Clinical trial NCT01663259
Conditions: Squamous Cell Carcinoma of the Oropharynx HPV
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2011-01-01; Completion date: 2019-09-01
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Taking into account the excellent prognosis of patients with HPV-positive oropharyngeal cancer with \< 10 pack-year smoking, the investigators hypothesize that reducing the intensity of therapy for these patients will reduce treatment sequelae, notably long-term dysphagia, without affecting their cure rates. The main Aim is to assess whether reducing treatment intensity, by replacing concurrent chemotherapy with cetuximab, will indeed achieve improved long-term toxicity.

The primary objectives include the following: to confirm that reducing treatment intensity in patients with HPV-related oropharyngeal cancer and \< 10 pack-year smoking history by replacing concurrent chemotherapy with concurrent cetuximab, does not significantly increase the proportion of patients whose tumors recur, compared to our previous experience in similar patients receiving chemo-RT and to compare the toxicity in patients receiving cetuximab-RT to similar patients treated with 7 weeks of chemotherapy concurrent with RT ("standard therapy") in UMCC 2-21.

Detailed description:
The investigators have shown in past experience a high success in getting rid of oropharyngeal cancer (tonsil or base of tongue cancer) using chemotherapy and radiation therapy in patients who have not smoked, or only smoked a minimal amount of cigarettes or equivalent. In these patients, the cancer is thought to be caused by a virus (Human Papilloma Virus, or HPV). HPV is a virus that infects the epidermis (outermost layer of skin) and mucous membranes of humans. In general, patients with HPV-related cancer such as yours have a better prognosis compared with patients whose tumors are smoking-related. Taking into account the good prognosis, it is possible that reducing the intensity of therapy will not affect the high rate of tumor control, while reducing the side-effects of therapy. In this study, the investigators plan to reduce the intensity of treatment by replacing the currently used chemotherapy drugs with an FDA approved drug, cetuximab, which is a monoclonal antibody to a growth factor which helps cancer cells grow. By opposing the effect of the growth factor, cetuximab may help radiotherapy kill cancer cells without a lot of effect on the normal tissue. It differs from chemotherapy in its more selective activity against tumors compared to normal tissue Cetuximab has the chance to preserve the high rate of success in killing the tumor but may reduce the side effects and complications of therapy in comparison to chemotherapy drugs.

The investigators would also like to know if taking cetuximab has any effect on certain cancer-related molecules in the cancer and the normal cells inside the cheek. They would like to test this by taking a small biopsy of the tumor, as well as a swab of the inside of the cheek, before and shortly after the start of therapy.

Arms: arm 1: None
Interventions: intervention 1: Cetuximab intervention 2: Radiotherapy
Intervention descriptions: intervention 1: Before Radiotherapy patients you will receive a single loading dose of cetuximab. Patients will also have two additional biopsies before and after cetuximab to determine how the tumor is affected. A Cetuximab infusion will also be delivered once a week during radiotherapy.Radiation will be started (70 Gy in 35 fractions over 7 weeks to the gross tumor, 50-60 Gy to subclinical target volumes) five days a week until the total dose of radiation prescribed by the doctor is reached. Radiation will be delivered concurrent with weekly cetuximab 250 mg/m2, delivered on Monday or Tuesday each week. In order to evaluate swallowing problems from radiotherapy, patients will undergo an evaluation of swallowing by videofluoroscopy (VF). Quality of Life questionnaires will be given before therapy and periodically up to 36 months after therapy. In order to assess if the tumor was completely eradicated, CT-PET scan will be performed 3 months after the completion of therapy. intervention 2: Radiation will be started (70 Gy in 35 fractions over 7 weeks to the gross tumor, 50-60 Gy to subclinical target volumes) five days a week until the total dose of radiation prescribed by the doctor is reached. Radiation will be delivered concurrent with weekly cetuximab 250 mg/m2, delivered on Monday or Tuesday each week.

Protocol documents:
Prot_SAP_000.pdf: 
Reduced-Intensity Therapy for Advanced Oropharyngeal Cancer in Non-Smoking Human 
Papilloma Virus (HPV)-16 Positive Patients 
(UMCC 2009.078) 
Principal Investigator: 
Michelle Mierzwa, M.D.  
Department of Radiation Oncology 
Co-Investigators: 
Francis Worden, M.D. 
Carol Bradford, M.D.  
Gregory Wolf, M.D.  
Mark Prince, M.D.  
Jeffery Moyer, M.D.  
Joseph Helman, M.D.  
Brent Ward, M.D.  
Susan Urba, M.D.  
Jonathan McHugh, M.D. 
Matthew Schipper, Ph.D. (statistician)
Version Date:   March 20, 2018
NCT01663259


UMCC 2009.078, Protocol v. 10/10/11 
 
 2 
TABLE OF CONTENTS 
 
 
1.0  INTRODUCTION .......................................................................................................................... 3 
2.0  STUDY HYPOTHESIS AND RATIONALE  ............................................................................... 6 
3.0  OBJECTIVES ................................................................................................................................. 6 
4.0  INCLUSION CRITERIA  ............................................................................................................... 6 
5.0  EXCLUSION CRITERIA .............................................................................................................. 7 
6.0  PRE-TREAMENT EVALUATION  .............................................................................................. 7 
7.0  STUDY DESIGN ............................................................................................................................ 8 
8.0  RADIOTHERAPY ....................................................................................................................... 14 
9.0  EVALUATION OF RESPONSE TO TREATMENT .................................................................. 14 
10.0  EVALUATION OF TOXICITY AND QUALITY OF LIFE ..................................................... 15 
11.0  STUDY CALENDAR ................................................................................................................ 16 
12.0  MEASUREMENT OF RESPONSE ........................................................................................... 16 
13.0  CRITERIA FOR DISCONTNUATION OF TREATMENT  ..................................................... 16 
14.0  DRUG INFORMATION ............................................................................................................ 17 
15.0  EGFR ANALYSIS ...................................................................................................................... 19 
16.0  OTHER THERAPY .................................................................................................................... 20 
17.0  ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ............................... 20 
18.0  DATA AND SAFETY MONITORING ..................................................................................... 25 
19.0  QUALITY ASSURANCE AND AUDITS ................................................................................. 26 
20.0  STATISTICAL CONSIDERATIONS................................................................................ 26 
21.0  REFERENCES ........................................................................................................................... 31 
APPENDICES ..................................................................................................................................... 33 
 


UMCC 2009.078, Protocol v. 10/10/11 
 
 3 
1.0  
INTRODUCTION 
Improved outcomes of patients with head and neck cancer are achieved with the 
administration of concurrent chemoradiotherapy, compared with radiotherapy alone (1), however, this 
improvement is associated with increased toxicity, primarily acute mucositis and late dysphagia (2). 
Efforts to improve the therapeutic ratio for oropharyngeal cancer include customization of the intensity 
of therapy to important prognostic factors, and using advanced radiotherapy to reduce doses to the 
anatomical structures whose damage causes dysphagia. These issues are the subjects of the proposed 
study and are discussed below. 
 
Over the past three decades, there has been an increase in the incidence of tonsil and tongue squamous 
cell carcinomas.[3, 4] Recent evidence in the literature as well as from our own studies has identified 
high-risk human papillomavirus (HPV), particularly HPV-16 (as well as other high risk HPV 
types), as a causative agent for a subset of HNSCCs, accounting for over 60% of squamous 
cell carcinomas of the oropharynx (SCCOP) in the United States.[5-9] HPV-positive SCCOP has a 
distinct risk factor profile[5] and oncogenic mechanism[10, 11] and portends a more favorable 
prognosis than HPV-negative SCCOP.[5, 12-17] 
 
Conflicting data exist on the combined effect of HPV and smoking on prognosis. Some investigators 
have found that non-smoking patients with HPV-positive tonsillar squamous cell carcinoma have a 
better disease-specific survival rate than their smoking counterparts.[13] HPV induced and tobacco-
related HPV-negative SCCOP are widely considered to represent distinct clinical entities. However, 
our observations of patients with HPV-induced SCCOP who use tobacco indicate that they have a worse 
prognosis than non-users, suggesting that this is a third category of SCCOP (9). 
 
Despite the favorable prognosis associated with, HPV-positive tumors, this biologic marker has not yet 
been used to determine therapeutic management. We postulate that there are two subsets of HPV-positive 
SCCOP patients; those who are cured by current therapies but may be suffering unnecessary morbidity 
from over-treatment and those who are at higher risk for disease progression and require more 
aggressive therapies. In prior work, we have investigated tobacco use and the HPV-16 biomarker as 
variables that can differentiate patients to one of those two subgroups, thereby allowing clinicians 
to safely develop more selective therapies for subsets of HPV-positive SCCOP patients. 
 
One hundred and twenty-four patients with newly diagnosed, stage III or IV SCCOP whose tumors 
were analyzed for HPV presence and type were included in this study. Patients were treated according 
to one of two consecutive treatment protocols at the University of Michigan. Of the 124 patients, one 
hundred two were HPV-positive (82.3%) and 22 (17.7%) were HPV negative. Thirty- two (32/102, 
32.4%) had disease progression (DM, LR, or SP). Seventeen patients (17/124, 13.7%) developed DMs 
(12 HPV-positive; 5 HPV-negative), nine (9/124; 7.3%) developed LRs (5 HPVpositive; 4 HPV-
negative), and 8 (8/124; 6.5%) developed SPs (5 HPV-positive; 3 HPV-negative). Of thirty-three HPV-
positive never-tobacco users, only one patient had disease progression (DM) (1/32, 3%), and an 
additional patient had a second primary in the oral cavity. Approximately two- thirds (68%) of the 102 
HPV-positive patients were former or current tobacco users. Of these 69 patients, 18 (26%) developed 
a total of 20 disease progression events. All of the 22 HPV-negative SCCOP patients were tobacco 
users at some time. Twelve of the 22 (55%) HPV-negative former or current tobacco users had disease 
progression events (five DMs, four LRs, and three SPs). Sixteen 


UMCC 2009.078, Protocol v. 10/10/11 
 
 4 
(16/22; 72.7%) of the HPV-negative patients were current tobacco users; of these, eight (8/16; 50%) had 
disease progression events (four DMs, three LRs, and one SP). Of the six HPV-negative former tobacco 
users, (4/6; 68%) developed disease progression events. In conclusion, in this series of 124 patients 
with advanced SCCOP, HPV-positive never-tobacco users had 93% disease-specific survival, a 
6% risk of developing a DM or SP, and no evidence of LR tumors. Thus, less aggressive treatments 
that reduce morbidity may be more appropriate for the subset of HPV-positive SCCOP patients who 
never used tobacco. The protein p 1 6ink4 also known as CDKN2A is normally undetectable, however 
it is strongly upregulated when the HPV E7 oncoprotein is expressed. Thus, this protein is an accepted 
surrogate marker for transcriptionally active HPV in HPV induced tumors. In our study, (Worden 
et al JCO, 2008) the association between p16 expression and HPV presence had a p value of 0.0001. 
Since this test can be rapidly performed in pathology on the pretreatment biopsy tissue this assay will 
be used to categorize a tumor as HPV positive. HPV type and copy number will be assessed after all 
of the specimens have been collected. The assay will be the Sequenome Attosense Technology 
developed at U of M by Dr. David Kurnit and licensed to Sequenom. 
 
