Safety and Efficacy of Radiation and Cetuximab Plus Intratumoral EGFR Antisense DNA in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma
Phase: PHASE1
Conditions: Squamous Cell Carcinoma, Head and Neck Cancer
Sponsor: The University of Texas Health Science Center at San Antonio

CTRC# 11-47 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
Official Study Title:  Safety and Efficacy Evaluation of Radiation and Cetuximab plus 
Intratumoral EGFR Antisense DNA in Patients with Locally Advanced Head and Neck Squamous 
Cell Carcinoma (CTRC# 11- 47) 
 
 
NCT number: NCT 01592721 
 
 
IRB Approval Date: 11/02/2016 
 
 
Unique Protocol ID: CTRC 11-47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CTRC# 11-47 
 
 
Protocol Changes for the Revised Protocol dated October 25, 2016 for the study: Safety and 
Efficacy Evaluation of Radiation and Cetuximab plus Intratumoral EGFR Antisense DNA 
in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma (CTRC# 11- 
47) 
 
PREVIOUSLY READ: Cover page and Section 4 (page 11) 
 
Cover Page: 
PRINCIPAL INVESTIGATOR 
Woondong Jeong, MD 
Assistant Professor of Medicine 
Cancer Therapy & Research Center 
By Regulatory Affairs at 2:56 pm, Oct 25, 2 
UT Health Science Center at San Antonio 
7979 Wurzbach Road MC8232 
Zeller Building- 6th Floor 
San Antonio, TX 78229 
E-mail jeongw@uthscsa.edu 
Phone number: 210-450-5956 
Fax number: 210-450-1686 
 
Section 4, page 11: 
For questions regarding the eligibility of subjects, Woondong Jeong, MD, should be contacted 
at (210) 450-5956. 
 
NOW READS: 
 
Cover Page: 
PRINCIPAL INVESTIGATOR 
Anand Karnad, MD 
Assistant Professor of Medicine 
Cancer Therapy & Research Center 
UT Health Science Center at San Antonio 
7979 Wurzbach Road Zeller Building- 4th Floor 
San Antonio, TX 78229 
E-mail karnad@uthscsa.edu 
Phone number: 210-450-1267 
Fax number: 210-450-0417 
 
Section 4, page 11: 
For questions regarding the eligibility of subjects, Anand Karnad, MD, should be contacted at 
(210) 450-1267. 
RATIONALE: Principal Investigator changed from Dr. Woondong Jeong to Dr. Anand Karnad 
due to the departure of Dr. Jeong from CTRC. 
 
 
 
 
 
 
Page 1 of 1 
List of changes 11-47, 10/25/16 protocol 
12-131H, Karnad, Form B, 11-02-16, AMD.doc 

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CTRC# 11-47 
 
 
Safety and Efficacy Evaluation of Radiation and Cetuximab plus Intratumoral EGFR Antisense DNA 
in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma 
 
CTRC# 11-47 
 
IND 15043 
 
 
PRINCIPAL INVESTIGATOR 
Anand Karnad, MD 
Assistant Professor of Medicine 
Cancer Therapy & Research Center 
UT Health Science Center at San Antonio 
7979 Wurzbach Road Zeller Building- 4th Floor 
San Antonio, TX 78229 
E-mail karnad@uthscsa.edu 
Phone number: 210-450-1267 
Fax number: 210-450-0417 
 
 
 
 
CO-INVESTIGATORS 
See 1572 
 
 
 
 
Cancer Therapy & Research Center at 
The UT Health Science Center at San Antonio 
Institute for Drug Development 
7979 Wurzbach Road 
San Antonio, TX 78229 
 
 
 
Version Date: October 25, 2016 
By Regulatory Affairs at 2:52 pm, Oct 25, 2016 

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TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE....................................................................................................... 1 
1.1 
Locoregionally Advanced Disease (AJCC Stages III and IV) ....................................................... 1 
1.2 
Comorbidities in Patients with Head and Neck Cancer ................................................................ 1 
1.3 
Epidermal Growth Factor Receptor (EGFR) ................................................................................. 2 
1.4 
Cetuximab .................................................................................................................................... 2 
1.5 
EGFR Antisense DNA therapy ..................................................................................................... 7 
1.6 
Phase I Trial of EGFR AS in Patients with Recurrent SCCHN ..................................................... 8 
1.7 
Study Rationale ............................................................................................................................ 8 
2. 
OBJECTIVES ........................................................................................................................................ 9 
3. 
SELECTION OF PATIENTS ................................................................................................................. 9 
3.1 
Eligibility Criteria ........................................................................................................................... 9 
3.2 
Exclusion Criteria ....................................................................................................................... 10 
4. 
PATIENT REGISTRATION ................................................................................................................. 11 
5. 
TREATMENT PLAN ............................................................................................................................ 12 
5.1 
Cetuximab Administration .......................................................................................................... 12 
5.2 
Intratumoral EGFR AS ............................................................................................................... 13 
5.3 
Radiation therapy ....................................................................................................................... 15 
6. 
ADVERSE EVENTS ........................................................................................................................... 22 
6.1 
Adverse Drug Reactions Due to Gene Therapy ......................................................................... 22 
6.2 
Reporting Adverse Events .......................................................................................................... 23 
6.3 
Data Safety and Monitoring Plan (DSMP) .................................................................................. 25 
6.4 
PI Review ................................................................................................................................... 26 
7. 
MANAGEMENT OF CETUXIMAB ADVERSE REACTIONS AND DOSE MODIFICATIONS .............. 30 
7.1 
Cetuximab Dose Modifications ................................................................................................... 30 
7.2 
Management of Infusion Reactions ............................................................................................ 30 
7.3 
Treatment of Isolated Drug Fever ............................................................................................... 31 
7.4 
Management of Pulmonary Toxicity ........................................................................................... 31 
7.5 
Management of Dermatologic Toxicity ....................................................................................... 31 
7.6 
In-Field Toxicities During Radiation: Radiation Mucositis/Dysphagia/Dermatitis ........................ 32 
7.7 
Retreatment Criteria for Cetuximab ............................................................................................ 32 
7.8 
Duration of Therapy/Withdrawal from Study ............................................................................... 32 
8. 
MEASUREMENT OF RESPONSE ..................................................................................................... 33 
8.1 
Methods of Measurement ........................................................................................................... 33 
9. 
STUDY PARAMETERS ...................................................................................................................... 34 
9.1 
Evaluations at Screening/Baseline ............................................................................................. 34 
9.2 
Evaluations During Treatment .................................................................................................... 34 
9.3 
Evaluations at Follow-Up ............................................................................................................ 35 
9.4 
Study Parameters Table ............................................................................................................. 36 
10. DRUG FORMULATION AND PROCUREMENT ................................................................................. 37 
10.1 
EGFR Antisense ......................................................................................................................... 37 
10.2 
Cetuximab (C225, ERBITUX) ..................................................................................................... 38 
11. STATISTICAL CONSIDERATIONS .................................................................................................... 41 
11.1 
Primary Endpoint ........................................................................................................................ 41 
11.2 
Secondary Clinical Endpoints ..................................................................................................... 42 
11.3 
Accrual ....................................................................................................................................... 42 
11.4 
Safety Evaluation During the Second Stage .............................................................................. 42 

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11.5 
Hypothesis Testing and Operating Characteristics for Correlative-Study Endpoints .................. 45 
11.6 
Additional Analyses .................................................................................................................... 46 
12. RECORDS TO BE KEPT .................................................................................................................... 47 
13. CORRELATIVE STUDIES .................................................................................................................. 48 
13.1 
Reverse Phase Protein Microarrays (RPPA) .............................................................................. 48 
13.2 
IHC Analysis of Tissue Microarrays ............................................................................................ 51 
14. REFERENCES ................................................................................................................................... 53 
APPENDIX I 
ECOG Performance Status ................................................................................................. A1 
APPENDIX II   Template for Reporting Adverse Events in Human Gene Transfer Trials ............................ A2 
APPENDIX III   Supplemental Efficiency and Distribution Data .................................................................... A3 

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RESEARCH STUDY ABSTRACT 
 
Background 
The Epidermal Growth Factor Receptor (EGFR) is highly expressed in SCCHN and its overexpression is 
associated with poor patient outcome. EGFR is a promising target of anticancer therapy. We have 
developed EGFR antisense DNA as a safe and potentially efficacious treatment for SCCHN as shown in a 
previous phase I study conducted at the University of Pittsburgh. Cetuximab (Erbitux or C225) is a 
chimerized EGFR monoclonal antibody that has produced positive results in a phase III trial in SCCHN 
when added to radiation therapy and was approved by the FDA for the treatment of locally advanced 
SCCHN. Radiation plus cetuximab is considered a standard treatment, especially for patients who are not 
good candidates for chemotherapy. In the current study, we plan to evaluate the addition of intratumoral 
EGFR antisense DNA (EGFR AS) to standard radiation with concurrent cetuximab. 
 
Objectives 
1. To evaluate the safety of the combination of intratumoral EGFS AS DNA with standard cetuximab and 
radiation. 
2. To evaluate the locoregional progression-free survival in selected patients with locally advanced 
SCCHN treated with intratumoral EGFR AS DNA combined with standard radiation plus cetuximab. 
3. To evaluate other efficacy parameters, including the objective response rate, distant control and 
overall progression-free survival, and overall survival. 
4. To determine the effect of EGFR antisense therapy on EGFR-related biomarkers. We will use reverse 
phase protein microarrays (RPPA) and immunohistochemical (IHC) analysis of tissue microarrays 
(TMA), on baseline and post-treatment tumor tissue, to determine the expression level and modulation 
of a panel of EGFR and EGFR-pathway related biomarkers, including (but not necessarily limited to) 
EGFR, pEGFR, Src, pMAPK, STAT3, pSTAT3, pSTAT5, pSTAT1, pAKT, p38, p21, p27, PARP, E- 
cadherin, p-ErbB3, and Ki67. 
5. To examine the transfection of the EGFR antisense gene therapy in vivo. 
 
Subject population 
We will enroll patients with SCCHN who are suitable for intratumoral injections of EGFR antisense. Please 
see section 3 for detailed eligibility criteria. 
 
Treatment plan 
EGFR AS will be administered by direct intratumoral injection using direct visualization, endoscopy, or 
imaging-guidance (ultrasound) as clinically determined (see sections 5 and 7 for detailed treatment plan 
and dose modifications). Patients will receive a total of up to 7 weekly intratumoral injections of EGFR 
antisense (or less if there is no identifiable tumor) starting 2 weeks prior to radiation (see schema on the 
next page). Patients will receive standard radiation 70 Gy/200 cGy/daily, 5 days/week, with concurrent 
cetuximab 250 mg/m2, after a loading dose of 400 mg/m2 2 weeks prior to starting radiation. 

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Stage III/IV SCCHN 
R 
E 
G 
I 
S 
T 
E 
R 
(stage IVA-C or 
recurrent in the first 
stage of the study) 
 
 
Statistical Design and Sample Size 
The study will be conducted in two-stages. In the first stage, 11 patients with stage IVA-C or recurrent 
disease will be evaluated for safety. If the regimen is deemed safe, a total of 31 patients with stage III or 
IVA-B, previously untreated SCCHN will be enrolled in the second stage of the study (see section 11). 
 
STUDY SCHEMA 
 
 
 
 
 
Radiation once daily, 200 cGy/day, 5 days/week x 7 weeks, to 70 Gy 
 
 
Cetuximab 400 mg/m2 IV day, loading dose 2 weeks prior to starting RT 
Cetuximab 250 mg/m2 IV weekly, 1 week prior to and during radiation (until radiation completion) 
 
Intratumoral EGFR AS injections weekly until no identifiable tumor or to a maximum of 7 weeks, 
starting 2 weeks prior to radiation, after the initiation of cetuximab. The same lesion (primary tumor or 
lymph node), which will be the dominant and more accessible tumor, will be injected during treatment 
with EGFR AS. 
 
Tumor biopsies will be performed prior and after 2 weeks of cetuximab plus EGFR AS (prior to starting 
radiation). 
1 2 3 4 5 6 7 

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1. 
BACKGROUND AND RATIONALE 
 
Approximately 40,000 new cases of head and neck cancer are diagnosed annually in the United States.1 
Of these patients, two-thirds present with locoregionally advanced disease (AJCC stage III or IV) and one- 
third with early stage disease (AJCC stage I or II). At presentation 10% of patients may be found to have 
involvement of distant organs, most commonly the lung. In addition, 20% of patients will develop clinically 
detected distant metastases over the course of their disease. In autopsy series up to 50% of patients with 
head and neck cancer are found to have metastases.2,3 Approximately 90% of all head and neck 
malignancies are squamous cell carcinomas. 
 
1.1 
Locoregionally Advanced Disease (AJCC Stages III and IV) 
 
Systemic agents, such as traditional chemotherapy and more recently cetuximab, an EGFR 
inhibitor, have been incorporated into the standard therapy of locally advanced HNSCC. For 
certain primary sites, such as oropharynx, nasopharynx, and larynx, nonsurgical management with 
radiation plus systemic therapy is favored because it leads to good survival results and potentially 
better function outcomes and organ preservation. For patients with resectable locally advanced 
head and neck cancer, surgery and postoperative radiation plus cisplatin is now considered 
standard therapy. 
 
