Conditions: Head and Neck Cancer
Keywords: SCC Head and Neck Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
This is a single-arm, phase II trial to characterize the clinical outcome of standard of care, cetuximab concurrent with radiation, in a special population (head and neck cancer patients who cannot tolerate concurrent chemoradiotherapy due to advanced age, poor performance status or concurrent illness), and to determine if biomarker response to a loading dose of cetuximab is predictive of that outcome.

Detailed description:
Primary Objective 1: Determine changes in tumor EGFR, pEGFR, downstream signaling and novel phosphoproteins following a loading dose of cetuximab in patients who are poor candidates for chemoradiation (age =70 years or with significant co-morbidities) and are therefore treated with cetuximab with radiation.

Primary Objective 2: Characterize clinical outcomes, including local recurrence, progression-free survival and overall survival in these patients, and correlate these clinical outcomes with the changes in tumor EGFR, pEGFR, downstream signaling, and novel phosphoproteins.

Primary Objective 3: Describe the toxicity, in particular mucositis/dysphagia, of this regimen.

Secondary Objective 1: Conduct normal mucosa EGFR assessment for comparison with tumor sample.

Secondary Objective 2: Correlate HPV presence and titer with p53 status and clinical outcome.

Arms:
arm 1: None

Interventions: intervention 1: Cetuximab intervention 2: 50-60 Gy and 70 Gy
Intervention descriptions: intervention 1: Patients will receive a single dose of cetuximab 400 mg/m (Day 0). On day 7 (+/- 1 day), a repeat biopsy will be performed. Radiation concurrent with weekly cetuximab 250 mg/m. intervention 2: Within approximately 4 days (after single dose of Cetuximab), definitive radiation will begin (70 Gy in 35 fractions to the gross tumor, 50-60 Gy to subclinical target volumes) concurrent with weekly cetuximab 250 mg/m.

Protocol document:
Prot_SAP_000.pdf: 
1 
A Phase II Study of RT Concurrent with Cetuximab in Patients with Locally Advanced Head 
and Neck Squamous Cell Carcinoma Who Do Not Qualify For Standard Chemotherapy  
Due To Age>70 Or Co-Morbidities 
(UMCC 2009.009) 
Principal Investigator:  
Shruti Jolly, M.D.1, 2 
Department of Radiation Oncology 
Co-Investigators: 
Michelle Mierzwa, M.D. 1 
Theodore Lawrence, M.D. Ph.D. 1
Kemp Cease, M.D.2 
Susan Urba, M.D.1 
Francis Worden, M.D.1   
Carol Bradford, M.D.1
Gregory Wolf, M.D.1 
 
Mark Prince, M.D.1, 2 
Jeffrey Moyer, M.D.1, 2  
Joseph Helman, M.D.1, 2  
Brent Ward, M.D.1 
Erin McKean, M.D.1
Kelly Malloy, M.D.1
Matthew Spector, M.D.1 
Andrew Shuman,  M.D.1 
Michelle Kim, M.D.1,2
Matthew Schipper, Ph.D.1 (statistician) 
1 University of Michigan Health System 
1500 East Medical Center Drive 
Ann Arbor, MI 48109 
2 Veterans Affairs Health System 
2215 Fuller Road 
Ann Arbor, MI 48105 
Version:  May 3, 2018 
NCT00904345


2 
 
 
TABLE OF CONTENTS 
 
1.0 
     Introduction..………………………………………………….3 
 
2.0 
     Objectives.....………………………………………………….6 
 
3.0 
     Inclusion Criteria……...……...……………………………….7 
 
4.0 
     Exclusion Criteria….………………………………………….7 
 
5.0 
     Pre-treatment…………………….……………………………7 
 
6.0 
     Schema………………………………………………………  8 
 
7.0 
     Study Design………………………………………………….8 
 
8.0 
     Study Calendar..………………………………………………14 
 
9.0 
     Measurement of Response……………………………………14 
 
10.0 
     Criteria for Discontinuation of treatment…………………… 15 
 
11.0 
     Drug Information……………………………………………. 15 
12.0 
     Radiation Therapy……………………………………………18 
13.0 
     EGFR Analysis……………………………………………….19 
14.0 
     Other Therapy………………………………………………...20 
 
15.0 
     Informed Consent……………………………………………. 20 
16.0           Patient Registration………………………………………….. 20 
 
17.0           Adverse Drug Events………………….…………………….. 21 
18.0           Reporting Procedures……….……………………………….. 23 
19.0           Data and Safety Monitoring…………………………………..24 
20.0           Clinical Monitoring Procedures ……………………………...25 
21.0           Statistical Considerations……………………………………. 26 
 
22.0           References…………………………………………………….30 
 
23.0           Appendix……………………………………………………...35 
 
 
 
 


3 
1.0  Introduction 
For most patients with locoregionally advanced head and neck cancer, chemoradiotherapy can 
improve local control and survival, and can achieve organ preservation. This was first demonstrated 
in the Veterans Affairs Cooperative Study Group prospective randomized landmark trial comparing 
an organ preservation approach (induction chemotherapy followed by definitive radiation, based on 
chemotherapy response) to the standard treatment of laryngectomy with radiation 1. Sixty six percent 
of the surviving patients had successful larynx preservation with no decrease in survival. Subsequent 
trials at multiple other institutions have confirmed these results 2-5. 
 
Unfortunately, this improved tumor outcome resulting from the administration of concurrent 
chemoradiotherapy does not extend to older patients and those with coexisting medical conditions 
and poor performance status. In the RTOG 91-11 Intergroup Study, the rate of high-grade toxic 
effects was greater with the chemotherapy-based regimens (81% vs. 61% with radiotherapy alone).  
The rate of grade 3 and 4 acute mucositis was 20% and 24% in the chemotherapy followed with 
radiotherapy and the radiotherapy alone arms, respectively, and was doubled in the concurrent 
chemoradiotherapy arm (43% p < 0.05). Also, more deaths that may have been related to therapy 
were reported in the concurrent chemoradiotherapy arm (5%, compared with 3% in each of the other 
arms). Enhanced toxicity, primarily mucositis and late dysphagia, were also reported in other studies 
of concurrent chemoradiotherapy. Mucositis and dysphagia are the main barriers to winning the 
battle against head and neck cancer 6-9.  
 
Therefore, it is not surprising that age has a dramatic impact on the benefit of concurrent 
chemotherapy with radiation. A meta-analysis of over 15,000 patients, evaluating the impact of age 
on patients treated with either concurrent chemoradiotherapy or altered fractionation revealed no 
benefit to older patients (age>70years)10.  This lack of benefit is due, in part, to increased morbidity 
and mortality of treatment.  This study addresses the need to develop less toxic therapies for patients 
who are older and/or have co-morbidities.    
 
EGFR1 plays a key role in head and neck cancer, in that its over-expression is associated with more 
aggressive behavior, and its blockade increases the survival of patients treated with radiation without 
increasing toxicity. We hope to determine the pharmacodynamic profile of response in patients 
receiving cetuximab and radiation, so that we can determine who benefits from this extremely 
expensive and moderately toxic therapy.  
 
 
1.1 Study Hypothesis and Rationale 
Bonner et al investigated the benefit of the addition of cetuximab to radiation.  It was 
concluded that cetuximab improves locoregional control and reduces mortality 
without increasing the common toxic effects associated with radiotherapy to the head 
and neck 11. In our study, we propose to select locally advanced head and neck cancer 
patients, who are older than age 70 or are not deemed candidates for chemotherapy. 
This group was not extensively investigated in the earlier randomized trial, in that 
                                                 
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. 
 


4 
90% of patients in the Bonner study had a KPS of 80 or greater, and the median age 
of the patients was 57 11.  The primary end-point of this trial is to characterize local 
progression free survival in these patients, when treated with cetuximab+radiation. 
 
