       75% of previous dose 
Neurotoxicity 
     CTC grade 
Grade 0-1 
                      100% of previous dose           
Grade 2 
                      100% of previous dose           
 
If on the day of scheduled treatment with Pemetrexed the absolute neutrophil 
count (ANC) is < 1200, or platelet count is < 75,000, hold treatment until ANC ≥ 
1200 and platelets are > 75,000, then treat at a dose adjusted according to the 
ANC and /or platelet nadir. 
 
7.3 
Phase I portion of the study 
 
 
For the Phase I portion of this protocol a standard 3+3 design will be used 
Erlotinib dose will be escalated from 100 mg to 125 mg and 150 mg po daily or 
until DLT develops in 2/6 patients. If 2 or 3 of the original 3 patients (or 3+ out of 
6) of the first set of patients have a DLT at erlotinib (100 mg) then both 
pemetrexed and erlotinib will be reduced by 25%.    
           After the third patient at a given dose is accrued, enrollment will be 
suspended until 6 weeks after that patient completes therapy or until his 
mucositis or any other toxic effect at the end of treatment becomes less or equal 
to grade II, whichever comes first, to allow for monitoring of signs and symptoms 
of toxicity. 
            
            Dose-Limiting Toxicity (DLT) – For purpose of escalating/de-escalating 
the dose of erlotinib/ Pemetrexed, dose-limiting toxicity is defined as grade IV 
mucositis or dermatitis lasting more than 3 days, or grade III or IV mucositis 
lasting 6 weeks or longer from the completion of therapy, or any other grade III or 
IV toxicity, regardless of duration and which do not respond to treatment 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 38 
(diarrhea, rash) or need to delay treatment for more than 2 weeks because of 
any type of toxicity during the re-irradiation segment of the treatment. Erlotinib 
and pemetrexed administration should be stopped if interstitial lung disease 
develops.  Grade IV hematologic toxicity should not alter erlotinib dose or 
escalation. Pemetrexed dose should be adjusted accordingly. 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 39 
7.4 Essential protocol-specific adverse events to be collected  
 
 
Category 
AE term 
Ref. 
page 
in 
CTCAE 
At baseline 
Gastro-intestinal 
Dysphagia 
21 
Pulmonary/ Upper 
Respiratory 
Edema, larynx (includes need or existence of 
tracheostomy) 
57 
During Treatment 
Pulmonary/ Upper 
Respiratory 
Edema, larynx (includes need or existence of 
tracheostomy) 
57 
Gastro-intestinal 
Dysphagia 
 
Diarrhea 
 
Dermatology/Skin 
 
Pruritus/Itching 
21 
Rash/desquamation [face (out of RT field), trunk, 
extremities] 
15 
 
Rash: Acne/acneiform 
15 
Nail changes 
15 
Rash inside the RT field: dermatitis associated with 
radiation- Select: Radiation (radiation dermatitis may be 
exacerbated by erlotinb and pemetrexed, but in-field skin 
changes are graded using the radiation scale) 
15 
Rash inside the RT field: dermatitis associated with 
radiation- Select: Chemoradiation 
15 
During Follow up 
 
 
Auditory 
 
Hearing 
2 
Pulmonary/Upper 
Respiratory 
Edema, larynx (includes need for tracheostomy) 
57 
Gastrointestinal 
Dysphagia (difficulty swallowing)  
21 
Mucositis/stomatitis (clinical exam)- [specify oral cavity, 
pharynx, or larynx primary site] 
24 
Dermatology/Skin 
Rash/desquamation [for late effects/scarring out 
of RT field – face, trunk, or extremities] 
15 
 
Induration/fibrosis (skin and subcutaneous tissue) 
44 
 
Osteonecrosis (includes necrosis of mandible, maxilla, 
skull) 
45 
Musculoskeletal/ 
Soft Tissue 
Soft tissue necrosis (MUCOSAL ulceration 
requiring wound care, hyperbaric, or surgical 
intervention) 
46 
Musculoskeletal/ 
Soft Tissue 
Soft tissue necrosis (DERMIS/SOFT TISSUE 
ulceration requiring wound care, hyperbaric, or 
surgical intervention) 
46 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 40 
8. 
CRITERIA FOR STUDY DISCONTINUATION 
 
 
Patients should be discontinued from the study treatment in the following 
instances: 
 
 Progression of disease 
 Inability to tolerate erlotinib dose of 50 mg/day in CRT  
 Inability to tolerate erlotinb dose of 75 mg /day for both non-
smokers and smokers in the maintenance portion of their treatment 
 Patients who require more than 2 weeks break from RT because of 
toxicity in the re-irradiation segment of the treatment 
 Medical or ethical reasons, or noncompliance 
 Patient request 
 Patient death 
 
The patients may be discontinued from the follow-up assessments for the 
following reasons: 
 Patient refusal 
 Patient’s withdrawal of consent 
 Patient death 
 Patient noncompliance 
 Patients who were unable to conclude the CRT portion of the 
protocol 
 
 
9. 
REPORTING OF ADVERSE EVENTS 
 
9.1 
Adverse Event and Reporting Definitions 
 
 
An adverse event or adverse experience is any untoward medical 
occurrence in a clinical investigation patient who is administered a medicinal 
product.  An adverse event can be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  Pre-existing 
conditions that increase in frequency or severity or change in nature during or as 
a consequence of use of a drug are also considered as adverse events.  Adverse 
events may also include pre- or post-treatment complications that occur as a 
result of protocol-mandated procedures (eg, invasive procedures such as 
biopsies). 
  
An AE does not include: 
 Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
transfusion).  The condition that leads to the procedure is the adverse 
event 
 Situations where an untoward medical occurrence has not occurred (eg, 
hospitalization for elective surgery, social and/or convenience admissions) 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 41 
 Overdose of either study drug or concomitant medication without any 
signs or symptoms unless the patient is hospitalized for observation. 
 
 
The relationship to study drug therapy should be assessed using the 
following definitions: 
 
Not Related:  Evidence exists that the AE has an etiology other than the 
study drug (eg. pre-existing condition, underlying disease, intercurrent 
illness, or concomitant medication). 
 
Possibly/Probably Related:  A temporal relationship exists between the 
event onset and administration of the study drug.  It cannot be readily 
explained by the patient’s clinical state, intercurrent illness or concomitant 
therapies.  In case of cessation or reduction of the dose, the event abates 
or resolves and reappears upon re-challenge.  It should be emphasized 
that ineffective treatment should not be considered as causally related in 
the context of AE reporting.   
 
 
A serious adverse event is defined as any adverse drug experience 
occurring at any dose that results in any of the following outcomes:  
 
 Death 
 Life-threatening situation (patient is at immediate risk of death) 
 Inpatient hospitalization or prolongation of existing hospitalization 
(excluding those for study therapy, disease-related procedures, palliative 
or hospice care, or placement of an indwelling catheter, unless associated 
with other serious events) 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect in the offspring of a patient who received 
study drug 
 Other:  Important medical events that may not result in death, be 
immediately life-threatening, or require hospitalization, may be considered 
an SAE when, based upon appropriate medical judgment, they may 
jeopardize the patient or may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
Examples of such events are: 
Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
Blood dyscrasias or convulsions that do not result in hospitalization 
Development of drug dependency or drug abuse 
 
For the Phase 1 portion of the study:  All adverse events should be reported to 
the coordinating site within 24 hours of learning of the event. 
 
A teleconference between all site Principal Investigator’s will be held at least 
monthly to review toxicity data. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 42 
For the Phase 2 portion of the study:  All serious adverse events should be 
reported to the coordinating site within 24 hours of learning of the event.  For all 
other events, the adverse events log should be sent to the coordinating site 
within 5 business days of the patient being seen. 
 
9.2 
Reporting of Serious Adverse Events Associated with Erlotinib 
 
 
All serious adverse events that are considered related to Erlotinb 
treatment must be recorded on a MedWatch 3500 Form (see Appendix 4) and 
faxed within one business day to:   
 
 
OSI Drug Safety 
Fax number: 303 546 7706 
 
MedWatch 3500 Reporting Guidelines: 
 
 
Note: MedWatch 3500 forms and other information related to MedWatch 
reporting are available at http://www.fda.gov/medwatch/index.html and in Appendix 
4. 
 
 
In addition to completing appropriate patient demographic, suspect 
medication and reporter information, the report should include the following 
information within the Event Description of the MedWatch 3500 form: 
 
- Protocol description (and number, if assigned) 
- Description of event, severity, treatment, and outcome if known 
- Supportive laboratory results and diagnostics 
- Investigator’s assessment of the relationship of the adverse event to 
each investigational product and suspect medication 
 
 
 
For questions related to safety reporting, contact OSI Drug Safety at 
303-546-7869.   
 
 
Additional reporting requirements for grade 4 and grade 5 events: all 
grade 4 and grade 5 adverse events will be reported via the Safety and Toxicity 
Review Committee (STRC) notification procedure(see Appendix 5). 
 
 
  9.3 Reporting of Serious Adverse Events Associated with Pemetrexed 
         
Study site personnel must notify Lilly or its designee in 24h of any “serious” 
(defined below) adverse event experienced by a patient.   
 
Serious events are defined as those that result in: 
 Death. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 43 
 Initial or prolonged inpatient hospitalization. 
 A life-threatening situation (where the patient is at immediate 
risk of death). 
 Severe or permanent disability. 
 Congenital anomaly. 
 Or, is significant for any other reason. 
            Serious adverse events will be collected for 30 days after the last dose of 
study drug and serious adverse events occurring 30 days after a patient is 
discontinued from the study will NOT be reported unless the investigator feels 
that the event may have been caused by the study drug or a protocol procedure.  
Study-specific clinical outcomes of death because of disease progression are 
exempt from serious adverse event reporting, unless the investigator deems 
them related to use of the study drug.  Hospitalization for study drug 
administration is not a serious adverse event. 
            In general, serious adverse events assessed as clearly being due to 
disease progression and not due to study drug(s) should be excluded from 
adverse event reporting. However, in cases where the specificity or severity of an 
event is not consistent with the risk information, the event should be reported. 
 
            Global Product Safety Fax Number for all SAEs for Pemetrexed is:   
  1-866-644-1697 or 317-453-3302. 
 
 
10. 
EVALUATION OF RESPONSE 
 
 
We will use RECIST (Response Evaluation Criteria In Solid Tumors) (see 
Appendix 7) for evaluation of response. For the purposes of this study, patients 
should be evaluated for response at 4 weeks after completion of RT, and then 
every 6 mo. In addition to a baseline CT scan/MRI scan, confirmatory scans 
should be obtained at 4 weeks, 8 weeks and every 6 mo afterward. These 
techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously. PET/CT scans will be also performed at 8 weeks initially and then 
in the same time with CT scans (optional). PET/CT will not be used to define 
response, but mainly for early detection of relapse, second malignancies, distant 
metastasis. 
 
10.1    Definitions 
 
Measurable Disease and Non-measurable disease 
 
     Will be defined by Recist 1.1 criteria.  
 