A meta-analysis that included 63 randomized studies conducted between 1965 and 1993, 
demonstrated an absolute survival benefit of 8% at 5 years with concomitant chemotherapy and 
radiotherapy versus radiation therapy alone.4 More recently, multiple randomized phase III trials 
have conclusively demonstrated that concurrent chemoradiotherapy is superior to radiation  
therapy alone in locally advanced head and neck cancer.5-10 The above trials predominantly 
enrolled patients with unresectable head and neck cancer, whereas three of these trials were site- 
specific.6,8,10 Three randomized trials used combined chemotherapy with platinum and 5-FU along 
with conventional or hyperfractionated radiotherapy.5-7and three others used cisplatin with 
conventional radiation.8-10 Most of these studies favored concomitant chemoradiotherapy with an 
approximately 20% gain in survival at three to five years (approximately 30% versus 50%), 
whereas the study by Forastiere et al showed that concomitant chemoradiotherapy with cisplatin in 
resectable laryngeal cancer is superior in terms of laryngeal preservation.10 Cetuximab has been 
added to radiation in a large randomized study.11 
 
1.2 
Comorbidities in Patients with Head and Neck Cancer 
 
Due to their frequent history of exposure to tobacco and alcohol patients with head and neck 
cancer are in high risk for other co-morbidities associated with tobacco and alcohol, such as 
coronary artery disease, chronic obstructive pulmonary disease, and liver disease.12,13 These 
comorbidities are significantly increased in the elderly.14 In addition, patients with head and neck 
cancer are at high risk for the development of second primary tumors, synchronous or 
metachronous, that may involve the head and neck region as well as other organs, predominantly 
the lung.15,16 A significant number of patients are ineligible for clinical trials due to poor 
performance status or comorbidities. The experience with chemotherapy and radiotherapy in these 
patients as well as the elderly is limited. 

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1.3 
Epidermal Growth Factor Receptor (EGFR) 
 
The epidermal growth factor receptor (EGFR) is a member of the erb B receptor tyrosine kinase 
family that includes erb B-2, erb B-3, and erb B-4.17 It consists of an extracellular ligand-binding 
domain, a transmembrane region that anchors the receptor to the plasma membrane, and a 
cytoplasmic region containing a tyrosine kinase domain. Among the known natural ligands of 
EGFR include epidermal growth factor (EGF) and transforming growth factor (TGF- ) which both 
activate the receptor by binding to the extracellular domain and inducing the formation of receptor 
homodimers or heterodimers, followed by internalization of the receptor/ligand complex and auto- 
phosphorylation. It is now accepted that the EGFR signal transduction network plays an important 
role in multiple tumorigenic processes, including cell cycle progression, angiogenesis, and 
metastasis, as well as protection from apoptosis.17,18 In this signal network, erb B-2 is the major 
partner of EGFR because activated heterodimer complexes containing erb B-2 are more stable at 
the cell surface than complexes containing other EGFR family members.19,20 In addition erb B-2 
can decrease the rate of ligand dissociation from the cognate receptor EGFR.21 
 
1.4 
Cetuximab 
 
Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively 
inhibits the binding of epidermal growth factor and other ligands, such as transforming growth 
factor–alpha.22 Binding of cetuximab to the EGFR blocks phosphorylation and activation of 
receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and 
decreased matrix metalloproteinase and vascular endothelial growth factor production. The EGFR 
is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. 
 
Human Pharmacokinetics 
 
Cetuximab administered as monotherapy or in combination with concomitant 
chemotherapy or radiotherapy exhibits nonlinear pharmacokinetics.22 The area under the 
concentration time curve (AUC) increased in a greater than dose proportional manner as 
the dose increased from 20 to 400 mg/m2. Cetuximab clearance (CL) decreased from 0.08 
to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses >200 mg/m2, it 
appeared to plateau. The volume of distribution (Vd) for cetuximab appeared to be 
independent of dose and approximated the vascular space of 2-3 L/m2. 
 
Following a 2-hour infusion of 400 mg/m2 of cetuximab, the maximum mean serum 
concentration (Cmax) was 184 µg/mL (range: 92-327 µg/mL) and the mean elimination 
half-life was 97 hours (range 41-213 hours). A 1-hour infusion of 250 mg/m2 produced a 
mean Cmax of 140 µg/mL (range 120-170 µg/mL). Following the recommended dose 
regimen (400 mg/m2 initial dose/250 mg/m2 weekly dose), cetuximab concentrations 
reached steady-state levels by the third weekly infusion with mean peak and trough 
concentrations across studies ranging from 168 to 235 and 41 to 85 µg/mL, respectively. 
The mean half-life was 114 hours (range 75-188 hours). 

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Clinical Studies of Cetuximab in Head and Neck Cancer 
 
The addition of cetuximab to radiation produced promising results in a phase I trial in 
patients with locally advanced head and neck cancer.23 Sixteen patients were treated with 
radiation therapy plus cetuximab. Cetuximab was delivered as a loading dose of 100 to 
500 mg/m2, followed by weekly infusions of 100 to 250 mg/m2 for 7 to 8 weeks. There was 
one grade 4 allergic reaction. Most acute adverse effects were associated with radiation 
(xerostomia, mucositis, and local skin toxicity). All patients achieved an objective response 
(13 patients had a complete response). Based on these promising results, a phase III trial 
of radiation with or without cetuximab in stage III/IV head and neck cancer was conducted 
and recently reported results. The addition of cetuximab resulted in improved locoregional 
control and survival whereas the rate of mucositis was comparable between arms (see 
more details below).24 Based on the results of this study, cetuximab was approved by the 
FDA for the treatment of locally advanced SCCHN in combination with radiation and as 
monotherapy for patients with SCCHN who failed cisplatin-based chemotherapy. 
 
The efficacy and safety of cetuximab were studied in combination with radiation therapy in 
a randomized, controlled trial of 424 patients with locally or regionally advanced squamous 
cell carcinoma of the head and neck versus radiation alone. In a multicenter controlled 
clinical trial, 424 patients with Stage III/IV SCC of the oropharynx, hypopharynx, or larynx 
with no prior therapy were randomized 1:1 to receive cetuximab plus radiation therapy 
(211 patients) or radiation therapy alone (213 patients). Stratification factors were 
Karnofsky Performance Status (60-80 versus 90-100), nodal stage (N0 versus N+), tumor 
stage (T1-3 versus T4 using American Joint Committee on Cancer 1998 staging criteria), 
and radiation therapy fractionation (concomitant boost versus once-daily versus twice 
daily). Radiation therapy was administered for 6-7 weeks as once daily, twice daily, or 
concomitant boost. The planned radiation therapy regimen was chosen by the investigator 
prior to enrollment. For patients with ≥N1 neck disease, a post-radiation therapy neck 
dissection was recommended. Starting 1 week before radiation, cetuximab was 
administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly for the duration of 
radiation therapy (6-7 weeks). All cetuximab-treated patients received a 20 mg test dose 
on Day 1. Cetuximab was administered 1 hour prior to radiation therapy, beginning week 
2. Of the 424 randomized patients, 80% were male and 83% were Caucasian. The median 
age was 57 years (range 34-83). There were 258 patients enrolled in US sites (61%) and 
166 patients (39%) in non-US sites. Ninety percent of patients had baseline Karnofsky 
Performance Status 80% or greater; 60% had oropharyngeal, 25% laryngeal, and 15% 
hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. The patient 
characteristics were similar across the study arms. Fifty-six percent of the patients 
received radiation therapy with concomitant boost, 26% received once-daily regimen, and 
18% twice-daily regimen. 
 
The primary endpoint of this phase III randomized trial was locoregional control and the 
sample size was adequate to show a 13% improvement in 1-year locoregional control 
(from 44% to 57%). Study results were remarkable and demonstrated an overwhelming 
superiority of the combined modality arm versus the radiation alone arm: locoregional 
control rate at 2 years was 50% versus 41% (HR 0.68, p=0.005); progression-free survival 
at 2 years was 46% vs. 37% (HR 0.70, p=0.006); overall survival at 3 years was 55% vs. 

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45% and the median survival 49 vs. 29 months (HR 0.74, p=0.03). The survival advantage 
achieved with the addition of cetuximab to radiation is comparable with the one achieved 
with the addition of chemotherapy to radiation. In a meta-analysis, the addition of 
concurrent chemotherapy to radiotherapy for the treatment of locally advanced SCCHN 
was shown to result in an 8% survival benefit at 5 years.4 Similar to the study of Bonner et 
al. in most randomized studies that compared concurrent chemoradiotherapy to 
radiotherapy alone, the survival benefit seemed to have derived from an improvement in 
locoregional control.25  Another important observation was that acute in-field toxicities, 
such as stomatitis and dermatitis, that are exacerbated when chemotherapy is added to 
radiation and are the most dreadful toxicities of combined modality therapy, were 
comparable between the two arms. Dermatologic toxicities, such as acneiform rash and 
pruritus, and infusional reactions were predominantly seen, as expected, in the cetuximab 
arm. Late toxicities were also comparable between the two arms. 
 
Table 1 Clinical Efficacy of Radiation+Cetuximab in Locoregionally Advanced SCCHN 
 
Cetuximab + 
Radiation 
(n = 211) 
Radiation Alone 
(n = 213) 
Hazard Ratio 
(95% Confidence 
Interval) 
Stratified 
Log-rank 
p-value 
Locoregional Control 
Median Duration 
24.4 mo 
14.0 mo 
0.68 (0.52-0.89) 
0.005 
1-year 
63% 
55% 
2-year 
50% 
41% 
3-year 
47% 
34% 
Overall Survival 
Median Duration 
49.0 mo 
29.3 mo 
0.74 (0.57-0.97) 
0.03 
2-year 
62% 
55% 
3-year 
55% 
45% 
 
Single-Arm Trial in SCCHN 
 
Cetuximab alone was studied in a single-arm, multicenter clinical trial in 103 patients with 
recurrent or metastatic SCCHN with documented progression within 30 days after 2-6 
cycles of a platinum-based chemotherapy. Patients received a 20 mg test dose of 
cetuximab on Day 1, followed by a 400 mg/m2 initial dose, and 250 mg/m2 weekly until 
disease progression or unacceptable toxicity. Upon progression, patients were given the 
option of receiving cetuximab plus the platinum regimen that they failed prior to  
enrollment. Tumor response and progression were assessed by an Independent 
Radiographic Review Committee (IRC). The median age was 57 years (range 23-77), 82% 
were male, 100% Caucasian, and 62% had a Karnofsky Performance Status of 80% or 
higher. The objective response rate on the monotherapy phase was 13% (95% confidence 
interval (7%-21%). Median duration of response was 5.8 months (range 1.2-5.8 months). 
Since expression of EGFR has been detected in nearly all patients with head and neck 
cancer, patients enrolled in the head and neck cancer clinical studies were not required to 
have immunohistochemical evidence of EGFR expression prior to study entry. 

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Safety of Cetuximab in Clinical Trials in Patients with Head and Neck Cancer 
 
Except where indicated, the data described below reflect exposure to cetuximab in 208 
patients with locally or regionally advanced SCCHN who received cetuximab in 
combination with radiation. Cetuximab was administered as monotherapy in 103 patients 
with recurrent or metastatic SCCHN. Of the 103 patients receiving cetuximab 
monotherapy, 53 continued to a second phase with the combination of cetuximab plus 
chemotherapy. Patients receiving cetuximab plus radiation therapy received a median of 8 
doses (range 1-11 infusions). The population had a median age of 56; 81% were male and 
84% Caucasian. Patients receiving cetuximab monotherapy received a median of 11 
doses (range 1-45 infusions). The population had a median age of 57; 82% were male and 
100% Caucasian. The most serious adverse reactions associated with cetuximab in 
combination with radiation therapy in patients with head and neck cancer were: 
 
• 
Infusion reaction (3%) 
• 
Cardiopulmonary arrest (2%) 
• 
Dermatologic toxicity (2.5%) 
• 
Mucositis (6%) 
• 
Radiation dermatitis (3%) 
• 
Confusion (2%) 
• 
Diarrhea (2%) 
 
Fourteen (7%) patients receiving cetuximab plus radiation therapy and 5 (5%) patients 
receiving cetuximab monotherapy discontinued treatment primarily because of adverse 
events. 
 
The most common adverse events seen in 208 patients receiving cetuximab in 
combination with radiation therapy were acneform rash (87%), mucositis (86%), radiation 
dermatitis (86%), weight loss (84%), xerostomia (72%), dysphagia (65%), asthenia (56%), 
nausea (49%), constipation (35%), and vomiting (29%). 
 
The most common adverse events seen in 103 patients receiving cetuximab monotherapy 
were acneform rash (76%), asthenia (45%), pain (28%), fever (27%), and weight loss 
(27%). 
 
The data in the table below are based on the experience of 208 patients with 
locoregionally advanced SCCHN treated with cetuximab plus radiation therapy compared 
to 212 patients treated with radiation therapy alone.26 

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Table 2 Incidence of Selected Adverse Events (10%) in Patients with Locoregionally Advanced 
SCCHN 
 
Body System 
Preferred Term 
Cetuximab plus Radiation 
(n=208) 
Radiation Therapy Alone 
(n=212) 
Grades 1 – 4 
Grades 3 and 4 
Grades 1 – 4 
Grades 3 and 4 
% of Patients 
Body as a Whole 
Asthenia/Malaise 
56 
4 
48 
5 
Fever1 
29 
1 
13 
<1 
Headache 
19 
<1 
8 
<1 
Infusion Reaction2 
15 
3 
2 
0 
Infection 
13 
1 
9 
1 
Chills1 
16 
0 
5 
0 
Digestive 
Mucositis/Stomatitis 
93 
56 
94 
52 
Xerostomia 
72 
5 
71 
3 
Dysphagia 
65 
26 
63 
30 
Nausea 
49 
2 
37 
2 
Constipation 
35 
5 
30 
5 
Vomiting 
29 
2 
23 
4 
Anorexia 
27 
2 
23 
2 
Diarrhea 
19 
2 
13 
1 
Dyspepsia 
14 
0 
9 
1 
Metabolic/Nutritional 
Weight Loss 
84 
11 
72 
7 
Dehydration 
25 
6 
19 
8 
Respiratory 
Pharyngitis 
26 
3 
19 
4 
Cough Increased 
20 
<1 
19 
0 
Skin/Appendages 
Acneform Rash3 
87 
17 
10 
1 
Radiation Dermatitis 
86 
23 
90 
18 
Application Site Reaction 
18 
0 
12 
1 
Pruritus 
16 
0 
4 
0 
1 Includes cases also reported as infusion reactions. 
2 Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or 
“anaphylactoid reaction” or any event on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, 
“fever”, “chills”, “chills and fever” or “dyspnia”. 
3 Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin” or 
“exfoliative dermatitis”. 
 