We also propose to develop a molecular pharmacodynamic predictor of local control 
after treatment with combination cetuximab-radiation. We hypothesize that tumor 
EGFR degradation and other markers of down-stream EGFR inhibition as well as 
novel phosphoproteomic markers observed in tumor biopsies taken 7 days after the 
administration of cetuximab, will predict the effectiveness of cetuximab-radiation. 
The first biopsy will be obtained prior to administration of the loading dose of 
cetuximab. Prior to initiation of cetuximab concurrent with radiation, on Day 7, 
following the cetuximab loading dose, a tumor biopsy for the biomarkers will be 
obtained. We hypothesize that tumors that do not demonstrate the changes that 
correlate with response after cetuximab in the in vivo preclinical studies are more 
likely to progress following cetuximab-radiation therapy compared to those that show 
changes that correlate with response. If our hypothesis is validated, we will gain a 
tool that will help identify patients who are most likely to benefit from radiation and 
cetuximab, a very expensive and moderately toxic treatment. 
 
In the Bonner trial and in the Vermorken12  study there was an increased survival 
benefit that was associated with oropharynx sites.  High risk HPV (human papilloma 
virus) infection has been implicated both as an etiologic factor and as a prognostic 
factor for survival and response to therapy.  HPV is also typically associated with a 
younger cohort of patients, however as the high risk HPV infected cohort ages, we do 
expect to see more patients in their 70s and beyond who will have HPV-related head 
and neck cancers.  Thus, we postulate the EGFR inhibition will work better in HPV 
positive tumors.  We will investigate the presence of HPV in the tumor tissue biopsies 
by a variety of assays.  We will also examine the p53 status using RNA isolated from 
the tumor biopsy since HPV positive tumors most frequently have wild type p53 
which may also contribute to the high response rate of these tumors.   
 
1.2 EGFR inhibitors in head and neck cancer 
Initial in vitro studies demonstrated that prolonged exposure of cells to EGF could 
enhance the effects of radiation in head and neck cancer cells 13, 14. 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 apoptosis15. Furthermore, there was an inverse correlation between EGFR 
expression levels and radiation response 16-18. This relationship between EGFR 
expression and poor prognosis was confirmed in human head and neck carcinoma 
samples 19. A variety of preclinical studies have demonstrated that EGFR inhibitors 
can increase radiation sensitivity in both in vitro and in vivo model systems 20-26. 
While the majority of studies have reported additive effects resulting from the 
combination of EGFR antagonists and radiotherapy in vitro, the same combination 
produces synergistic effects in xenograft models 20, 21, 27-29. This may be secondary to 
EGFR inhibitors and radiation impact on several downstream signaling pathways 30. 
These include pathways regulating cellular proliferation and apoptosis, which would 


5 
be evident in both in vitro and in vivo, and pathways regulating angiogenesis 20, 29 and 
tumor invasion 31, 32, which might be detectable only in tumor xenograft models. 
 
While preclinical studies have highlighted the potential therapeutic gains that could 
be achieved by adding EGFR inhibitors to radiation, the best validation of this 
combination has been from the results of clinical trials in head and neck cancer. A 
phase III clinical trial demonstrated that, in a cohort of 424 patients with 
locoregionally advanced squamous cell carcinoma of the head and neck, the addition 
of cetuximab nearly doubled the median survival of patients (compared to 
radiotherapy alone), from 28 to 54 months. This study represented the first major 
success achieved by the addition of an EGFR antagonist to radiotherapy. This 
improvement was achieved without enhanced toxicity. Notably, the rates of 
pharyngitis and weight loss were identical in the two arms 11. 
 
1.3 Predicting response to combination cetuximab-radiation 
While we hope that we can simply substitute cetuximab for cisplatin-based 
chemotherapy and achieve the same rate of local control as with chemoradiotherapy 
without the increased toxicity of chemotherapy, we must also entertain the possibility 
that only a fraction of these patients will be able to achieve tumor control using this 
strategy.  Therefore, it would be very valuable to be able to predict in advance those 
patients who will be able to achieve local control with cetuximab and radiation 
therapy. However, previous efforts to predict the response to EGFR inhibition using 
the pre-therapy EGFR expression levels have failed. For instance, responses to 
cetuximab in patients with metastatic colorectal cancer occur in the absence of EGFR 
staining by immunohistochemistry33. Furthermore, the strength of EGFR staining 
using immunohistochemistry does not predict response to EGFR inhibitors combined 
with chemotherapy 34. Previous efforts to predict response in patients with head and 
neck cancer based on pretreatment EGFR levels have also failed 35.  (Lung cancer 
may be an exception in this case as mutation of the EGFR may correlate with 
response 36, but these mutations are rare in head and neck cancer.) One other recent 
discovery on the biomarkers of response suggests that patients whose tumors do not 
have K-ras mutations have a significantly higher disease control rate than patients 
with K-ras mutations when treated with cetuximab in colorectal cancers.37   However, 
K-ras mutation in head and neck cancers is rare, therefore this finding will not be 
useful for these patients. 38 
 
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 39, 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. Indeed, a substantial literature has elucidated these EGFR signaling 
pathways, which offers candidate molecules. Our preclinical data and the literature 


6 
suggest that changes in total EGFR, pEGFR, pSTAT3, and Bcl-XL, EGFR copy 
number, EGFRvIII status, and NFB may predict response to cetuximab-radiation. 
Additionally, we postulate that EGFR variant 3 (EGFRvIII) expression may predict 
response to cetuximab, since tumors that express primarily this variant are less likely 
to respond to cetuximab blockade than tumors that express the full length receptor.  
The vIII form is reported to be intrinsically active and thus blocking ligand binding 
with the antibody should not be effective.  Sok et al.40  reported that 42% of head and 
neck tumors in their series expressed EGFRvIII.  We will assess vIII expression using 
RT-PCR with RNA isolated from the research biopsy. 
 
1.3.1 
In addition to the known downstream effectors of EGFR signaling, it is 
likely that there are additional downstream targets whose status could 
add to the known predictive markers described above.  Proteomic 
techniques permit one to assess thousands of potential proteins as 
possible markers. As much of the key signaling is mediated by 
phosphorylations and dephosphorylations rather than changes in total 
protein levels, investigators have focused on the phosphoproteome as a 
likely source of new candidates 41, 42. Several groups have used these 
approaches to assess EGF stimulation 43, which has confirmed known 
pathways and elucidated new targets 44.  We are unaware of previous 
efforts to apply this powerful technology toward the discovery of 
novel predictors of the effectiveness of combined radiation-cetuximab.  
We are likewise unaware of studies that have tested the clinical 
response of EGFR variant three expressing head and neck tumors 
treated with cetuximab.  We postulate that tumors expressing only 
wild type EGFR will be more responsive than those that express 
variant III.   
 
2.0 Objectives 
2.1 Primary 
2.1.1 
Determine changes in tumor EGFR, pEGFR, downstream signaling, 
and novel phosphoproteins following a loading dose of cetuximab in 
patients who are poor candidates for chemoradiation (age ≥70 years or 
with significant co-morbidities) and are therefore treated with 
cetuximab and radiation. 
2.1.2 
Characterize clinical outcomes, including local recurrence, 
progression-free survival and overall survival in these patients, and 
correlate these clinical outcomes with the changes in tumor EGFR, 
pEGFR, downstream signaling, and novel phosphoproteins.  
2.1.3 
Describe the toxicity, in particular mucositis/dysphagia, of this 
regimen.  
 
2.2 Secondary 
2.2.1 
Conduct normal mucosa EGFR assessment for comparison with tumor 
sample. 
2.2.2 
Correlate HPV presence and titer with p53 status and clinical outcome. 


7 
 
3.0 Inclusion Criteria 
3.1 Patients must have pathologically-confirmed, previously untreated, clinically 
accessible (without general anesthesia) locally advanced squamous cell 
carcinoma of the larynx, hypopharynx, oropharynx, oral cavity or nonresectable 
head and neck squamous cell carcinomas of the skin.   
3.2 Patients will be limited to: 
 ≥ 70 years of age, OR 
 with co-morbidities that preclude treatment with standard platinum-based 
chemotherapy, as determined by the treating physician, OR 
 KPS≤80, OR 
 Creatinine clearance <30cc/min 
3.3 Laboratory criteria: 
3.3.1 
WBC > 3500/ul, granulocyte > 1500/ul 
3.3.2 
Platelet count > 100,000/ul 
3.3.3 
Total Bilirubin < 1.5 X ULN 
3.3.4 
AST and ALT < 2.5 X ULN 
3.4 Patients must give documented informed consent to participate in this study. 
 