 
Target Lesions 
 
  
All measurable lesions up to a maximum of two lesions per organ and five  

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 44 
  
lesions in total representative of all involved organs should be identified as 
 
target lesions and recorded and measured at baseline.  Target lesions  
 
  
should be selected on the basis of their size (lesions with the longest  
 
  
diameter) and their suitability for accurate repeated measurements (either   
  
by imaging techniques or clinically).  A sum of the longest diameter (LD)   
  
for all target lesions will be calculated and reported as the baseline sum  
 
  
LD. The baseline sum LD will be used as a reference by which to 
 
characterize the objective tumor response. 
 
 
Non-target Lesions 
 
 
All other lesions (or sites of disease) should be identified as non-target 
 
lesions and should also be recorded at baseline.  Non-target lesions 
 
include measurable lesions that exceed the maximum numbers per organ 
 
or total of all involved organs as well as non-measurable lesions.  
 
Measurements of these lesions are not required but the presence or 
 
absence of each should be noted throughout follow-up.  
 
 
Clinical Lesions   
 
 
Clinical lesions will only be considered measurable when they are 
 
superficial (e.g., skin nodules and palpable lymph nodes, mucosal lesions       
that can be delineated and measured by endoscopic examination).  In the 
case of skin lesions, documentation by color photography, including a ruler 
to   
 
estimate the size of the lesion, is recommended. 
  
 
 
10.2 
Response Criteria 
 
 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR):   At least a 30% decrease in the sum of the longest     
diameter (LD) of target lesions, taking as reference 
the baseline sum LD 
Progressive Disease (PD):  At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum 
LD recorded since the treatment started or the 
appearance of one or more new lesions 
 
Stable Disease (SD):     Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 45 
reference the smallest sum LD since the treatment 
started. 
 
The non-target lesions will not be measured. 
 
10.3  
 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be classified as having “symptomatic deterioration.” 
 
 
 
10.4 
Confirmatory Measurement/Duration of Response 
 
 
To be assigned a status of PR or CR, changes in tumor measurements must 
be confirmed by repeat assessments that should be performed 4 weeks after the 
criteria for response are first met.  In the case of SD, follow-up measurements 
must have met the SD criteria at least once after study entry at a minimum 
interval of 6 weeks. 
 
       The duration of overall response is measured from the time measurement 
criteria are met for CR or PR until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started.  
 
Progression Free Survival at one year is defined as the percentage of 
patients who are alive at one year after beginning of their concurrent re-
irradiation and chemotherapy without loco-regional progression of their 
disease as measured by CT scan or MRI using RECIST 1.1 criteria (see 
Appendix 7) (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  
 
Survival is measured from the first day of CRT to date of death. 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 46 
10.5   Efficacy Endpoints 
 
 Progression Free Survival and Overall Survival will be examined and 
reported at 1 year. 
 Patients will continue to be followed up according to the above schedule 
and Median Progression Free Survival, Median Overall Survival as well as 
Overall survival at 1 year and at 2 years will be determined and reported. 
 In addition tumor Objective Response measured by CT scan or MRI will 
be examined. 
 In addition, quality of life as measured by speech, swallow, nutrition and 
pain will be examined.  
 Biomarkers predictors of response and tissue prognostic markers will be 
searched as well. 
 
Using data from the RTOG 99-11 trial we will be able to compare with the 
1-year PFS rate, as well as the 1-year and 2-year Overall Survival rates 
and Median Overall Survival measured and determined through our 
protocol. 
 
10.6 Safety Endpoints 
 
For the phase I portion of the study the definition of MTD for erlotinib is the 
primary endpoint. As secondary endpoints we will evaluate acute toxicity and 
tolerability of the combined re-irradiation with radiosensitizing drugs: pemetrexed 
and erlotinib. 
 
Dose-Limiting Toxicity (DLT) – for purpose of escalating/de-escalating the 
dose of erlotinib/ Pemetrexed, dose-limiting toxicity is defined as grade IV 
mucositis or dermatitis lasting more than 3 days, or grade III or IV mucositis 
lasting 6 weeks or longer from the completion of therapy, or any other grade 
III or IV toxicity, regardless of duration and which do not respond to treatment 
(diarrhea, rash) or need to delay treatment for more than 2 weeks because of 
any type of toxicity during the re-irradiation segment of the treatment. 
Erlotinib and pemetrexed administration should be stopped if interstitial lung 
disease develops.  Grade IV hematologic toxicity should not alter erlotinib 
dose or escalation. Pemetrexed dose should be adjusted accordingly. 
 
11. 
SAMPLE SIZE AND STATISTICAL CONSIDERATIONS 
 
 
For the Phase I portion of this protocol a standard 3+3 design will be used. 
Here 3 patients will be enrolled at the first dose of erlotinib (100 mg). If there are 
no DLTs then the dose of erlotinib will be escalated from 100 to 125 mg.  If 1/3 
patients have a DLT at 100 mg then an additional 3 patients will be enrolled.  If 
0/3 of these patients have a DLT then the dose of erlotinib will be escalated to 
125 mg.  If 1/3 of these additional patients have a DLT (total 2/6) at 100 mg then 
the MTD will be set at 100 mg.  If 2 or 3 of the original 3 patients (or 3+ out of 6) 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 47 
of the first set of patients have a DLT at erlotinib (100 mg) then both pemetrexed 
and erlotinib will be reduced by 25%.   
 
           After the third patient at a given dose is accrued, enrollment will be 
suspended until 6 weeks after that patient completes therapy or until his 
mucositis or any other toxic effect at the end of treatment becomes less or equal 
to grade II, whichever comes first, to allow for monitoring of signs and symptoms 
of toxicity. 
 
 
If the first dose (100 mg erlotinib) is found to be tolerable (i.e., 0/3 patients 
have DLTs) then 3 additional patients will be enrolled at 125 mg.  If 2/3 patients 
have a DLT at this level we will reduce the dose of erlotinib back to 100mg and 
test 3 additional patients at this dose.  (Or if 3/6 have a DLT at this level we will 
reduce back to 100 mg (i.e., 1 /3 have DLT and then 2/3 additional patients have 
DLT). 
 
 
If 125 mg erlotinib is found to be tolerable then 3 additional patients will be 
enrolled at 150 mg. If 2/3 patients have a DLT at this level we will reduce the 
dose of erlotinib back to 125 mg and test 3 additional patients at this dose.   (Or if 
3/6 have a DLT at this level we will reduce back to 125 mg (i.e., 1/3 have DLT 
and then 2/3 additional patients have DLT) 
 
 
Thus, with this design a minimum of 9 patients are needed (3 at 100, 125 
and 150 mg erlotinib) if no DLTs are observed and a maximum of 18 patients 
could be used if 6 patients were needed at all possible doses. Based on this 
dose escalation plan, the probabilities of dose escalation for various true DLT 
rates are given below: 
 
 
 
 
For example, if the true DLT is 60% at a dose level, there is a 8% chance 
that the dose would be escalated.  Once the MTD is determined an additional 22 
patients will be enrolled into the Phase II portion of the protocol. 
 
 
In the Phase II protocol there will be a total of at least 25 patients (possibly 
28 patients if 6 are enrolled during the Phase I component at the chosen dose) 
evaluated at the chosen dose (3 (or 6) from the Phase I component and 22 
additional patients).  With this number patients enrolled we will be able to 
estimate the true 1 year PFS survival rate with a precision of no worse than +/- 
19.6% when estimating a 95% confidence interval for the rate of PFS.  The 
True DLT Rate 
Probability of Dose Escalation 
20% 
71% 
30% 
49% 
40% 
31% 
50% 
17% 
60% 
8% 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 48 
following table shows the width of 95% confidence intervals for different 1-year 
PFS rates. 
 
 
Proportion with 1 year PFS 
Width of Confidence Interval with n=25 
.30 
+/- 18.0 
.35 
+/- 18.7 
.40 
+/- 19.2 
 
In addition to estimating the 1-year PFS rate (with 95% confidence 
intervals), we will perform a secondary analysis that will compare this rate to that 
found in the RTOG 99-11 study (Sections 1.1 and 10.5).   
 
 
Survival analysis method will also be used to estimate the median 1-year 
PFS and 1-year overall survival rates.  
 
One-year, 2-year overall survival rates and median survival will also be 
compared between this protocol and the RTOG 99-11 study referenced in 
Sections 1.1 and 10.5. 
 
 
In the Phase II component of the trial there will be additional secondary 
endpoints measured. These include quality of life assessments and swallowing 
assessments. For each of these measurements, we will assess the mean and 
95% confidence intervals for continuous outcomes. 
 
 
Many of these outcomes will be assessed at multiple time points, thus 
analyses examining repeated measurements will be made. In addition, a pre-post 
comparison will be made to assess the magnitude of change exhibited during the 
course of the protocol. This will be performed to assess the residual alterations of 
quality of life and swallowing.  
 
 
We will be testing whether the post treatment outcomes measured at 12 
months are improved (or worsened) from the pre-treatment levels. We will use 
paired t-tests to make these comparisons with the Null Hypothesis that there is 
no change in outcome versus a 2-sided alternative hypothesis that there is a 
change.  
 
 
The goal of this test is to rule out a statistically significant worsening and 
still be able to detect an improvement if it occurs. A 95% confidence interval for 
the difference in the outcome measures will be constructed. If this interval 
includes 0, we will conclude that there is not conclusive statistical evidence that 
there is an improvement or worsening. If the interval does not include 0 we can 
determine whether there was a significant improvement (or worsening) 
depending on which side of the 0 the interval is on. 
 
With 25 patients (at least) included in the Phase II component, we will 
have 80% power to detect an effect size of .584 with a 2-sided test using a paired 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 49 
t-test to compare pre and post outcome (i.e. quality of life) levels. This implies 
that we can detect a difference equal to 58.4% of a standard deviation in the 
change in quality of life over time. Since there will be additional intermediate time 
points available for analysis, we can examine the change in quality of life taking 
these measurements into account and likely increase our precision when 
estimating the treatment effect. 
 
 
In addition to the above efficacy related endpoints, we will examine acute 
and chronic toxicities that occur in this protocol.  We will examine the grade and 
type of toxicities that occur and also compare these to what has been observed 
in previous trials (RTOG 99-11) to see whether the toxicity profiles of patients on 
this protocol are better than what has been observed previously.  To do this we 
will compare mainly rates of Grade 4 and 5 toxicities between the two protocols 
using chi-square tests. 
 
           The total sample size for the Phase I plus II portions of this protocol will be 
between 31 and 40 patients. We expect to enroll about 9-10 patients per year. As 
soon as Phase I portion of the study is finished we might consider looking for 
another participating center, if needed, to try to finish the study enrollment in no 
more than 3 years. 
 
12.  TISSUE/SPECIMEN SUBMISSION  
 
 
For patients who have consented to participate in the tissue/blood 
component of this study.  
 
           Wake Forest University encourages participants in protocol studies to 
consent to the banking of their tissue. Tissue Bank provides tissue specimens to 
investigators for planned and future translational research studies. Translational 
research studies integrate the newest research findings into current protocols to 
investigate important biologic questions. 
 