Late Radiation Toxicity 
 
The overall incidence of late radiation toxicities (any grade) was higher in cetuximab in 
combination with radiation therapy compared with radiation therapy alone. The following 
sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), 
subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), 
esophagus (44% versus 35%), skin (42% versus 33%), brain (11% versus 9%), lung (11% 
versus 8%), spinal cord (4% versus 3%), and bone (4% versus 5%). The incidence of 

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Grade 3 or 4 late radiation toxicities were generally similar between the radiation therapy 
alone and the cetuximab plus radiation treatment groups. 
 
 
1.5 
EGFR Antisense DNA therapy 
 
We have previously demonstrated up-regulation of EGFR (mRNA and protein) in tumors and 
normal mucosa several centimeters away from the tumor, compared with expression levels in 
normal mucosa from patients without cancer.27,28 We also detected increased EGFR levels in 
premalignant lesions (that correlate with the degree of dysplasia) which progress to invasive 
cancer suggesting that up-regulation of EGFR occurs early in squamous epithelial 
carcinogenesis.29 Based on these results, we designed experiments to down-modulate receptor 
expression and examined the effects of such modulation strategies on proliferation and target 
protein expression. EGFR was targeted using 3 different approaches including down-modulation of 
EGFR mRNA using antisense oligonucleotides, and blocking the function of the mature protein at 
two sites, the ligand-binding domain and the kinase domain. All 3 strategies resulted in growth 
inhibition of SCCHN cells but had no effect on the proliferation rate of corresponding normal cells  
in vitro.30 
 
A novel approach for EGFR inhibition is the use of antisense oligonucleotides that can be injected 
intratumorally and inhibit EGFR and its signaling pathway. In the past several years, we have 
investigated successfully the down-modulation of EGFR mRNA using antisense oligonucleotides.30 
To extend these initial observations to an in vivo model, we generated an EGFR antisense 
expression construct designed for intratumoral injection. The criteria for selecting a gene transfer 
vector were to: 1) transfect a high percentage of tumor cells in vivo; 2) generate high expression 
levels of EGFR antisense RNA in each cell; and 3) demonstrate an anti-tumor response following 
treatment. To accomplish this, we selected the U6 small nuclear RNA promoter, which has been 
engineered to express short antisense RNA sequences under the control of RNA polymerase III.31 
U6 is a small, stable RNA that exists as an abundant nuclear ribonucleoprotein (U6 snRNP) in all 
human cells where it plays central roles in both spliceosome assembly and catalysis in nuclear 
pre-mRNA splicing. Compared with other RNA polymerase III-transcribed genes, such as tRNA, 
the U6 gene has no control region located within the sequence encoding the structural component 
of the RNA. Thus, nearly all of the structural U6 core can be replaced with any other sequence 
without affecting transcript production.32 
 
We cloned an oligonucleotide (39 bp) targeting the ATG start site of human EGFR in the antisense 
orientation under the control of the U6 promoter into the pNGVL1 plasmid backbone containing a 
kanamycin resistance marker. The pNGV1 plasmid had been previously approved for use in 
clinical trials. The pNGVL1 backbone was modified to eliminate the residual CMV promoter 
sequences to avoid potential interference with the U6 promoter. 
 
Using a murine xenograft head and neck squamous cell carcinoma model system, repeated 
intratumoral administration of the antisense (but not the corresponding sense) EGFR gene therapy 
construct (25 µg/3x week for a total of approximately 8 injections), significantly inhibited the growth 
of established tumors (approximately 2 mm in diameter). The inhibition of tumor growth was 
sustained up to several weeks following cessation of therapy. Examination of the treated tumor 
nodules revealed diminished expression of the EGFR protein. Although the mechanism of 

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decreased tumor growth is not completely understood, increased apoptosis rates were detected in 
the EGFR antisense-treated tumors compared with tumors treated with the corresponding sense 
construct.33 Although the preclinical studies were originally performed using cationic liposomes, 
recent studies have suggested that liposomes only modestly augment gene transfer in vivo and 
may contribute to toxicity. We subsequently repeated our experiments in tumor-bearing animals 
and found that anti-tumor effects were observed without the use of liposomes. Therefore, we used 
injection of DNA alone (naked DNA) in our phase I clinical study. 
 
1.6 
Phase I Trial of EGFR AS in Patients with Recurrent SCCHN 
 
Previous studies have reported negligible toxicity following intratumoral administration of DNA.26,34 
Our preclinical studies suggest that 60 µg of antisense DNA decreases tumor progression.33 
Therefore, we implemented a rapid dose escalation (100% increment increase between tiers) in 
the phase I clinical study of EGFR AS. Eligible patients had recurrent SCCHN and have previously 
failed other treatments. Patients received weekly intratumoral injections for 4 weeks. The dose of 
EGFR AS was escalated in successive cohorts of patients (classic “3+3” design) as follows: level 1 
- 60 µg/60 µL, level 2 - 120 µg/120 µL, level 3 - 240 µg/240 µL, level 4 - 480 µg/480 µL, level 5 - 
960 µg/960 µL, and level 6 - 1.92 mg/1.92 mL. A total of 17 patients were enrolled. We reported 
results at the ASCO 2007 meeting.35 No grade 3 or 4 or any dose limiting toxicities were observed 
at any dose level. A dose of up to 1.92 mg/1.92 mL of EGFR AS was well tolerated. There were 
four adverse events related to EGFR AS in this trial. All events were grade 1 and included two 
episodes of injection site pain/swelling, one episode of edema and one episode of lethargy. No 
dose limiting toxicities were observed at any dose level. One patient developed dehydration that 
was thought to be unrelated to the drug injection. Five of 17 patients (29%) achieved an objective 
response: 2 patients had a complete response and 3 patients had a partial response. In order to 
demonstrate transfection of the EGFR AS gene into the tumors, we performed polymerase chain 
reaction (PCR) analysis on DNA extracted from pre- and post-treatment patient tissue specimens. 
We were able to detect EGFR AS in the tissue specimens taken two weeks after the last EGFR AS 
injection in both non-responders and responders. Moreover, we observed that STAT3 and EGFR 
expression levels at baseline correlated with efficacy outcomes. The final manuscript is in 
preparation. 
 
1.7 
Study Rationale 
 
The incorporation of novel targeted therapies to radiation therapy is of particular interest in head 
and neck cancer, and may improve efficacy without significantly increasing toxicity. Cetuximab is 
an EGFR inhibitor that is a potent radiosensitizer and has increased the survival of patients with 
stage III/IV head and neck cancer when added to radiation therapy. We would like to enhance the 
standard therapy of locally advanced SCCHN by incorporating intratumoral EGFR AS injections, a 
novel and promising locoregional treatment, to standard radiation and cetuximab. We hypothesize 
that the addition of a second EGFR-targeted agent that inhibits EGFR at the intracellular level will 
improve the antitumor effect of standard radiation and cetuximab. Preliminary preclinical data from 
our group support this hypothesis. Based on our data, intratumoral EGFR AS therapy has shown 
promise as single treatment modality. The addition of EGFR AS to standard radiation and 
cetuximab may further increase treatment efficacy and is of major interest. The goal of this study is 
to evaluate the safety, efficacy, and secondarily, the biologic effects in patients with locally 
advanced SCCHN of an antisense gene targeting the EGFR in combination with standard therapy 

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with radiation and cetuximab, a systemic EGFR inhibitor. 
 
 
2. 
OBJECTIVES 
 
• 
To evaluate the safety of the combination of intratumoral EGFR AS DNA with standard cetuximab 
and radiation. 
• 
To evaluate the locoregional control (primary endpoint), in patients with locally advanced SCCHN 
treated with intratumoral EGFR antisense DNA combined with standard radiation plus cetuximab. 
• 
To evaluate the toxicities associated with the above treatment. 
• 
To evaluate other efficacy parameters, including the objective response rate, distant control and 
overall progression-free survival, and overall survival. 
• 
To determine the effect of EGFR antisense therapy on EGFR and EGFR-related biomarkers. We 
will use reverse phase protein microarrays (RPPA) and immunohistochemical (IHC) analysis of 
tissue microarrays (TMA), on baseline and post-treatment tumor tissue, to determine the 
expression level and modulation of a panel of EGFR and EGFR-pathway related biomarkers, 
including (but not necessarily limited to) EGFR, pEGFR, Src, pMAPK, STAT3, pSTAT3, pSTAT5, 
pSTAT1, pAKT, p38, p21, p27, PARP, E-cadherin, p-ErbB3, and Ki67. We hypothesize that the 
baseline expression or modulation of one or more EGFR signaling proteins will correlate with 
objective response rate and locoregional control after combined modality treatment. 
• 
To examine the transfection of the EGFR antisense gene therapy in vivo. 
 
3. 
SELECTION OF PATIENTS 
 
3.1 
Eligibility Criteria 
 
• 
First stage 
Patients with AJCC 7th edition stage IVA-IVC or recurrent or metastatic head and neck cancer will 
be eligible. Patients with M1 disease must have asymptomatic or low volume distant metastasis 
and require palliation for local and regional disease. 
• Second stage (phase II part) 
Patients with AJCC 7th edition stage III-IVB (T1-T4, N1-3M0) head and neck cancer, except WHO 
type II and III nasopharyngeal cancer, including unknown primary tumors. 
• 
Histologically or cytologically confirmed diagnosis of squamous cell carcinoma or variants or poorly 
differentiated carcinoma. 
• 
Unidimensionally measurable disease (RECIST criteria). 
• 
ECOG Performance Status of 0-2 
 
• 
In the second stage of the study, therapy will be administered with a curative intent and patients 
should not have recurrent disease or distant metastasis. 
• 
Primary tumor and/or lymphadenopathy should be technically suitable for intratumoral injections. 
The Otolaryngologist specialist on the head and neck team will determine this feasibility. 

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• 
Participating patients should agree to undergo a tumor biopsy at baseline as well as approximately 
2 weeks later as specified in study schema. 
• 
Prior treatment 
• 
First stage: any prior treatment, except prior therapy, which specifically and directly targets 
the EGFR pathway, administered within the last 6 months. No prior radiation therapy to  
the head and neck. 
• 
Second stage: no prior chemotherapy, biologic/molecular targeted therapy (including any 
prior therapy which specifically and directly targets the EGFR pathway), or radiotherapy for 
head and neck cancer. 
• 
Prior surgical therapy will consist only of incisional or excisional biopsy, including tonsillectomy, 
and organ sparing procedures, including neck dissection. Any non-biopsy surgical procedure for 
head and neck cancer must have taken place at least one month before initiating protocol 
treatment, at the treating physician’s discretion. 
• 
Patients must have organ and marrow function as defined below: 
 
Absolute neutrophil count 
1,000/µL 
Platelets 
75,000/µL 
Hemoglobin 
10 g/dL 
Total bilirubin 
<2 x upper normal institutional limits 
Creatinine clearance 
> 20 mL/min 
 
• 
Age of 18 years. 
• 
Because radiation therapy is known to be teratogenic and EFGR inhibitors may have teratogenic 
potential, women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control) prior to study entry and for the duration of study 
participation, and for 3 months after completing study treatment. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should inform her treating 
physician immediately. 
• 
Informed consent must be obtained from all patients prior to beginning therapy. Patients should 
have the ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
• 
Severe renal insufficiency (creatinine clearance < 20 mL/min) 
• 
Treatment with anticoagulants, except when used to maintain the patency of a central venous line, 
or INR >1.5, or PTT ratio >1.5. 
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or 
psychiatric illness/social situations that would limit compliance with study requirements. Significant 
history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, 
uncontrolled congestive heart failure. 
• 
Patients may not be receiving any other investigational agents. 
• 
No history of prior malignancy, with the exception of curatively treated squamous cell or basal 
carcinoma of the skin or in situ cervical cancer, DCIS or LCIS of the breast, localized early stage 

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prostate cancer, or malignancy that has been treated with a curative intent with a 3-year disease- 
free survival. 
• 
Pregnant women are excluded from this study because cetuximab, EGFR AS, and radiation have 
the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk 
for adverse events in nursing infants secondary to treatment of the mother with cetuximab and 
EGFR AS, breastfeeding should be discontinued if the mother is treated with cetuximab. The 
effects of cetuximab and EGFR AS on the developing human fetus at the recommended 
therapeutic dose are unknown. For this reason women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control) prior to study 
entry and for the duration of study participation. Should a woman become pregnant or suspect she 
is pregnant while in this study, she should inform her treating physician immediately. 
• 
HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study 
because of possible drug interactions with cetuximab. Appropriate studies will be undertaken in 
patients receiving combination anti-retroviral therapy when indicated. HIV status of the patient will 
be obtained from the patient’s history via discussion with the investigator. HIV testing is not 
required. 
• 
Prior severe infusion reaction to a monoclonal antibody. 
• 
Patients who are not informed of and are not willing to comply with the investigational nature of the 
study and have not signed a written informed consent in accordance with institutional and good 
clinical practice guidelines. 
• 
Phase 2 ONLY (second stage) – Subjects with M1 disease will be excluded. 
 