4.0 Exclusion Criteria 
4.1 Prior head and neck malignancy, or history of other prior non-head and neck 
malignancy within the past 3 years (excluding skin cancer and early stage 
treated prostate cancer). 
4.2 Prior head and neck radiation or chemotherapy. 
4.3 Documented evidence of distant metastases. 
4.4 Patients with nasopharyngeal carcinoma. 
4.5 Any medical or psychiatric illness, which, in the opinion of the principal 
investigator, would compromise the patient’s ability to tolerate this treatment. 
4.6 Patients with psychiatric/social situations that would limit compliance with 
study requirements are not eligible. 
4.7 Patients with prior anti-epidermal growth-factor receptor antibody therapy 
(antibody or small molecule). 
4.8 Patients residing in prison. 
 
5.0 Pre-treatment 
5.1 Complete history and physical examination, examination by Otolaryngology, 
Radiation Oncology, and Medical Oncology, complete documentation of extent 
of primary tumor and regional disease.  
5.2 Satisfactory biopsy of the primary tumor confirming pathologic diagnosis. 
5.3 Complete dental evaluation (at the discretion of physician). 
5.4 Completion of laboratory studies: Comprehensive panel, including Magnesium 
and CBCP with differential. 
5.5 Diagnostic CT scan or MRI of the head and neck. 
5.6 Initial staging CT-PET scan (at the discretion of physician). 
5.7 Baseline toxicity evaluation. 


8 
 
 
6.0 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.0 Study Design 
7.1 Overview 
Patients will receive a single dose of cetuximab 400 mg/m2 (Day 0). On day 7 (+/- 1 
day), a repeat biopsy will be performed. Within approximately 4 days, definitive 
radiation will begin (70 Gy in 35 fractions to the gross tumor, 50-60 Gy to subclinical 
target volumes) concurrent with weekly cetuximab 250 mg/m2. Twelve to 14 weeks 
following the completion of cetuximab-radiation, patients will undergo standard 
restaging and treatment, including CT-PET, repeat laryngoscopy and tumor site 
biopsies. Patients with evidence of persistent tumor may undergo surgical salvage 
and/or neck dissection.  
 
7.2 Research Component (Treatment with cetuximab and associated biopsies) 
All patients will sign an informed consent for clinical and research biopsies. All 
biopsies will be performed by an otolaryngologist or oral surgeon who is a co-
investigator of the study. The proposed tissue accrual should be adequate for all of the 
proposed studies. 
7.2.1 
Research Biopsy #1:  Patients will be consented and enrolled in this 
study prior to this biopsy.  The biopsy will be performed no more 
than 4 weeks prior to the loading dose of cetuximab. It will be 
performed under local anesthesia (in the event a patient requires 
further clinical staging or confirmation of diagnosis under general 
anesthesia, the research biopsy may be performed at that time.)  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 within 4 weeks of the 
loading dose of Cetuximab.   
7.2.2 
Research Biopsy #2: This will be done 7 days (+/- 1 day) after the 
cetuximab loading dose (Day 0).   
7.2.3 
Normal Oral Mucosa Sampling: Baseline EGFR of the normal oral 
mucosa will be obtained by buccal swab or normal mucosa biopsy. If 
using buccal swabs, at least 3 normal oral mucosa buccal swab 
Enrolled
Day 0 
 
 
Cetuximab 
Loading 
Dose 
(400mg/m2) 
Day 7 
(+/- 1 day) 
 
Research 
Tumor Biopsy 
#2 and EGFR 
of Normal Oral 
Mucosa 
Research 
Tumor 
Biopsy #1 
and EGFR 
of Normal 
Oral 
Mucosa 
Start daily 
RT and 
weekly 
cetuximab 
(250 mg/m2) 
Follow Up 


9 
samples will be acquired. This sampling will occur at both Research 
Biopsy #1 and Research Biopsy #2. 
 
7.3 Cetuximab/Radiation Schedule: Cetuximab will be delivered as standard of care 
per the package insert.  
7.3.1 
Day 0:  Patients will receive a single dose of cetuximab 400 mg/m2. 
7.3.2 
Day 7 (+/- 1 day):  Biopsy #2 will be obtained 
7.3.3 
Following the biopsy, within approximately 4 days, daily radiation 
therapy with weekly cetuximab will be initiated. 
7.3.4 
Patients will receive weekly cetuximab 250 mg/m2. On days of 
radiation therapy and cetuximab administration, cetuximab will be 
given prior to radiation therapy.  
 
 
7.4 Cetuximab Dose Levels and Modifications 
 
 
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. 
 
 
7.4.1 
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 7.4.5) 
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 – 49,000/mm3) 
Decrease by 1 dose level with occurrence 
4 (<25,000/mm3) 
Decrease by 1 dose level with occurrence 


10 
7.4.2 
Cetuximab Dose Modification for Non-Hematologic Toxicity 
 
NCI CTCAE Toxicity Grade 
(CTCAE v. 4.0) 
Cetuximab Dosea,b,c,d 
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                               
 
No dosage adjustment 
 
 
Decrease by 1 dose level 
Grade 4 despite maximal 
medical management             
Decrease by 1 dose level 
Headache 
 
≥ Grade 3 
Decrease infusion rate by 50% 
≥ Grade  3 despite decreased 
 infusion rate and use of analgesic 
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. 
 
aFor CTCAE Grade < 2 non-hematologic toxicity not described above, maintain dose level of drug. 
bProvided that all the retreatment criteria are met as detailed in section 7.4.5. 
cDose levels are relative to the previous dose.  Dose reductions of cetuximab below the –2 dose level will not be 
allowed. 
dIn any case of cetuximab treatment delay, there will be no reloading infusion, and all subsequent treatments 
will be at the assigned dose level. 
 
 
 
 


11 
7.4.3 
Management of Cetuximab Hypersensitivity Reactions 
 
CTCAE Grade 
Hypersensitivity Reaction 
Grade 1 
Transient rash, drug fever <380C 
(<100.40F), 
 
Grade 2 
 
Urticaria, drug fever > 380C (> 
100.40F), and/or asymptomatic 
bronchospasm 
 
Grade 3 
 
Symptomatic bronchospasm, 
requiring parenteral medication(s), 
with or without urticaria; allergy-
related edema/angioedema 
 
Grade 4 
 
Anaphylaxis 
 
7.4.3.1  Symptoms of hypersensitivity reactions should be managed per institutional 
chemotherapy infusion policy guidelines. 
 
7.4.3.2  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 or co-investigator should be contacted immediately to 
discuss and grade the reaction. 
 
7.4.5 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. 
 
7.4.5 
Retreatment Criteria for cetuximab 
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 10.0): 
 Acne-like rash is  Grade 2 (see Section 7.4.6) 
 Grade 3 - 4 hematologic toxicities have resolved to  CTC Grade 2  


12 
 Grade 3 - 4 non-hematologic toxicities have resolved to ≤ CTC 
Grade 2, (except fatigue (asthenia), anorexia and alopecia) 
 
7.4.6 
Acne-Like Rash (rash acneiform or 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 acneiform or rash maculo-papular.” The cetuximab 
dose alteration scheme is outlined in the figure below. If a subject 
experiences a Grade 3 acne-like rash (rash acneiform or rash maculo-
papular), 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; topical 
corticosteroids are not recommended. If there are subsequent 
occurrences of a Grade 3 acne-like rash (rash acneiform or rash 
maculo-papular), 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 (rash acneiform or rash maculo-papular) 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 (rash acneiform or rash maculo-
papular), cetuximab therapy will be discontinued. 
 