 
In this study, tissue and blood will be submitted to the Wake Forest 
University tissue bank for the purpose of conducting biomarker studies as 
described below and for banking for future translational research. Submission of 
tissue and blood is highly recommended. 
 
 
Samples should be batch shipped when requested by Wake Forest.  
Samples can be shipped Monday through Thursday.  The samples should be 
shipped overnight on dry ice to the following address: 
 
 
Wake Forest Cancer Center 
Tumor Tissue  Core Facility 
c/o Greg Kucera 
Hanes Building Rm 4032 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 50 
Medical Center Blvd 
Winston-Salem, NC 27157 
 
 
 
For accomplishing secondary objective 5 in section 2.3,  every effort will 
be made to obtain tumor tissue as well as normal tissue for research purpose at 
the time of the initial biopsy performed for the diagnosis purpose, in order to 
avoid any additional biopsy procedure.  The tumor samples collected from the 
patients will be stored in the Tumor Tissue Core Laboratory after appropriate 
preparations (see appendix 1). The same procedures will be applied in case of 
recurrent or progressive tumor.  Whenever a patient has recurrent or progressive 
tumor that requires biopsy for diagnosis, we will ask for an additional piece to be 
removed and saved in the Tumor Tissue Bank for research purpose. 
 
Buccal mucosa and blood samples will be collected before and after chemo-
radiation treatment and at the time of tumor progression. Buccal mucosa 
samples will be saved in liquid nitrogen and blood samples will be stored as 
serum, plasma and buffy coat, after appropriate preparations (see appendix 1), 
according to the Tumor Tissue Core Laboratory protocol, approved and 
supervised by IRB. Although not required for participation in this study, collection 
of buccal mucosa and blood samples from patients before and after treatment 
with erlotinib is strongly encouraged.  The saved buccal mucosa can be used in 
lieu of normal tissue if such a sample has not be banked. 
 
 
The collection of patient tissue samples (neoplasms and matched 
adjacent normal tissue) is monitored by the Wake Forest University (WFU) IRB 
(Protocol Number BG98-391), including maintenance of patient confidentiality 
and the HIPAA-compliant sample database. The tissue as well as blood samples 
are kept in the Tumor Tissue Core Laboratory of the 4th floor of the Hanes 
Building, which is either manned by a member of the Tumor Tissue Core 
Laboratory or is locked at all times. The Core Lab’s database resides on the 
Comprehensive Cancer Center of Wake Forest University’s (CCCWFU) secure 
server behind the WFUHS firewall with HIPAA-compliant security. The database 
is only accessible by the Tumor Tissue Core personnel.   
 
 
 
The Tumor Tissue Core Lab preserves tissues precisely characterized as 
to location and  histology, and makes these samples available to investigators as 
fresh material for cell culture or as fresh-frozen tissues to be stored  at -80oC.  
 
 
Our current standard procedures within CCCWFU are as follows:  
 
1) the consent form includes language that allows for resected tissues to 
be used for research purposes as needed to meet the objectives of the current 
study and the blood and remaining tissue to be stored for future investigations;  
 
2) samples are handled initially in the operating room pathology laboratory 
with a first priority that ensures that diagnostically relevant information is 
preserved prior to any research uses;  

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 51 
 
3) tissues for research use are only those that are deemed in excess of 
the materials normally necessary for diagnostic purposes and would otherwise 
be disposed as well as the biopsy specimens especially collected for research 
purpose. 
 
4) the samples are collected and handled by personnel specifically trained 
to protect the integrity of the tissue and patient confidentiality;  
 
5) tissues are preserved by fresh freezing in liquid nitrogen, unless a 
specific project requires a specialized use, such as the preparation of primary 
cultures, requiring different handling;  
 
6) the samples are deidentified by giving samples from a given patient a 
unique code number that separates any patient information from the retrieved 
information about the sample in a secure database;  
 
7) a Web-based search engine listing of specific information is derived 
from the Tumor Tissue Core database that is accessible only by investigators of 
the CCCWFU, and these search results contain information regarding the type of 
tissue and the numbers of samples available; and  
 
8) the tissue is distributed to investigators of this trial for which it was 
collected to meet the proposed objectives. Blood specimens and additional 
remaining tissue can be accessed for future studies only after those future 
projects are reviewed by the WFU IRB and by the Tumor Tissue Committee, who 
oversee the research uses of tissues at the time of distribution.  
 
 
 
Buccal mucosa and blood samples obtained at an outside institution will 
be processed in a similar manner (see appendix 1) and will be kept at -80oC.  
Tumor specimens will be fresh-frozen in liquid nitrogen.  Transportation to the 
Wake Forest University Tumor Tissue Bank will be assured by the Wake Forest 
University Tumor Tissue Bank on a regular basis. 
 
            According to the secondary objective 2.5 of this protocol we plan to 
evaluate the level of EGFR phosphorylation using Liquid Chromatography-
Tandem Mass Spectrometry (LC-MS/MS).  Phosphorylation of specific tyrosine 
residues within the cytoplasmic domain of EGFR is part of the initial activation 
process that occurs upon ligand binding. These phosphotyrosine residues 
subsequently serve as docking sites for intracellular signaling molecules. We 
plan to measure by nano LC-MS/MS the level of phosphorylation of different 
tyrosine residues within the cytoplasmic domain of EGFR in tumor tissue 
(primary tumor and nodal metastasis whenever tissue available) and report it to 
that in normal tissue from the same patient. Recruited adaptors to the EGFR 
phosporylated sites: Grb2, Shc, NSP1, and NSP2, SCK will be identified and 
measured in the same experiment.  We will measure other molecules considered 
in the literature as markers of activation of different signaling pathways 
downstream of EGFR such as PLC-1, Cbl/Cbl-B, Ras-Raf-MEK-MAPKs, PI3K- 
Akt-ribosomal S6K, STAT 3, c-Src, SAPKs, PAK-JNKK-JNK and PKC and 
corroborate the results with the pattern of EGFR phosphorylation in the C-
terminal region and with the recruited adaptors. Measuring the accumulative 
changes in overall phosphorylation, rather than dynamic changes at specific sites 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 52 
might explain the failure in correlating the level of EGFR phosphorylation and 
activation with the response to EGFR inhibitors.   
 
We plan to corroborate these findings with P-AKT and P-ERK measured 
by classic immunohistochemistry method and with the patients' response to 
treatment and prognosis. 
 
We also plan to measure Thymidylate synthase (TS) and p53 levels in 
tumor tissue (as available) and correlate with response to treatment. In some 
preliminary clinical studies evidence was postulated for a combined predictive 
role for TS and p53 for response to antifolates such as Pemetrexed. TS and p53 
will be measured by PCR or immunohistochemistry, depending on tissue 
availability. 
Any remaining tissue after performing the above mentioned research 
analysis as well as the blood specimens will be stored in our Tissue Bank and a 
separate IRB approved protocol will be required to access these specimens for 
future studies. 
 
13. 
RETENTION OF RECORDS 
 
Documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence should be retained for at least 2 years 
after the investigation is completed. 
 
14. 
PUBLICATION PLAN 
 
 
Plans to disseminate the results of this trial:  We expect to be able to 
present the phase 1 results at the 2011 ASCO meeting.  In addition we will 
submit these results to Journal of Clinical Oncology (JCO) in 2011. 
 
The phase 2 trial results we expect to present to the 2012 ASCO meeting 
and we plan to submit the final phase 2 results to JCO in 2012. We expect to 
have a separate publication of quality of life and swallowing study results as well 
as a separate publication of correlative tissue results by 2013. 
 
15. Multi-Institutional Monitoring Plan 
15.1.  SAE Reporting  
 
Each investigator is responsible for submitting SAEs and unexepected AEs to 
their Institutional Review Board/Ethics Committee according to their institutional 
guidelines. 
 
Any serious or unexpected event, which occurs to any patient in the course of 
their treatment on this study or within 30 days following cessation of treatment, 
must be reported immediately to WFU, by telephone 336-713-6767 within 24 
hours of the investigator learning of its occurrence.  When calling to report an 
event, please clearly state the protocol number (CCCWFU 60107) and the 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 53 
patient identification number, along with the event description and grade. The 
immediate reports should be followed promptly by detailed, written reports.   
 
Whenever FDA Form 3500 (MEDWATCH)  must be faxed to OSI Drug Safety or 
to Eli Lilly for all SAEs which are unexpected, fatal or life-threatening experience 
and associated with the use of the drug, a copy must be faxed to WFU within 48 
hours.   
 
The patient must be followed up until clinical recovery is complete and/or 
laboratory results have returned to normal. This may mean that follow-up will 
continue after the patient has completed the trial. 
15.2.  
Registration Procedures 
 
All patients must be registered with the Protocol Office at Wake Forest University 
before enrollment to study.  Prior to registration, eligibility criteria must be 
confirmed with the Research Nurse Coordinator Anne Flynn, RN, BSN at 336-
713 6956 . To register a patient, call the Protocol Office at 336-713-6767 Monday 
through Friday, 9:00AM-4:30PM EST. 
15.3.  
Study Monitoring 
 
 
Personnel from the Protocol Office at the Wake Forest University will 
monitor the trial. Clinical Research Associates may periodically visit the 
investigative site to assure proper conduct of the trial and proper collection of the 
data. The investigators at each site will allow the monitor to review all source 
documents used in the preparation of the case reports. The Oncology Protocol 
Office at Wake Forest University can be reached at 336-713-6913 . 
 
All study flow sheets should be sent to the CRA on a monthly basis for 
monitoring.  Flow sheets may be sent via e-mail to Claire Kimbrough 
(ckimbro@wakehealth.edu) or faxed to 336-713-6773.  Please make sure the 
cover page clearly identifies the source documents contained. 
 
All study forms should be sent to the coordinating site within one week of patient 
completion.   
15.4.       Required Documentation 
 
Before the study can be initiated at any site, the following documentation must be 
provided to the Protocol Office at Wake Forest University Health Sciences. 
 Written documentation of IRB approval of protocol (identified by title, 
protocol version and date of approval) for each site.  
 IRB membership list 
 Current curricula vitae and documentation of professional licensure of the 
Principal Investigator and co-Investigators listed on the 1572.  