4. 
PATIENT REGISTRATION 
 
Patients must not start protocol treatment prior to registration. Treatment should start within five 
working days after registration. Subjects can be enrolled after eligibility criteria are met by calling 
the site research nurse or study liaison: 
 
Ofelia Romero, RN 
Clinical Research Nurse III 
Department of Clinical Investigations 
Institute for Drug Development 
Cancer Therapy and Research Center at UTHSCSA 
Mail Code 8229 
7979 Wurzbach Road, Suite Z413 
San Antonio, Texas 78229 
Office: (210) 450-1810 
Fax: (210) 614-4418 
Email: romeroo@uthscsa.edu 
 
For questions regarding the eligibility of subjects, Anand Karnad, MD, should be contacted at (210) 450- 
1267. 
 
Registration will require the following information: 

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1) your name, telephone and pager number; 
2) protocol name and number; 
3) date treatment begins; 
4) subject name; 
5) date of birth; 
6) subject hospital medical record number; 
7) primary study physician; 
8) primary treatment institution; 
9) confirmation of eligibility; 
10) copies of the informed consent signature page; and 
11) verification that the informed consent was signed. 
 
5. 
TREATMENT PLAN 
 
• 
Loading dose of cetuximab 400 mg/m2 IV over 120 minutes 2 weeks prior to starting radiation. 
• 
Cetuximab 250 mg/m2 IV over 60 minutes weekly, the week prior and during days of radiation, until 
radiation is completed (diphenhydramine hydrochloride [Benadryl] premedication 30-60 minutes 
prior to cetuximab infusion as required, see 5.1). 
• 
Intratumoral EGFR AS injections weekly x 7 weeks (or less if there is no identifiable tumor), 
starting 2 weeks prior to radiation and after cetuximab is administered. Subsequent EGFR AS 
injections can be given before or after cetuximab is administered. Injections will be in the primary 
and/or lymph nodes. One site will be injected per weekly session. The intratumoral EGFR AS 
injections should occur during the same calendar day due to CTRC scheduling. If it is necessary 
the antisense injection can be scheduled within 1 business day of the original schedule date and 
then resume the original schedule. 
• 
EGFR AS will be administered by direct intratumoral injection using direct visualization, 
endoscopy, or imaging-guidance (ultrasound) as clinically determined. The same lesion (primary 
tumor or lymph node) will be injected during treatment. 
• 
Radiation therapy 70 Gy, 200 cGy/daily, 5 days/week (see 5.3). Radiation will start on a Monday, 
Tuesday, or Wednesday. Cetuximab will be given prior to radiation. 
• 
A tumor biopsy will be performed prior to starting cetuximab and 2 weeks later but prior to starting 
radiation. 
• 
In the first stage, after three (3) subjects are enrolled and have received all EGFR AS injections, 
there will be a two-week waiting period to assess adverse events before enrolling additional 
subjects. After the two-week period, additional subjects may be enrolled. 
 
5.1 
Cetuximab Administration 
 
In an effort to prevent an infusion reaction, all patients should be premedicated with 
diphenhydramine hydrochloride [Benadryl] 50 mg (or an equivalent antihistamine) by IV given 30- 
60 minutes prior to the first dose of cetuximab. Premedication may be administered prior to 
subsequent doses, but at the Investigator’s discretion, the dose of diphenhydramine (or a similar 
agent) may be reduced. 

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The initial dose of cetuximab is 400 mg/m2 intravenously administered over 120 minutes, followed 
by weekly infusions at 250 mg/m2 IV over 60 minutes. The infusion rate of cetuximab must never 
exceed 5 mL/min. Patients must be continuously observed during the infusion for signs of 
anaphylaxis. 
 
Patients will be closely monitored for treatment-related adverse events, especially infusion 
reactions (see management of cetuximab adverse events) during the infusion and the post- 
infusion observation hour, if necessary. For the initial cetuximab infusion, vital signs should be 
monitored pre-infusion, ½ hour into the infusion, and at the end of the infusion, and, if needed, 1 
hour post-infusion. For subsequent infusions, vital signs should be taken pre- and post-infusion; 
however, it is recommended that the patient be observed for 1 hour post infusion. Patients who 
have developed an infusion reaction in the past will be observed for >1 hour, if necessary. 
 
 
For the duration that patients are on study therapy, adverse event monitoring will 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. 
 
5.2 
Intratumoral EGFR AS 
Injections 
The treatment will be administered in the outpatient setting. Pretreatment tumor biopsies 
will be performed in the operating room at the time of diagnosis or in the outpatient setting 
under local anesthesia. Intralesional (primary tumor or cervical metastases) EGFR AS will 
be administered weekly until there is no identifiable tumor or a maximum of 7 weeks. 
 
• 
EGFR AS will be administered by direct intratumoral injection using direct 
visualization, endoscopy, or imaging-guidance (ultrasound) as clinically determined. 
Injection sites may be treated before injection with EMLA cream (or equivalent) to 
minimize discomfort. The primary tumor or cervical metastases will be injected with a 
single dose of DNA and monitored. The tumor will be inoculated with a 25-gauge 
needle in an attempt to maximize the distribution of the gene transfer formulation in 
the injected lesion. Specifically, the needle will be introduced into the center of the 
tumor and the injection will be performed slowly as the needle is withdrawn from the 
tumor. Each dose will be given 7 days (+/- 2 days) after the previous dose. The same 
lesion (primary tumor or lymph node), which will be the dominant and most accessible, 
will be injected during treatment in each patient. In the first stage, after three (3) 
subjects are enrolled and have received all EGFR AS injections, there will be a two- 
week waiting period to assess adverse events. After the two-week period, additional 
subjects may be enrolled. 
 
To determine the in vivo efficacy of the antisense gene and the consequences of EGFR 
antisense gene therapy, we will obtain tumor biopsies under local anesthesia in the 

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outpatient setting, at the time or after the second dose of EGFR AS and after the second 
cetuximab dose, in addition to the pretreatment biopsy. Therefore, the tumor will be 
biopsied 2 times. When possible, we will biopsy adjacent areas of the tumor at each time 
point to determine heterogeneity of transfection and EGFR expression. When possible, 
additional biopsies will be obtained from non-injected areas that are more than 2 cm apart 
from an injection site. A comparison of biopsies from injected and non-injected lesions will 
provide the opportunity to assess the added effect of EGFR AS. Prior injection sites will be 
marked and attempts will be made to perform biopsies in the area of prior inoculation(s). 
Biopsies will be delivered to Drs. Carew and Nawrocki’s laboratory at CTRC and to Dr. 
Grandis’ laboratory at UPCI for molecular studies. The presence of EGFR antisense DNA 
in the tumors will be determined using PCR. EGFR and EGFR pathway will be evaluated 
using RPPAs and IHC (see correlative studies section). 
 
Jennifer S. Carew, PhD or 
Steffan T. Nawrocki, Ph.D. 
Co-Director, Preclinical Research 
CTRC Institute for Drug Development 
Assistant Professor 
Department of Medicine/Division of Hematology and Medical Oncology 
University of Texas Health Science Center at San Antonio 
7979 Wurzbach Road, MC 8232 
Room G437 
San Antonio, TX 78229 
Phone: 210-450-3894 
Email: Nawrocki@uthscsa.edu 
Email: Carew@uthscsa.edu 
 
Julie Bauman, MD 
University of Pittsburgh 
Head and Neck Cancer Signaling Laboratory 
BST-W911 
Pittsburgh, PA 15213 
Phone: 412-647-5280 
Email: baumanje@upmc.edu 
 
 
EGFR AS Dose 
 
Patients will receive a total EGFR AS dose of 1.92mg/1.78mL on each weekly treatment. 
This dose may be delivered equally in the same tumor site per weekly session, the primary 
tumor or cervical lymph nodes. 
 
Dose/Schedule Modifications 
 
There will be no dose reductions. However, weekly doses will be omitted in the setting of 
locoregional toxicities (even if those are thought to be related to radiation). 

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Based on prior experience, the expected toxicities of EGFR AS therapy may include local 
discomfort at the injection site, edema, bleeding and cutaneous erythema when the 
treatment is administered. 
 
Treatment with EGFR AS will be held in the setting of grade 3 or 4 mucositis/dermatitis. 
 
Treatment with EGFR AS will be discontinued if there is cellulitis at the injection site 
requiring antibiotic therapy or grade 4 locoregional toxicities within the injected site 
develop (such as bleeding or tissue necrosis). 
 
Duration of Therapy 
 
Each patient will receive up to 7 weekly treatments. Treatment may be discontinued earlier 
if there is no identifiable tumor, a patient withdraws from study, develops intolerable 
toxicities, or their disease progresses (see section 7.8). 
 
Gene Transfer Efficiency and Biologic Activity 
 
These studies require a tissue biopsy and will be performed prior to initiation of therapy 
and on the second week of therapy. Tumor tissue will be biopsied for molecular studies as 
defined elsewhere. In order to demonstrate transfection of the EGFR AS gene into the 
tumors, we will perform polymerase chain reaction (PCR) analysis on DNA extracted from 
pre- and post-treatment patient tissue specimens. Samples will be taken directly to Dr. 
Grandis’ laboratory and the assays will be performed under her direction at the time points 
indicated above.  Samples from San Antonio will be sent to Dr. Grandis via Drs. Carew 
and Nawrocki’s laboratory. 
 
5.3 
Radiation therapy 
 
Radiation therapy will be standard of care for participating institutions. 
 
5.3.1 
Physical Factors 
 
Equipment: Linear accelerator with appropriate photon and electron energies for 
supplemental boosting to the nodes. 
 
Photon energies of 4 to 6 MV and/or appropriate electron energies for boosting the nodes 
are allowed. Photon energies > 6 MV may be utilized when appropriate to boost target 
localized centrally. 
 
Minimum treatment distance must be ≥ 80 cm SSD (or SAD for isocentric techniques). 
 
5.3.2 
Localization Requirements 
 
5.3.2.1 Simulation 
 
Simulation of all fields is mandatory. Patients must be reproducibly 

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immobilized. Radio-opaque markers should be used to delineate the extent of 
nodal disease and whenever possible, the primary tumor, if conventional 
treatment planning is used. The use of customized Cerrobend blocks or 
multileaf collimator is recommended to shape the field and limit dose to 
normal structures. For CT simulation, IV contrast is recommended and the 
data should be acquired using 3 mm slice width and spacing using the spiral 
mode of scanner. 
 
5.3.2.2 Verification 
 
Checking the films should be done weekly. Beam portal films must be obtained to 
each field. 
 
5.3.2.3 Electron fields utilized for supplemental nodal boosting must be verified 
by portal verification, simulation, or diagram. 
 
5.3.3 
Radiation Dose 
 
Treatment to the primary tumor and upper neck will be given at 2 Gy/fraction once each 
day, five days a week. A total dose of 70 Gy/35 fractions/7 weeks will be delivered. Fields 
must be reduced to exclude the spinal cord at 36 Gy with dose calculated in the central 
plane. The entire neck must be irradiated to a total dose of at least 46- 50 Gy (even in N0 
stage) at anatomic levels of lymph nodes usually 2-4 cm beneath the skin surface. 
Clinically positive neck nodes should also receive a dose of 70 Gy/35 fractions given 
continuously for 7-8 weeks. An electron beam should be used to supplement the dose to 
the posterior cervical chain nodes after the spinal cord has been shielded. Hence, the total 
dose to the primary tumor and clinically positive nodes will be 70 Gy. The anterior lower 
neck will be treated at 2 Gy/fraction once a day (3 cm depth or at depth determined by 3D 
imaging) from the anterior to a total dose of 46-50 Gy/25 continuous fractions (if clinically 
negative) in 5 weeks. The maximum dose permitted to the spinal cord will not exceed 45 
Gy as determined by a separate off-axis point dose calculation. 
 
5.3.4 
Target Volume Irradiation and Radiation Doses 
 
5.3.4.1 A combination of lateral opposing fields are recommended for the 
treatment of the primary tumor site and upper neck. A single anterior AP 
field will be used to treat the lower neck below the fields of the primary 
tumor/upper neck. When there is clinically involved lymph nodes in the 
lower neck, an additional posterior (PA) field may be necessary to deliver 
a supplemental dose to the positive nodes. All fields must be treated at 
each treatment session. The upper and lower fields should be matched 
using a “three dimensional” technique (i.e., appropriate rotation of the 
treatment table and appropriate angulation of the collimator or beam split 
technique). However, if such a three-dimensional match is not possible, 
the upper neck and supraclavicular fields may be abutted at the skin. The 
latter case, a small block should be placed either in the lower lateral 
position in the upper neck fields, or in the midline of the anterior 

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supraclavicular field (whichever is appropriate and does not block tumor) 
to the shield areas of potential overlap of diverging beams over the spinal 
cord. 
 
5.3.4.2 Upper Neck Primary Volume 
 
The primary treatment fields should encompass the primary tumor and/or 
suspected lymph node disease in the upper neck using the shrinking field 
technique as follows: 
 
The initial target volume should include the primary tumor, positive nodes 
with an approximately 3.0 cm margin and the next echelon of uninvolved 
lymphatic nodal drainage sites to a dose of 50 Gy. Included in the target 
volume is the first field reduction occurring off the spinal cord at 36 Gy. 
 