The Epidermal Growth Factor receptor (EGFR1) plays a key role in head and neck cancer, in that its 
over-expression is associated with more aggressive behavior. In our prior study of 
oropharynx cancer patients treated with induction chemotherapy followed by chemo/RT we 
observed that EGFR intensity was associated with marginally poorer response to CRT (p=0.055) and 
poorer overall survival (p=0.001) and (p=0.002). Higher HPV titer/lower EGFR intensity as 
combined markers were associated with better overall survival (pHPV=0.03, pEGFR=0.008) and 
disease specific survival (pHPV=0.016, pEGFR=0.01) (Kumar et al. JCO 2008). High EGFR 
expression may modify the effect of HPV on response to therapy and outcome, thus targeting EGFR 
together with radiation in HPV-positive non-smokers is a reasonable strategy. Bonner et al 
investigated the benefit of the addition of cetuximab, a monoclonal antibody to EGFR, concurrent with 
radiation for locally advanced HN cancer. Cetuximab improved locoregional control and survival 
compared with RT alone, while common toxic effects associated with radiotherapy, notably mucositis, 
did not increase compared to RT alone (18). Subset analysis showed that patients with oropharyngeal 
cancer were those who mainly benefited from concurrent cetuximab-RT. The advantage of 
cetuximab-RT compared with RT alone regarding local-regional control was 10%, which is similar or 
higher than the advantage reported in multiple randomized studies for chemo-RT compared with RT 
alone. A separate analysis showed that the addition of cetuximab has not affected adversely patient-
reported QOL (18a). The combination of cetuximab-RT however has not been adopted as standard of 
care for advanced FIN cancer because to date there has not yet been a randomized study comparing 
cetuximab-RT to chemo-RT. However, in the sub-group of patients with local/regional advanced 
oropharyngeal cancer whose prognosis is excellent, cetuximab-RT may offer a reduced-intensity 
regimen, compared with chemo-RT, thereby reducing toxicity without affecting excellent survival 
outcomes. 
 
One of the possible explanations for the good prognosis of HPV-related cancers in nonsmokers is a 
high sensitivity of EGFR in these tumors and high tendency for degradation following therapy. We 
propose to assess both the level and degradation of EGFR soon after the administration of the loading 
dose of cetuximab in order to compare these with smoking-related oropharyngeal tumors treated on 
1 Abbreviations: CR, complete response; EGFR, epidermal growth factor receptor; 
MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; PR, partial response; RT, radiation 
treatment/therapy; STAT, signal transducer and activator of transcription; TMA, tissue microarray. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 5 
other UMCC protocols. Initial in vitro studies demonstrated that prolonged exposure of cells to EGF 
could enhance the effects of radiation in head and neck cancer cells (19, 20). It is likely that this 
radiosensitivity was achieved through EGF-induced EGFR degradation. Additional studies showed 
that monoclonal antibodies that target EGFR could increase radiation- induced apoptosis (21). 
Furthermore, there was an inverse correlation between EGFR expression levels and radiation 
response (22-23). This relationship between EGFR expression and poor prognosis was confirmed 
in human head and neck carcinoma samples (24-27). Previous efforts to predict the response to EGFR 
inhibition using the pre-therapy EGFR expression levels have failed. Although the focus for developing 
a predictive assay has been on assessing pretreatment paraffin embedded specimens, it seems possible 
that a predictive assay may require determining the response to treatment (i.e. a pharmacodynamic 
endpoint). As has been noted by Mendelsohn and Balsega (28), successful application of EGFR 
targeted therapy may require not only the presence of activated EGFR, but also that the cancer 
depends on this pathway for cell survival. This dependence ("addiction") might be best determined 
not simply by assessing pretreatment specimens, but by comparing pre- and post-treatment specimens 
to determine if the inhibitor has actually inhibited both EGFR phosphorylation and downstream 
signaling. For example, in patients with rectal cancer receiving cetuximab-based chemo-irradiation, 
disease-free survival was better in patients if EGFR expression was upregulated in the tumor after the 
initial cetuximab dose (28a). In this protocol we plan to assess EGFR and its down-stream signaling 
both pre-therapy and following the loading dose of coniximah, in order to address this issue. 
 
In order to reduce dysphagia after chemo-irradiation, in recent years, we have utilized highly conformal 
radiotherapy (intensity modulated radiotherapy, IMRT) sparing specific anatomical structures, 
pharyngeal constrictors and the glottic and supraglottic larynx, which we have previously identified as 
structures whose damage is the likely cause of long-term dysphagia (28). We have demonstrated that 
it is possible to reduce the doses to these structures without under-treating the target volumes (29). In 
a phase II study in patients with oropharyngeal cancer treated with chemoRT (weekly carboplatin 
and taxol concurrent with a 7-week course of IMRT that spared the swallowing structures and 
delivered a total of 70 Gy tumor dose) we have demonstrated high local- regional tumor control 
rates (94%) (30). There were no tumor recurrences near the spared swallowing structures in 104 
patients. Prospective evaluation of swallowing, including objective studies of swallowing 
(videofluoroscopy, VF), patient-reported, and observer-rated dysphagia, are encouraging (Feng et 
al, manuscript in preparation). Notably, strong statistically significant correlations were found 
between each of the three measures of dysphagia and the doses delivered to the swallowing structures 
(29, 30). While these relationships do not prove cause-and-effect relationships, they strengthen 
the hypothesis that reducing the doses to these structures as much as possible can yield clinically 
significant improvement in dysphagia. 
 
Taking into account the high local-regional control rates achieved in our oropharyngeal cancer 
patients after 7 weeks of concurrent chemo-RT, we hypothesize that additional gains in our efforts to 
reduce treatment sequelae may be achieved if we could safely reduce the intensity of therapy in 
those patients who are most likely to respond completely. A recent analysis of RTOG study comparing 
accelerated to standard fractionation concurrent with chemotherapy, found that in the oropharyngeal 
sub-set of patients, those tumors  were HPV(+) fared better than those with HPV(-) tumors. 
Furthermore, the risk of death increased significantly with each pack-year of tobacco smoking. Using 
recursive-partitioning analysis, patients were classified as having low-risk of death if they had HPV(+) 
tumors, smoking history of <10 pack year or equivalent, tumor stage <T4 and nodal stage <N3 (Ang 
KK et al, NEJM 2010;363:24-35). In this protocol we will select patients with oropharynx cancer (OP) 
cancer who are at low risk according to these criteriafor reduced treatment intensity, using RT concurrent 
with cetuximab instead of chemotherapy. This therapy will be compared to our experience in the past 


UMCC 2009.078, Protocol v. 10/10/11 
 
 6 
few years using full dose chemo-RT, and will use the same detailed measures of toxicity, specifically 
measures of dysphagia, for comparison. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 7 
2.0  
STUDY HYPOTHESIS AND RATIONALE 
Taking into account the excellent prognosis of patients with HPV-positive oropharyngeal 
cancer with < 10 pack-year smoking , we hypothesize that reducing the intensity of therapy for 
these patients will reduce treatment sequelae, notably long-term dysphagia, without 
affecting their cure rates. The main Aim is to assess whether reducing treatment 
intensity, by replacing concurrent chemotherapy with cetuximab, will indeed achieve 
improved long-term toxicity. This Aim will be tested in a prospective study in which acute and 
long-term sequelae will be graded by observers (using CTCAE v4.0) and by patients (via HN-
specific QOL questionnaires).  Dysphagia will also be assessed objectively by 
videofluoroscopy. These measures will be compared to our historical control group 
(consisting of non-smoking patients with advanced oropharyngeal cancer who received 
standard-intensity chemo-RT and were evaluated by the same tools on UMCC protocol 2-21). 
Strict stopping rules will be enacted to ensure that reducing treatment intensity does not increase 
tumor failures compared with our previous results using standard therapy. 
 
EGFR expression and down-stream signaling will be tested before and after the loading dose of 
cetuximab (before radiotherapy starts). We hypothesize that in this population with good 
prognosis, EGFR downstream inhibition after cetuximab test dose will be achieved in the large 
majority of patients, and that these characteristics will differ significantly from the 
characteristics of EGFR inhibition which will be observed in poor-prognosis oropharyngeal 
patients who smoke and/or have HPV- tumors.  (These patients will be treated on a different, 
parallel protocol in which the intensity of therapy will be increased and in whom EGFR 
level will also be examined before and after a loading dose of cetuximab.) 
 
3.0  
OBJECTIVES  
3.1 
Primary Objectives 
3.1.1 To confirm that reducing treatment intensity in patients with HPV related 
oropharyngeal cancer and < 10 pack-year smoking history by replacing 
concurrent chemotherapy with concurrent cetuximab, does not significantly 
increase the proportion of patients whose tumors recur, compared to our 
previous experience in similar patients receiving chemo-RT. 
3.1.2  To compare the toxicity in patients receiving cetuximab-RT to similar patients 
treated with 7 weeks of chemotherapy concurrent with RT ("standard therapy") 
in UMCC 2-21. 
 
3.2 
Secondary Objectives 
3.2.1  Characterize the changes in tumor EGFR, pEGFR, downstream signaling, 
following a loading dose of cetuximab. 
3.2.2  Compare normal mucosa EGFR to EGFR in the tumor sample. 
3.2.3  Explore if baseline EGFR, Bc1xL, p53 and p16 tumor expression are related 
to treatment response. 
 
4.0  
INCLUSION CRITERIA 
 
4.1 
Patients must have pathologically-confirmed, previously untreated, stage III-
IV(excluding N3 or T4) squamous cell carcinoma of the oropharynx, without evidence 


UMCC 2009.078, Protocol v. 10/10/11 
 
 8 
of distant metastasis 
4.2 
Pretreatment tumor biopsy with sufficient tumor for HPV or p16 analysis is required. 
The tumor must be HPV(+) or p16(+) 
4.3 
Smoking history <10 pack-year or equivalent  (including cigarettes, cigars, pipes, 
chewing tobacco, and/or marijuana.)  One cannabis joint is equivalent to 5 cigarettes.  
(Aldington etal, Thorax 2007; 62:1058-1063) 
Smoking status definitions (National Health Interview Survey and Behavioral Risk 
Factor Surveillance System (Nelson DE etal al, Am J Pub Health 2003;93:1335): 
• Smokers: smoking now every day or some days in past month 
• Quitters: at least 100 cigarettes/lifetime and not smoking in the past 1-12 months 
• Former smoker: at least 100 cigarettes/lifetime and not smoking >12 months 
• Never smokers: <100 cigarettes (or equivalent)/lifetime 
4.4 
KPS > 80 (see Appendix A) 
4.5 
Patients must undergo pre-treatment endoscopic tumor staging and PET-CT scanning 
4.6 
Laboratory criteria: 
• 
WBC > 3500/ul 
• 
granulocyte > 1500/ul 
• 
Platelet count > 100,000/ul 
• 
Total Bilirubin < 1.5 X ULN 
• 
AST and ALT < 2.5 X ULN 
 
4.7  
Creatinine clearance >30 cc/min 
 
4.8 
Patients must sign study specific informed consent 
 
4.9 
Patients must have, in the opinion of a treating physician, tumor that is accessible to 
biopsy in the clinic. 
 
5.0  
EXCLUSION CRITERIA 
 
5.1 
Prior head and neck malignancy or history of other prior non-head and neck 
malignancy (excluding skin cancer and early stage treated prostate cancer) within the 
past 3 years 
5.2 
Prior head and neck radiation or chemotherapy 
5.3 
Any medical or psychiatric illness, which in the opinion of the principal investigator, 
would compromise the patient's ability to tolerate this treatment or limit compliance 
with study requirements 
 
5.4 
Patients residing in prison 
5.5 
Patients with prior anti-epidermal growth-factor receptor antibody therapy (antibody or 
small molecule) 


UMCC 2009.078, Protocol v. 10/10/11 
 
 9 
 
6.0  
PRE-TREATMENT EVALUATION 
 
 6.1  
Complete history and physical examination (including smoking status), multidisciplinary 
examination by Surgical, Radiation and Medical Oncology, documentation of extent of 
primary tumor and regional disease 
6.2  
Satisfactory biopsy of the primary tumor confirming pathologic diagnosis, HPV or 
p16 positivity, and specimen submission to the Radiation Oncology research 
laboratory.  
 6.3 
Buccal swab 
6.4 
Complete dental evaluation, as per standard of care for patients receiving radiation 
therapy 
6.5 
CBCP with differential and Comprehensive panel, including Magnesium 
 6.6 
Initial staging PET-CT scan 
 6.7 
Baseline toxicity, QOL, and swallowing function assessments 
 
7.0 
 STUDY DESIGN  
 
7.1 
Schema 
7.1.1 
Cetuximab loading dose followed by daily radiation therapy with weekly 
cetuximab  
7.1.2 
Toxicity assessment, QOL, videofluoroscopy:  pre-therapy and periodically 
after therapy 
7.1.3 
Tumor biopsy and mucosal swabs for EGFR expression: pre-therapy and 
after the loading dose of cetuximab. 
 