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 54 
 U.S. Food and Drug Administration (FDA) Form 1572, signed by the 
Principal Investigator at the participating center. The names of any sub-
investigators at the participating center must appear on this form. 
Investigators must also complete all regulatory documentation as required 
by local regulations. This includes any required human subjects training 
required by the site’s local IRB.  
 Human subject protections documentation (e.g. NIH, CITI) for all research 
personnel (e.g. study coordinators, data managers and other research 
personnel).  
 IRB approved study informed consent and HIPAA consent form. HIPAA 
consent language can be included within the study informed consent. 
Please note that all informed consent forms should be reviewed and 
approved by the WFU protocol office prior to submission to the site’s 
designated IRB.  
 Laboratory certifications (CAP, CLIAs) and laboratory reference value 
ranges for each laboratory listed on the site’s 1572.  
 Executed clinical research contract 
 Any approval memos from IRB for protocols, continuing reviews, and 
approved informed consents 
 Signed WFUHS Conflict of Interest Form 
15.5 Adherence to the Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol. Any deviation from 
the protocol must have prior approval by the WFU Principal Investigator and 
must be recorded and explained. 
15.6 Amendments to the Protocol 
 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at WFU. The written 
amendment will be sent to investigators and must be submitted to the IRB at the 
investigator's site for approval. It should also be noted that when an amendment 
to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required. 
15.7 Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 55 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
15.8 Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the 
flowsheet.  Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification of 
proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 56 
16. 
REFERENCES 
 
1.  Wong SJ; Machtay Ml, and Li Y:  Locally recurrent, previously irradiated head 
and neck cancer:  concurrent re-irradiation and chemotherapy, or chemotherapy 
alone?  JCO 24(17):2653-2658, 2006 
 
2.  Kao J, Garofalo MC, Milano MT, Chmura SJ, Citron JR, and Haraf DJ:  
Reirradiation of recurrent and second primary head and neck malignancies: a 
comprehensive review.  CA Treat Rev 29:21-30, 2003.  
 
3. Chmura SJ, Milano MT, and Haraf DJ:  Reirradiation of recurrent head and 
neck cancers with curative intent.  Semin Oncol 31:816-821, 2004.  
 
4. Spencer SA, Harris J, Wheeler RH, Machtay M, Schultz C, Spanos W, Rotman 
M, Meredith R:  RTOG 96-10: Reirradiation with concurrent hydroxyurea and 5-
Fluorouracil in patients with squamous cell cancer of the head and neck.  Int J 
Radiation Oncology Biol Phys 51(5):1299-1304, 2001.  
 
5. Horwitz EM, Harris J, Langer CJ, Nicolaou N, Kies M, Curran W, Wong SJ, 
Ang K:  Concurrent split course hyperfractionated radiotherapy (Hfx RT), cisplatin 
(DDP) and paclitaxel (P) in patients with recurrent, previously irradiated 
squamous cell carcinoma of the head and neck (SCCHN): update of RTOG 
9911.  JCO 23(16S):5577 2005 ASCO Annual Meeting Proceedings (I of II)(June 
1 supplement). 
 
6. Salama JK, Vokes EE, Chmura SJ, Milano MT, Kao J, Stenson KM, Witt ME, 
Haraf DJ:  Long-term outcome of concurrent chemotherapy and reirradiation for 
recurrent and second primary head-and-neck squamous cell carcinoma. Int J 
Radiation Oncology Biol Phys 64(2)382-391, 2006.  
 
7. Machtay M, Rosenthal DI, Chalian AA, Lusting R, Hershock D, Miller L, 
Weinstein GS, Weber RS:  Pilot study of postoperative reirradiation, 
chemotherapy, and amifostine after surgical salvage for recurrent head-and-neck 
cancer: Int J Radiation Oncology Biol Phys: 59(1):72-77, 2004.  
 
8. Spencer S, Wheeler R, Peters G, Meredith R, Beenken S, Nabel L, Wooten A, 
Soong S-J, Salter M: Phase 1 trial of combined chemotherapy and reirradiation 
for recurrent unresectable head and neck cancer. Head&Neck,25(2):118-22,2003  
 
9. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL:  
Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor 
tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell 
cancer of the head and neck.  JCO 22(1):77-85, 2004.  
 
10. Vokes EE, Chu E:  Anti-EGFR therapies: clinical experience in colorectal, 
lung, and head and neck cancers:  Oncology 20(5 suppl 2):15-25, 2006.   

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 57 
 
11. Chinnalyan P, Huang S, Vallabhaneni G, Armstrong E, Varambally S, 
Tomlins SA, Chinnaiyan AM, Harari PM:  Mechanisms of enhanced radiation 
response following epidermal growth factor receptor signaling inhibition by 
erlotinib (Tarceva®).  Cancer Research 65(8):3328-3335, 2005.  
 
12. Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A:  EGFR tyrosine 
kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor 
(HIF)-1-independent and HIF-1-dependent mechanism.  Cancer Research 
66(6):3197-3204, 2006.  
 
13. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ:  
Effects of smoking on the pharmacokinetics of erlotinib.  Clinical Cancer 
Research 12(7 pt 1):2166-2171, 2006.   
 
14. Cohen MH, Johnson JR, Wang YC, Sridhara R, Pazdur R: FDA drug 
approval summary: pemetrexed for injection (Alimta) for the treatment of non-
small cell lung cancer. Oncologist 10(6):363-268, 2005.   
 
15. Boyer MJ, Rivory LP, Clarke SJ:  Pemetrexed: single-agent and combination 
phase I study overview:  Seminars in Oncology 29(6 Suppl 18):18-23, 2002.  
 
16. Niyikiza C, Hanauske AR, Rusthoven JJ, Calvert AH, Allen R, Paoletti P, 
Bunn PA Jr:  Pemetrexed safety and dosing strategy.  Seminars in Oncology 
29(6 Suppl 18):24-29, 2002.   
 
17. Paz-Ares L, Ciruelos E, Garcia-Carbonero R, Castellano D,Lopez-Martin A, 
Cortes-Funes H:  Pemetrexed in bladder head and neck, and cervical cancers.  
Seminars in Oncology. 29(6 Suppl 18):69-75, 2002.   
 
18. Adjei AA: Pemetrexed in the treatment of selected solid tumors. (review) 
Seminars in Oncology 29(2 suppl 5):50-53, 2002.   
 
19. Huber PE, Bischof M, Jenne J, Heiland S, Peschke P, Saffrich R, Grone HJ, 
Debus J, Lipson KE, Abdollahi A:  Trimodal cancer treatment: beneficial effects 
of combined antiangiogenesis, radiation, and chemotherapy.  Cancer Research 
65(9):3643-3655, 2005.  
 
20. Mauceri HJ, Seethara S, Salloum RM, Vokes ED, Weichselbaum RR:  Alimta 
and concurrent ionizing radiation.  International Journal of Oncology 19(4):833-
835, 2001.    
 
21. Selwert TY, Connell PP, Mauer AM, Hoffman PC, George CM, Szeto L, 
Salgia R, Posther KE, Nguyen B, Haraf D, Vokes EE:  A phase I study of 
pemetrexed, carboplatin, and concurrent radiotherapy in patients with locally 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 58 
advanced or metastatic non-small cell lung or esophageal cancer.  Clinical 
Cancer Research. 13(2 Pt 1):515-522, 2007.   
 
22. List MA, Siston A, Haraf D, et al. Quality of life and performance in advanced 
head and neck cancer patients on concomitant chemoradiotherapy: A 
prospective examination. J Clin Oncol. 17:1020-8, 1999 
 
23. Kotz T, Costello R, Li Y, Posner MR. Swallowing dysfunction after 
chemoradiation for advanced squamous cell carcinoma of the head and neck. 
Head & Neck 26:365-372. 
 
24. Murry T, Madasu R, Martin A, Robbins T. Acute and chronic changes in 
swallowing and quality of life following intraarterial chemoradiation for organ 
preservation in patients with advanced head and neck cancer. Head & Neck 
20:31-37. 
 
25. Eisbruch A, Lyden T, Bradford CR, Dawson LA, Haxer MJ, Miller AE, Teknos 
TN, Chepeha DB, Hogikyan ND, Terrell JE, Wolf GT. Voice and swallowing 
outcomes of an organ-preservation trail for advanced laryngeal cancer. Intern J 
Rad Oncol Biol Phy 53:23-28, 2002. 
 
26. Fung K, Lyden TH, Lee J, Urba SG, Worden F, Eisbruch A, Tsien C, Bradford 
CR, Chepeha DB, Hoikyan ND, Prince MEP, Teknos TN, Wolf GT. Voice and 
swallowing outcomes of an organ-preservation trial for advanced laryngeal 
cancer. Intern J Rad Oncol Biol Phy 63:1395-1399, 2005. 
 
27. Lazarus CL, Logemann JA, Pauloski BR, Rademaker AW, Larson CR, Mittal 
BB, Pierce M. Swallowing and tongue function following treatment for oral and 
oropharyngeal cancer. J Speech Lang Hear Res 43:1011-1023, 2000. 
 
28. Kulbersh BD, Rosenthal EL, McGrew BM, Duncan RD, McColloch NL, Carroll 
WR, Magnuson JS. Pretreatment, preoperative swallowing exercises may 
improve dysphagia quality of life. Laryngoscope 116:883-886. 
 
29. Chen AY, Frankowski R, Bishop-Leone J, Hebert T, Leyk S, Lewin J, et al. 
The development and validation of a dysphagia-specific quality-of-life 
questionnaire for patients with head and neck cancer: the M. D. Anderson 
dysphagia inventory, Arch Otolaryngol Head Neck Surg 127(7):870-876, 2001. 
 
 
30. Guo L, Kozlosky CJ, Ericsson LH, Daniel TO, Cerretti DP, Johnson RS: 
Studies of ligand-induced site-specific phosphorylation of epidermal growth factor 
receptor; J Am Soc Mass Spectrum 14:1022-1031, 2003.   
 
31. Thelemann A, Petti F, Griffin G, Iwata K, Hunt T, Settinari T, Fenyo D, Gibson 
N, Haley JD:  Phosphotyrosine signaling networks in epidermal growth factor 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 59 
receptor overexpressing squamous carcinoma cells:  Molecular & Cellular 
Proteomics 4:356-376, 2005.   
 
32. Hanna N, Shepherd FA, Fossella FV, Pereira JR, Marinis FD, Pawel JV, 
Gatzemeier U, Chang T, Tsao Y, Pless M, Muller T, Lim HL, Desch c, Szondy K, 
Gervais R, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized 
Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non–Small-Cell 
Lung Cancer Previously Treated With Chemotherapy JCO May 1 2004: 1589-
1597 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 60 
17.0 APPENDICES 
 
 APPENDIX 1 
Blood and Buccal Mucosa Collection Instructions 
 
APPENDIX 2 
Example of Smoker Status Case Report Form 
 
APPENDIX 3 
Example of Investigational Product Accountability Log  
 
APPENDIX 4 
Form 3500 Medwatch 
 
APPENDIX 5 
Mandatory (STRC) Safety and Toxicity Review Committee 
(Previously CROC) 
 
APPENDIX 6 
Registration Guidelines 
 
APPENDIX 7 
RECIST 1.1 Performance Status Criteria 
 
APPENDIX 8  
Common Terminology Criteria for Adverse Events  
 
 
 
 
(CTCAE) version 3.0 for grading of all adverse events  
 
APPENDIX 9 
FACT H&N Survey 
 
APPENDIX 10 
PSS-HN Survey 
 
APPENDIX 11 
MD Anderson Dysphagia Inventory (MDADI) Questionnaire  
 
APPENDIX 12 
ECOG Performance Status Scale 
 
APPENDIX 13 
Master Flow Sheet 
 
APPENDIX 14 
Tumor Measurement Form 
 
APPENDIX 15 
CYP3A4 and CYP1A2 Inhibitors/ Inducers 
 
 
APPENDIX 16         Swallowing Portion Data Collection Form 
 
APPENDIX 17         Specimen Log 
 
APPENDIX 18         AE Log

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 61 
 
APPENDIX 1    Blood Collection Instruction 
 
Serum Collection: 
Using four (4) or more 1ml cryovials, label them with the study and case number, 
collection date and time, and clearly mark cryovials “serum”. 
Process: 
1. Allow one 5ml red top tube to clot for 30 minutes at room temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM at 4° Celsius for 10 min.  
3. Aliquot a minimum of 0.5 ml serum into each of the four 1ml cryovials labeled 
with the study and case numbers, collection date and time, and clearly mark 
specimens as “serum”. 
4. Store serum at –80° Celsius in Dr. Kucera’s lab until ready to use. 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED. 
 