The second field reduction will occur at 50 Gy and continue to 60 Gy with 
the new target volume encompassing the primary tumor and known areas 
of nodal disease as well as areas at high risk for lymph node involvement 
with approximately 2.0 cm margin. 
 
The third and final field reduction will occur at 60 Gy and continue to 70 
Gy with the new target volume encompassing the primary tumor and 
known areas of nodal disease with at approximately 1.0 cm margin. 
 
As a general rule, both ipsilateral and contralateral posterior cervical 
nodal chain and the adjacent echelon of uninvolved lymphatic nodal 
drainage sites will be treated to a dose of 46-50 Gy/5 weeks. 
 
5.3.5 
Lower Neck Volume 
 
A single lower neck field will be used to treat the lower neck and the supraclavicular 
fossae. When there is (are) positive node(s) in the lower neck, an additional posterior field 
may be necessary to deliver a supplemental dose to the positive node(s). The boost dose 
should not exceed 4 Gy. 
 
The lower border of the lower neck field will be just below the clavicular head with 
appropriate margins when there are positive nodes in the supraclavicular fossa. The 
lateral borders of the lower neck field will extend to the intersection of the 
sternocleidomastoid muscle and the clavicle. 
 
For all patients with clinically positive nodes greater than 6 cm, or with clinically positive 
supraclavicular nodes, a mediastinal “T” field may be used. The lateral limbs of the T field 
will extend below the clavicular heads with margin, and the central portion of the field 
extends 5 cm more inferiorly to include the upper mediastinum. 
 
5.3.6 
Boost Doses 

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Additional boost doses may be given through reduced field to persistent tumor and/or 
clinically positive nodes, or to compensate for significant interruptions in radiation therapy 
treatments (i.e., > 57 elapsed days). The additional boost dose should not exceed 4 Gy 
(i.e., 70 Gy maximum). The spinal cord must be excluded from any boost field. 
 
5.3.7 
Dose Calculations 
 
Photon Beam Portal Arrangements 
 
Dose specification for two parallel-opposed coaxial equally-weighted beams is to be on 
the central ray at mid-separation of the beams. 
 
Dose specification for two or more intersecting beams is at the intersection of the central 
ray of the beams. 
 
For other complex treatment arrangements, dose is specified at the center of the clinical 
target volume. 
 
Note: There may be several target volumes. 
 
For a single anterior AP lower neck field, the prescribed does will be delivered at a depth 
of 3.0 cm as determined by an off-axis “supraclavicular point”. A deeper prescription point 
may be required if distance to the supraclavicular fossa is greater or with clinically involved 
nodes. When AP-PA fields are used to treat the lower neck, the dose shall be prescribed 
at the mid-separation of the two beams along the central ray. 
 
5.3.8 
Isodose Distributions 
 
Isodose distribution at central axis is required. All treatment volumes and critical structures 
should be indicated. Complete isodose curves are required. Attempts should be made to 
keep the dose variation within the planning target volume to be within +/- 5% of the target 
dose. 
 
5.3.9 
Electron Beam Dose Specifications 
 
The target dose shall be prescribed at the depth of maximum dose. The energy and field 
size shall be chosen so that the target volume is encompassed within 90% of the 
prescribed dose. 
 
5.3.10 Time and Dose Modifications 
 
Treatment interruptions are strongly discouraged. Treatment breaks must be clearly 
indicated in the treatment record when they occur. If the total treatment interruptions 
exceed ten treatment days, the treatment will be considered a protocol deviation. The 
interruption of radiation therapy for grade 4 mucositis/dermatitis/dysphagia is at the 
discretion of the treating oncologist. 

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The maximum permitted spinal cord dose is 45 Gy. 
 
Mandibular osteoradionecrosis will rarely occur if pretreatment dental evaluation is 
conducted prior to radiation therapy treatment. Pretherapy extractions of badly diseased 
teeth should be carried out with conservation of restorable teeth when possible. If an 
extraction site in the mandible has to be included in the irradiated field, 10 to 14 days 
should be allowed for healing before the initiation of irradiation. 
 
Radiotherapy Guidelines/IMRT 
 
5.3.11 
Intensity Modulated Radiation (IMRT) is allowed in the study. 
 
5.3.11.1 
Following are the proposed radiotherapy guidelines: 
 
All patients will have immobilization devices with treatment planning based on 
Computerized Tomography (CT) information in treatment position. The CT slice 
thickness through target will be 3 mm. 
 
CT, PET, and MRI data will be used to define the various targets and contour normal 
structures. MRI information will be used when indicated. Image fusion will be used to 
relate CT/MRI data when necessary. 
 
The field sizes and arrangements will be at the discretion of the attending Radiation 
Oncologist. ICRU 50 guidelines will be used for various Tumor and Target 
Nomenclature. 
 
The Gross Tumor Volume (GTV): All gross disease determined from clinical 
examination and radiographic studies (CT/PET/MRI). 
 
The Clinical Target Volume (CTV): The area that potentially contains microscopic 
disease. Lymph node groups at risk of microscopic disease will be outlined as part of 
corresponding CTV. The margin between each GTV and corresponding CTV can vary 
from 0.2 cm to 2.5 cm depending upon the proximity to the critical and uninvolved 
structures. 
 
The Planning Target Volume (PTV): Provides a margin around CTV to compensate for 
internal motion and set up errors. Typically a 5 mm margin may be used around CTV. 
 
5.3.11.2 
Radiation Target and Dose Specifications 
 
The following is the definition of targets and their dose specifications. 
 
Primary Target (PTV3): Includes PTV’s of primary tumor and the lymph nodes containing 
disease. The dose will be 70 Gy at 2 GY/ fractions. 
 
Secondary Target (PTV2): Includes PTV’s of area at moderate to high risk of microscopic 
disease i.e. first echelon nodes. The dose will be 60 Gy. 

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Tertiary Target (PTV1): Includes PTV’s of areas that are at low risk of microscopic disease 
i.e. second echelon lymph nodes. The dose will be approximately 46-50 Gy. 
 
Low Neck 
The midjugular, low jugular, and supraclavicular nodes can be treated with IMRT or 
alternatively with an AP field that is beam split to the IMRT fields. Dose Volume 
Histograms (DVH) will be generated for each plan. Radiation doses will be as outlined 
above. 
 
 
Treatment Planning 
Either forward or inverse planning can be used in order to achieve the following: 
 
The radiation dose will be prescribed to the isodose line that encompass 95% of PTV. 
No more than 15% of the PTV will receive >110% of the prescribed dose. 
The maximum dose within PTV does not exceed >25% of the prescribed dose. 
 
No more than 1% of the tissue outside PTV will receive >110% of the prescribed dose. 
No more than 1% of any PTV will receive < 93% of the prescribed dose. 
Tissue heterogeneity correction is mandatory. 
 
The planning priorities include critical normal structure constraints followed by prescription 
goals. 
 
Normal Tissues: The appropriate normal organs will be contoured. Dose Volume 
Histograms (DVH) will be generated. An attempt will be made to keep the maximum 
radiation doses to the following organs as follows: 
 
Brain Stems: 
54Gy 
Optic Nerve/Chiasm: 
55 Gy 
Spinal Cord: 
45 Gy 
Mandible/TM Joint: 
70 Gy or 1 cc of the PTV not to exceed 75 Gy 
Larynx 
70 Gy 
 
Parotid Glands: Attempt will be to achieve mean dose ≤ 26 Gy in at least one gland or at 
least 20cc of the combined volume of both parotid glands will receive < 20 Gy or at least 
50% of the gland will receive < 30 Gy (should be achieved in at least one gland). 
 
Other Normal Structures: Submandibular/sublingual glands, inner and middle ears, eye, 
lens will be considered low priority. The aim should be to decrease the doses as much as 
possible without compromising target. 

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5.3.12 Amifostine is not permitted. 
 
5.3.13 Pilocarpine (Salagen) is allowed as per physician discretion. If used, all details 
must be recorded on the data forms. 
 
5.4 
Salvage Surgery 
Salvage surgery may be performed after radiation, if there is local and/or regional 
progression of disease. 
 
Elective (planned) neck dissection or other surgery required for residual but not 
progressive disease will NOT be considered treatment failure. 
Surgical removal (salvage) of the primary tumor: Directed biopsies at the site of the index 
lesions should not be performed in the absence of suspicion for relapse. Criteria for biopsy 
after radiation includes a persistent mucosal abnormality or imaging studies that are 
suspicious for persistent or recurrent disease. 
 
Surgical removal (salvage resection) of the primary tumor should be performed if biopsy- 
proven cancer remains more than two months after completion of chemoradiotherapy. 
This will be considered progression of disease for the evaluation of the primary endpoint. 
The nature of the surgical resection should be dictated by the extent of tumor at the initial 
evaluation. The operation should be conducted using accepted criteria for primary surgical 
treatment of the cancer. 
 
Neck dissection: A neck dissection is recommended if a palpable or worrisome 
radiographic abnormality persists in the neck 8 weeks after completion of therapy. 
 
Cervical lymphadenectomy should encompass the original levels of lymph node 
involvement. Preservation of the accessory nerve, jugular vein, and sternomastoid muscle 
is encouraged if consistent with complete removal of all residual nodal disease; however, 
the extent of the neck dissection will be at the discretion of the surgeon. 
 
5.5 
Supportive Care 
 
All supportive measures consistent with optimal patient care will be given throughout the 
study. 
 
Concomitant Drugs 
 
The use of G-CSF, erythropoietin or amifostine is not allowed during radiotherapy. No 
other antitumor agents will be given during protocol therapy. 
 
Prophylactic placement of a gastrostomy tube before treatment begins is at the discretion 
of the treating physician. Gastrostomy tube placement is strongly recommended in 
patients with significant dysphagia and weight loss at baseline. 
 
Aggressive oral and skin care and analgesics are recommended. 

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The use of amifostine is not permitted. Pilocarpine (Salagen) is not encouraged during 
treatment but is allowed. If used, it should be recorded in the treatment forms. 
 
6. 
ADVERSE EVENTS 
 
This study will utilize the NCI CTCAE version 4.0 for toxicity and Adverse Event (AE) reporting 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. 
 
Infusion reactions should be graded according to allergic reaction/hypersensitivity. Caution must be 
exercised with every cetuximab infusion, as there were patients who experienced their first severe infusion 
reaction during later infusions. 
 
6.1 
Adverse Drug Reactions Due to Gene Therapy 
 
Note: A patient has died while being treated on a gene therapy protocol. That protocol used very 
high amounts of virus directly injected into the liver and treated a very different disease with a 
different gene than the one used in this study. This gene therapy protocol does not use a virus. 
The underlying disease that this patient had also made him more susceptible to complications of 
the gene therapy. 
 
Risk of Cancer 
 
When retroviral vectors enter a normal cell in the body, the DNA of the vector inserts itself 
into the normal DNA in that cell; this process is called integration. Most integration is 
expected to cause no harm to the cell or to the subject. However, there is a chance that 
there may be some regions of the normal human DNA where integration of the viral 
vector’s DNA may result in activation of neighboring genes. For example, if one of these 
genes were a growth factor, this may cause uncontrolled division of the cell, resulting in a 
cancer. This type of event has occurred in one animal study in mice where the vector 
integration site correlates with the occurrence of cancer in these mice. 
 
More recently, the first reports of a similar event have been identified in two children who 
received a retroviral vector in an experimental gene transfer clinical trial for X-linked 
Severe Immunodeficiency (X-SCID) conducted in France, not under the jurisdiction of the 
United States Food and Drug Administration (FDA). While most of the children who 
participated in this clinical trial appear to have been cured of their disease, these two 
children developed leukemia (a form of cancer of the blood) approximately 30 and 36 
months, respectively, after receiving the gene therapy treatment. These children had 
extensive testing done to determine the cause of the leukemia. A group of experts in this 
field looked at all the test results and concluded that the gene transfer caused the 
leukemia. These children appear to be responding to the treatment of his/her leukemia, 
but his/her long-term prognosis in unknown at this time. 
 
The risk of another cancer, including leukemia, developing in subjects who participate in 
this study, is unknown; however, in contrast to the French study this protocol does not use 
a virus. 

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Soreness and/or bleeding at the injection site. 
 
Local inflammation (redness or swelling and/or discomfort) at the injection site. 
 
Fever, reactions at the injection site of the gene transfer, which could develop into local 
ulcers or sores that could get infected. 
 
Note: Administration of cancer gene transfer has been used before, although this specific 
EGFR antisense study drug has not been previously given to cancer subjects. It is not 
known what impact this gene transfer will have on future conventional chemo/radiation 
treatments or future reproductive capabilities. 
 
6.2 
Reporting Adverse Events 
 
All adverse events which are considered to be related to the research study must be 
reported to the UT Health Science Center Institutional Review Board. All serious adverse 
events that meet the UT Health Science Center Institutional Review Board’s criteria for 
reporting can be found website at (http://research.uthscsa.edu/irb/). 
 
6.2.1 Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. (The term "life-threatening" in the definition of "serious" refers to an event 
in which the patient was at risk of death at the time of the event; it does not refer to an event, 
which hypothetically might have caused death if it were more severe). 
• Requires inpatient hospitalization or prolongation of present hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
 
Is a medically important event that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above, or involves suspected transmission via a medicinal product of 
an infectious agent. 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; any organism, 
virus, or infectious particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy), 
pathogenic or non pathogenic, is considered an infectious agent. 
 
6.2.2 
NIH guidelines for reporting serious adverse events for trials involving gene transfer 
agents or recombinant DNA molecules are found at http://www4.od.nih.gov/oba/rdna.htm. 
 