7.2 
Overview 
 
 
 
Patients who smoked < 10 pack-year with p16(+) or HPV(+) tumors will be enrolled. 
 
Patients will receive a single dose of cetuximab 400 mg/m2 (Day 0). On day 7 (+/- 2 
days), a repeat biopsy will be performed for EGFR expression, if it can be done 
without general anesthesia.  Within 4 days, definitive radiation will be started (70 Gy 
in 35 fractions over 7 weeks to the gross tumor, 50-60 Gy to subclinical target 
volumes) concurrent with weekly cetuximab 250 mg/m2, delivered on Monday or 
Tuesday each week. 
 
Twelve to 14 weeks (+/- 1 month) following the completion of therapy, patients will 
undergo standard restaging evaluation, including PET-CT, endoscopy and repeat 
tumor site biopsies if deemed necessary.  
 
Toxicity evaluation: Observer-rated toxicity according to CTCAE v4.0, patient- 
reported QOL (HNQOL, UWQOL, and XQ questionnaires), and videofluoroscopy 
(VF), will be performed before and periodically after therapy. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 10 
  
7.3 
HPV or p16 tumor status for eligibility requirements will be determined in biopsy 
tissue by immunohistochemical analysis by standard biotin-avidin complex technique 
performed on formalin-fixed, paraffin-embedded tissue sections using mouse 
monoclonal antibodies to p16INK4A (Biocare Medical, Concord, CA, dilution 1:200) 
following heat-induced antigen retrieval with 0.1M citrate buffer (pH 6.0). Positive 
staining results consist of diffuse and strong staining of both cytoplasm and nucleus 
in tumor tissues. 
 
 7.4 
In addition, a standardized assay of HPV type and copy number may be performed .in 
the cancer center DNA core. In brief, HPV analysis involves real-time competitive 
polymerase chain reaction and matrix-assisted laser desorption/ionization-time of 
flight mass spectroscopy separation of products on a matrix-loaded silicon chip array. 
This method uses primers designed to amplify the E6 region to detect 13 high-risk 
HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). 
 
 
7.5  
EGFR Status 
7.5.1 
Clinical Staging Biopsy 
A diagnostic pretreatment biopsy tissue block (not just submitted slides) 
suitable for isolation of DNA for HPV or p16 testing is required for inclusion 
in the study. This pre-treatment tumor biopsy will be used for diagnostic 
pathology, initial p16 analysis or in situ HPV hybridization analysis. The tissue 
blocks will also be used for creating tissue microarrays for biomarker analysis. 
Tissue cores from the biopsy will be taken for DNA isolation for HPV testing, 
p16 testing, p53 analysis, or other mutations. 
 
7.5.2 
Research Biopsies 
Two research biopsies will be obtained. These research biopsies will be 
delivered directly to the Radiation Oncology research laboratory. The pre-
treatment research biopsy (5-10 mm3) will be taken prior to therapy to assess 
baseline EGFR pathway activation. This pre-treatment biopsy will be 
performed for research purposes if a suitable clinical biopsy specimen is not 
available.  A clinical specimen will be suitable if the biopsy was performed at 
UMHS within 30 days of consent.  The second biopsy will be obtained 7 days 
(+/-2 days) after the loading dose of cetuximab and will be examined for 
changes in EGFR pathway activation. Both biopsies will be performed in the 
clinic, under local anesthesia, by an otolaryngologist or oral surgeon who is a 
co-investigator of the study.  The second biopsy will only be obtained if it can 
be done without general anesthesia. 
 
 
7.6 
Normal Oral Mucosa Sampling 
Baseline EGFR of the normal oral mucosa may be obtained by buccal swab. At least 3 
normal oral mucosa buccal swab samples will be acquired.  Similarly, post-cetuximab 
buccal swab will be performed on day 7 (+/- 2 days) after cetuximab. 
  
7.7 
Schedule 


UMCC 2009.078, Protocol v. 10/10/11 
 
 11 
  
 
7.7.1 
Day 0:  Patients will receive a single loading dose of cetuximab 400 mg/m2 
 
7.7.2 
Day 7 (+/- 2 days): Second buccal mucosa swab will be obtained.  Second 
biopsy will be obtained if it can be done without general anesthesia.  
 
7.7.3 
Daily radiation therapy with weekly cetuximab (250 mg/m2) will be initiated 
within 4 days 
 
  
7.8 
Cetuximab Dose Levels 
 Starting Dose 
Dose Level —1 
Dose Level —2 
 
Cetuximab 
400 mg/m2 (day 0) 
250 mg/m2 (day 7 and 
weekly during RT) 
 
200 mg/m2 (weekly) 
 
150 mg/m2 (weekly) 
NOTE: Once the dosage of Cetuximab has been decreased, it will remain at that level unless further 
dose reductions are required, at which time all dosages will remain at that level. Dosages CANNOT 
be increased once a dose reduction has taken place. 
 
 
7.9 
Cetuximab Dose Modification for Hematologic Toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aDose levels are relative to the starting dose in the previous cycle.  Dose reductions of Cetuximab below the 
–2 dose level will not be allowed. 
bProvided that all the retreatment criteria are met (see section 7.1.3) 
cOne reading of oral temperature  ≥38.5ºC and ANC ≤ 500 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
Cetuximab Dose a,b at Start of Subsequent 
Cycles of Therapy 
Neutropenia 
 
1 (1500-1999/mm3) 
Maintain dose level 
2 (1000-1499/mm3) 
Maintain dose level 
3 (500-999/mm3) 
Decrease by 1 dose level with occurrence 
4 (<500/mm3) 
Decrease by 1 dose level with occurrence 
 
 
Neutropenic Feverc 
Decrease by 1 dose level 
 
 
Thrombocytopenia 
 
1 (≥75,000/mm3) 
Maintain dose level 
2 (50,000- 74,999/mm3) 
Maintain dose level 
3 (25,000 – 49,999/mm3) 
Decrease by 1 dose level with occurrence 
4 (<25,000/mm3) 
Decrease by 1 dose level with occurrence  


UMCC 2009.078, Protocol v. 10/10/11 
 
 12 
7.10  
Cetuximab Dose Modifications for Non-Hematologic Toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aFor 
CTCAE Grade ≤ 2 non-hematologic toxicity not described above, maintain dose level of drug, provided 
that all the retreatment criteria are met as detailed in section 7.1.3. 
bDose levels are relative to the previous dose. Dose reductions of cetuximab below the —2 dose level will 
not be allowed. 
cIn any case of cetuximab treatment delay, there will be no reloading infusion, and all subsequent 
treatments will be at the assigned dose level. 
 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
Cetuximab Dose a, b, c 
Fatigue (Asthenia) 
≥ Grade 3 
Decrease by 1 dose level 
Nail changes (Paronychia)  
Grade 2 
Decrease by 1 dose level 
Diarrhea 
Grade 3 despite maximal 
medical management 
 
Grade 3 recurrent, despite 
maximal medical management 
 
Grade 4 despite maximal 
medical management 
 
No dosage adjustment 
Decrease by 1 dose level 
Decrease by 1 dose level 
Headache 
≥ Grade 3 
 
≥ Grade 3 despite decreased 
infusion rate and use of analgesic 
Decrease infusion rate by 50% 
Decrease dose by 1 dose level 
Stomatitis/Mucositis 
All patients are evaluated weekly. The dosage 
adjustments will be determined by the practicing 
clinicians at each visit. If a reduction is required, the dose 
will be decreased by 1 dose level. If > 2 dosage reductions 
are required, Cetuximab will be discontinued. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 13 
7.11  
Management of Cetuximab Hypersensitivity Reactions 
CTCAE Grade Hypersensitivity Reaction 
Grade 1 
Transient flushing or rash, drug fever <38ºC 
(<100.4ºF); intervention not indicated 
Grade 2 
Intervention or infusion interruption 
indicated; responds promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, narcotics); 
prophylactic medications indicated for 
<=24 hrs 
Grade 3 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
(e.g., renal impairment, pulmonary infiltrates) 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
 
a Symptoms of hypersensitivity reactions should be managed per institutional chemotherapy infusion policy 
guidelines. 
b Study Therapy Retreatment Following Hypersensitivity Reactions:  Once a cetuximab 
infusion rate has been decreased due to an allergic/hypersensitivity reaction, it will remain decreased for 
all subsequent infusions.  If the subject has a second allergic/hypersensitivity reaction with the slower infusion 
rate, the infusion should be stopped, and the subject should receive no further cetuximab treatment. If a subject 
experiences a Grade 3 or 4 allergic/hypersensitivity reaction at any time, the subject should receive no further 
cetuximab treatment. If there is any question as to whether an observed reaction is an allergic/hypersensitivity 
reaction of Grades 1-4, the Principal Investigator should be contacted immediately to discuss and grade the 
reaction. 
 
 
 
7.12  
Cetuximab Special Instructions 
If cetuximab is omitted for more than four consecutive infusions for toxicity due to 
cetuximab, or for an intercurrent illness (e.g., infection) requiring interruption of 
therapy, the subject should be discontinued from further cetuximab therapy. If 
toxicities prevent the administration of cetuximab, the subject may continue to receive 
radiation therapy. 
 
 
7.13  
Retreatment Criteria for cetuximab 
7.13.1 Cetuximab  may only be administered if all of the following criteria are met 
regardless of cycle, providing no criteria for discontinuation are met (see 
Section 13.0). 


UMCC 2009.078, Protocol v. 10/10/11 
 
 14 
 
7.13.2 Acne-like rash is ≤ Grade 2 (see Section 7.14) 
 
7.13.3 Grade 3 - 4 hematologic toxicities have resolved to ≤ CTC Grade 2 
7.13.4 Grade 3 - 4 non-hematologic toxicities have resolved to ≤ CTC Grade 2, 
(except fatigue (asthenia), anorexia and alopecia) 
7.14 
Acne-Like Rash (rash maculo-papular) 
  
 
The dose of cetuximab will be adjusted for Grade 3 acne-like rash. The severity 
of these events will be graded according to the criteria for the CTC term "rash maculo-
papular." The cetuximab dose alteration scheme is outlined in the figure below. If a 
subject experiences a Grade 3 acne-like rash, cetuximab therapy is to be held for up 
to four consecutive infusions (see table below). The Investigator could also consider 
concomitant treatment with topical and/or oral antibiotics and topical corticosteroids. 
If there are subsequent occurrences of a Grade 3 acne-like rash, cetuximab therapy may 
again be omitted for up to four consecutive weeks. Treatment may resume with 
reduced doses of cetuximab if the skin toxicity has resolved to Grade 2 or less. 
Cetuximab dose reductions are permanent. Cetuximab will be discontinued if 
there is a subsequent occurrence of a fourth episode of Grade 3 acne-like rash or there 
are more than four consecutive infusions held. The subject should be followed weekly 
until resolution of the rash. If a subject experiences a Grade 4 acne-like rash, 
cetuximab therapy will be discontinued. 
 