Plasma: 
Using three (3) or more 1ml cryovials, label them with the study and case 
number, collection date and time, and clearly mark cryovials “plasma”. 
Process: 
1. Centrifuge specimen within one hour of collection in a standard clinical 
centrifuge at ~2500 RPM at 4° Celsius for 10 minutes. 
2. If the interval between specimen collection and processing is anticipated to be 
greater than one hour, keep specimen on ice until centrifuging is done. 
3. Carefully pipette and aliquot a minimum of 0.5ml plasma into each of the 1ml 
cryovials labeled with the study and case numbers, collection date and time, and 
clearly mark specimens as “plasma”. 
4. Store at a minimum –80° Celsius in Dr. Kucera’s lab until ready to use. 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED. 
 
Buffy coat: 
 
For explanation of Buffy coat, please refer to the picture below. 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 62 
 
Using three (3) or more 1ml cryovials, label them with the study and case 
number, collection date and time, and clearly mark cryovials “buffy coat”. 
Process: 
1. Centrifuge EDTA (purple top) tube within one hour of collection in a standard 
clinical centrifuge at ~2500 RPM at 4° Celsius for 10 minutes. 
2. If the interval between specimen collection and processing is anticipated to be 
greater than one hour, keep specimen on ice until centrifuging is done. 
3. Carefully remove plasma close to the buffy coat and set plasma aside (can be 
used to send plasma samples – see above instructions). 
4. Remove the buffy coat cells carefully and place into the 1ml cryovials labeled 
“buffy coat” (it is okay if a few packed red cells are inadvertently collected in the 
process). Clearly mark the tubes with date and time of collection. 
4. Store buffy coat samples frozen in Dr. Kucera’s lab until ready to use. 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED. 
 
 
Buccal Mucosa 
Recommended brushes: Cytosoft Cytology Brushes, Medical Packaging 
Corporation,   cat # CYB/100. They can be provided by WFUCCC. 
1. Brushings of cheek mucosa on both sides should be obtained.  
2. An initial very gentle cleaning brushing on a larger area should be performed.  
Discard the brush. 
3. After cleaning, use a new brush and brush gently (to avoid any bleeding), 
about 10 times up and down along the cheek mucosa. Rotate the brush 1800 and 
repeat the procedure on the other cheek mucosa. Cut (as needed to fit in) and 
discard the brush tip in a 15 ml conical tube containing 5 ml of NS.  
4. Transport immediately to the lab.  
5. Process as described below:  
This procedure is performed under aseptic conditions in the laminar flow hood. 
a. Label one 1ml cryovial with study and case number, collection data and 
time, and clearly mark cryovial “buccal cells”. 
b. Swirl brush in the solution contained within the 15mL conical tube to 
remove as much cellular material as possible. 
c. Discard brush and centrifuge 15ml conical tube at 1500rpm for 10 minutes 
to pellet the buccal cells.   
d. Remove pellet and place into 1mL cryovial.  Removing some supernatant 
will occur, and that will be removed with the next centrifugation. 
e. Centrifuge again at 1500rpm for 10 min and remove all remaining 
supernatant. 
f. Store at a minimum of -80°C until ready to use. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 63 
APPENDIX 2         Example of Smoker Status Case Report Form 
 
XXXX ASSESSMENTS 
CIGARETTE SMOKING HISTORY AT REGISTRATION 
 
 Date of evaluation:   _____________________ 
 
          DD     MMM     YYYY 
1.  Please indicate one of the following: 
 
 Subject never smoked cigarettes. 
 Subject has smoked < 100 cigarettes in a lifetime and stopped.  
 
Indicate when stopped:  < 1 month 
 1 month-1 year 
 > 1 year  
 Subject has smoked > 100 cigarettes in a lifetime and stopped. 
 
Indicate when stopped:  < 1 month 
 1 month-1 year 
 > 1 year 
 
Average number of cigarettes smoked per day:  _____   Number of years smoked: _____ 
 
  Subject is currently smoking cigarettes. 
 
Average number of cigarettes smoked per day:  _____   Number of years smoked: _____ 
OTHER TOBACCO/NICOTINE HISTORY AT REGISTRATION 
1.  Please indicate one of the following: 
 Subject never used other tobacco or nicotine products.  Do not complete question 2. 
 Subject currently or in the past has used other tobacco or nicotine products.  Complete question 2. 
2.  If a user of tobacco/nicotine products, indicate frequency used and/or how long ago product use stopped. 
 
Cigars/Pipes      Not Applicable 
 
Frequency used:  at least once daily  at least once weekly  at least once monthly 
 
Product stopped:  current  
 < 1 month 
 1 month-1 year 
 > 1 year 
 
 
Oral Tobacco Products      Not Applicable 
 
Frequency used:  at least once daily  at least once weekly  at least once monthly 
 
Product stopped:  current 
 < 1 month 
 1 month-1 year 
 > 1 year 
 
 
Nicotine Replacement Therapy      Not Applicable 
 
Frequency used:  at least once daily  at least once weekly  at least once monthly 
 
Product stopped:  current 
 < 1 month 
 1 month-1 year 
 > 1 year 
 
 
Other, please specify:  
 
 
 
      Not Applicable 
 
Frequency used:  at least once daily  at least once weekly  at least once monthly 
 
Product stopped:  current 
 < 1 month 
 1 month-1 year 
 > 1 year 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 64 
APPENDIX 3  Example of Investigational Product Accountability Log 
 
INVESTIGATIONAL PRODUCT: 
BRIEF STUDY DESCRIPTION: 
STUDY NUMBER: CCCWFU 60107 
INVESTIGATOR NAME:   
SITE NUMBER: 
SITE NAME:   
DISPENSING UNIT (ie, pack, vial, tablet etc.): 
STRENGTH: 
 
DISPENSING AREA: 
 
 
Date Patient’s 
Initials 
Patient’s 
I.D. 
Number 
Dose 
Quantity 
Dispensed 
or 
received 
Balance 
Forward 
Investigational 
Product 
Identifier 
Expiry 
Date 
Recorder’s 
Initials 
Balance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 65 
APPENDIX 4                     MedWatch Form 3500 LINK 
 
 
MEDWATCH REPORT 
 
 
It is important that if a MedWatch report is needed the report is forwarded to 
STRC for review along with your initial report. Steps on how to report may be 
found at the following website: 
 
http://www.fda.gov/medwatch/how.htm 
 
A copy of the MedWatch report can be found at the following website: 
http://www.fda.gov/medwatch/safety/3500a.pdf. 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 66 
APPENDIX  5    Mandatory (STRC) Safety and Toxicity Review Committee 
 (Previously CROC) 
(SAE) Serious Adverse Event Notification Procedure 
 
Mandatory STRC SAE Reporting Requirements – Revised 1/23/2012 
 
This document describes STRC reporting and use of the electronic submission form that 
is submitted for unexpected grade 4 and any grade 5 (death during treatment) SAEs on 
CCCWFU Institutional trial patients. There are multiple entities that require reporting of 
SAEs. Each entity has different rules for what is reported, and how it is reported.  
 
Rules used by other entities (Institutional Review Board (IRB), AdEERS, MedWatch, etc.) 
should NOT be used to evaluate whether an event should be reported to STRC. Only the 
rules for reporting described in this document should be considered. 
 
As defined in the NCI summary IV reporting guidelines, CCCWFU Institutional studies 
covered by these reporting requirements are defined as: In-house, internally reviewed 
trials, including those collaborative studies conducted with industry sponsorship in 
which the center is a primary contributor to the design, implementation, and 
monitoring of the trial, or participation in a multi-site trial initiated by an institutional 
investigator at another center.  Institutional trials are almost always authored by a 
researcher here at CCCWFU. Institutional protocols are labeled NCI Code=”I” for 
Institutional on the protocol screen in ORIS. Cooperative group protocols are not 
considered Institutional, but Research Base trials are classified as Institutional. 
 
The STRC is responsible for reviewing SAEs for CCCWFU Institutional studies, as defined 
above. STRC currently requires that unexpected grade 4 and all grade 5 SAEs on these 
trials be reported to them for review. All Clinical Research Management (CRM) staff 
members assisting a PI in documenting and reporting an SAE that qualifies for STRC 
reporting are responsible for informing a clinical member of the STRC by phone, 
followed by informing the entire committee via the required email notification. 
 
THESE REPORTING REQUIREMENTS APPLY TO EVERYONE WORKING WITH CANCER 
CENTER INSTITUTIONAL PROTOCOLS. 
 
What is considered an SAE under this mandatory procedure? 
Any unexpected grade 4 event not including routinely experienced events per protocol 
(e.g. myelosuppression) and all grade 5 events (death on treatment) should be 
reported. The patient is considered “on-treatment” as defined in the protocol, which 
can extend days/weeks/months past the last date of actual treatment.  
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 67 
Table 1: Summary of STRC Reporting Requirements for Institutional Pilot, Phase 1, 
Phase 2  
and Phase 3 Trials  
 
 
 
STRC reporting may not be appropriate for specific expected adverse events for 
protocols. In those situations the adverse events that will not require STRC reporting 
must be specified in the text of the approved protocol. 
 
STRC notification responsibilities of the person handling the reporting/documenting of 
the SAE: 
 
1. Make a phone call to the appropriate clinical member of the STRC as listed below 
(page if necessary)—see note 2 below 
2. Submit the STRC Notification Form WITHIN 24 HOURS of first knowledge of the event. This 
form is found at either the ORIS main menu page or by going to 
http://ccc.wakehealth.edu/oris/strc.aspx. 
This will ensure that all persons that the event applies to will be notified; remember 
to file a copy of your confirmation. (Form instructions will walk you through the 
required fields, consult the help page for further instructions.) 
3. Ensure that you document that the appropriate persons on the STRC has been 
contacted. 
4. Follow up with/update the clinical member of STRC regarding any new 
developments or information obtained during the course of the SAE investigation 
and reporting process. 
 
 
ADVERSE EVENT 
Grade 1, Grade 2, Grade 3 
 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Unlikely 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Possible 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Probable 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Definite 
Not 
Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 68 
 
Elements needed to complete the electronic STRC form: 
1. ORIS Patient ID (PID) 
2. Name of STRC Clinician notified/Date/Time/Comments. 
3. Grade of event. 
4. Is this related to protocol treatment? 
5. Is suspension of the protocol needed? 
6. Is any change to consent or protocol needed? 
7. Was the nature or severity of the event unexpected? 
8. Date of the event. 
9. Brief description of the event using approved CTC version terminology. 
10.  Date of last study dose before event. 
11. Relevant tests/labs. 
12. Most importantly make sure that the Investigator assigns attribution to 
the reported event (grade) using the appropriate CTCAE version for the 
protocol. 
 