Management of Cetuximab Acne-Like Rash 
 


13 
7.5 
Evaluation of Response to Treatment 
7.5.5 
Careful evaluation of tumor extent will be recorded for both the 
primary tumor and regional nodes at specified intervals by the treating radiation oncologist, medical 
oncologist or otolaryngologist, who are co-investigators of the study.. CT-PET scans will be used at 
the discretion of the clinician to supplement clinical exams.  However, it is not necessary for 
imaging abnormalities to revert to normal in order for a patient to be considered a clinical CR.   
7.5.6 
Biopsy of any persistent neck nodes is required at the 12-14 week 
post cetuximab-radiation laryngoscopy.   Patients with any nodes initially > 3 cm in size who are 
CT-PET positive at 12-14 weeks post cetuximab-RT will undergo neck dissection.  Patients whose 
CT-PET shows a complete response (CR) at 12 weeks post cetuximab-RT, will undergo clinical 
observation. 
7.5.7 
Diagnostic CT-PET scans may be obtained prior to scheduled 
endoscopies for tumor assessment.  
7.5.8 
Outpatient clinical examinations will be performed as comparable to 
clinical practice:  at approximately 1 month following completion of RT and then approximately 
every 2 months during years 1 and 2.  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. 
 
7.6 
Evaluation of Toxicity and Quality of Life 
7.6.5 
Validated xerostomia-related and general quality of life 
questionnaires (Appendix C), and Common Toxicity Criteria Adverse Events (CTCAE, v.4) 
observer related items, will be collected before, during and after radiation therapy as indicated in the 
study calendar.  As part of data collection related to the quality of life measures, pre and post-
treatment employment status will also be recorded. 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. 
 
 


14 
  
8.0 
Study Calendar 
 
Assessment 
Pre-
Treatment* 
Day 0 
Loading 
Dose 
Day 7 
Weekly 
during RT† 
1 mo post 
RT2 
12-14 wks 
post RT2 
Follow 
Up Years 
1 and 22 
H&P/Physician 
Evaluation1 
X 
 
 
X 
X 
X 
X 
Research 
Biopsy 
X** 
 
X 
 
 
 
 
 
Dental 
Evaluation3 
X 
 
 
 
 
 
 
COMP, Mg 
X 
 
 
X 
 
X 
 
CBCP with 
diff 
X 
 
 
X 
 
X 
 
CT-PET3 
X 
 
 
 
 
X 
 
CT or MRI of 
head/neck 
X 
 
 
 
 
 
 
Toxicity 
Evaluation 
X 
 
 
X 
X 
X 
X 
QOL 
Questionnaire 
X 
 
 
end of 
treatment 
X 
X 
X 
Cetuximab 
 
X 
 
X 
 
 
 
 
* The pre-treatment period is prior to the administration of the cetuximab loading dose.  The pre-treatment 
toxicity evaluation and QOL Questionnaire may be completed at the time of consent.  When a patient is 
determined eligible and enrolled, data will be used.  If patient is not eligible or not enrolled, the data will not be 
used and the subject will be deemed a screen failure.  The forms will be kept with the Informed Consent in the 
study record.   
** Research biopsy #1 must be within 4 weeks of loading dose (Day 0) 
† Radiation therapy will start within approximately 4 days following Day 7 (+ or – a day) biopsy 
 
1Evaluations pre-treatment are by Radiation Oncology, Otolaryngology, and Medical Oncology.  Evaluations 
weekly during RT are generally by Radiation Oncology via standard on-treatment notes.  Evaluations in follow 
up will be by Radiation Oncology, Otolaryngology, and/or Medical Oncology.  It is not necessary for patients to 
be seen by more than one discipline at each follow up visit.  
2Follow up:  Examinations will be performed as comparable to clinical practice: at approximately 1 month 
following completion of RT and then approximately every 2 months during years 1 and 2.  At approximately 
12-14 weeks post-RT, patients will have clinical restaging performed for disease evaluation.  A PET or MRI is 
acceptable for this restaging.  Toxicity Evaluation and QOL Questionnaires will be collected at each of these 
visits.  Biopsies, labs and imaging studies will be performed as clinically indicated.  For years 3 - 5, all follow 
up will be as clinically indicated and patients will only be followed for disease status and survival. 
3 Pre-treatment PET-CT and pre-treatment dental evaluation preferred, but these will be ordered at the 
discretion of the treating physician.   
 
 
9.0 
Measurement of Response   
9.4 
Tumor Clearance  
A primary clinical endpoint of this study is progression-free survival.  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 or MRI) examination assessed within 
approximately 3 months after the completion of treatment.  Complete response will 


15 
be defined as complete disappearance of disease (in which case 9.2 will apply to 
assess relapse) or residual radiographic abnormality (which cannot be safely biopsied) 
that is not considered to be tumor (in which case section 9.3 will apply to assess 
progression).  
 
9.5 
Local or Regional Relapse 
Relapse is defined as reappearance of tumor after complete response. If possible, 
relapse should be confirmed by biopsy. 
9.6 
Local or Regional Progression 
Progression is defined as an estimated increase in the size of the tumor (product of the 
perpendicular diameters of the two largest dimensions) of greater than 25%, taking as 
reference the smallest value of all previous measurements or appearance of new areas 
of malignant disease. 
9.7 
Distant Metastasis 
Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended 
where possible. A solitary, spiculated lung mass/nodule is considered a second 
primary neoplasm unless proven otherwise. 
9.8 
Second Primary Neoplasm 
Tumor reappearing with the initial and immediate adjoining anatomical region of the 
primary will be considered local recurrence. Multiple lung nodules/masses are 
considered distant metastases from the index cancer unless proven otherwise. 
 
10.0 
Criteria for Discontinuation of Treatment 
In the absence of treatment delays due to adverse events, treatment may continue through 
completion of concurrent chemoradiotherapy and consolidation chemotherapy or until one of the 
following criteria applies: 
 
 
Local-regional disease progression 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse events(s) 
 
Patient decides to withdraw from the study 
 
General or specific changes in the patient's condition render the patient unacceptable for   further treatment 
in the judgment of the investigator. 
If treatment is interrupted due to a non-dose-limiting adverse event or any reason other than toxicity, such as a 
holiday, bad weather, or a transportation problem, the duration of therapy will be extended accordingly.  If a patient 
misses a day of radiation and chemotherapy, then the weekly chemotherapy should be delivered the next day and the 
missed radiation fraction will be given after the completion of planned treatments.  
 
Patients who exhibit local-regional tumor progression will discontinue all study procedures and 
will be medically managed.  For the purposes of the research, they will continue to be followed 
for toxicity and survival.  These patients may be treated with other agents.   
 
11.0 
Drug Information: Cetuximab 
 
The product will be provided from commercial supply.  
11.4 
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 


16 
including protein A chromatography, ion exchange chromatography, low pH 
treatment, and nanofiltration. Cetuximab is not known to be a vesicant.  
11.5 
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 8º 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. 
11.6 
Safety Precautions  
Appropriate mask, protective clothing, eye protection, gloves and Class II vertical-
laminar-airflow safety cabinets are recommended during preparation and handling. 
11.7 
Preparation and Administration:  
11.7.5 
Cetuximab is provided by ImClone 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. 
11.7.6 
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. 
11.7.7 
Cetuximab may be administered via a gravity drip, 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 or Gravity Drip 
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.  Use a gravity drip or 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 


17 
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-m 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 
 
11.7.8 
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. 
11.7.9 
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 
container or syringe is 8 hours at room temperature or 12 hours in the refrigerator. 
 
11.8 
Adverse Events:  
 Hematologic:  Leukopenia 
 Gastrointestinal: Nausea, vomiting, diarrhea, anorexia, mucous membrane 
disorder, stomatitis, reduced kidney or liver function 
 Dermatologic:   Rash, acne, dry skin, pruritus 
 Circulatory: Deep vein thrombosis 
 Neurological: Confusion, disorientation, seizure, coma; rarely, encephalitis 
 Allergy: Allergic reaction, anaphylactoid reaction 
 Other: Asthenia, fever, dyspnea, headache, chills, nail disorder, myalgia, 
arthralgia 
 
 
 


18 
12.0 
Radiation Therapy 
12.4 
General Considerations:  
All the patients in this study will receive definitive radiotherapy. Definitive 
radiotherapy will begin one week following the administration of the loading dose of 
cetuximab. 
 