Management of Cetuximab Acne-Like Rash 
 
 


UMCC 2009.078, Protocol v. 10/10/11 
 
 15 
8.0  
RADIOTHERAPY 
 
8.1 
Immobilization, imaging and target definitions 
8.1.1  
The technical details of RT planning will correspond to standard of 
care at the Department of Radiation Oncology as previously 
published (29). 
8.1.2  
Target doses will be similar to the doses delivered in standard practice: 70 Gy 
at 2.0 Gy/fraction to primary tumor and to lymph nodes with clinical/radiological 
evidence of metastases, and 56-63 Gy at 1.6-1.8 Gy/fraction to subclinical 
disease around the primary tumor or to the surgical tumor excision bed, and to 
the lymph nodes at risk of metastasis, all in 35 fractions, over 7 weeks. 
 
  
8.2 
Optimization goals regarding the salivary glands will be: 
8.2.1  Mean dose to the parotid glands <26 Gy (at least one gland). 
8.2.2  The dose to the volumes of the submandibular glands and oral cavity outside 
the targets will be minimized. 
8.2.3 
The doses to the swallowing structures (pharyngeal constrictors, glottic and 
supraglottic larynx) outside the targets will be minimized, aiming at mean 
dose < 50 Gy. 
 
 
8.3 
OPTIMIZATION CONSTRAINTS WILL BE: 
8.3.1 
The maximal target PTV dose will be 110% of the prescribed 
dose.  
8.3.2  The minimum target PTV doses will be > 99% of the 
prescribed dose. 
8.3.3  The maximal dose outside the targets will be <105% of the 
prescribed dose delivered to at least 0.5 cc. volume. 
8.3.4  The maximal dose to the spinal cord, expanded 0.5 cm, will 
be < 50 Gy, to the non-expanded cord < 45 Gy, to the optic 
pathways < 50 Gy and to the brainstem <54 Gy. 
 
9.0  
EVALUATION OF RESPONSE TO TREATMENT 
9.1 
Evaluation of tumor extent will be recorded for the primary tumor and regional 
nodes at each f/u interval. PET-CT scans will be performed 12-14 weeks (+/- 1 
month) after the completion of therapy to assess response. 
9.2  
Patients with any nodes who are PET-CT positive at 12-14 weeks (+/- 1 month) 
post cetuximab-RT may be considered for neck dissection. Patients with palpable 
residual nodes at 3 months whose PET-CT shows a complete response (CR) may 
undergo clinical observation and periodic PET scans according to the judgment of 
the treating clinicians. 
9.3  
Clinical examinations will be performed as comparable to clinical practice: at 1 
month after the completion of therapy and then every 2 months during years 1 and 
2, and at 3-month intervals during year 3, after which follow-up will be performed 
according to clinical practice. Allowable windows for these exams are +/- 1 month.  


UMCC 2009.078, Protocol v. 10/10/11 
 
 16 
Clinical examinations will be performed by medical oncology, radiation oncology, 
and/or surgical oncology. To meet the examination requirements, patients need to be 
seen by at least one discipline (but not all three) during the aforementioned time 
intervals. 
 
9.4 
Once 
patients 
discontinue 
treatment 
(Section 
13.0) 
or 
have 
tumor 
progression/recurrence, they will be followed as clinically indicated for 3 years 
following the completion of radiation and/or cetuximab. 
 
10.0 
EVALUATION OF TOXICITY AND QUALITY OF LIFE 
10.1 Validated quality of life questionnaires: HNQOL, UWQOL-HN, and XQ (Appendix 
B) will be given to patients before and periodically after radiation (1, 3, 6, 12, 18, 
24 and 36 months, with a +/- 1 month window for each). Common Toxicity Criteria 
Adverse Events (CTCAE, v.4.0) observer related items will be gathered weekly during 
treatment and at every follow- up clinic visit through 3 years. As part of data collection 
related to the quality of life measures, pre and post-treatment employment status will 
also be recorded, as well as Performance Status Scale. Patients may be asked for this 
information during a clinic visit or contacted via phone. The study team will attempt to 
obtain this information from all enrolled patients. 
10.2 Objective evaluation of swallowing will be made by videofluoroscopy and 
esophagogram. They will be performed in patients receiving definitive RT and 
chemotherapy. A baseline study will be performed either before RT starts or on one of 
the first five days of RT. Three follow-up studies will be done: one study at 3 to 4 
months following RT completion (+/- 1 month), one study at 11 to13 months 
following RT completion (+/- 1 month), and one study at 24 months following RT 
completion (with the acceptable window of 2 months prior or 6 months post). Each subject 
will be asked to swallow various food consistencies in varying amounts (5-15 m1). The 
consistencies included thin liquid barium (diluted with water) followed with non- diluted 
barium, followed with a puree, soft food (fruit mixed with barium) and a solid 
(shortbread cookie) coated with barium. The examinations will be recorded and 
analysis of the 3 phases of swallowing: oral, pharyngeal and esophageal will be made. 
Assessment will focus on bolus manipulation and control, bolus passage including 
cohesion, motility, and timing. The timing or duration of each swallowing phase will 
be determined. Also, the amount and incidence of aspiration and penetration, 
laryngeal sensation (response to penetrant/ aspirate) and residue/pooling after the 
swallow will be recorded. Laryngeal sensation will be determined to be good, reduced 
or poor. Reduced sensation would be consistent with a cough reflex that is delayed or 
intermittent. Poor sensation is defined when subjects elicit no spontaneous cough reflex 
or throat clear. These subjects are considered to be "silent" aspirators. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 17 
11.0  
STUDY CALENDAR 
 
 
Assessment 
Pre- 
Treatment* 
Day 0 
Loading 
Dose 
Day 7 
(+/- 2 
days) 
Weekly 
during 
Treatment† 
12-14 wks 
post RT  
(+/- 1 month) 
Follow 
Up3 
H&P/Physician 
Evaluation 
X 
 
 
X 
X 
X 
Smoking status 
and tumor HPV or 
p16 
determination 
X 
 
 
 
 
 
Biopsy 
X 
 
X1 
 
 
 
Buccal swab 
X 
 
X1 
 
 
 
COMP, Mg 
X 
 
 
X 
X 
 
CBCP with diff 
X 
 
 
X 
X 
 
PET-CT 
X 
 
 
 
X2 
 
Dental Evaluation 
X 
 
 
 
 
 
Toxicity Evaluation 
X 
 
 
X 
X 
X 
QOL Questionnaire 
X 
 
 
 
X 
X 
Videofluoroscopy 
X 
 
 
 
X 
X 
Cetuximab 
 
X 
 
X 
 
 
 
* The pre-treatment period is prior to the administration of the cetuximab loading dose 
† Radiation therapy will start within 4 days following Day 7 biopsy 
 
1Research biopsy will be performed 7 days (+/- 2 days) after cetuximab.  This second biopsy will 
only be obtained if it can be done without general anesthesia. 
2Restaging PET-CT will be obtained at 12-14 weeks. 
3Follow Up:  Examinations will be performed as comparable to clinical practice:  at 1 month after the 
completion of therapy and then every 2 months during years 1 and 2, and at 3-month intervals during year 3.  
Toxicity evaluation will be collected at each visit.  Quality of Life Questionnaires will be given to 
patients at follow-up visits 1, 3, 6, 12, 18, 24 and 36 months.  Videofluoroscopy will be performed at 3, 12, 
and 24 months after therapy.  Allowable windows for all these time points are +/- 1 month.  
 
Note:  Once patients discontinue treatment (Section 13.0) or have tumor progression/recurrence, they will be 
followed as clinically indicated for 3 years following the completion of radiation and/or cetuximab. 
 
12.0  
MEASUREMENT OF RESPONSE 
Tumor Clearance 
A patient will be considered to have a complete response if there is no measurable or 
palpable tumor either on clinical or radiographic (CT-PET scan) examination assessed within 3 
months after the completion of treatment. Complete response will be defined as complete 
disappearance of disease or residual radiographic abnormality that is not considered to be 
tumor. 
 
13.0  
CRITERIA FOR DISCONTINUATION OF TREATMENT 
Unacceptable adverse event(s), intercurrent illness which prevents further administration of 
treatment, patient preference, progressive disease, life threatening or other unacceptable drug-
related toxicity, changes in the patient's condition that render the patient unacceptable for 


UMCC 2009.078, Protocol v. 10/10/11 
 
 18 
further treatment in the judgment of the investigators. 
 
14.0  
DRUG INFORMATION:  CETUXIMAB 
14.1 
Formulation:  Cetuximab is an anti-EGFR receptor humanized chimeric monoclonal 
antibody. Cetuximab is expressed in SP2/0 myeloma cell line, grown in large scale 
cell culture bioreactors, and purified to a high level purity using several 
purification steps including protein A chromatography, ion exchange 
chromatography, low pH treatment, and nanofiltration. Cetuximab is not known to be 
a vesicant. 
14.2 
Supply:  The product is formulated to 2 mg protein/mL with phosphate buffered saline, 
pH 7.2 ± 0.2 and aseptically filled into sterile glass vials, 100 mg per 50 cc vial, and 
stored as a liquid at 2 to 8° C. Each vial contains the following active and inactive 
ingredients per 1.0 ml: 2 mg of cetuximab, 145 nmol/L sodium chloride, and 10 mmol/L 
sodium phosphate. 
14.3 
Safety Precautions: Appropriate mask, protective clothing, eye protection, 
gloves and Class II vertical-laminar-airflow safety cabinets are recommended during 
preparation and handling. 
14.4 
Preparation and Administration: 
14.4.1 Cetuximab is available commercially  as an injectable solution, in single-use, 
ready-to-use 50-mL vials containing 2 mg/mL of product. Cetuximab 
requires no dilution. Cetuximab should not be mixed with or diluted with 
other drugs or solutions for infusion such as 5%-glucose. 
14.4.2 The dose and volume of the study drug to be infused are dependent upon 
the patient's actual BSA. The infusion rate must never exceed 10 
mg/minute (5 mL/minute). The dose may subsequently be reduced for 
individual patients, depending on a patient's toxicity. For the duration that 
patients are on cetuximab therapy, adverse event monitoring should be done 
continuously. Patients will be evaluated for adverse events at each 
visit and are to be instructed to call their physician to report any adverse 
events between visits. 
14.4.3 Cetuximab may be administered via an infusion pump or syringe pump. 
Cetuximab administration requires an in-line low protein-binding 0.22 
micron filter. Note:  one filter per dose should be sufficient, but further 
filters can be used if a filter becomes blocked.   
 
Administration via Infusion Pump 
Calculate the appropriate volume of cetuximab based on the dose and using 
an appropriate sterile syringe (min 50 mL) draw up the required volume 
from the vial(s).  Add the cetuximab into a sterile evacuated container or 
bag (glass administration containers are not recommended).  Do not shake.  
Attach an infusion line with a low protein binding 0.22 micron in-line filter.  