The Clinical Members of STRC to Notify by Phone or Page: 
 
Bayard Powell, MD – Director-at-Large, CCCWFU; Chair, PRC; Section Head, 
Hematology/Oncology.  6-7970 / 6-2701 / Pager 806-9308 
 
Antonius Miller, MD – Hematology Oncology 3-4392 / 6-7414 / Pager 806-7789 
 
Glenn Lesser, MD – Hematology Oncology 6-9527 / 6-0256 / Pager 806-8397 
 
Kathryn Greven, MD – Vice Chair – Radiation Oncology. 3-3600 / Pager 806-8314 
 
Marissa Howard-McNatt, MD – General Surgery 6-0545 / 806-6438 
 
 
Definition of Unavailable: As a general guideline if the first clinician that is 
contacted does not respond to the phone call or page within a reasonable 
amount of time, then initiate contact with their backup.  Give the back-up a 
reasonable amount of time to respond to a phone call or page before contacting 
another member. This is a general guideline.  You must use your best judgment 
as a clinical research professional given the time of day, severity of the SAE, and 
other circumstances as to when it is appropriate to contact backup clinicians.  If 
the event occurs near the end of day, then leave messages (voice or email) as 
appropriate and proceed with submitting your STRC notification form.  The 
important criteria is that have taken reasonable steps to notify and document 
that you have initiated some type of contact to one or more of the clinical 
members of STRC. 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 69 
 
 
STRC CLINICAN RESPONSIBILITY: 
 
It is the responsibility of the STRC clinician to review all reported events, 
evaluate the events as they are reported; and communicate a response to the 
Investigator, event reporter and the members of STRC. The review will include 
but not be limited to the information reported; there may be times when 
additional information is needed in order for an assessment to be made further 
communication directly with the investigator may be warranted. STRC reserves 
the right to agree with the investigator’s assessment if STRC does not agree with 
the investigator STRC reserves the right to suspend the trial pending further 
investigation. 
 
AMENDMENTS TO PREVIOUS REPORTS 
 
If you are not able to supply all pertinent information with the initial submission, 
once the additional information is available do not submit a new report. Go to 
the original email that was received by STRC and others “reply to all” and entitle 
your email “Amendment for (list date of event and patient ID) this will avoid 
duplications of the same event. List the additional information which you are 
reporting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 70 
APPENDIX 6                          CCCWFU # 60107 
 
REGISTRATION GUIDELINES 
 
The following guidelines have been developed in order to ensure timely registration of 
your patient. 
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer 
control trial, must be registered with the CCCWFU Protocol Registrar within 24 hours of 
Informed Consent.  For affiliate sites, please register patients with the CCCWFU Protocol 
Registrar within 72 hours.  Patients should be registered prior to the initiation of 
treatment.   
 
In order to ensure prompt registration of your patient, please: 
1. Complete the Eligibility Checklist (attached) 
2. Complete the Protocol Registration Form (attached) 
3. Alert the WFUHS registrar by phone, and then send the signed Informed Consent 
Form, Eligibility Checklist and Protocol Registration Form to the registrar, either 
by fax or 
 e-mail. 
 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
              *Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
4. Please fax/e-mail ALL eligibility source documents with registration.  Patients 
will not be registered without all required supporting documents. 
Note:  If labs were performed at an outside institution, please provide a printout of the 
results.  Please ensure that the most recent lab values are sent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 71 
CCCWFU # 60107 Eligibility Checklist                                                                 Page 1                               
Yes No N/A Inclusion Criteria (All responses must be YES in order to enter study) 
Eligibility 
Confirmation 
(registrar) 
 
 
 
Does the patient have pathologically (histologically or cytologically) 
confirmed diagnosis of recurrent or second primary squamous cell 
carcinoma (SCC) of the oral cavity, oropharynx, hypopharynx, larynx, 
or recurrent neck metastases with unknown primary? 
 
 
 
 
Does the patient have disease with tumor measurable on the CT 
scan/MRI? 
 
 
 
 
Does the patient have no definitive evidence of distant metastasis? 
(Not applicable for patients enrolled in the Phase I, first two Erlotinib 
dose levels) 
 
 
 
 
Is the patient found unresectable by a preliminary ENT evaluation or 
has refused surgery? 
 
 
 
 
Does the patient have a prior history of head and neck radiation for 
Head and Neck Squamous Cell Carcinoma to no more than 72 Gy and 
most (>75%) of the recurrent or second primary tumor volume should 
be in areas previously irradiated to > 45 Gy? 
 
 
 
 
Is the patient’s entire tumor volume included in a treatment field that 
limits the total spinal cord dose to 54 Gy (prior plus planned dose)? 
 
 
 
 
Has the patient recovered from the acute side effects of prior surgery, 
chemotherapy, or radiation therapy?  (A minimum time period of at 
least 6 months should have elapsed from prior radiation treatment 
until enrollment in the study.) 
 
If applicable, date of prior radiation therapy: 
_____/_____/_____ to _____/_____/_____ 
 
 
 
 
Has the patient has received chemotherapy as a component of their 
primary tumor treatment, but not for recurrent or metastatic disease?  
No prior treatment with systemic anti-EGFR inhibitors or Pemetrexed 
is permitted. 
 
 
 
 
Does the patient have an ECOG performance status of 0-1? 
 
 
 
 
Is the patient 18 years or older? 
 
 
 
 
ANC                          > 1500/µl               ___ ___.___ 
 
 
 
 
Platelet Count            > 100,000/µl         ___ ___.___ 
 
 
 
 
Total Bilirubin          < 1.5                     ___ ___.___ 
 
 
 
 
AST/ALT                 < 2X the ULN      ___ ___.___ 
 
 
 
 
Creatinine                 < 1.5                     ___ ___.___ 
 
 
 
 
Creatinine Clearance > 45                     ___ ___.___ 
 
 
 
 
Is the patient willing and able to take folic acid and vitamin B12 
supplementation and interrupt aspirin or other non-steroidal anti-
inflammatory agents for a 5-day period (8 day period for long acting 
agents such as piroxicam) before entering the study? 
 
 
 
 
Is the patient able to understand and willing to give verbal and written 
informed consent prior to beginning therapy?   
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 72 
CCCWFU # 60107 Eligibility Checklist                                                                 Page 2                               
 
Yes No N/A Exclusion Criteria (All responses must be NO in order to enter study) 
Eligibility 
Confirmation 
(registrar) 
 
 
 
Does the patient have Nasopharyngeal Carcinoma? 
 
 
 
 
Does the patient have uncontrolled intercurrent illness including, but 
not limited to, ongoing or active infection or psychiatric illness/social 
situations that would limit compliance with study requirements, 
significant history of uncontrolled cardiac disease; i.e., uncontrolled 
hypertension, unstable angina, recent myocardial infarction (within 
prior 3 months), uncontrolled congestive heart failure, and 
cardiomyopathy with decreased ejection fraction? 
 
 
 
 
Does the patient have active Interstitial Lung Disease? 
 
 
 
 
Does the patient have a presence of third space fluid which cannot be 
controlled by drainage? 
 
 
 
 
Is the patient receiving any other investigational agents? 
 
 
 
 
Is the patient pregnant?  Breastfeeding should be discontinued. Prior 
to study enrollment, WOCBP must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk 
factors for an unintentional pregnancy. Men enrolled on this study 
should understand the risks to any sexual partner of childbearing 
potential and should practice an effective method of birth control. 
Subjects who are WOCBP and sexually active males must be willing 
to use effective contraception while on study. 
 
If applicable, pregnancy test:   Positive  or   Negative 
 
 
 
 
 
If a WOCBP, has the patient been instructed to contact the 
Investigator immediately if they suspect they might be pregnant? 
 
 
 
 
Is the patient known HIV-positive? 
 
 
 
 
 
 
 
 
 
 
 
Signature: ________________________________________ Date: _________________ 
 
Please send source documentation with Eligibility Form.  
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 73 
CCCWFU # 60107 Protocol Registration Form                                                    Page 3 
DEMOGRAPHICS 
Patient: Last Name: _____________________ 
First Name: ____________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ 
DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
SEX:   
  Male            
  Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: _____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 
PM, Monday – Friday. 
 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, 
faxed or e-mailed to the registrar at 336-713-6772 or registra@wakehealth.edu. 
 
 
 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to 
registration) 
 YES 
  NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 74 
CCCWFU # 60107 Eligibility Source Documentation Checklist                         Page 4                      
(to be submitted with Protocol Registration Form) 
Source Documents Needed 
 or 
N/A 
1 
Pathology report confirming diagnosis of recurrent or second primary squamous 
cell carcinoma (SCC) of the oral cavity, oropharynx, hypopharynx, or recurrent 
neck metastases with unknown primary. 
 
2 
CT scan/MRI showing patient has disease with measurable tumor. 
 
3 
Source documentation showing no definitive evidence of distant metastasis.   
 
4 
Dictation from preliminary ENT evaluation showing patient is unresectable or has 
refused surgery. 
 
5 
Radiation treatment summary indicating that the patient has received prior head 
and neck radiation to no more than 72 Gy and most (> 75%) of the recurrent or 
second primary tumor volume should be in areas previously irradiated to > 45 Gy. 
  
6 
Documentation that the entire tumor volume must be included in a treatment field 
that limits the total spinal cord dose to 54Gy (prior plus planned dose). 
 
7 
Dictation documenting that patient has recovered from the acute side effects of 
prior surgery, chemotherapy or radiation therapy.  If applicable, dictation 
documenting that a minimum time period of at least 6 months has elapsed from 
prior radiation treatment until enrollment in the study. 
 
8 
Dictation documenting patient has not received chemotherapy as a component of 
their recurrent or metastatic disease and no prior treatment with systemic anti-
EGFR inhibitors. 
 
9 
Dictation documenting an ECOG performance status 0-1. 
 
10 
Most recent MD dictation (H&P) documenting patient ≥ 18 years old. 
 
11 
Lab report documenting all initial required lab values. 
 
12 
Documentation that patient is willing and able to take folic acid and vitamin B12 
supplementation and interrupt aspirin or other non-steroidal anti-inflammatory 
agents for a 5 day period (8 day period for long acting agents such as piroxicam) 
before entering the study. 
 
13 
Copies of all informed consent documents. 
 
14 
Dictation showing that the patient does not have Nasopharyngeal Carcinoma. 
 
15 
Dictation showing that the patient does not have uncontrolled intercurrent illness 
including, but not limited to, ongoing or active infection or psychiatric 
illness/social situations that would limit compliance with study requirements, 
significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, 
unstable angina, recent myocardial infarction (within prior 3 months), 
uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection 
fraction. 
 