12.5 
Radiation Fields:  
The treatment volumes will be individualized for each patient depending upon the 
extent of disease. Tumor volumes will be outlined on the planning CT scans with the 
aid of CT-PET to ensure adequate irradiation of the pre-cetuximab tumor volume. 
Treatment techniques will aim at adequate irradiation of the clinical and the sub-
clinical disease. The therapy goals, specifying the intended doses to the primary 
tumor and lymph node metastases, will be detailed in the therapy chart. A CT-based 
display of the isodoses will be recorded, such that it will be feasible to assess whether 
the intended (prescribed) isodoses cover the targets adequately. 
12.6 
Doses:  
Tumor doses will be expressed in Gy. The prescribed doses should encompass the 
targets. Treatment plans will be generated demonstrating adequate coverage of the 
target volume. The dose across the target volume should not vary by more than +/- 
10% of the prescribed dose. When an anterior-posterior low neck field is treated, the 
dose will be prescribed to 3cm depth. For electron beam treatments, the dose will be 
prescribed to the depth at which maximum dose is obtained (Dmax). When treating 
the posterior cervical nodes, either six or nine MeV electrons may be used. Treatment 
will be delivered daily, five days per week, 2.0 Gy per fraction. Total dose to gross 
disease will be 70 Gy and subclinical disease dose will be 50-60 Gy. Intensity 
Modulated Radiation Therapy (IMRT) will be used to decrease dose to the normal 
critical structures when appropriate, as determined by the treating radiation 
oncologist. 
12.7 
Immobilization and Positioning:  
All patients will be treated in a position that affords maximal daily reproducibility. 
Commonly, it will be in the supine position. Immobilization devices such a head 
masks or bite blocks are mandatory to ensure that target volumes are adequately 
treated. Cradles or arm restraints may be needed to allow adequate exposure of the 
lower neck area in selected patients.  
12.8 
Simulation and CT Scanning: 
All patients will undergo simulation including a CT scan. Treatment planning CT 
scans with or without contrast will be obtained on each patient prior to the first week 
of cetuximab to ensure adequate radiation of the pre-cetuximab tumor extent. 
12.9 
Technical Factors: 
Equipment - Megavoltage equipment with a source to skin distance of 100cm (or 
source-axis distance), or greater, will be used. Megavoltage machines with an energy 
equal to 6 MV photons will be used, rarely higher energy may be used if necessary.  
12.10 
Treatment Planning: 
CT based planning may be used for the total course of radiation, especially if 
necessary for parotid sparing purposes. Otherwise, the final boost may be planned or 
the full course of radiation may be planned using orthogonal simulation fields alone, 


19 
using the information from the pre-cetuximab planning CT for verification of the 
adequacy of the radiation fields. 
12.11 
Treatment Interruptions: 
It is expected that the entire treatment for definitive irradiation will be completed in 
about 7-8 weeks. Treatment interruptions due to symptomatic mucositis or skin 
reactions are rare. In the case of severe mucositis, preventing appropriate nutritional 
intake, a gastric tube or dobhoff tube will be inserted and radiation will continue 
uninterrupted at the discretion of the treating physician. Weight will be recorded 
weekly in the Radiation Oncology chart. If the patient's weight loss exceeds 10% of 
the initial weight or if the patient is malnourished before radiation, a feeding tube 
may be inserted by an appropriately trained physician (surgeon, gastroenterologist, 
interventional radiologist) as defined by clinical practice. 
 
13.0 
EGFR analysis  (General Laboratory Guidelines) 
The primary goal of this analysis is to determine whether cetuximab given at the clinically 
recommended dose, will inhibit EGFR phosphorylation and down-stream signaling effects within the 
tumor as well as the normal mucosa following therapy. In addition, the activation of EGFR and 
various down-stream signaling markers will be measured using immunoblotting as well as immuno-
histochemical analysis in both normal and tumor samples at baseline and post-treatment.  
 
13.4 
Pre-Cetuximab tumor 
The initial pre-treatment punch-biopsy specimen (about 3x3x3 mm) of the tumor will 
be collected in the presence of a laboratory personnel and will be immediately frozen 
in dry-ice ethanol bath in Tissue-Tek O.C.T Compound (Sakura Finetek,Torrance, 
CA) to ensure the integrity of tissue and phosphoproteins for both immunoblotting 
and immunohistological analysis of samples. We will be able to take 3 cores for TMA 
construction from a single 3x3x3 mm biopsy and will expect to have enough material 
to get about 30-50 4-5 micrometers thick sections for immunohistochemical analysis. 
13.5 
Method of Assessment of EGFR Expression in Tumor After Cetuximab 
Loading Dose 
At the time of the second biopsy, four core biopsies from different areas of the tumor as well as swab 
of the normal appearing mucosa will be obtained. Four core biopsies will be processed with one core 
used in high-throughput immunoblot analysis, one core will be fixed in formalin to be embedded in 
paraffin, one core will be frozen and fixed in Tissue-Tek OCT for immunofluorescence analysis and 
one core will be used for RNA and DNA isolation using Trizol. EGFR phosphorylation analysis 
using immunoblotting and immunohistochemistry will be performed in the surgical specimen and 
immunofluorescence analysis will also be performed if sufficient tissue is available using standard 
methods. Interpretations of the staining will be performed according to the standard guidelines. The 
EGFR and critical associated down-stream signaling pathways will be analyzed post- induction 
therapy, including p-EGFR and total EGFR, p-ERK1/2, p-AKT, p27, Ki-67, and p-STAT3, and 
other markers that we may discover in our preclinical studies. EGFRvIII expression and p53 
mutation analysis will be assessed on cDNA obtained from total RNA converted with RT-PCR. 
Genomic DNA from the tumor biopsy will be used to test for HPV presence and type as carried out 
by PCR-mass spect using the AttoSense assay at SensiGen, LLC. 
 
14.0 
Other Therapy 


20 
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. 
 
15.0 
Informed Consent 
15.4 
All patients with squamous carcinoma of the head and neck, who are    
candidates for definitive radiation, will be screened for participation in this study. 
15.5 
Alternative treatment options include chemoradiation, radiation therapy alone, 
or palliative chemotherapy.  
15.6 
Patients who meet the inclusion criteria will be approached for possible 
participation in this study. The nature of the investigation will be described to the patient including 
the risks and side effects of study treatments, the potential benefit of the study to themselves and 
others, the time commitment and frequency of patient visits and the clinical evaluations they will be 
required to undergo. The patient will then have the opportunity to ask questions. The patient will be 
given the IRB approved informed consent form for consideration. Each patient will be allowed to 
read (or have read to them) the informed consent form and understand before discussing consent 
with the investigator. If consent to participate is granted, the patient’s signature will be obtained on 
the informed consent form. The original form will be kept in the patient’s research chart and a copy 
will be given to the patient. 
 
16.0 
Patient Registration 
Patient registration for this trial will be centrally managed by the Clinical Trials Office of 
The University of Michigan Comprehensive Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the 
Informed Consent document will be initially documented by the participating site on the 
Screening and Enrollment Log provided by the Clinical Trials Office. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to 
submitting patient registration request to the Clinical Trials Office. After patient 
eligibility has been determined, a copy of the completed Eligibility Worksheet together 
with all the pertinent de-identified source documents will be submitted by the requesting 
site to the Clinical Trials Office, either by fax or by email to 
   
 
A Multi-Site Coordinator of the Clinical Trials Office, who acts as the registrar, will 
review the submitted documents and process the registration. Sites should inform the 
Multi-Site Coordinator of a potential registration by 5 p.m. on the day prior to 
registration.  Same day registrations cannot be guaranteed.   
 