UMCC 2009.078, Protocol v. 10/10/11 
 
 19 
Use an infusion pump for administration.  Set and control the rate as noted 
above and infuse the whole dose. 
Administration via Syringe Pump 
Calculate the appropriate volume of cetuximab based on the dose and using 
an appropriate sterile syringe (min 50 mL) draw up the required volume 
from the vial(s).  Do not shake.  Remove the needle, and put the syringe 
into the syringe pump.  Attach tubing with a low protein-binding 0.22 
micron filter.  Set and control the rate as described above.  Make sure that 
the whole dose has been infused.  
 
Studies have been conducted to demonstrate the compatibility of cetuximab 
drug product with various infusion systems.  Some examples of materials, 
IV containers, infusion sets, and filters tested and recommended for use 
with cetuximab are listed below.  For further examples of approved 
materials, please see the Investigator Brochure.  
 
Recommended IV Containers  
 
IntraVia IV Bag with PVC Ports, Model No. 2J8002 (Baxter Healthcare 
Corporation) 
 
EVA IV Bag, Model No. 2B8152 (Baxter Healthcare Corporation) 
 
LifeCare IV Bag, Model No. 7951-12 (Abbott Laboratories) 
 
Recommended Infusion Sets 
 
 Vented Continu-Flo Solution Set, Model No. 2C6541s (Baxter Healthcare 
Corporation) to be used with an in-line filter set, Model No. 2679 (Abbott 
Laboratories) 
 
Vented Paclitaxel Set with 0.22-µm downstream high-pressure in-line 
filter, Model No.  
2C7553 (Baxter Healthcare Corporation) 
 
 
 
Recommended Filters 
 
Vented Continu-Flo Solution Set, Model No. 2C6541s (Baxter Healthcare 
Corporation) to be used with an in-line filter set, Model No. 2679 (Abbott 
Laboratories) 
 
Intrapur Plus (B.  Braun AG) reference number 409 9800 
 
Poly-lined filtered Extension set (Alaris Medical Systems) reference number 
C20350 
 14.4.4 Normal saline should be use to clear the infusion set of residual 
cetuximab. The delivered drug product is > 95% for all recommended infusion 
sets when flushed with 50 mL of normal saline. Use a separate line for 
cetuximab infusion. 
14.4.5 Storage Requirements/Stability: Cetuximab must be stored under 
refrigeration at +2°C to +8°C (+36°F to +46°F). DO NOT FREEZE 
CETUXIMAB. Drug supplies must be kept in a secure, limited access storage 
area under the recommended storage conditions. Once cetuximab is removed 
from the vial, the recommended maximum storage time in the infusion 


UMCC 2009.078, Protocol v. 10/10/11 
 
 20 
container or syringe is 8 hours at room temperature or 12 hours in the 
refrigerator. 
15.0  
EGFR ANALYSIS 
The primary goal of this analysis is to determine whether cetuximab given at the clinically 
recommended dose will affect EGFR, phospo-EGFR and down-stream signaling within the tumor 
as well as in the normal mucosa. The protein levels of EGFR, pY845-EGFR and various down-
stream signaling molecules will be measured by immunoblotting as well as immuno-
histochemical analysis in both normal and tumor samples at baseline and post-treatment as 
described previously (26). 
 
 
15.1 
Pre-Therapy Tumor Sample Collection and Initial Processing 
The initial pre-treatment punch-biopsy specimen for research (about 3x3x3 mm) of the 
tumor and mucosa cells (or a buccal swab) will be collected in ice cold saline containing 
a cocktail of protease (Roche Diagnostic Co., Indianapolis, IN) and phosphatase 
inhibitors (Sigma, St. Louis, MO) in the presence of laboratory personnel from Dr. 
Mukesh Nyati's laboratory. The sample will be divided into 2 parts. The first part will be 
fixed in 10% phosphate buffered formalin and will be stored in paraffin blocks for 
immunohistochemistry, and second part will be used to extract proteins for 
immunoblotting. 
 
15.2 
Method of Assessment of EGFR Expression in Tumor After Cetuximab Loading Dose  
At the time of the second biopsy a tumor specimen (about 5x5x5mm ) along with 
buccal swab will be collected. The tumor specimen will be divided into 3 parts. The 
first two parts will be processed as described in section 15.3.1. When feasible the 
3rd part will be used to isolate RNA in Dr Tom Carey's laboratory. EGFRvIII expression 
and p53 mutation analysis will be assessed on cDNA obtained from total RNA 
converted with RT-PCR. 
 
 
15.3 
Sample Preparation and Analysis 
15.3.1 High-throughput immunoblotting and isolation of RNA and DNA for genetic 
studies:  
Tumor samples will be processed immediately for protein extraction in Dr 
Nyati's laboratory. A total of 200 gg total protein will be subjected to 
electrophoresis on a 2D 4 to 12% bis-tris precast gel (Invitrogen, Carlsbad, 
CA) and transferred onto a PVDF membrane. A Miniblotter 28 dual system 
(Immunetics, Cambridge, MA) will be used to probe all the antibodies in 
duplicate. After incubating the membrane with different antibodies 
overnight, membranes will be washed and probed with horseradish 
peroxidase conjugated IgG (Cell Signaling Technology, Beverly, MA), diluted 
1:5,000 in TBST for 1 hr at room temperature; the antigen—antibody 
complexes will be visualized by enhanced chemiluminescence (ECL-Plus; GE 
Biosciences, Piscataway, NJ). The films then will be scanned, and the bands 
analyzed using NIH ImageJ software. Proteins to be assessed include phospho 
and total forms of EGFR, AKT, Src, STAT3, in addition to total p27, PARP, 
Bel-XL will also be assessed. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 21 
 
Isolation of DNA (from the FFPE pretreatment diagnostic biopsy) and RNA 
(from the research biopsy when possible) will be carried out using DNAeasy 
and RNAeasy (both from Qiagen) on the remaining sample according to the 
manufacturers instructions. 
 
 
 
15.3.2 Immunohistochemistry and Scoring of TMA:  
One high-density TMA will be constructed using a manual tissue arrayer 
(Beecher Instruments, Silver Spring, MD, USA) at the core facility at the 
University of Michigan using standard methods. Tissue cores from the regions 
of interest (tumor tissues, before and after treatment) will be targeted for 
transfer to the recipient array block. At least three 0.6 mm diameter replicate 
tissue cores will be sampled from each subregion of the selected sample. The 
final TMA will consist of approximately 160 cores. After construction, 4 gm 
sections will be cut, and hematoxylin and eosin staining will be performed on 
the initial slide to verify the histology. Serial 4 gm sections will be further cut 
and transferred to positively charged slides, these sections will be subjected to 
standard immunohistochemical staining procedures. Dr Nyati's lab have 
validated both total and phospho-antibodies that can be used successfully on 
formalin fixed tissue (26). The stained test slides will be reviewed by the head- 
and —neck pathologist co-investigator (Dr McHugh) for the expected pattern and 
appropriate intensity. The information about expected and appropriate staining 
for each antibody will be discussed with the other investigators to confirm the 
scoring criteria. The TMAs will be then stained by the staff at the Tissue Core. 
Each tissue core will be scored by a board certified oral and maxillofacial 
pathologist who is blinded as to the identity of the cores. Each tissue core will be 
scored for intensity of SCC cells staining: 1, undetectable; 2, weak; 3, 
moderate; 4, strong. Multiple TMA core measurements from the same subject 
will be averaged. This average score in its continuous scale will be used in all 
analyses. 
 
16.0  
OTHER THERAPY 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented as concomitant medication. 
 
17.0  ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
Data on all adverse events grade 2 or greater regardless of relationship to study treatment will 
be collected from the start of study treatment on day 1 and will continue to be collected for 30 
days after the last Cetuximab and radiation dose.  Adverse events believed related to treatment 
with Cetuximab and/or radiation will continue to be collected for 3 years following end of 
study treatment, as outlined on the study calendar, and captured as Late Adverse Events. 
Serious adverse events will continue to be followed until resolution or clearly determined to 
be due to a patient’s stable or chronic condition or intercurrent illness(es). The investigator is 
responsible for the detection and documentation of events meeting the criteria and definition 
of an AE or SAE as provided in this protocol. During the study, when there is a safety 
evaluation, the investigator or site staff will be responsible for detecting AEs and SAEs, as 
detailed in this section of the protocol. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 22 
 
17.1 
Definitions 
The definitions of adverse events (AEs) and serious adverse events (SAEs) are given 
below. The following definitions of terms are guided by the International Conference 
on Harmonization and the US Code of Federal Regulations and are included here 
verbatim. It is the responsibility of the principal investigator to ensure that all staff 
involved in the trial is familiar with the content of this section. 
 
17.1.1 Adverse Events (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal 
(investigational) product. 
 
Examples of an AE include: 
 
• Significant or unexpected worsening or exacerbation of the 
condition/indication under study. 
 
• Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity (grade) of the condition. 
 
• New conditions detected or diagnosed after investigational product 
administration even though may have been present prior to the start of the 
study. 
 
• Signs, symptoms, or the clinical sequelae associated with a suspected 
interaction of the investigational product with a concomitant medication. 
 
• Signs, symptoms, or the clinical sequelae associated with a suspected 
overdose of either investigational product or a concurrent medication. 
 
Any medical condition or laboratory abnormality with an onset date before 
initial Cetuximab administration is considered to be pre-existing in nature.  
 
Any known pre-existing conditions that are ongoing at time of study entry, and 
any events of Grade 3 or 4 severity that occur up to 30 days before study entry 
(even if resolved prior to study entry) should be considered medical history and 
recorded in the appropriate section of the case report form. 
 
All adverse events grade 2 or greater occurring from initial investigational 
product administration through 30 days following the last dose of Cetuximab 
and/or radiation must be recorded as an adverse event in the patient’s source 
documents and on the CRF regardless of frequency, severity (grade) or 
assessed relationship to Cetuximab and/or radiation.  


UMCC 2009.078, Protocol v. 10/10/11 
 
 23 
 
In addition to new events, any increase in the frequency or severity (i.e., 
toxicity grade) of a pre-existing condition that occurs after the patient begins 
Cetuximab and radiation is also considered an adverse event. 
 
17.1.2 Serious Adverse Events (SAE) 
A serious adverse event is an AE which occurs after the initial dose of 
Cetuximab, during treatment, or within 30 days of the last dose of cetuximab 
and/or radiation that fulfills one or more of the following criteria regardless of 
cause or assessed relationship to therapy. 
 
Any untoward medical occurrence that at any dose: 
 
- Results in death, 
 
- Is life-threatening 
NOTE: The term ‘life-threatening’ in the definition of ‘serious’ refers to any 
adverse drug experience that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might 
have caused death.  
 
- Requires inpatient hospitalization or prolongation of hospitalization  
NOTE: In general, hospitalization signifies that the patient or subject has been 
detained (usually involving at least an overnight stay) at the hospital for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or out-patient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered an AE. Planned hospitalization 
for surgical procedures, either related or unrelated to the patients cancer is not 
considered a serious adverse event. 
 
- Results in persistent or significant disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability 
to conduct normal life functions.  
 
-Is a congenital abnormality/birth defect. 
 