6.2.3 
The PI will report SAEs on trials involving gene transfer agents or recombinant DNA 

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molecules to the IRB according to their requirements. 
6.2.4 
FDA Guidelines for Adverse Event Reporting 
 
All adverse events meeting the definition of serious, unexpected and associated to the 
research intervention will be reported to the IRB according to their guidelines found on the 
IRB’s website and the IND file according to the following guidelines and FDA definition of 
events: 
 
Associated with the use of the drug: There is a reasonable possibility that the experience 
may have been caused by the drug. 
 
Disability: A substantial disruption of a person's ability to conduct normal life functions. 
 
Lifethreatening adverse drug experience: Any adverse drug experience that places the 
patient or subject, in the view of the investigator, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more 
severe form, might have caused death. 
 
Serious adverse drug experience: Any adverse drug experience occurring at any dose that 
results in any of the following outcomes: death, a life threatening adverse drug experience, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant disability/ incapacity, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life threatening, or require hospitalization may be 
considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
Unexpected adverse drug experience: Any adverse drug experience, the specificity or 
severity of which is not consistent with the current investigator brochure; or, if an 
investigator brochure is not required or available, the specificity or severity of which is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. "Unexpected," as used in this definition, 
refers to an adverse drug experience that has not been previously observed (e.g.,  
included in the investigator brochure) rather than from the perspective of such experience 
not being anticipated from the pharmacological properties of the pharmaceutical product. 
 
6.2.5 
IND Safety Reports 
 
The sponsor shall notify FDA and all participating investigators in a written IND safety 
report of: 
 
Any adverse experience associated with the use of the drug that is both serious and 
unexpected. 
 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 

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Each notification shall be made as soon as possible and in no event later than 15 calendar 
days after the investigators initial receipt of the information. 
Telephone and facsimile transmission of safety reports. The sponsor/investigator shall also 
notify FDA by telephone or by facsimile transmission of any unexpected fatal or life 
threatening experience associated with the use of the drug as soon as possible but in no 
event later than 7 calendar days after the sponsor's initial receipt of the information. 
 
6.3 
Data Safety and Monitoring Plan (DSMP) 
 
A Data and Safety Monitoring Plan is required for all an individual protocols conducted at 
CTRC. All protocols conducted at CTRC are covered under the auspices of the CTRC 
Institutional Data Safety Monitoring Plan. 
 
The CTRC Institutional DSMP global policies provide individual trials with: 
• Institutional policies and procedures for institutional data safety and monitoring, 
• An institutional guide to follow, 
• Monitoring of protocol accrual by the CTRC protocol review committee, 
• Review of study forms and orders by the forms committee, 
• Tools for monitoring safety events, 
• Independent monitoring and source data verification by the CTRC QA monitor/auditor, 
• Monitoring of UPIRSO’s by the director of quality assurance and DSMC, 
• Determining level of risk (priority of audit level score – pals), 
• Oversight by the data safety monitoring committee (DSMC), and 
• Verification of protocol adherence via annual audit for all investigator initiated studies 
by the CTRC quality assurance division. 
 
Monitoring Progress and Safety 
Due to the risks associated with participation in this protocol, the CTRC DSMB #2 in 
conjunction with the Principal Investigator will perform assessment of adverse events, 
adverse event trends and treatment effects on this study. The CTRC DSMB #2 acts as an 
independent DSMB for IIS conducted at CTRC. The CTRC DSMB #2 will monitor data 
throughout the duration of a study to determine if continuation of the study is appropriate 
scientifically and ethically. An additional layer of review is provided by the CTRC Data 
Safety Monitoring Committee (DSMC) who will review DSMB quarterly reports. 
 
Baseline events and adverse events will be captured using the CTRC Master Adverse 
Events Document for each patient using CTCAE V. 4.0 for the grading and attribution of 
adverse events. Usage of the CTRC Master Adverse Events Document centrally 
documents: 
• The event and grades the seriousness of the event, 
• If the event was a change from baseline, 
• The determination of the relationship between the event and study intervention, 
• If the event was part of the normal disease process, and 
• What actions were taken as a result of the event. 
 
Safety Definitions: 

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For this study, the following safety definitions will be applicable: 
 
Adverse Event Definition: An adverse event (AE) is defined as any untoward or 
unfavorable medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research for this study, all adverse events will 
be documented starting with specify here when you want to start collecting adverse event 
information, generally this would be with the first dose of the study drug and ending 30 
days after the last dose of study drug is received. 
 
Serious Adverse Event Definition: is any adverse event that: 
1. 
Results in death; 
2. 
Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
3. 
Results in inpatient hospitalization or prolongation of existing hospitalization; 
4. 
Results in a persistent or significant disability/incapacity; 
5. 
Results in a congenital anomaly/birth defect; or 
6. 
Based upon appropriate medical judgment may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
this definition 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRSO) Definition: 
Unanticipated problem involving risk to subjects or others includes any incident, 
experience or outcome that meets all of the following criteria: 
 
A. 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the subject 
population being studied (note: the unfounded classification of a serious adverse event as 
“anticipated” constitutes serious non-compliance); 
B. 
Definitely related or probably related to participation in the research; and 
C. 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or recognized 
 
Reporting Requirements 
For this study, the Master Adverse Events Documents collected on patients for this 
protocol will be reviewed by the Principal Investigator on a quarterly basis to determine if a 
serious safety problem has emerged that result in a change or early termination of a 
protocol such as: 
• Dose modification, 
• Suspending enrollment due to safety or efficacy, or 
• Termination of the study due to a significant change in risks or benefits. 
 
6.4 
PI Review 

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The PI will provide the DSMB #2 with the quarterly findings for discussion and review during their 
meetings. 
 
As per the CTRC DSMP, any protocol modifications, problematic safety reports, unanticipated 
problems, and suspension or early termination of a trial must be reported to the DSMB #2 and all 
members of the research team. Furthermore, the PI of this study will promptly notify all study 
affiliates, the UTHSCSA IRB, the CTRC DSMC, and the FDA via a FDA Form 3500Aa written IND 
safety report of any adverse events that are either serious and/or unexpected. Suspension and 
early termination of a trial must also be reported immediately to the Director of Quality Assurance 
who will promptly notify the sponsor and the UTHSCSA IRB. 
 
The PI will review the Master Adverse Events documents to determine the significance of the 
reported events and will provide findings using the Investigator Initiated Study Quarterly DSMC 
Report Form on a quarterly basis with the DSMB #2. The DSMB #2 will review the information 
provided by the PI and report to the CTRC DSMC on a quarterly basis, unless an emergent issue 
has been identified. The Investigator Initiated Study Quarterly DSMC Report Form includes 
information on adverse events, current dose levels, number of patients enrolled, significant 
toxicities per the protocol, patient status (morbidity and mortality) dose adjustments with observed 
response, and any interim findings.  Any trend consisting of three or more of the same event will 
be reported to the CTRC DSMC for independent review outside of the quarterly reporting cycle, 
which begins three months following protocol start up. The DSMB #2 will also provide its findings 
to the CTRC’s Regulatory Affairs Division so that it may be provided to the UTHSCSA IRB with the 
protocol’s annual progress report. Conflict of interest is avoided by the independent reviews of the 
CTRC DSMB #2 and by ongoing independent review of UPIRSO trends by the Director of Quality 
Assurance. 
 
All SAE and UPRISO’s will be reported following CTRC, UTHSCSA institutional and FDA guidelines 
UTHSCSA SAE/UPRISO REPORTING REQUIREMENTS For IIS that the PI holds the IND 
Type Event 
Report to 
Timeframe 
All AE, SAE and UPIRSO 
Regulatory Affairs and DQA 
ASAP 
All AE, SAE and UPIRSO 
FDA on form 3500A 
within 7 calendar days by 
telephone and 15 calendar 
days using the Form 3500A 
SAE 
PI at UTHSCSA 
within 24 hours 
SAE 
UTHSCSA IRB 
Annually 
UPIRSO - all 
PI at UTHSCSA 
within 24 hours 
UPIRSO - all 
FDA 
within 7 days 
UPIRSO - life threatening 
UTHSCSA IRB/UTHSCSA OCR 
within 48 hours 
UPIRSO - non-life threatening 
UTHSCSA IRB/UTHSCSA OCR 
within 7 days 
 
 
Expedited Reporting for Phase II and III Studies (including hospitalization* 
 
UNEXPECTED EVENT 
EXPECTED EVENT 
GRADES 2 - 3 
GRADES 4 - 5 Regardless GRADES 1 - 3 
GRADES 4 - 5 Regardless of 

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DSMB #2 (for Solid Tumors) 
 
 
Attribution of 
Possible, 
Probable or 
Definite 
of Attribution 
Attribution 
Expedited report 
within 10 working 
days 
Grade 1 - Adverse 
Event Expedited 
Reporting NOT 
required.) 
Report by phone to IDB 
within 24 hrs. Expedited 
report to follow within 10 
working days. 
This includes all deaths 
within 30 days of the last 
dose of treatment with an 
investigational agent 
regardless of attribution. 
Any late death attributed to 
the agent (possible, 
probable, or definite) should 
be reported within 10 
working days. 
Adverse Event 
Expedited 
Reporting NOT 
required. 
Expedited report, including Grade 5 
Aplasia in leukemia patients, within 10 
working days. 
This includes all deaths within 30 days 
of the last dose of treatment with an 
investigational agent regardless of 
attribution. 
Any late death attributed to the agent 
(possible, probable, or definite) should 
be reported within 10 working days. 
Grade 4 Myelosuppression or other 
Grade 4 events that do not require 
expedited reporting will be specified in 
the protocol. 
* For Hospitalization Only — Any medical event equivalent to CTC Grade 3, 4, 5 which 
precipitated hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of requirements for Phase of study, expected or unexpected and attribution. 
 
Expedited reporting may not be appropriate for specific expected adverse events for certain later 
Phase II and Phase III protocols. In those situations the adverse events that will not have 
expedited reporting must be specified in the text of the approved protocol. An expected Grade 3 
event that is definitely related to the investigational agent is only to be reported if the patient is 
hospitalized using the generic reporting criteria. For instance, in a trial of an investigational agent 
where Grade 3 diarrhea requiring hospitalization is expected, only diarrhea requiring ICU care 
(Grade 4) might be designated for expedited reporting. 
 
Serious adverse events on NCI sponsored trials utilizing a commercially available agent (with no IND’s 
involved) will additionally be reported via the FDA’s Medwatch program. 
 
Assuring Compliance with Protocol and Data Accuracy 
As with all studies conducted at CTRC, the PI has ultimate responsibility for ensuring protocol 
compliance, data accuracy/integrity and responding to recommendations that emanate from 
monitoring activities. Protocol compliance, data accuracy and reporting of events is further ensured 
by an annual audit conducted by the Data Safety Officer, whose audit report is shared with the PI, 
the research team, and will be reviewed by the CTRC DSMC. 
 
CTRC DSMB Membership 
The CTRC has two DSMB’s with a primary set of members specific to the histology of the study 
consisting of UTHSCSA faculty and staff. This Protocol will utilize DSMB#2 for Solid Tumor Studies. 
 
 

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Kevin Kelly, MD 
Ting Lu, MD 
Richard Meier, MD 
Wendy Crabbe, PA, MSN, RN 
Melissa Nashawati, MPA 
Yuanyuan Liang, PhD 
 
 
As per NCI guidelines and to eliminate conflict of interest (financial, intellectual, 
professional, or regulatory in nature), the CTRC DSMB specific to this study will not treat patients 
on this protocol. Usage of the DSMB specific to the histology has been created to ensure that 
experts in that histology are represented on the DSMB assembled for this protocol, but may be 
expanded, at the PI’s discretion, to include other members which may include: 
• 
Experts in the fields of medicine and science that are applicable to the study (if not currently 
represented on the DSMB), 
• 
Statistical experts, 
• 
Lay representatives, 
• 
Multidisciplinary representation, from relevant specialties including experts such as 
bioethicists, biostatisticians and basic scientists, and 
• 
Others who can offer an unbiased assessment of the study progress. 
 
Additional or alternate membership of in the DSMB is selected by the DSMC chair, in conjunction with 
the PI of this protocol. 
 
 
CTRC DSMB Charter and Responsibilities 
The CTRC DSMB will provide information on the membership composition, including qualifications and 
experience to both the UTHSCSA IRB and CTRC PRC for review. The CTRC DSMB for this study will act 
as an independent advisory board to the PI and will report its findings and recommendations to the PI, the 
UTHSCSA IRB and the CTRC DSMC. CTRC DSMB reports will utilize the Investigator Initiated Study 
Quarterly DSMC Report Form and meetings will occur on a quarterly basis to review any updates from the 
prior meeting. 
 
Once the protocol is activated, if not already established elsewhere in the protocol the CTRC DSMB will 
establish and provide: 
• Procedures for maintaining confidentiality; 
• Statistical procedures including monitoring guidelines, which will be used to monitor the identified 
primary, secondary, and safety outcome variables; 
• Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants or 
the ethics of the study; 

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• Plans for changing frequency of interim analysis as well as procedures for recommending protocol 
changes; 
• Recommendation of dose escalation, MTD recommendation of early termination based on efficacy 
results; 
• Recommendation of termination due to unfavorable benefit-to-risk or inability to answer study 
questions; 
• Recommendation of continuation of ongoing studies; 
• Recommend modification of sample sizes based on ongoing assessment of event rates; and 
• Review of final results and publications. 
 