An email will be sent by the registrar to the requesting site registrar to confirm patient 
registration and to provide the study identification number that has been assigned to the 
patient. In addition, a copy of the completed Section Two of the Eligibility Worksheet 
signed and dated by the registrar, will be faxed back to the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered 
screen failures, and documented as such in the Screening and Enrollment Log. These 


21 
patients will not have study identification number assigned to them, and will not receive 
study treatment 
 
17.0 
Adverse Drug Events 
1.  
 Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. 
Data on adverse events will be collected from the time of the initial investigational agent 
administration through the two year study.  Serious Adverse Events (SAEs) 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. The definitions of AEs and SAEs are given 
below. 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. 
 
Any medical condition or laboratory abnormality with an onset date before agent 
administration is considered to be pre-existing in nature. Any known pre-existing 
conditions that are ongoing at time of study entry should be considered medical history.  
 
All adverse events occurring from the initial investigational agent administration through 
the two year study calendar must be recorded as an adverse event in the patient’s source 
documents regardless of frequency, severity (grade) or assessed relationship to the 
investigational agent/intervention.  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 taking the investigational agent/intervention is also considered an adverse 
event.  All moderate events (grade 2) and hematologic serious events (grade 3) due to the 
patient’s cancer or the treatment which are common toxicities and expected will be 
excluded from this data collection. These will be noted in the patient’s medical records.  
 
All adverse events specified in the Case Report Form Completion Guidelines will be 
recorded in the study database (Velos) 
 
17. 1 Definitions 
 
Adverse event 
Adverse event means any untoward medical occurrence associated with the use of a  
medical treatment or procedure regardless of whether or not considered related to the 
medical treatment or procedure.  
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure, without any judgment about 
causality.  
  
Unexpected 


22 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the 
current application. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure referred only to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. "Unexpected," as used in this definition, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under investigation. 
 
 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or sponsor (UNIVERSITY OF MICHIGAN), it results in any of the 
following outcomes:  
o 
Death 
o 
A life-threatening adverse event 
o 
Inpatient hospitalization or prolongation of existing hospitalization 
o 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o 
A congenital anomaly/birth defect.  
o 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the course 
of the study. Preplanned hospitalizations or procedures for preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment should not 
be considered SAEs. Hospitalization or prolongation of hospitalization without a 
precipitating clinical AE (for example, for the administration of study therapy or other 
protocol-required procedure) should not be considered SAEs. However, if the preexisting 
condition worsened during the course of the study, it should be reported as an SAE. 
  
Life-threatening 
An adverse event is considered “life-threatening” if, in the view of either the investigator 
or sponsor, its occurrence places the patient or subject at immediate risk of death. It does 
not include an adverse event that, had it occurred in a more severe form, might have 
caused death. 
 


23 
 
 
17.2 Adverse Event Characteristics 
 
CTCAE term  
 
Adverse events (AEs) will use the descriptions and grading scales found in the revised 
National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE). 
 
A copy of the CTCAE version 4 can be downloaded from the CTEP home page: 
http://ctep.info.nih.gov/reporting/ctc.html 
 
 
Attribution of the AE: 
 
The investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the investigational agent. 
Probable – The AE is likely related to the investigational agent. 
Possible – The AE may be related to the investigational agent. 
Unlikely – The AE is doubtfully related to the investigational agent. 
Unrelated – The AE is clearly NOT related to the investigational agent. 
 
 
18.0     Reporting Procedures 
 
Serious adverse Events (SAEs) should be reported to the Principal Investigator and Multi-Site 
Coordinator within 48 hours of awareness of the event. SAEs will be reported using the CTO 
SAE form in Velos.  
 
Principal Investigator: Shruti Jolly, MD 
 
 
 
 
Multi-Site CoordinationFax 
 
Email:
 
 
 Follow-up information must also be reported within 48 hours of receipt of the 
information.  
 
Investigators must report SAEs to their local Institutional Review Board per their 
institutions guidelines.  
 
The Multi-Site Coordinator will be responsible for distributing all SAE reports to 
participating institutions.  
 


24 
18.1 
Exceptions to SAE Reporting 
The following adverse events are excluded from SAE reporting: 
 
 Hospitalization secondary to expected cancer morbidity 
 
 Admission for palliative care or pain management 
 
 Planned hospitalizations for surgical procedures either related 
or unrelated to the patient’s cancer. 
 
 Emergency Department visits not related to study treatment 
 
 
 
 
19.0 
Data and Safety Monitoring 
The Data and Safety Monitoring Board (DSMB) of The University of Michigan 
Comprehensive Cancer Center (UMCCC) is the DSMB for this study.  This 
committee is responsible for the review and monitoring the study’s scientific 
progress, accrual rate and any serious adverse events. 
 
Each participating site is required to have its own Data and Safety Monitoring 
Committee (DSMC) for the study.  This committee will be composed of the local site 
principal investigator, site co-investigator(s), site data manager or study coordinator 
and other members of the study staff involved in the conduct of the trial.  During the 
committee’s bimonthly meeting, the principal investigator will discuss matters related 
to: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
These meetings are to be documented by the site data manager or study coordinator 
using the Protocol Specific Data and Safety Monitoring Report (DSMR), signed by 
the site principal investigator or co-investigator.  Each site is required to submit the 
completed DSMR to the Multi-Site Coordinator at the University of Michigan 
Clinical Trials Office on a quarterly basis together with other pertinent documents. 
 
Similarly, protocol deviations are to be documented using the Notice of Protocol 
Deviation Form and requires the signatures of both the sites data manager or study 
coordinator and the site principal investigator [or co-investigator]. These reports are 
to be sent to the University of Michigan Clinical Trials Office within 7 calendar days 
of awareness of the event and on a quarterly basis with the Protocol Specific Data and 
Safety Monitoring Report. 


25 
 
The Clinical Trials Office is responsible for collating all the Data and Safety 
Monitoring Reports from all the participating sites, and providing the information to 
the Data Safety Monitoring Board. 
 
20.0     Clinical Monitoring Procedures 
 
Clinical studies coordinated by The University of Michigan Comprehensive Cancer Center 
(UMCCC) must be conducted in accordance with the ethical principles that are consistent with 
Good Clinical Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Clinical Trials Office (CTO) of the 
UMCCC. Monitoring visits will be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted 
by the Clinical Trials Office. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study database 
and assembled a study reference binder.  The site’s principal investigator and his study staff should 
make every effort in attending the site initiation meeting. Study–related questions or issues 
identified during the site initiation meeting will be followed-up by the appropriate UMCCC 
personnel until they have been answered and resolved. 
 
The first annual monitoring visit should occur after the first five study participants are enrolled or 
twelve months after a study opens, whichever occurs first.  The initial annual visit is not justified 
unless there is at least one participant enrolled on a study.  At a minimum, a routine monitoring visit 
will be done at least once every 12 months, or once during the course of the study if the study 
duration is less than 12 months.  The purpose of these visits is to verify: 
 
 Adherence to the protocol 
 Completeness and accuracy of study data and samples collected 
 Proper storage, dispensing and inventory of study medication 
 Compliance with regulations 
 
Monitoring visits may be in the form of a site visit or a review of the documents at the CTO. During a 
monitoring visit to a site, access to relevant hospital and clinical records must be given by the site 
investigator to the CTO representative conducting the monitoring visit to verify consistency of data 
collected on the CRFs with the original source data.  While most patient cases will be selected from 
patients accrued since the previous monitoring visit, any patient case has the potential for review.  At 
least one or more unannounced cases will be reviewed, if the total accruals warrant selection of 
unannounced cases.  
 
The Clinical Trials Office expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a suitable 
environment will be provided for review of study-related documents. Any issues identified during 
these visits will be communicated to the site and are expected to be resolved by the site in a timely 
manner.  For review of study-related documents at the CTO, the site will be required to ship or fax 
documents to be reviewed.   


26 
 
Participating site will also undergo a site close-out upon completion, termination or cancellation of a 
study to ensure fulfillment of study obligations during the conduct of the study, and that the site 
Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without a site visit if all of the following apply: 
 
 No patient has signed the Informed Consent Form and has enrolled into the study 
 Investigational agent has not been dispensed 
 All investigational agent and materials have been returned as defined for the study or 
destroyed and accounted for properly. 
 