16 
Documentation that the patient does not have active Interstitial Lung Disease. 
 
17 
Documentation that the patient does not have presence of a third space fluid which 
cannot be controlled by drainage. 
 
18 
Documentation that the patient is not receiving any other investigational agents. 
 
19 
Lab results indicating negative pregnancy test for WOCBP. 
 
20 
Documentation that the patient is not known HIV-positive. 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 75 
APPENDIX 7  Response Evaluation Criteria in Solid Tumors (RECIST) Quick 
Reference: (http://ctep.cancer.gov/forms/quickrcst.doc) 
1. ELIGIBILITY 
Only patients with measurable disease at baseline should be included in 
protocols where objective tumor response is the primary endpoint.  
 
2. MEASURABLE DISEASE 
The presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.  
 
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter  20 mm using conventional techniques or 10 
mm with spiral CT scan. 
Non-measurable lesions - all other lesions, including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm with spiral CT scan), 
i.e., bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and 
also abdominal masses that are not confirmed and followed by imaging 
techniques; and: 
 
 All measurements should be taken and recorded in metric notation, using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment.  
 The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up.  
 Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of 
the lesion, is recommended.  
 
1.1.1 Methods of Measurement –  
 CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment. Conventional CT 
and MRI should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen and 
pelvis. Head and neck tumors and those of extremities usually require specific 
protocols. 
 Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.  
 When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, 
a possible alternative to clinical measurements of superficial palpable lymph 
nodes, subcutaneous lesions and thyroid nodules. US might also be useful to 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 76 
confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination. 
 The utilization of endoscopy and laparoscopy for objective tumor evaluation 
has not yet been fully and widely validated. Their uses in this specific context 
require sophisticated equipment and a high level of expertise that may only 
be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in 
specialized centers. However, such techniques can be useful in confirming 
complete pathological response when biopsies are obtained. 
 Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response when all lesions have disappeared. 
 Cytology and histology can be used to differentiate between PR and CR in 
rare cases (e.g., after treatment to differentiate between residual benign 
lesions and residual malignant lesions in tumor types such as germ cell 
tumors). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
 All measurable lesions up to a maximum of five lesions per organ and 10 
lesions in total, representative of all involved organs should be identified as 
target lesions and  recorded and measured at baseline.  
 Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically).  
 A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor. 
 All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these 
lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
 
1.2 
Response Criteria 
1.2.1 Evaluation of target lesions 
* Complete Response (CR): Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD 
* Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new 
lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 77 
1.2.2 Evaluation of non-target lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization 
of tumor marker level 
* Incomplete Response/         
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal 
limits 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (1)  
(1) Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the 
progression status should be confirmed later on by the review panel (or study chair). 
 
1.2.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment started). In general, the 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria  
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1.2.4  
 Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be classified as having “symptomatic deterioration”. Every effort 
should be made to document the objective progression even after 
discontinuation of treatment.  
 In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response status. 
 
1.2.5 Confirmation 
 The main goal of confirmation of objective response is to avoid overestimating 
the response rate observed.  In cases where confirmation of response is not 
feasible, it should be made clear when reporting the outcome of such studies 
that the responses are not confirmed. 
 To be assigned a status of PR or CR, changes in tumor measurements must 
be confirmed by repeat assessments that should be performed no less than 4 
weeks after the criteria for response are first met. Longer intervals as 
determined by the study protocol may also be appropriate.  

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 78 
 In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval (in general, not less than 6-
8 weeks) that is defined in the study protocol  
 
1.2.6 Duration of overall response 
 The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever status is recorded first) until the first 
date that recurrence or PD is objectively documented, taking as reference for 
PD the smallest measurements recorded since the treatment started. 
 
1.2.7 Duration of stable disease 
 SD is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
 The clinical relevance of the duration of SD varies for different tumor types 
and grades. Therefore, it is highly recommended that the protocol specify the 
minimal time interval required between two measurements for determination 
of SD. This time interval should take into account the expected clinical benefit 
that such a status may bring to the population under study.  
 
2 
RESPONSE REVIEW 
 For trials where the response rate is the primary endpoint it is strongly 
recommended that all responses be reviewed by an expert(s) independent of 
the study at the study’s completion.  Simultaneous review of the patients’ files 
and radiological images is the best approach.  
 
3 
REPORTING OF RESULTS 
 All patients included in the study must be assessed for response to treatment, 
even if there are major protocol treatment deviations or if they are ineligible.  
Each patient will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) 
early death from malignant disease, 6) early death from toxicity, 7) early death 
because of other cause, or 9) unknown (not assessable, insufficient data). 
 All of the patients who met the eligibility criteria should be included in the 
main analysis of the response rate.  Patients in response categories 4-9 
should be considered as failing to respond to treatment (disease progression).  
Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate.  Precise definitions for 
categories 4-9 will be protocol specific. 
 All conclusions should be based on all eligible patients. 
 Subanalyses may then be performed on the basis of a subset of patients, 
excluding those for whom major protocol deviations have been identified (e.g., 
early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the 
basis for drawing conclusions concerning treatment efficacy, and the reasons 
for excluding patients from the analysis should be clearly reported.   
 The 95% confidence intervals should be provided. 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 79 
APPENDIX 8                Common Toxicity Criteria Version 3 
 
 
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse 
Events Version 3.0, DCTD, NCI, NIH, DHHS. March 31, 2003 
(http://ctep.cancer.gov) Publish Date: May 22, 2003 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 80 
APPENDIX 9                                   FACT-H&N 
 
Below is a list of statements that other people with your illness have said are 
important.  By circling one (1) number per line, please indicate how true 
each statement has been for you during the past 7 days. 
 
 
 
PHYSICAL WELL-BEING 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
GP
1 
 
I have a lack of energy ............................................... 
0 
1 
2 
3 
4 
GP
2 
 
I have nausea ............................................................. 
0 
1 
2 
3 
4 
GP
3 
 
Because of my physical condition, I have trouble 
meeting the needs of my family .................................. 
0 
1 
2 
3 
4 
GP
4 
 
I have pain .................................................................. 
0 
1 
2 
3 
4 
GP
5 
 
I am bothered by side effects of treatment ................. 
0 
1 
2 
3 
4 
GP
6 
 
I feel ill ......................................................................... 
0 
1 
2 
3 
4 
GP
7 
 
I am forced to spend time in bed ................................ 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
GS
1 
 
I feel close to my friends ................................................ 
0 
1 
2 
3 
4 
GS
2 
 
I get emotional support from my family .......................... 
0 
1 
2 
3 
4 
GS
3 
 
I get support from my friends ......................................... 
0 
1 
2 
3 
4 
GS
4 
 
My family has accepted my illness ................................ 
0 
1 
2 
3 
4 
GS
5 
 
I am satisfied with family communication about my 
Illness ............................................................................. 
0 
1 
2 
3 
4 
GS
6 
 
I feel close to my partner (or the person who is my 
main support) ................................................................. 
0 
1 
2 
3 
4 
Q1 
 
Regardless of your current level of sexual activity, 
please answer the following question.  If you prefer 
not to answer it, please check this box         and go to 
the next section. 
 
 
 
 
 
GS
7 
 
I am satisfied with my sex life ........................................ 
0 
1 
2 
3 
4 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 81 
By circling one (1) number per line, please indicate how true each 
statement has been for you during the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GE
1 
 
I feel sad ..................................................................... 
0 
1 
2 
3 
4 
GE
2 
 
I am satisfied with how I am coping with my illness ... 
0 
1 
2 
3 
4 
GE
3 
 
I am losing hope in the fight against my illness .......... 
0 
1 
2 
3 
4 
GE
4 
 
I feel nervous .............................................................. 
0 
1 
2 
3 
4 
GE
5 
 
I worry about dying ..................................................... 
0 
1 
2 
3 
4 
GE
6 
 
I worry that my condition will get worse ...................... 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
FUNCTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GF
1 
 
I am able to work (include work at home) ...................... 
0 
1 
2 
3 
4 
GF
2 
 
My work (include work at home) is fulfilling ................... 
0 
1 
2 
3 
4 
GF
3 
 
I am able to enjoy life ..................................................... 
0 
1 
2 
3 
4 
GF
4 
 
I have accepted my illness ............................................. 
0 
1 
2 
3 
4 
GF
5 
 
I am sleeping well .......................................................... 
0 
1 
2 
3 
4 
GF
6 
 
I am enjoying the things I usually do for fun .................. 
0 
1 
2 
3 
4 
GF
7 
 
I am content wit the quality of my life right now ............. 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 82 
By circling one (1) number per line, please indicate how true each 
statement has been for you during the past 7 days. 
 
 
 
 
ADDITIONAL CONCERNS 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
H&N
1 
 
I am able to eat the foods that I like ...........................
0 
1 
2 
3 
4 
H&N
2 
 
My mouth is dry ..........................................................
0 
1 
2 
3 
4 
H&N
3 
 
I have trouble breathing ..............................................
0 
1 
2 
3 
4 
H&N
4 
 
My voice has its usual quality and strength................
0 
1 
2 
3 
4 
H&N
5 
 
I am able to eat as much food as I want ....................
0 
1 
2 
3 
4 
H&N
6 
 
I am unhappy with how my face and neck look .........
0 
1 
2 
3 
4 
H&N
7 
 
I can swallow naturally and easily ..............................
0 
1 
2 
3 
4 
H&N
8 
 
I smoke cigarettes or other tobacco products ................
0 
1 
2 
3 
4 
H&N
9 
 
I drink alcohol (e.g. beer, wine, etc.) ...............................
0 
1 
2 
3 
4 
H&N
10 
 
I am able to communicate with others ............................
0 
1 
2 
3 
4 
H&N
11 
 
I can eat solid foods ........................................................
0 
1 
2 
3 
4 
H&N
12 
 
I have pain in my mouth, throat or neck .........................
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 83 
APPENDIX 10       Performance Status Scale for Head and Neck Cancer               
 
 
 
 
 
Patients (PSS-HN)  
 
PID _______________      Date _______________      Visit # _______________ 
 
Common Functions evaluated: 
 
1.) Eating in public __________  
2.) Understandability of speech ___________ 
3.) Normalcy of diet ___________ 
The higher the score, the better the ability of the patient to function. 
 
Choose one answer for each of the 3 parameters. 
 
 
 
 
 
 
 
Parameter 1 
 
Performance 
Points 
Eating in public 
No restriction of place, food or companion 
(can eat out at any opportunity) 
100 
 
No restriction of place, but restricts diet 
when in public (eats anywhere but limits diet 
to foods that can be handled easily like 
liquids) 
75 
Eats only in the presence of selected 
persons in selected places 
50 
Eats only at home in the presence of 
selected persons 
25 
Always eats alone 
0 
Parameter 2 
Performance 
Points 
Understandability 
Of speech 
Always understandable 
100 
 
Understandable most of the time; occasional 
repetition necessary  
75 
 
Usually understandable; face-to-face contact 
necessary 
50 
 
Difficult to understand 
25 
 
Never understandable; may use written 
communication 
0 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 84 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parameter 3 
Performance 
Points 
 
Normalcy of diet 
Full diet with no restrictions 
100 
 
Peanuts 
90 
 
All meats 
80 
 
Carrots, celery 
70 
 
Dry bread and crackers 
60 
 
Soft, chewable foods 
50 
 
Soft foods requiring no chewing 
40 
 
Pureed foods 
30 
 
Warm liquids 
20 
 
Cold liquids 
10 
 
Nonoral feedings (tube feeding, etc.) 
0 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 85 
APPENDIX 11            The M.D. Anderson Dysphagia Inventory 
This questionnaire asks for your views about your swallowing ability. This information will help us understand how you 
feel about swallowing.  The following statements have been made by people who have problems with their 
swallowing. Some of the statements may apply to you.  Please read each statement and CIRCLE the response which 
best reflects your experience in the past week. 
 