7. 
MANAGEMENT OF CETUXIMAB ADVERSE REACTIONS AND DOSE MODIFICATIONS 
 
All toxicities will be graded according to NCI Common Toxicity Criteria AE version 4.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
7.1 
Cetuximab Dose Modifications 
 
Cetuximab will be held or its dose reduced to dose level -1 or -2 (see below) for the following toxicities 
(see sections 7.4 and 7.5). 
 
Cetuximab will NOT be held or reduced for hematologic toxicities. 
Dose levels for cetuximab are as follows: 
Table 3: Cetuximab Dose Levels 
 
  Weekly Cetuximab dose 
 
Starting dose 
250 mg/m2 
Dose Level -1 
200 mg/m2 
Dose Level -2 
150 mg/m2 
 
There will be no dose level reductions below a weekly dose of 150 mg/m2. 
 
7.2 
Management of Infusion Reactions 
 
Severe infusion reactions require the immediate interruption of cetuximab therapy and permanent 
discontinuation from further treatment. Appropriate medical therapy including epinephrine, 
corticosteroids, intravenous antihistamines, bronchodilators, and oxygen should be available for 
use in the treatment of such reactions. Patients should be carefully observed until the complete 
resolution of all signs and symptoms. 
 
In clinical trials, mild to moderate infusion reactions were managed by slowing the infusion rate of 
cetuximab and by continued use of antihistamine pre-medications (e.g., diphenhydramine 
hydrochloride [Benadryl]) in subsequent doses. If the patient experiences a mild or moderate 
(Grade 1 or 2) infusion reaction, the infusion rate should be permanently reduced by 50%. For 

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grade 1 or 2 reactions manifesting only as delayed drug fever, see below. 
 
Cetuximab should be immediately and permanently discontinued in patients who experience 
severe (Grade 3 or 4) infusion reactions. 
 
7.3 
Treatment of Isolated Drug Fever 
 
In event of isolated drug fever, the investigator must use clinical judgment to determine if the fever 
is related to the study drug or to an infectious etiology. 
 
If a patient experiences isolated drug fever, for the next dose, pre-treat with acetaminophen or 
non-steroidal anti-inflammatory agent (investigator discretion), repeat antipyretic dose 6 and 12 
hours after cetuximab infusion. The infusion rate will remain unchanged for future doses. 
 
If a patient experiences recurrent isolated drug fever following premedication and post-dosing with 
an appropriate antipyretic, the infusion rate for subsequent dosing should be 50% of previous rate. 
If fever recurs following infusion rate change, the investigator should assess the patient’s level of 
discomfort with the event and use clinical judgment to determine if the patient should receive 
further cetuximab. 
 
7.4 
Management of Pulmonary Toxicity 
 
In the event of acute onset (grade > 2) or worsening pulmonary symptoms which are not thought 
to be related to underlying cancer, cetuximab therapy should be interrupted and a prompt 
investigation of these symptoms should occur. If ILD is confirmed, cetuximab should be 
discontinued and the patient should be treated appropriately. 
 
7.5 
Management of Dermatologic Toxicity 
 
Patients developing dermatologic toxicities while receiving cetuximab should be monitored for the 
development of inflammatory or infectious sequelae, and appropriate treatment of these symptoms 
initiated. Dose modifications of any future cetuximab infusions should be instituted in case of 
severe (grade 3) acneiform rash. Treatment with topical and/or oral antibiotics should be 
considered; topical corticosteroids are not recommended. 
 
If a patient experiences severe acneiform rash, cetuximab treatment adjustments should be made 
according to the following table. In patients with mild and moderate skin toxicity, treatment should 
continue without dose modification. 

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Grade 3 
 
Table 4 Cetuximab Dose Modification Guidelines 
Cetuximab 
Outcome 
Cetuximab Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.6 
In-Field Toxicities During Radiation: Radiation Mucositis/Dysphagia/Dermatitis 
 
No cetuximab dose adjustments for grade 3 or less radiation mucositis, dysphagia, dermatitis. 
 
Grade 4 radiation mucositis/dysphagia or dermatitis that develops at any time will require 
permanent dose reduction of cetuximab by one dose level on all subsequent cycles. If radiation is 
given in the setting of grade 4 radiation mucositis/dysphagia/dermatitis, cetuximab will be 
administered with a dose reduction by one dose level. 
 
Delays in radiation as strongly discourages. Short delays may be required for the management of 
grade 3 /4 toxicities. If RT is held because of in-field toxicities, hold cetuximab until RT is resumed. 
 
EGFR AS will be held for grade 3 or 4 in-field toxicities (see section 5.2.3). 
 
 
 
7.7 
Retreatment Criteria for Cetuximab 
 
Cetuximab may only be administered if all the following criteria are met regardless of cycle, 
providing no criteria for discontinuation are met: 
 
• 
Acne-like rash is grade 2 or less 
• 
All other grade 3 or 4 non-hematologic out-of-field toxicities (except fatigue, electrolyte 
abnormalities, anorexia, pain) have improved to grade 2 or less. 
• 
For in-field toxicities see section 7.6 
 
7.8 
Duration of Therapy/Withdrawal from Study 
Criteria for removal from study are: 
Acneform Rash 
Modification 
1st occurrence 
Delay infusion 1 to 2 weeks 
Improvement 
No Improvement 
Continue at 250 mg/m2 
Discontinue cetuximab 
2nd occurrence 
Delay infusion 1 to 2 weeks 
Improvement 
No Improvement 
Reduce dose to 200 mg/m2 
Discontinue cetuximab 
3rd occurrence 
Delay infusion 1 to 2 weeks 
Improvement 
No Improvement 
Reduce dose to 150 mg/m2 
Discontinue cetuximab 
4th occurrence 
Discontinue cetuximab 

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• 
Disease progression, 
• 
Study closure, 
• 
Unacceptable adverse event(s) as defined in dose modification or other unacceptable AEs, 
• 
Patient decision to withdraw from the study, or 
• 
In the judgment of the investigator, further treatment would not be in the best interest of the 
patient. 
• 
Pregnancy: Pregnant participants will continue to be followed for the duration of the 
pregnancy. 
 
8. 
MEASUREMENT OF RESPONSE 
 
Response will be evaluated in this study using the international criteria proposed by the Response 
Evaluation Criteria in Solid Tumors (RECIST v1.1) Committee.36 
 
8.1 
Methods of Measurement 
 
Imaging based evaluation is preferred to evaluation by clinical examination. The same imaging 
modality must be used throughout the study to measure disease. 
 
CT and MRI 
 
CT and magnetic resonance imaging (MRI) are the best currently available and most 
reproducible methods for measuring target lesions. Conventional CT and MRI should be 
performed with contiguous cuts of 10 mm or less in slice thickness. Spiral CT should be 
performed by use of a 5 mm contiguous reconstruction algorithm. This specification 
applies to tumors of the chest, abdomen, and pelvis, while head and neck tumors, and 
those of the extremities require specific procedures. 
 
Chest X-Ray 
 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by an aerated lung. However, CT is preferable. A chest x-ray only 
needs to be done if clinically indicated by the treating physician. It is not required for study 
purposes. 
 
 
Tumor Markers 
 
Tumor markers alone cannot be used to assess response. If initially above the upper normal 
limit, a tumor marker must return to normal levels for a patient to be considered in complete 
clinical response when all tumor lesions have disappeared. 
 
Clinical Examination 

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FOR THIS STUDY evaluation of measurable disease in the primary site by ENT 
examination is allowed. 
 
Cytology and Histology 
 
Cytologic and histologic techniques can be used to differentiate between complete and 
partial response in rare cases (e.g., after treatment to differentiate residual benign lesions 
and residual malignant lesions in germ cell tumors). Cytologic confirmation of the 
neoplastic nature of any effusion that appears or worsens during treatment is required 
when the measurable tumor has met response or stable disease criteria. 
 
The pathologic response after biopsy or neck dissection post chemoradiotherapy will be 
recorded. 
 
9. 
STUDY PARAMETERS 
 
9.1 
Evaluations at Screening/Baseline 
(Performed within 4 weeks of registration unless otherwise indicated) 
 
• 
Sign informed consent 
• 
History and physical examination, including vital signs, weight and performance status 
determination (within 1 week of registration). 
• 
Complete blood counts, including platelets (within 1 week of registration). 
• 
Blood chemistry studies, including creatinine, electrolytes (K+, Na+, CI-, CO2), calcium, Mg 
(within 1 week of registration), PT/PTT and liver function tests, including bilirubin, AST 
(SGOT), ALT (SGPT), and alkaline phosphatase (within 1 week of registration). 
• 
Pregnancy (when applicable, within 3 days prior to treatment initiation) test. 
• 
CT and/or MRI of the neck and CT of the chest and other imaging studies as indicated for 
staging and baseline tumor measurements. Any scans used to document measurable disease 
should be done as close to study entry as possible and within 4 weeks prior to registration. 
• 
PET scan (optional) 
• 
Bone scan (if clinically indicated) 
• 
Dental evaluation (within 8 weeks of registration) 
• 
ENT evaluation/endoscopy (within 8 weeks of registration) 
• 
Swallowing assessment (within 8 weeks of registration) 
• 
Pretreatment biopsy 
 
9.2 
Evaluations During Treatment 
During treatment - weekly 
 
• 
History and physical examination. A focused evaluation of toxicities on a weekly basis will be 

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performed at a minimum. A complete history and physical examination is needed at least 
every 3 weeks. 
• 
CBC, platelets and creatinine/electrolytes 
• 
Liver function tests: Bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase. LFTs are 
required every 3 weeks or more frequently if indicated. 
• 
Vitals signs will be checked every time cetuximab is administered. 
• 
Tumor biopsy at baseline and after 2 weeks (prior to the start of radiation). 
 
9.3 
Evaluations at Follow-Up 
2 weeks after completion of radiation treatment 
• 
History and physical examination 
• 
Complete blood counts, including platelets 
• 
Blood chemistry studies, including creatinine, electrolytes (K+, Na+, CI-, CO2), Ca++, Mg++, 
and liver function tests, including bilirubin, AST (SGOT), ALT (SGPT), and alkaline 
phosphatase 
 
After completion of radiation (10 +/- 2 weeks after) 
 
• 
History and physical examination 
• 
Complete blood counts, including platelets 
• 
Blood chemistry studies, including creatinine, electrolytes (K+, Na+, CI-, CO2), Ca++, 
Mg++ENT evaluation/endoscopy 
• 
Liver function tests: Bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase 
• 
CT and/or MRI of neck 
• 
CT of chest 
• 
Response assessment by clinical and by radiographic evaluation (reported separately) in 
primary and lymph nodes 
• 
PET scan (optional) 
 
After completing treatment, patients will be seen every 3 months for 2 years and then every 6 
months for 3 years (i.e. until 5 years from radiation completion), and subsequently annually for a 
total of 10 years from study initiation (follow up evaluation will include assessment of late 
toxicities, such as dysphagia, G-tube feedings requirements, xerostomia, and others) 
 
• 
CT scans of chest and head and neck will be performed every 3 months for 1 year and then 
every 6 months until 3 years from the completion of radiation. Then, CT of the chest will be 
done on an annual basis 
 
• 
Swallowing assessments will be performed 3 months post radiation completion, and if 
problems persist, at 12 months post radiation 

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9.4 
Study Parameters Table 
 
Baseline 
During treatment 
and 2 weeks post 
RT 
10 +/- 2 weeks 
after RT 
Off therapy 
Follow-Up8 
Study treatment (See Section 5) 
X 
X 
History and physical exam 
X 
X9 
X 
X 
Height 
X 
Weight 
X 
X9 
X 
Vital signs 
X 
X9 
Toxicity assessment 
X 
X 
X 
Performance Status 
X 
X9 
X 
CBC, Differential, Platelets1 
X 
X9 
X9 
Creatinine, Electrolytes (K+, Na+, CI-, 
CO2), Mg++, Ca++ 
X 
X9 
X9 
Liver enzymes2 
X 
X (every3 weeks) 
X 
PT/PTT10 
X 
Chest X-ray 
X 
Pregnancy test3 
X 
HIV status obtained via history 
X 
CT or MRI of the head/neck 
X 
X 
X4,8 
CT of the chest 
X 
X 
X4,8 
Bone scan, if clinically indicated 
X 
Tumor measurements4,9 
X 
X 
X4,8 
PET scan (optional)5 
X 
X 
X 
Swallowing assessment6 
X 
X6 
Dental evaluation 
X 
Tumor Biopsy and correlatives7 
X 
X (after 2 weeks) 
ENT evaluation/endoscopy 
X 
X 
1. 
Complete blood counts with differential and platelet count should be performed. 
2. 
Liver function tests should include: Bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase. LFTs are 
required at least every 3 weeks during treatment. 
3. 
All females of childbearing potential must have a negative pregnancy test done within 3 days of initiation of 
treatment to rule out pregnancy. 
4. 
Tumor measurements will be made using physical examination, including endoscopic examination (clinically) and 
CT scans or MRI scans (radiographically). Clinical and radiographic assessments will be reported separately. 
Response in the primary and the neck will be reported separately as well. Tumor assessments will be performed 6-8 
weeks after completion of radiotherapy. Subsequently, repeat imaging with CT scans of chest and head and neck will 
be performed every 3 months for 1 year and then every 6 months for a total of 3 years from the time of radiation 
completion. Then, CT of the chest or chest x-ray will be done on an annual basis. 
5. 
Positron emission tomography (PET) scan or combined PET/CT scanning is optional. Results will be reported 
separately. 
6. 
Swallowing assessments will be performed at baseline and 3 months post radiation completion, and if problems 
persist, at 12 months post radiation. 
7. 
The following materials will be submitted: fresh frozen and paraffin-embedded tumor specimens for molecular 
studies. 
8. 
Patients will be followed every 3 months for 2 years and then every 6 months for 3 years, and subsequently annually 
for a total of 10 years from study initiation. 