 
20.1 
Quality Assurance and Audits 
The Data Safety Monitoring Board can request a ‘for cause’ audit of the trial if the 
board identifies a need for a more rigorous evaluation of study-related issues. A “for 
cause” audit would be conducted by the Quality Assurance Review Committee 
(QARC) of the University of Michigan Comprehensive Cancer Center. 
 
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 site investigator must immediately inform the 
Clinical Trials Office that such a request has been made. 
 
 
 
21.0 
Statistical Considerations 
21.1 
General Description:  This is a single-arm, Phase II trial to characterize the 
clinical outcome of standard of care, cetuximab concurrent with radiation, in a special 
population (head and neck cancer patients who cannot tolerate concurrent 
chemoradiotherapy due to advanced age, poor performance status or concurrent illness), 
and to determine if biomarker response to a loading dose of cetuximab is predictive of 
that outcome. 
21.2 
Number of patients:  Fifty evaluable patients will be accrued to the trial, which 
is expected to take 36 months.  A patient will be evaluable for the primary objectives if 
he or she undergoes Research Biopsy #1 and #2 and either completes the full course of 
cetuximab+RT or has cetuximab+RT stopped for toxicity.  Unevaluable patients will be 
replaced. 
21.3 
Analysis plan 
21.3.1 Primary Objective 1:  Determine changes in tumor EGFR, pEGFR, 
downstream signaling and novel phosphoproteins following a loading 
dose of cetuximab in patients who are poor candidates for 
chemoradiation (age ≥70 years or with significant co-morbidities) and 
are therefore treated with cetuximab+radiation.  These markers will be 
assessed in tumor biopsies harvested before and after the loading dose 
of cetuximab.  The initial analysis will use descriptive and graphical 
statistics to determine if any of the markers require transformation 
prior to analysis.  Markers may be assessed on a continuous, ordinal or 


27 
dichotomous scale; markers measured on a continuous scale will be 
analyzed via general linear models (possibly after transformation), 
while ordinal and dichotomous markers will be analyzed via 
cumulative logit and logistic regression analyses, respectively.  The 
primary questions to be answered in this objective are:  is the marker 
modulated by the loading dose of cetuximab; are there baseline clinical 
or demographic variables that are related to significant variation in 
biomarker response to the loading dose of cetuximab?  For continuous 
variables, the null hypothesis that the mean value of the change 
(absolute or percent of baseline) equals zero will be tested by means of 
a single sample t-test.  The second question will be answered by means 
of analysis of variance on baseline clinical and demographic variables.  
For dichotomous markers, patients will be stratified into elevated 
versus not elevated at baseline, and Wald tests on logistic regression 
parameter estimates will be used to test the null hypothesis that the 
proportion of patients changing state from baseline is different from 
0.5, and to determine if any subset of patients defined by clinical or 
demographic factors have proportions significantly different from 0.5.  
Ordinal markers will be handled in a similar fashion. 
 
21.3.2 Primary Objective 2  Characterize clinical outcomes, including local 
recurrence, progression-free survival and overall survival in these 
patients, and correlate these clinical outcomes with the changes in 
tumor EGFR, pEGFR, downstream signaling, and novel 
phosphoproteins.  Logistic regression and proportional hazards (Cox) 
regression will be used to relate clinical out (local recurrence, 
progression-free survival or overall survival) to changes in markers 
across the loading dose.  All of the markers will be analyzed, but 
markers that are modulated by the loading dose (identified in Primary 
Objective 1) will be of particular interest. 
 
21.3.3 Primary Objective 3  Describe the toxicity, in particular 
mucositis/dysphagia, of this regimen.  Adverse events will be tabulated 
by grade (NCI CTCAE v4), category (mucositis and dysphagia are 
expected to be the most common) and relatedness to treatment (not, 
unlikely, possibly, probably or definitely).  The proportion of patients 
experiencing Grade 3 or worse adverse events at least possibly related 
to treatment will be calculated, accompanied by a 95% exact binomial 
confidence interval.  Possible baseline demographic and clinical 
predictors of such toxicity may be evaluated by means of logistic 
regression, but, due to the low expected number of such toxicities, any 
such modeling will be strictly exploratory. 
 
21.3.4 Secondary Objective 1  Conduct normal mucosa EGFR assessment 
for comparison with tumor sample.  The change in tumor EGFR level 
across treatment, relative to EGFR in normal mucosa, will be 
evaluated by means of repeated measures ANOVA.   


28 
 
21.3.5 Secondary Objective 2  Correlate HPV presence and titer with p53 
status and clinical outcome.  HPV status (±) will be added to the 
models of Primary Objective 2 to determine if +HPV patients respond 
to therapy differently than -HPV patients, but, due to the limited 
expected number of +HPV patients, such analyses will be considered 
exploratory. 
 
21.4 
Justification of Design: While radiation with concurrent cetuximab has 
become the standard of therapy in patients with locally advanced squamous cell head 
and neck carcinoma, the clinical outcome of the therapy have not been systematically 
studied.  In addition, therapy with cetuximab is expensive, and, while less toxic than 
platinum-based therapies, is not without toxicity, and a screen for patients from whom 
cetuximab would be of benefit would be desirable.  Therefore, all patients on this 
protocol are treated the same, and the primary objectives are focused on comparing 
patients who do respond to patients who do not.  Because this is the standard of care, 
and these patients have no other treatment options, there is no provision for halting 
the trial due to low efficacy or excess toxicity (although therapy can, of course, be 
stopped in individual patients if clinically warranted).  The sample size is justified in 
terms of Primary Objective 2, specifically relating change in a continuous marker to 
progression-free survival.  Monte Carlo simulation was used to simulate the analysis 
of a single biomarker related to progression-free survival.  It was assumed that 50 
patients were accrued over 36 months, that the median survival was 22 months, the 
proportional hazards regression was performed six months after the last patients was 
treated, and that the biomarker was normally distributed.  The power of the null 
hypothesis of no marker effect (tested at α=0.05) was assessed as the effect size of the 
marker (here, represented as the difference between the mean of the marker for 
patients with PFS less than the median versus the mean of the marker for patients 
with PFS greater than the median, divided by the standard deviation) was increased 
from 0 to 1.5 standard units.  The result is shown in Figure 20.1, where it is seen that 
the power to reject the null hypothesis of no effect is at least 80% if the effect size is 
1.1 standard units or greater, which would be considered a moderately large effect. 
 


29 
 
Figure 20.1  Power of proportional hazards regression for a marker that discriminates 
between patients with greater than versus less than median progression-free survival. 