Or 
 
- Important medical events 
Events which may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, 
based upon appropriate medical judgment, they may jeopardized the patient or 
subject and may require medical or surgical intervention to prevent one of the 


UMCC 2009.078, Protocol v. 10/10/11 
 
 24 
outcomes listed in this definition. 
17.2 
Adverse Event Reporting Requirements 
 
17.2.1 All Serious Adverse Events 
 
17.2.1.1 Serious Adverse Event Reporting 
Serious adverse events reports are submitted via the MedWatch form 
or similar form. The MedWatch report must be submitted to the 
University of Michigan IRB and to the Principal Investigator. AEs 
reported as Serious Adverse Events must also be reported in routine 
study data submissions including the Data and Safety Monitoring 
Report, in addition to the IRB. 
 
17.2.1.2 Serious Adverse Event Reporting Timeline 
 
17.2.1.2.1  “Serious” adverse events which occur after the initial dose 
of Cetuximab, during treatment, or within 30 days of the 
last dose of Cetuximab or last fraction of radiation 
(including all deaths), MUST be reported immediately, i.e., 
within one day (24 hours) of being identified. 
 
17.2.1.2.2  An initial written report of the serious adverse event must 
be prepared using the Medwatch or similar form, and 
submitted within 48 hours of awareness of event. 
 
17.2.1.2.3  All fatal or life threatening serious adverse events must be 
reported IMMEDIATELY and then the initial SAE report 
submitted within 24 hours of awareness of event. 
 
17.2.1.2.4  This report should provide a detailed description of the 
adverse event. Additional information (i.e. hospitalization 
records) will be submitted if requested by the IRB or other 
governing body, and include protocol number and patient 
assigned study number. 
 
17.2.1.2.5 Copies of each report will be kept in the Investigator's File. 
The investigator will submit, on request, copies of all these 
reports to the relevant ethics committee. 
 
17.2.1.2.6  Serious Adverse Event (SAE) Reporting Follow-up 
Follow-up information will be submitted to the IRB 
following instructions above and within 7 days of 
becoming available. 
 
 
17.2.2  Clinical Laboratory Abnormalities and Other Abnormal Assessments as AE’s 
and SAE’s 
 
Abnormal laboratory findings (e.g., clinical chemistry and hematology) or 


UMCC 2009.078, Protocol v. 10/10/11 
 
 25 
other abnormal assessments (e.g., ECGs) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the 
definitions as defined in Section 17.1. Clinically significant abnormal 
laboratory findings or other abnormal assessments that are detected during the 
study or are present at baseline and significantly worsen following the start of 
the study will be reported as AEs or SAEs. However, clinically significant 
abnormal laboratory findings or other abnormal assessments that are associated 
with the disease being studied, unless judged by the investigator as more severe 
than expected for the patient’s condition, or that are present or detected at the 
start of the study and do not worsen, will not be reported as AEs or SAEs. The 
investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. 
 
17.2.3  Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
SAEs  
 
“Lack of efficacy” per se will not be reported as an AE. The signs and 
symptoms or clinical sequelae resulting from lack of efficacy will be reported 
if they fulfill the AE or SAE definition (including clarifications). Progressive 
disease found by scan or on clinical evaluation should be captured but not as 
an AE. 
 
17.2.4  If a subject begins another therapy for their disease (outside of a surgical 
intervention to remove their disease), the patient will be considered off study 
and adverse events will no longer be collected on this subject. 
 
17.2.5  Grading of Adverse Events 
The severity of all adverse events and laboratory abnormalities will be graded 
according to the US National Cancer Institute’s Common Terminology Criteria 
for Adverse Events version 4.0 (CTCAE). 
 
17.3  
Relationship to Cetuximab and Radiation 
 
Related Event: Any adverse event that has a temporal relationship to the administration 
of the investigational drug or research intervention, follows a known or suspected 
pattern of response, and for which an alternative cause may not be present, is definitely, 
probably, or possibly associated with the investigational drug/agent. Investigator needs 
to judge relatedness and be prepared to justify the judgment. 
 
• Definitely Related: The adverse event is clearly related to the investigational agent(s) 
or research intervention: the adverse event has a temporal relationship to the 
administration of the investigational agent(s) or research intervention, follows a known 
pattern of response, and no alternative cause is present. 
 
• Possibly Related: There is a reasonable possibility that the event may have been 
caused by or is linked in a significant way to the research; the adverse event has a 
temporal relationship to the administration of the investigational agent(s) or research 


UMCC 2009.078, Protocol v. 10/10/11 
 
 26 
intervention, follows a suspected pattern of response, but an alternative cause is 
present. 
 
• Probably Related: The adverse event is likely related to the investigational agent(s) 
or intervention: the adverse event has a temporal relationship to the administration of 
the investigational agent(s) or research intervention, follows a known or suspected 
pattern of response, but an alternative cause may be present. 
 
• Unlikely to be related: The adverse event is doubtfully related to the investigational 
agent(s) or intervention: the adverse event has a temporal relationship to the 
administration of the investigational agent(s) or research intervention, but follows no 
known or suspected pattern of response, and an alternative cause is present. 
 
• Unrelated (or Not Related): The adverse event is clearly NOT related to the 
investigational agent(s) or intervention: the adverse event has no temporal relationship 
to the administration of the investigational agent(s) or research intervention, follows 
no known or suspected pattern of response, and an alternative cause is present. 
 
Death: Deaths occurring within 30 days of the last study treatment are reportable events 
regardless of whether or not the investigators deem the death to be related to the study. 
If death occurs later than 30 days after the last study treatment AND the subject is still 
onstudy (i.e. subject would have had further follow-up or intervention/interaction had 
death not occurred), then the death may still be a reportable event. If the subject is NOT 
still on-study and there is no long-term follow-up, a late death does not need to be 
reported the IRBMED even if the investigator learns that the subject died.  
18.0  
DATA AND SAFETY MONITORING 
 
 
This trial will be monitored in accordance with the NCI approved University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Plan. 
 
The study specific Data and Safety Monitoring Committee (DSMC), consisting of the protocol 
investigators, data manager or designee and other members of the study team involved with the 
conduct of the trial, will meet quarterly or more frequently depending on the activity of the protocol 
to provide continuous review of the data and patient safety. The discussion will include matters 
related to the safety of study participants (SAE/UaP reporting), validity and integrity of the data, 
enrollment rate relative to expectations, characteristics of participants, retention of participants, 
adherence to the protocol (potential or real protocol deviations) and data completeness. 
At the regular DSMC meetings, the protocol specific Data and Safety Monitoring Report form will 
be completed. The report will be signed by the Principal Investigator or by one of the co‐
investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University of Michigan Comprehensive 
Cancer Center Data and Safety Monitoring Board (DSMB) on a quarterly basis for independent 
review. 
 
 


UMCC 2009.078, Protocol v. 10/10/11 
 
 27 
19.0 
QUALITY ASSURANCE AND AUDITS 
The Quality Assurance Review Committee (QARC) of The University of Michigan 
Comprehensive Cancer Center (UMCCC) performs quality assurance audits of investigator-
initiated clinical trials. Audits provide assurance that trials are conducted in compliance with 
the protocol. Further, they ensure that study data are collected, documented and reported in 
compliance with Good Clinical Practices (GCP) Guidelines and regulatory requirements. 
 
A QARC audit of each clinical trial is conducted annually. Audits occur within the month of 
the study’s initial IRB approval (provided the trial is open, and study accrual is greater than 
two subjects). 
 
All audit findings are reported by QARC to the UMCCC Data and Safety Monitoring Board. 
These findings are followed-up by the DSMB until they have been resolved. The DSMB can 
also request QARC for a ‘for cause’ audit of the trial if the board identifies a need for a more 
rigorous evaluation of study-related issues. A regulatory authority (e.g. FDA) may also wish 
to conduct an inspection of the study, during its conduct or even after its completion. If an 
inspection has been requested by a regulatory authority, the principal investigator must 
immediately inform the Clinical Trials Office that such a request has been made. 
 
20.0 
 STATISTICAL CONSIDERATIONS 
20.1 
Study Design 
This is a Phase II trial of seven weeks RT+cetuximab for head and neck cancer in 
patients with good prognoses to determine if this treatment will be at least as effective 
as, but less toxic than, standard therapy. A total of 43 patients will be enrolled in order 
to obtain 36 patients that complete radiation treatment and have both biopsies taken. 
Thus, both the clinical primary endpoints and scientific secondary endpoints can be 
analyzed, as EGFR tumor information is useful for determining potential mechanisms 
of resistance to cetuximab.  Based on the experience of UMCC 9921 and UMCC 2-
21, accrual is expected to average one patient per month.  To be considered evaluable, 
a patient must complete the full course of radiation/cetuximab.  If radiation and/or 
cetuximab was stopped or modified due to toxicity, the patient is still evaluable.  
Inevaluable patients will be replaced. 
 
20.2 
Early Stopping Rules for Toxicity or Lack of Efficacy 
In UMCC 9921 and UMCC 2-21, 2/32=6% of patients similar to those who will be 
treated in the current trial did not achieve tumor control. An early stopping rule will 
only be feasible for the identification of probability of treatment failure much higher 
than that. Table 1 describes the stopping rule for failure to control, which was derived 
using the method due to Thall, Simon and Estey [31], implemented in M.D. Anderson 
program multc98. Failure is defined as local-regional recurrence or metastasis, but 
not second primary cancer, nor microscopic disease found in elective neck 
dissection, nor PET findings without correlative clinical evidence of disease 
persistence or recurrence. For each number of patients enrolled, if at least as many 
failures as stated occurs (e.g., 2/5), accrual will be stopped. The rule was 
constructed to stop the trial if the probability that the failure rate of the experimental 
therapy exceeded 0.1625 (0.1 more than the historical rate) is at least 0.75. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 28 
# Patients 
# Failures 
5 
2 
10 
3 
15 
4 
20 
5 
25 
6 
30 
7 
Table 1  Stopping rule for failure to control tumor 
Because the trial will only be stopped early for failure, and the stopping rule does 
not constitute an interim analysis, there will be no adjustment to the p-values of the 
analyses in Section 20.4. 
20.3 
Analysis Plan 
  
20.3.1  Primary Objectives 
20.3.1.1 To confirm that reducing treatment intensity in non-smoking 
patients with HPV-related oropharyngeal cancer does not 
significantly increase the proportion of patients whose tumors 
recur, compared to our previous experience in similar patients 
receiving standard-intensity chemo-RT.  
The primary index of recurrence will be the proportion of patients 
who have local recurrence, distant metastases or second primaries 
(secondary analyses will be performed on each of these 
endpoints individually) within two years of the end of treatment. 
In the primary analysis, null hypothesis that the proportion of 
patients who fail is greater than 0.20 will be tested using an exact 
binomial test (at significance level a=0.20). The proportion of 
patients who recur will be calculated, with a 95% exact binomial 
confidence interval. 
20.3.1.2  To compare the toxicity in patients receiving reduced 
intensity treatment to similar patients treated with 7 weeks 
of chemotherapy concurrent with RT ("standard therapy') in 
UMCC 2-21.  
Dysphagia and mucositis are measured on continuous 
scales; there are both observer and patient reports. The 
null hypothesis of no difference in dysphagia and mucositis 
at three, twelve and twenty-four months posttreatment between 
the reduced-intensity therapy versus UMCC 2-21 will be tested 
(a=0.20) in a repeated measures analysis of covariance. In 
addition, the statistical significance of the difference between 
the current trial and UMCC 2-21 in the proportions of patients 
experiencing clinically significant (NCI CTCAE Grade 3 or 
worse) toxicities will be assessed using Fisher's exact test 


UMCC 2009.078, Protocol v. 10/10/11 
 
 29 
(a=0.20). 
20.3.2 Secondary Objectives 
20.3.2.1 To characterize the changes tumor EGFR, pEGFR, 
downstream signaling following a loading dose of 
cetuximab.  
Markers to be analyzed include, but are not limited to, EGFR 
and pEGFR. Some are measured on a continuous scale, and 
some on an ordinal scale. Continuous scale variables will 
be expressed as percent change from baseline, and the 
distribution will be characterized graphically (e.g., boxplot) 
and by descriptive statistics. After possible transformation 
(e.g., logarithmic), a single sample t-test will be used to 
evaluate the null hypothesis that the mean change equals 0. The 
percent change will be related to tumor control, progression-
free survival, and the various assessments of toxicity by linear 
regression, logistic regression, or proportion hazards (Cox) 
regression, as appropriate. Ordinal scale variables will be 
expressed as difference from baseline, followed by a similar 
analysis plan to relate the differences to clinical outcomes. 
Because this is a secondary objective, all of the analyses will 
be guided by descriptive displays of the data. 
20.3.2.2 Compare normal mucosa EGFR to EGFR in the 
tumor sample.  
Repeated measures linear models will be used to characterize 
the change in differences between normal mucosa and 
tumor EGFR across the loading dose of cetuximab and 
determine if there are significant demographic or clinical 
variables that affect that change. 
20.3.2.3 To explore if baseline EGFR, BclxL, p.53 and p16 
tumor expression are related to treatment response.  
The distributions of these markers in all patients, and in 
patients who do and do not respond, will be characterized by 
descriptive statistics (e.g., mean, median) and graphics 
(for example, boxplots). Because the number of treatment 
failures is likely to be small, these analyses will be considered 
strictly exploratory. 
 