My swallowing ability limits my day-to-day activities. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
E2. 
I am embarrassed by my eating habits.  
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
F1. 
People have difficulty cooking or me. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
P2. 
Swallowing is more difficult at the end of the day. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
E7. 
I do not feel self-conscious when I eat. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
E4. 
I am upset by my swallowing problem. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
P6. 
Swallowing takes great effort. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
E5. 
I do not go out because of my swallowing problem. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
F5. 
My swallowing difficulty has caused me to lose income. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
P7. 
It takes me longer to eat because of my swallowing problem. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
P3. 
People ask me, “Why can’t you eat that?” 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
E3. 
Other people are irritated by my eating problem. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 86 
P8. 
I cough when I try to drink liquids. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
F3. 
My swallowing problems limit my social and personal life. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
F2. 
I feel free to go out to eat with my friends, neighbors, and relatives. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
P5. 
I limit my food because of my swallowing difficulty. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
P1. 
I cannot maintain my weight because of my swallowing problems. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
E6. 
I have low self-esteem because of my swallowing problems. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
P4. 
I feel that I am swallowing a huge amount of food. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
F4. 
I feel excluded because of my eating habits. 
Strongly Agree 
 
Agree 
 
No Opinion 
Disagree  
Strongly Disagree 
 
Thank you for completing this questionnaire! 
 
 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 87 
 
APPENDIX 12         ECOG *PERFORMANCE STATUS SCALE 
 
This scale and criteria are used to assess how a subject’s disease is progressing, assess how the 
disease affects the daily living abilities of the subject, and determine appropriate treatment and 
prognosis. 
 
 
ECOG PERFORMANCE STATUS * 
GRADE 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self care, but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair 
5 
Dead 
 
 *ECOG = Eastern Cooperative Oncology Group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 88 
APPENDIX 13                             Master Flow Sheet 
The Comprehensive Cancer Center of Wake Forest University 
CCCWFU # 60107                                     Clinical Flowsheet                                              PAGE: ______                                     
Patient: 
 
 
PID #: 
 
 
Unit Number:  
 
 
NCBH M.D. 
 
 
Date: mm/dd/yy 
 
 
 
 
 
Cycle # / Day of Cycle 
/ 
/ 
/ 
/ 
/ 
Temp / Pulse / Resp / BP 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
Height/Weight/BSA in m2 
/          / 
/          / 
/          / 
/          / 
/          / 
ECOG PS 
 
 
 
 
 
 
 
 
 
 
 
WBC/ANC 
/ 
/ 
/ 
/ 
/ 
Seg / Band / Meta / Lymph 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
Mono / EOS / Bas / Pro 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
Hgb / Hct / Platelets  
/          / 
/          / 
/          / 
/          / 
/          / 
Na / K / CI / CO2 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
BUN / Creat / Gluc / Ca, Mg 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
Creatinine Clearence 
/          / 
/          / 
/          / 
/          / 
/          / 
Prot / Alb / T.Bili / AST 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
/        /        / 
ALT / AP / 
/          / 
/          / 
/          / 
/          / 
/          / 
PregTest/ EKG  
       /        /         
      /        /          
       /        /         
       /        /         
       /        /         
Others 
 
 
 
 
 
 
 
 
 
 
 
Tumor Evaluation 
 
 
 
 
 
Tumor size 
 
 
 
 
 
Nodes size 
 
 
 
 
 
Chest X-Ray 
 
 
 
 
 
CT Head and Neck 
 
 
 
 
 
CT scan Chest 
 
 
 
 
 
PET scan 
 
 
 
 
 
 
 
 
 
 
 
QOL Evaluations 
 
 
 
 
 
FACT-H&N 
 
 
 
 
 
PSS-HN 
 
 
 
 
 
MDADI 
 
 
 
 
 
Swallowing evaluation 
 
 
 
 
 
 
 
 
 
 
 
Chemotherapy Drugs: 
 
 
 
 
 
Tarceva (Erlotinib) 
 
 
 
 
 
Alimta (Pemexetred) 
 
 
 
 
 
Vit. B12 
 
 
 
 
 
Folic Acid 
 
 
 
 
 
Dexamethsone 
 
 
 
 
 
Leucovorin 
 
 
 
 
 
Others 
 
 
 
 
 
 
 
 
 
 
 
Toxicity: 
 
 
 
 
 
ECOG Performance Status  
 
 
 
 
 
Fatique  
 
 
 
 
 
Mucositis grade 
 
 
 
 
 
Nausea/vomiting 
 
 
 
 
 
Use of feeding tube 
 
 
 
 
 
Oral nutrition  
 
 
 
 
 
Skin 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
Other: 
 
 
 
 
 
 
 
 
 
 
 
Physician’s Signature 
 
 
 
 
 
PROG – Progression 
NC – No Change 
 
ABN – Abnormal 
 
STAT 
ND – Not Done 
So – Study Ordered 
 
WNL – Within 
Normal Limits 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 89 
APPENDIX 14 
            CCCWFU Measurement Form 
Instructions: Complete and submit this form as required by the protocol.  Do not leave any entries blank.  
Enter -1 to indicate that an answer is unknown, unobtainable, not applicable or not done.  Retain a copy for 
your records and submit original to the CCCWFU Data Management Center. 
 
 
CCCWFU Study Number: __________________________               CCCWFU Patient ID: ____________ 
 
Patient Name: ____________________________________               MRN: ________________________ 
 
WFUHS/Affiliate: ______________________________________________________________________ 
(Specify) 
 LIST ALL TARGET AND NON-TARGET SITES TO BE USED FOR RESPONSE 
Date of Observation (mm/dd/yy) 
 
 
 
 
 
 
Cycle: 
 
 
 
 
 
 
TARGET LESIONS 
 
 
 
 
 
 
Response Status (CR, PR, SD, PD) 
 
 
 
 
 
 
List sites for response: 
Means of 
Evaluation 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
1. 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
 
6. 
 
 
 
 
 
 
 
7. 
 
 
 
 
 
 
 
8. 
 
 
 
 
 
 
 
9. 
 
 
 
 
 
 
 
10. 
 
 
 
 
 
 
 
Total sum of LD for all Target Lesions: 
 
 
 
 
 
 
NON-TARGET LESIONS 
Response Status  
(CR, Incomplete Response/SD, PD): 
 
 
 
 
 
 
List sites for response 
Means of 
Evaluation 
 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
1. 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
 
6. 
 
 
 
 
 
 
 
7. 
 
 
 
 
 
 
 
8. 
 
 
 
 
 
 
 
Observer Signature: 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 90 
APPENDIX 15 
CYP3A4 and CYP1A2 Inhibitors/Inducers 
 
CYP3A4 Inhibitors 
CYP3A4 Inducers 
delaviridine 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
amiodarone 
aprepitant 
chloramphenicol 
cimetidine 
ciprofloxacin 
clarithromycin 
diethyl-dithiocarbamate 
diltiazem 
erythromycin 
fluconazole 
fluvoxamine 
gestoden 
itraconazole 
ketoconazole 
mifepristone 
nefazodone 
norfloxacin 
norfluoxetine 
mibefradil 
verapamil 
grapefruit juice 
efavirenz 
nevirapine 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
phenobarbital 
phenytoin 
rifampin 
St. John’s wort 
troglitazone 
pioglitazone 
rifabutin 
 
CYP1A2 Inhibitors 
CYP1A2 Inducers 
amiodarone 
cimetidine 
fluoroquinolones 
fluvoxamine 
furafylline 
methoxsalen 
mibefradil 
insulin 
methyl cholanthrene 
modafinil 
nafcillin 
beta-naphthoflavone 
omeprazole 
tobacco 
 
 
 
 
 
 
 
 
 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 91 
APPENDIX 16          CCCWFU 60107 – PI: Dr. Porosnicu  
Swallowing Portion Data Collection Form 
 
Participant Name: _______________________ 
 
 
Assessment Date: _______________________   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flexible Endoscopic Evaluation of Swallowing (FEES) 
 
Bolus Administered 
 
PAS Score (1-8) 
Thin Liquid 
  
 
  
 
  
Puree 
  
 
  
Solid 
  
 
DOSS Level (1-7): _________ 
Diet Description: 
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 92 
Appendix 17 Specimen Collection Log 
 
                              
Record of retained specimen samples 
 
 
Page       of       
 
 
 
Study short title 
CCCWFU 60107 -  Phase I/II Clinical Trial of Combined Re-Irradiation with 
Pemetrexed and Erlotinib Followed by Maintenance Erlotinib for Recurrent and 
Second Primary Squamous Cell Carcinoma of the Head and Neck 
Patient 
Initials 
 
Patient  
Study 
Number 
Patient 
consent 
provided? 
Y / N 
Date sample 
collected 
(dd/mm/yy) 
Sample Type 
Storage location 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 
      
      
Y 
N 
      
      
 

 
CCCWFU 60107 
 
Ver 09/06/2013 
Page 93 
Appendix 18 CCCWFU 60107 Adverse Event Log   
 
 
 
 
 
 
 
Page ____ of ____ 
 
PI: ____________________                                             PID: ____________________                     MRN: ____________________   
 
Adverse 
Event 
Description 
Cycle of 
Toxicity 
Onset 
Start 
Date 
 
Stop 
Date 
 
AE Type 
Grade  
(1-5) per  
CTC v. 3.0 
Attribution 
 
 
 
Dose 
Limiting  
Toxicity 
Serious 
 
 
 
Action Taken 
 
 
 
Treating 
Physician 
Initials/ 
Date 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-
threatening 
Death 
Other: ______ 
None 
Therapy 
Withheld 
Therapy D/C 
Therapy 
Adjusted 
Other: _____ 
N/A 
 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-
threatening 
Death 
Other: ______ 
None 
Therapy 
Withheld 
Therapy D/C 
Therapy 
Adjusted 
Other: _____ 
N/A 
 
 
 
 
 
Expected 
Unexpected 
Mild/1 
Moderate/2 
Severe/3 
Life-   
threatening/4 
Death/5 
Related 
Probably 
Possible 
Unlikely 
Unrelated 
 
Yes 
No 
No 
Hospitalization 
Disability 
Birth Defect  
Life-
threatening 
Death 
Other: ______ 
None 
Therapy 
Withheld 
Therapy D/C 
Therapy 
Adjusted 
Other: _____ 
N/A