30 
 
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Sheridan MT, O'Dwyer T, Seymour CB, et al. Potential indicators of radiosensitivity in 
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Akimoto T, Hunter NR, Buchmiller L, et al. Inverse relationship between epidermal growth 
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Milas L, Fan Z, Andratschke NH, et al. Epidermal growth factor receptor and tumor response 
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19. 
Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on 
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20. 
Milas L, Mason K, Hunter N, et al. In vivo enhancement of tumor radioresponse by C225 
antiepidermal growth factor receptor antibody. Clinical Cancer Research 2000;6:701-708. 
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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. 
22. 
Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 
modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the 
head and neck. Cancer Res 1999;59:1935-1940. 
23. 
Rao GS, Murray S, Ethier SP. Radiosensitization of human breast cancer cells by a novel 
ErbB family receptor tyrosine kinase inhibitor. International Journal of Radiation Oncology 
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24. 
Bonner JA, Raisch KP, Trummell HQ, et al. Enhanced apoptosis with combination 
C225/radiation treatment serves as the impetus for clinical investigation in head and neck 
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25. 
Bianco C, Bianco R, Tortora G, et al. Antitumor activity of combined treatment of human 
cancer cells with ionizing radiation and anti-epidermal growth factor receptor monoclonal 
antibody C225 plus type I protein kinase A antisense oligonucleotide. Clin Cancer Res 
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26. 
Shintani S, Li C, Mihara M, et al. Enhancement of tumor radioresponse by combined 
treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine 
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cancer. Int J Cancer 2003;107:1030-1037. 
27. 
Solomon B, Hagekyriakou J, Trivett MK, et al. EGFR blockade with ZD1839 ("Iressa") 
potentiates the antitumor effects of single and multiple fractions of ionizing radiation in 
human A431 squamous cell carcinoma. Epidermal growth factor receptor. Int J Radiat Oncol 
Biol Phys 2003;55:713-723. 
28. 
Saleh MN, Raisch KP, Stackhouse MA, et al. Combined modality therapy of A431 human 
epidermoid cancer using anti-EGFr antibody C225 and radiation. Cancer Biotherapy and 
Radiopharmaceuticals 1999;14:451-463. 
29. 
Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor 
receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle 
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30. 
Harari PM, Huang SM. Modulation of molecular targets to enhance radiation. Clin Cancer 
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31. 
Li J, Lin ML, Wiepz GJ, et al. Integrin-mediated migration of murine B82L fibroblasts is 
dependent on the expression of an intact epidermal growth factor receptor. J Biol Chem 
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32. 
Raben D, Helfrich B, Chan DC, et al. The effects of cetuximab alone and in combination 
with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 2005;11:795-805. 


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33. 
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with tumors that do not express the epidermal growth factor receptor by 
immunohistochemistry. J Clin Oncol 2005;23:1803-1810. 
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immunohistochemical expression and prognosis in a multicentre clinical trial of 93 patients 
with advanced primary ovarian epithelial cancer (GINECO group). Br J Cancer 
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35. 
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Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA, Poplin EA, Hidalgo M, 
Baselga J, Clark EA, Mauro DJ. Expression of epiregulin and amphiregulin and K-ras 
mutation status predict disease control in metastatic colorectal cancer patients treated with 
cetuximab. Journal of Clinical Oncology 2007;25:3230-3237. 
38. 
Ruiz-Godoy LM G-CC, Gonzalez NEH, Suchil BL, Perez-Cardenas E, Sanchez-Perez Y, 
Suarez-Roa ML, Meneses A. Mutational analysis of K-ras and Ras protein expression in 
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biology and treatment of cancer. J Clin Oncol 2003;21:2787-2799. 
40. 
Sok JC, Coppelli FM, Thomas SM, et al. Mutant epidermal growth factor receptor 
(EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. 
Clin Cancer Res 2006;12:5064-5073. 
41. 
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42. 
Oda Y, Nagasu T, Chait BT. Enrichment analysis of phosphorylated proteins as a tool for 
probing the phosphoproteome. Nature Biotechnology 2001;19:379-382. 
43. 
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44. 
Blagoev B, Kratchmarova I, Ong SE, et al. A proteomics strategy to elucidate functional 
protein-protein interactions applied to EGF signaling. Nature Biotechnology 2003;21:315-
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45. 
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46. 
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 23.0   Appendix 
 
Appendix A 
 
 


33 
 
 
KARNOFSKY PERFORMANCE SCALE (KPS) 
 
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 
 


34 
Appendix B 
 
 
Sample Collection and Analysis 
Both pre- and post-treatment punch-biopsy specimens (about 3x3x3 mm) of the tumor will be 
collected and immediately placed in ice-cold saline containing a cocktail of protease (Roche 
Diagnostic Co., Indianapolis, IN) and phosphatase inhibitors (Sigma, St. Louis, MO). The sample 
will be then divided into three parts:   
 
1. The first part will be fixed in formalin and will be used for the construction of a tissue 
microarray.  
2. The second part will be homogenized and total proteins will be directly extracted using 
Laemmli buffer for immunoblotting. 
3. The third part will be used for DNA and RNA extraction for assessment of HPV, p53 status 
and EGFRvIII expression. 
 
In addition, Tunnel assay will also be performed to analyze the apoptosis in all the samples under 
investigation.   
 
High-throughput immunoblotting and isolation of RNA and DNA for genetic studies: 
Tumor samples are collected and immediately stored in Allprotect Tissue Reagent from Qiagen.  
They are then divided and one portion is homogenized for protein extraction 45, 46.  A total of 200 
µg 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 1:25,000 
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, Bcl-XL and 
novel proteins for which we have either commercially available or custom-raised antibodies.  
Isolation of DNA and RNA will be carried out using DNAeasy and RNAeasy (both from Qiagen) on 
the remaining sample according to the manufacturers instructions.   
Apoptosis Determination: 
TUNEL assays will be performed using the In Situ Cell Death Detection Kit (Roche Molecular 
Diagnostics, Laval, Quebec, Canada). Slides will be evaluated by two investigators and three areas 
from each core will be identify based as -, +, and +++ based on relative staining intensity. These 
selected areas will be lifted to build a tissue micro-array for the analysis of the specific effects of 
treatment and to understand the mechanism of action of the cell death. 
 
Immunohistochemistry and Scoring of TMA:   
Antigen is retrieved from formalin-fixed tumor sections, in citrate buffer using a pressure cooker. 
Standard procedures are used for immunofluorescence. 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 


35 
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 200 cores. After construction, 4 µm sections 
will be cut, and hematoxylin and eosin staining will be performed on the initial slide to verify the 
histology. Serial 4 µm sections will be further cut and transferred to positively charged slides, these 
sections will be subjected to standard immunohistochemical staining procedures. Use of this 
established core enables the investigators to have access to over 200 commercially available 
antibodies that have been tested and validated for immunohistological use.  Any antibodies not 
previously validated will be tested on slides made from "test arrays". These are tissue microarrays 
prepared from multiple tissue sources (e.g. normal mucosa, skin, brain, lymph nodes, gut, lung, 
spleen, liver, kidney etc., plus corresponding neoplastic tissues) created by the UM Cancer Center 
Tissue Procurement Core and available to the investigators.  The stained test slides will be reviewed 
by certified pathologist 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. An example of TMA cores is shown in Figure 2. Data 
analysis will be performed by Dr. Normolle. Multiple TMA core measurements from the same 
subject will be averaged.  This average score in its continuous scale will be used in all analyses.   
 
Immunofluorescence studies:  
Immunofluorescence studies are semi-quantitative and are to be used if available antibodies do not 
perform well for quantitative immunohistochemical analysis. For this purpose high-resolution grey 
scale images are captured using a fluorescent microscope equipped with a Hamamatsu camera 
(Hamamatsu, Japan). The relative intensities of fluorescence are obtained using Wasabi software 
(Bridgewater, N.J).  
Processing of the score data and statistical analysis: 
All the intensities as obtained by Wasabi software will be entered into an excel spreadsheet. The 
spreadsheets will be then processed by using the software TMA-Deconvoluter 1.06, Cluster, and 
TreeView programs adapted for TMA analysis. The processed score data will be then analyzed with 
the SPSS for Windows statistical software package (SPSS version 11; SPSS, Chicago, IL).  
 


36 
Appendix C: Quality of Life Questionnaires 
 
 
Quality of Life Questionnaire 
 
Study #__________ 
Initials___________ 
Date of questionnaire______________ 
 
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. 
 
 
 


38 
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. 
 
VIII.   TASTE 
 
10     I can taste food normally. 
20     I can taste most foods 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:______________________________________________________________________________ 
________________________________________________________________________________________ 
 


39 
Patient Name ____________________________________   Reg No. ________________ 
Hospital ________________________________________ 
 
Date of Questionnaire _____________________________ 
 
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: 
 
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 
 


40 
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? 
_________________________________________________________________________________________________
_________________________________________________________________________________________________
_________________________________________________________________________________________________ 
 


41 
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. 
 
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 
 
 


42 
2 (continued). 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 
 
 
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) 
 
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 
 
 
 


43 
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, got to question 6 (next page) 
 
 
 
 
 
 
 
 
 
          Yes 
           No 
5A.  If yes, did your doctor declare  
you unable to work due to your head  
and neck condition or treatment? 


44 
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?