 
20.4  
Justification of Design 
 
 
20.4.1  Early stopping rule for tumor control 
The operating characteristics of the stopping rule were analyzed using the 
simulation tool in multc98. The probability the trial will be stopped early, and 
the distribution of the expected sample sizes, was calculated under the 


UMCC 2009.078, Protocol v. 10/10/11 
 
 30 
assumption that the true probability of failure varied from 0.06 to 0.6. The 
operating characteristics are displayed in Table 2. For instance, if the true 
probability of failure equaled 0.2, 0.59 of the trials stopped early, 50% of the 
trials stopped after accruing 20 or fewer patients, and 25% of the trials stopped 
after accruing five or fewer patients. 
Sample Size Percentiles 
True P(Failure) 
P(Stop Early) 
10 
25 
50 
75 
90 
0.06 
0.05 
35 
35 
35 
35 
35 
0.2 
0.59 
5 
5 
20 
35 
35 
0.3 
0.91 
5 
5 
10 
15 
30 
0.4 
0.99 
5 
5 
5 
10 
15 
0.5 
0.99 
5 
5 
5 
5 
19 
 
  
Table 2  Operating characteristics of stopping rule for treatment failure 
 
20.4.2 Power of primary analysis endpoints 
20.4.2.1  The ultimate goal of this research program is to conduct a randomized 
noninferiority trial to demonstrate that reducing the intensity of 
therapy in low-risk patients reduces the probability of toxicity while 
not increasing the probability of tumor recurrence. Such a trial will 
require hundreds of patients and will be possible only in the 
cooperative group setting. The purpose of this Phase II trial is to 
provide preliminary evidence that reduced intensity therapy is 
practical, and to provide initial evidence of efficacy and toxicity that 
can be used to design such a trial. The use of the relatively high 
significance level (a=0.2) is not uncommon in early Phase II (e.g., 
Simon two-stage) trials with limited sample sizes. Out of 33 non-
smoking HPV+ patients in the UMCC 2-21 reference set, three 
patients have died disease-free, and one patient has died from distant 
metastases. One additional patient in this group has developed a 
second primary tumor in the oral cavity. All other patients are alive 
and disease-free. Because the number of events is low, a 
time-to-event analysis is impractical, and analyses for sub-
populations are also unlikely. Because the power will be modest even 
if the observed failure rates are 2-3 times the control rate, this trial 
will not definitively test that reduced intensity treatment is as 
effective as standard chemoradiation, but, if successful, will accrue 
sufficient data to motivate a true non-inferiority trial. 
 
20.4.2 
The power calculations for the toxicity endpoints (Primary Objective 
2) will be represented by dysphagia, which is considered the most 
important. In UMCC 2-21, the patient-reported eating domain score 
of the HNQOL instrument increased from 10.5±14.9 (mean±standard 
deviation) pre-RT to 25.7+18.9 twelve months after treatment. 
Videofluoroscopy scores increased from 2.37±1.35 pre-RT to 


UMCC 2009.078, Protocol v. 10/10/11 
 
 31 
3.7±1.18 twelve months after treatment. The power of the repeated 
measures analysis for Primary Objective 2 for these endpoints was 
assessed by Monte Carlo simulation as the mean twelve month value 
was reduced from the twelve-month level in UMCC 2-21 (0% 
decrease) to the baseline UMCC 2- 21 level (100% decrease). 
 
20.4.3 
The hypothesis test for Primary Objective 2 will have at least 80% 
power for the video fluoroscopy score if the reduced intensity 
treatment achieves a decrease in dysphagia of 58% or greater 
compared to UMCC 2-21. The power is somewhat lower for the 
HNQOL assessment. 


UMCC 2009.078, Protocol v. 10/10/11 
 
 32 
21.0 
REFERENCES 
1. 
Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to loco-regional therapy 
of head and neck cancer: three metaanalyses of updated individual data. lancet 
2000;355:949-55. 
2. 
Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia and aspiration 
after chemoradiation for head and neck cancer. J Clin Oncol 2006;24:2636-26433. Shiboski, 
C.H., B.L. Schmidt, and R.C. Jordan, Tongue and tonsil carcinoma: increasing trends in the 
U.S. population ages 20-44 years. Cancer, 2005. 103(9): p. 1843-9. 
4. 
Sturgis, E.M. and P.M. Cinciripini, Trends in head and neck cancer incidence in relation to 
smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? 
Cancer, 2007. 110(7): p. 1429-35. 
5. 
Gillison, M.L., et al., Distinct risk factor profiles for human papillomavirus type 16-positive 
and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst, 2008. 
100(6): p. 407-20. 
6. 
Gillison, M.L., et al., Evidence for a causal association between human papillomavirus and a 
subset of head and neck cancers. J Natl Cancer Inst, 2000. 92(9): p. 709-20. 
7. 
Kim, S.H., et al., HPV integration begins in the tonsillar crypt and leads to the alteration of 
p16, EGFR and c-myc during tumor formation. Int J Cancer, 2007. 120(7): p. 1418-25. 
8. 
Kreimer, A.R., et al., Human papillomavirus types in head and neck squamous cell 
carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prey, 2005. 
14(2): p. 467-75. 
9. 
Worden, F.P., et al., Chemoselection as a strategy for organ preservation in advanced 
oropharynx cancer: response and survival positively associated with HPV 16 copy number. J 
Clin Oncol, 2008. 26(19): p. 3138-46. 
10. 
Herrero, R., Chapter 7: Human papillomavirus and cancer of the upper aerodigestive tract. J 
Natl Cancer Inst Monogr, 2003(31): p. 47-51. 
11. 
Ragin, C.C., F. Modugno, and S.M. Gollin, The epidemiology and risk factors of head and 
neck cancer: a focus on human papillomavirus. J Dent Res, 2007. 86(2): p. 104-14. 
12. 
Fakhry, C., et al., Improved survival of patients with human papillomavirus-positive head 
and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst, 2008. 
100(4): p. 261-9. 
13. 
Hafkamp, H.C., et al., Marked differences in survival rate between smokers and nonsmokers 
with HPV 16-associated tonsillar carcinomas. Int J Cancer, 2008. 122(12): p. 2656-64. 
14. 
Li, W., et al., Human papillomavirus positivity predicts favourable outcome for squamous 
carcinoma of the tonsil. Int J Cancer, 2003. 106(4): p. 553-8. 
15. 
Licitra, L., et al., High-risk human papillomavirus affects prognosis in patients with 
surgically treated orophwyngeal squamous cell carcinoma. J Clin Oncol, 2006. 24(36): p. 
5630-6. 
16. 
Ragin, C.C. and E. Taioli, Survival of squamous cell carcinoma of the head and neck in 
relation to human papillomavirus infection: review and meta-analysis. Int J Cancer, 2007. 
121(8): p. 1813-20. 
17. 
Sisk, E.A., et al., Human papillomavirus and p53 mutational status as prognostic factors in 
head and neck carcinoma. Head Neck, 2002. 24(9): p. 841-9. 
18. 
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell 
carcinoma of the head and neck. N Engl J Med 2006;354:567-578. 
18a.    Curran D, Giralt J, harari P, et al. Quality of life in head and neck cancer patients 
after treatment with high-dose radiotheraopy alone or in combination with cetuximab. JCO 
2007;25:2191-2197. 


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19. 
Kwok TT, Sutherland RM. Enhancement of sensitivity of human squamous carcinoma cells 
to radiation by epidermal growth factor. J Natl Cancer Inst 1989;81:1020-1024. 
20. 
Bonner JA, Maihle NJ, Folven BR, et al. The interaction of epidermal growth factor and 
radiation in human head and neck squamous cell carcinoma cell lines with vastly different 
radiosensitivities. Int J Radiat Oncol Biol Phys 1994;29:243-247. 
21. 
Balaban N, Moni J, Shannon M, et al. The effect of ionizing radiation on signal transduction: 
Antibodies to EGF receptor sensitize A431 cells to radiation. Biochimica Et Biophysica Acta-
Molecular Cell Research 1996;1314:147-156. 
22. 
Sheridan MT, O'Dwyer T, Seymour CB, et al. Potential indicators of radiosensitivity in 
squamous cell carcinoma of the head and neck. Radiat Oncol Investig 1997;5:180-186. 
23. 
Akimoto T, Hunter NR, Buchmiller L, et al. Inverse relationship between epidermal growth 
factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 
1999;5:2884-2890. 
24. 
Milas L, Fan Z, Andratschke NH, et al. Epidermal growth factor receptor and tumor response 
to radiation: In vivo preclinical studies. International Journal of Radiation Oncology Biology 
Physics 2004;58:966-971. 
25. 
Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on 
survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer 
Res 2002;62:7350-7356. 
26. 
Nyati MK, Maheshwari D, Hanasoge S, et al. Radiosensitization by pan ErbB inhibitor CI- 
1033 in vitro and in vivo. Clin Cancer Res 2004;10:691-700. 
27. 
Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the 
biology and treatment of cancer. J Clin Oncol 2003;21:2787-2799. 
28. 
Eisbruch A, Rasch C, et al. Dysphagia and aspiration after chemoirradiation of head and neck 
cancer: Which anatomical structures are affected and can they be spared by IMRT? Int J rad 
Onc Biol Phys 2004 
28a.   Debucquoy A et al. Molecular response to cetuximab and efficacy of preoperative cetuximab-
based chemoradiation in rectal cancer. JCO 2009;27:2751-7. 
29. 
Feng FY, Kim HM, Lyden TH, et al. Intensity modulated radiotherapy of head and neck 
cancer aiming to reduce dysphagia: early dose-effect relationships for the swallowing 
structures. Int J rad onc Biol phys 2007;68:1289-1298. 
30. Feng FY et al. IMRT aiming to reduce dysphagia in HN cancer: Clinical and functional results. 
Presented at the 50th Annual Meeting of ASTRO, Boston MA Oct 2008. 
31. 
Thall P, Simon R, Estey E .Bayesian sequential monitoring designs for single-arm clinical 
trials with multiple outcomes. Statistics in Medicine 1995, 14: 357-379. 
32. 
Aldington S et al.  Effects of Cannabis on Pulmonary Structure, Function, and Symptoms.  
Thorax 2007; 62: 1058-1063.   


UMCC 2009.078, Protocol v. 10/10/11 
 
 34 
APPENDIX A 
 
 
KARNOFSKY PERFORMANCE SCALE  
 
100      Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most personal needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death not imminent 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 


35 
 
APPENDIX B 
 
QUALITY OF LIFE QUESTIONNAIRES 
 
 


36 
 
Quality of Life Questionnaire 
UMCC 2009.078 
 
Study ID # ___________ 
 
 
 
Initials ____________________ 
Completed By:  __________________________ 
Date Completed___________________ 
 
Each of the following items lists different numbered statements. Think about what each statement says, 
then place a circle around the one statement that most closely describes how you have been feeling during 
the past week, including today. Please circle only one statement for each item. 
 
I.  PAIN (General) 
 
A. 
General 
10  
I have no pain. 
20  
There is mild pain not needing medication. 
30  
I have moderate pain--requires regular medication (codeine or non-narcotic). 40 I have severe 
pain controlled only by narcotics. 
50  
I have severe pain not controlled by narcotics. 
 
B. 
Mouth 
10  
I have no pain in my mouth. 
20  
I have mild pain but it is not affecting my eating. 
30  
I have moderate pain which is affecting my eating. 
40  
I have severe pain and need medication in order to eat. 
50  
I have severe pain and cannot eat even with the medication. 
 
C. 
Throat 
10  
I have no pain in my throat. 
20  
I have mild pain but it is not affecting my eating. 
30  
I have moderate pain which is affecting my eating. 
40  
I have severe pain and need medication in order to eat. 
50 
I have severe pain and cannot eat even with the medication. 
 
II.  DISFIGUREMENT 
 
10  
There is no change in my appearance.  
20   
The change in my appearance is minor. 
30   
My appearance bothers me but I remain active. 
40   
I feel significantly disfigured and limit my activities due to my appearance. 
50   
I cannot be with people due to my appearance. 
 
III.  ACTIVITY 
 
10 
I am as active as I have ever been. 
20   
There are times when I can't keep up with my old pace, but not often. 
30   
I am often tired and I have slowed down my activities although I still get out. 40  I don't go out 
because I don't have the strength. 
50   
I am usually in a bed or chair and don't leave home. 
 


37 
 
IV.  RECREATION/ENTERTAINMENT 
10  
There are no limitations to recreation at home and away from home.  
20 
There are a few things I can't do but I still get out and enjoy life. 
30  
There are many times when I wish I could get out more but I'm not up to it. 
40  
There are severe limitations to what I can do, mostly I stay home and watch T.V.  
50  
I can't do anything enjoyable. 
V.  EMPLOYMENT 
10 
I work full time. 
20 
I have a part time but permanent job.  
30  
I only have occasional employment.  
40  
I am unemployed. 
50 
I am retired (circle one below) 
51     
 
not related to cancer treatment 
52          
due to cancer treatment 
VI.  EATING 
 
A. 
Chewing 
10 
I can chew as well as ever. 
20 
I have slight difficulty chewing solid foods. 
30 
I have moderate difficulty chewing solid foods. 
40 
I can only chew soft foods.  
50 
I cannot chew soft foods. 
 
B. 
Swallowing 
10 
I swallow normally 
20 
I cannot swallow certain solid foods.  
30 
I can only swallow soft foods.  
40 
I can only swallow liquid foods.  
50 
I cannot swallow. 
 
VII. SALIVA 
A. Amount 
10 
I have a normal amount of saliva  
20 
I have a mild loss of saliva 
30 
I have a moderate loss of saliva.  
40 
I have a severe loss of saliva.  
50 
I have no saliva. 
B. Consistency 
10 
My saliva has normal consistency. 
20 
  My saliva is slightly thicker. 
30  
My saliva is moderately thicker. 
40  
My saliva is extremely thicker. 
50  
I have saliva that dries in my mouth and/or on my lips. 
 
Study ID: ___________ 
 
 
 
 
 
UMCC 2009.078 


38 
 
VIII.  TASTE 
 
10  
I can taste food normally. 
20 
I can taste most food normally.  
30       I can taste some foods normally.  
40        I can taste few foods normally. 
50       I cannot taste any foods normally. 
 
IX. SPEECH 
 
10  
My speech is the same as always. 
20  
I have difficulty with saying some words, but can be understood over the phone.  
30  
I have moderate difficulty saying some words, and cannot use the phone.  
40  
Only family and/or friends can understand me. 
50  
I cannot be understood. 
 
X. MUCUS OR PHLEGM 
A. 
Amount 
10  
I have a normal amount of mucus.  
20  
I have a mild amount of mucus 
30  
I have a moderate amount of mucus.  
40  
I have a severe amount of mucus.  
50  
I have no mucus. 
B. 
Consistency 
10  
My mucus has normal consistency  
20  
My mucus is slightly thicker 
30       My mucus is moderately thicker  
40       My mucus is extremely thicker  
50        I have no mucus 
Comments: 
 
 
 
 
 
 
 
 
 
 
Study ID: ___________ 
 
 
 
 
 
UMCC 2009.078 
UMCC 2009.078 
 


39 
 
Study ID # ___________ 
 
 
 
Initials ____________________ 
Completed By:  __________________________ 
Date Completed___________________ 
 
Below are several questions that will help describe the dryness in your mouth and how that 
dryness affects your daily life.  Please encircle the number that corresponds to your condition 
during the last week in each of the following questions: 
1.  Rate the discomfort of our dentures due to dryness (if you do not wear dentures please 
check____) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
 Comfortable 
Extreme discomfort 
2.   
Rate the difficulty you experience in speaking due to dryness of your mouth and tongue: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
 
Easy 
Extremely Difficult 
3. 
Rate the difficulty you experience in chewing food due to dryness: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Easy 
Extremely Difficult 
4. 
Rate the difficulty you experience in swallowing food due to dryness: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
 
Easy 
Extremely Difficult 
5. 
Rate the dryness your mouth feels when eating a meal: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
 No Dryness 
Extremely Dryness 
6. 
Rate the dryness in your mouth while not eating or chewing: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
 No Dryness 
Extremely Dryness 
7. 
Rate the frequency of sipping liquids to aid in swallowing food: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
None required 
Extremely Frequent 
8. 
Rate the frequency of fluid intake required for oral comfort when not eating: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
None required 
Extremely Frequent 
 
9. 
Rate the frequency of sleeping problems due to dryness: 


40 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
 None 
Extremely Frequent 
 
10.  Does your mouth feel dry when eating a meal?  
 
Yes/No 
 
11.  Are you thirsty?  
 
 
 
 
 
Yes/No 
12.  Does the amount of saliva in your mouth seem to be: 
 
_____Too little 
_____Too much 
_____Don't notice it 
 
13. Do you have difficulties swallowing any food?  
 
Yes / No 
14. Do you sip liquids to aid in swallowing dry food? 
 
Yes / No 
15. Have you smoked in the last week? 
 
 
 
Yes / No 
If yes, how many packs? _________  
16. Do you drink alcohol more than twice a week?  
 
Yes / No 
17. Do you have any medical problem/disease for which you take 
 medication? 
 
 
 
 
 
 
Yes /No 
Which pills/medication do you take? 
 
 
 
 
Study ID: ___________ 
 
 
 
 
 
UMCC 2009.078 


41 
 
UMCC 2009.078 
 
Study ID # ___________ 
 
 
 
Initials ____________________ 
Completed By:  __________________________ 
Date Completed___________________ 
 
 
 
1.  As a result of your head and neck condition or treatment, over the past FOUR WEEKS how much have you 
been BOTHERED by your… 
 
 
  Not at all 
  Slightly 
  Moderately 
    A lot 
   Extremely 
 
 
A. Ability to talk to other people 
 
B. Ability to talk on the phone 
 
 
2.  As a result of your head and neck condition or treatment, over the past FOUR WEEKS how much have you 
been BOTHERED by problems with… 
 
 
 Not at all 
   Slightly 
  Moderately 
     A lot 
  Extremely 
 
A. Volume of your voice 
 
 
B. Clarity of your voice 
 
 
C. Difficulty opening your mouth 
 
 
D. Dryness in your mouth while eating 
 
 
E. Chewing food (for example,  
pain, difficulty opening or closing 
your mouth, moving food in your 
mouth, or teeth or denture problems) 
 
F. Swallowing liquids 
 
 
G. Swallowing soft foods and/or solids 
 
H. Your ability to taste food  
(For example, loss of taste,  
and/or loss of appetite due to  
poor taste) 
 
 
 
INSTRUCTIONS:  This survey is designed to assess how much you are bothered by your Head and Neck 
condition and/or treatment.  Please answer every question by marking one box.  If you are unsure about how to 
answer, please give the best answer you can. 


42 
 
 
 
I. 
Pain, burning, and/or discomfort 
  in your mouth, jaw, or throat 
 
J. 
Shoulder or neck pain 
 
 
3. Over the past  FOUR WEEKS, how often did you take pain medication?... 
 
Never      Rarely 
 Sometimes 
Frequently 
   Always 
 
 
 
 
4. Over the past FOUR WEEKS how much have you been bothered by… 
 
 
 Not at all 
  Slightly 
Moderately 
 A lot 
Extremely 
 
A. Concerns or worries about  
your appearance related to  
your head and neck condition or  
 treatment 
 
B. Emotional problems related  
 to your head and neck condition  
or treatment 
 
C. Embarrassment about your  
symptoms 
 
 
D. Frustration about your condition 
 
 
E. Financial worries due to medical  
problems 
 
 
F. Worries that your condition will  
get worse 
 
 
G. Physical problems related to your  
head and neck condition 
 
5.   Were you working (employed)                           Yes   
   No 
prior to being diagnosed with cancer? 
If no, go to question 6  
 
 
 
Yes 
          
No 
5A.  If yes, did your doctor declare  
you unable to work due to your head  
and neck condition or treatment? 
 
 
Study ID: ___________ 
 
 
 
 
 
UMCC 2009.078 
 


43 
 
 
6. Have there been other problems related to your head and neck condition that were not mentioned?  If 
so, please write them in the space below and tell us how much this problem has bothered you.  (For 
instance, if your treatment included surgical transfer of tissue from a donor site to the head and neck, 
does the donor site bother you) 
 
 
    Not at all 
      Slightly 
  Moderately 
 A lot 
Extremely 
 
 
A. __________________ 
 
B. __________________ 
 
C. __________________ 
 
 
7.  For the past FOUR WEEKS,  
please rate your OVERALL amount  
of disturbance or BOTHER  
 as a result of your head and neck 
cancer condition? 
 
8.  Overall how satisfied are you with 
your Head and Neck cancer care at  
this Hospital? 
 
9.  Overall how would you rate your response to treatment? 
Poor 
       Fair 
  Good 
Very Good 
 Excellent 
 
 
 
 
 
10.Approximately how long did it take you to answer this questionnaire? 
__________  Minutes 
 
 
 
 Not at all 
      Slightly 
  Moderately 
 A lot 
Extremely 
11.  How difficult was it to  
complete this questionnaire? 
 
 
 
 
 
 
 
 
Study ID: ___________ 
 
 
 
 
 
UMCC 2009.078