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9. 
During radiation, in the immediate 2 week period following RT completion, and the 6-10 week follow-up after RT 
completion; patients need a focused evaluation of toxicities on a weekly basis. However, a complete history and 
physical examination is only needed every 3 weeks. 
10. PT/PTT will be performed at baseline while the patient is receiving intratumoral injections or more frequent, if 
clinically indicated. 
11. All patients should be seen by a Medical Oncologist, an ENT surgeon, and a Radiation Oncologist prior to initiating 
therapy. Unresectability should be determined by a multidisciplinary team. 
 
10. 
DRUG FORMULATION AND PROCUREMENT 
 
10.1 
EGFR Antisense 
 
EGFR antisense DNA is plasmid DNA and will be prepared under conditions consistent with cGMP 
as described in CFR 210 and 211. Production will occur in the Center for Biomedicine and 
Genetics, the National Gene Vector Laboratory (NGVL) designated site at the Beckman Research 
Institute of the City of Hope in Duarte, California, under the direction of Dr. Larry A. Couture. 
Manufacturing and quality release testing will be performed as described in BB-MF 9778 (see 
cross reference authorization letter provided as an attachment). 
 
Drug Information 
Production of Plasmid DNA 
Plasmid DNA was produced under GMP conditions at the Center for Biomedicine and 
Genetics (CBG) at the City of Hope according to City of Hope’s Master File BB-MF-9778. 
Briefly, a bacterial Master Cell bank was produced in the STBLII competent cell line. Bacteria 
from the tested and released Master Cell Bank was used to inoculate “starter” and expansion 
cultures to seed 6 liter batches in a New Brunswick BioFlo3000 fermentor using proprietary 
bacterial media optimized for plasmid DNA production. The 6 liter culture was grown at 35°C 
for 20 4 hours with automated (PID loop) temperature, aeration and pH adjustment. 
Following fermentation the culture was harvested and bacterial pellets stored at -20°C for 
further processing. 
 
Bacteria were processed using a modified alkaline lysis method (Birnboim, H.C. and Doly, 
J.(1979) Nucl. Acids. Res. 7,1513-1522). Briefly, bacterial pellets are resuspended in 50mM 
Tris-Cl, 10mM EDTA and then lysed with an equal volume of 200mM NaOH, 1% SDS at room 
temperature. The lysate is neutralized with 3.0M potassium acetate and clarified by 
centrifugation to remove the bulk of proteins, lipid and bacterial genomic DNA. The clarified 
lysate is passed through a series of filters (50
0.2 ) and then concentrated 10-fold to 15-fold 
over a 30,000 NMWCO PES ultrafiltration device (Millipore ProFlux M12/Pellicon system). At 
this stage the concentrated lysate was held for 24 hours at 4°C. 
 
Concentrated lysate was further clarified using depth filtration in the presence of filter aid and 
RNA removal was achieved by size exclusion chromatography over Sepharose 6 Fast Flow
 
(GE Healthcare). Plasmid DNA devoid of RNA contaminants was treated with an endotoxin 
adsorbent to remove trace endotoxin contamination. The plasmid DNA was concentrated and 
reformulated into PBS using tangential flow filtration. Samples of the bulk material were taken 
for release testing with the balance of the material stored at -20 C. The bulk material that met 
the defined specifications for protein, endotoxin, RNA and contaminating bacterial genomic 

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DNA were thawed and pooled for fill and finish. 
 
Final fill of the plasmid DNA was preceded by end-point sterilization through a 0.2 m filter. Final 
product vials were transferred to Quality Assurance who coordinated final product testing and 
shipment of released material. 
 
EGFR Antisense Shipping 
 
EGFR antisense DNA is plasmid DNA, and is considered to be Biohazard I (BSL-1) since it 
does not contain viral elements, toxic proteins or oncogenes and will be shipped and handled 
as a research reagent as per biohazard material guidelines. The product will be supplied 
vialed and formulated in 1-2 mg/mL concentrations, stored at -80 C, and shipped on dry ice. 
Based on ICH recommendations, the product must be used within 3 hours from thawing of the 
product. Any/all unused product will be returned to the NGVL. EGFR antisense DNA will be 
sent from the University of Pittsburgh Pharmacy to our site's Investigational Drug Section 
(IDS). It will be shipped on dry ice for overnight delivery (Monday-Thursday). Upon arrival at 
IDS, drug will be inspected to ensure its intact/undamaged during shipping. 
 
10.2 
Cetuximab (C225, ERBITUX) 
 
Cetuximab is an anti-EGFR human-to-murine chimeric antibody. Cetuximab is 
expressed in SP2/0 myeloma cell line, grown in large scale cell culture bioreactors 
and purified to a high level purity using several purification steps including protein A 
chromatography, ion exchange chromatography, low pH treatment and nanofiltration. 
Cetuximab is not known to be a vesicant. 
 
Supplier/How Supplied 
Cetuximab is commercially available. The product is a sterile, clear, colorless liquid of 
pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous 
cetuximab particulates. Each single-use 50-mL vial contains 100 mg of cetuximab at a 
concentration of 2 mg/mL and is formulated in a preservative-free solution containing 
8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 
0.42mg/mL sodium phosphate monobasic monohydrate, and Water for injection, USP. 
 
Packaging and Labeling 
Cetuximab is supplied as a 50mL, single-use vial containing 100mg of Cetuximab at 
a concentration of 2mg/mL in phosphate buffered saline. The solution should be clear 
and colorless and may contain a small amount of easily visible white amorphous 
Cetuximab particulates. 
 
Storage Requirement/Stability 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE. 
Increased particulate formation may occur at temperatures at or below 0°C. This 
product contains no preservatives. Preparations of cetuximab in infusion containers 
are chemically and physically stable for up to 12 hours at 2°C to 8°C (36°F to 46°F) 
or up to 8 hours at controlled room temperature (20°C to 25°C; 68°F to 77°F). 
Discard any remaining solution in the infusion container after 8 hours at controlled 

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room temperature or after 12 hours at 2 to 8 C. Discard any unused portion of the 
vial. 
 
Preparation and Administration 
Cetuximab must not be administered as an IV push or bolus. 
 
Cetuximab must be administered with the use of a low protein binding 
0.22-micrometer in-line filter. 
 
Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at 
a concentration of 2 mg/mL in phosphate buffered saline. The solution should be clear 
and colorless and may contain a small amount of easily visible white amorphous 
cetuximab particulates. DO NOT SHAKE OR DILUTE. 
Cetuximab can be administered via infusion pump or syringe pump. 
Infusion Pump: 
• 
Draw up the volume of a vial using a sterile syringe attached to an appropriate needle 
(a vented spike or other appropriate transfer device may be used). 
• 
Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (eg, Baxter Intravia), ethylene vinyl acetate bags (eg, Baxter Clintec), 
DEHP plasticized PVC bags (eg, Abbott Lifecare), or PVC bags. 
• 
Repeat procedure until the calculated volume has been put in to the container. Use a 
new needle for each vial. 
• 
Administer through a low protein binding 0.22-micrometer in-line filter (placed as 
proximal to the patient as practical). 
• 
Affix the infusion line and prime it with cetuximab before starting the infusion. 
• 
Maximum infusion rate should not exceed 5 mL/min. 
• 
Use 0.9% saline solution to flush line at the end of infusion. 
 
Syringe Pump: 
• 
Draw up the volume of a vial using a sterile syringe attached to an appropriate needle 
(a vented spike may be used). 
• 
Place the syringe into the syringe driver of a syringe pump and set the rate. 
• 
Administer through a low protein binding 0.22-micrometer in-line filter rated for syringe 
pump use (placed as proximal to the patient as practical). 
• 
Connect up the infusion line and start the infusion after priming the line with 
cetuximab. 
• 
Repeat procedure until the calculated volume has been infused. 
• 
Use a new needle and filter for each vial. 
• 
Maximum infusion rate should not exceed 5 mL/min. 

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• 
Use 0.9% saline solution to flush line at the end of infusion. 
• 
Cetuximab should be piggybacked to the patient’s infusion line. 
Following the cetuximab infusion, a 1-hour observation period is recommended. 
Safety Precautions: 
Appropriate mask, protective clothing, eye protection, gloves, and Class II vertical- 
laminar-airflow safety cabinets are recommended during preparation and handling. 
Opened vials must be disposed of at the investigational center as chemotherapy or 
biohazardous waste provided documented procedures for destruction are in place. 
For questions regarding cetuximab destruction please contact BMS at (866) 339-4267 
or (203) 677-7017. 
 
Cetuximab therapy should be used with caution in patients with known 
hypersensitivity to Cetuximab, murine proteins, or any component of this product. 
 
It is recommended that patients wear sunscreen and hats and limit sun exposure 
while receiving cetuximab as sunlight can exacerbate any skin reactions that may 
occur. 
 
Cetuximab Records at Investigational Site(s) 
 
It is the responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site where 
investigational product is inventoried and disposed. Records or logs must comply with 
applicable regulations and guidelines, and should include: 
• 
Amount received and placed in storage area. 
• 
Amount currently in storage area. 
• 
Label ID number or batch number. 
• 
Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
• 
Amount dispensed to and returned by each patient, including unique patient 
identifiers. 
• 
Amount transferred to another area for dispensing or storage. 
• 
Non-study disposition (e.g., lost, wasted, broken). 
 
Drug Ordering and Accountability 
The ordering and drug accountability for Cetuximab will be handled per institutional 
Standard Operating Procedures (SOPs). 
 
It is the responsibility of the Investigator to ensure that a current record of study drug 
disposition is maintained at each study site where the study drug is inventoried and 

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disposed. Records or logs must comply with applicable regulations and guidelines. 
Nursing Implications 
Patients need monitoring for infusion reactions. Premedication with diphenhydramine 
hydrochloride [Benadryl] will be used as described in Sections 5.0 and 5.1. 
 
Diarrhea is a possible side effect of cetuximab. It can be managed with loperamide 
(Imodium). 
 
11. 
STATISTICAL CONSIDERATIONS 
 
11.1 
Primary Endpoint 
 
This is a 2-stage clinical trial. In the first stage, toxicity will be the primary endpoint. In the second 
stage (phase II component), the primary endpoint will be the locoregional progression free survival 
(PFS) at 1 year. Toxicities will also be evaluated during the second stage using continuous 
Bayesian monitoring as described below. 
 
Sample size for the primary objective: 11 evaluable patients (stage 1); 31 evaluable patients 
(stage 2) 
 
First stage: 11 evaluable patients. The safety-evaluable population for stage 1 consists of all 
patients who either complete the treatment regimen or withdraw from study by reason of toxicity. 
 
Toxicities due to EGFR AS in our previous phase I trial were negligible, and consisted of grade 1 
injection site pain and swelling. Because we will combine EGFR AS with radiation and cetuximab 
in the proposed clinical trial, a separate safety evaluation will be conducted. In the first stage 
(safety component), 11 patients will be treated and observed for serious adverse events (SAEs) 
that are due to EGFR AS (possibly, probably, or definitely), not cetuximab or radiation. In the first 
stage, after three (3) subjects are enrolled and have received all EGFR AS injections, there will be 
a two-week waiting period to assess adverse events. After the two-week period, additional 
subjects may be enrolled. Eligible patients will include stage IV or recurrent patients who would 
not be eligible for the subsequent study of efficacy, and their accrual to study is only for the 
assessment of safety. We seek to rule out an SAE rate of 20% or greater due to EGFR AS. If no 
grade 3/4 toxicities due to EGFR AS are observed among 11 patients, then an upper 90% 
confidence bound for the SAE rate is less than 20%. 
 
Second stage (phase II component): 31 evaluable patients. The efficacy-evaluable population 
consists of all patients who complete the treatment regimen. 
 
Sample size for the second stage of study is based on the primary endpoint: 1-year locoregional 
PFS. We use a historical control rate of 63% for 1-year locoregional PFS in patients on radiation 
and cetuximab, as reported by Bonner et al. To account for the inherent variability in this estimate, 
and to improve the likelihood that we can detect a true improvement with the addition of EGFR AS, 
we use the reasoning of Fazzari et al.45 which advocates setting the null hypothesis to the upper 
bound of the 75 percent confidence interval for the historical-control endpoint. By assuming that 1- 
year locoregional PFS as reported by Bonner et al follows an exponential distribution from a 

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sample of 211 patients, the upper 75th percent confidence bound for 1-year locoregional PFS is 
68%. Targeting a 50% reduction in the hazard rate for 1-year locoregional PFS under our 
treatment regimen implies that 1-year locoregional PFS would be improved to 83%. To achieve 
this objective, we plan a study with 2 years of patient accrual, 1 year of additional follow-up, and 
assume that 1-year locoregional PFS will have an exponential distribution. Under these 
assumptions, a 1-sided exponential test at α = 0.10 will provide 90% power with 31 patients. In 
addition, we plan to evaluate tumor response and locoregional progression in injected and non- 
injected lymph nodes. The rates of progression in injected versus non-injected regions will be 
compared by an exact test for two rates, implemented in StatXact 8. 
 
Total sample size 
 
A total of 42 evaluable patients will be accrued to study. 
 
Eleven patients will be treated in the first stage, which will assess the safety of the combination. 
Patients failing to complete treatment for reasons other than toxicity will be replaced. 
 
In the second stage, 31 efficacy-evaluable patients will be enrolled, provided safety is acceptable. 
 
11.2 
Secondary Clinical Endpoints 
 
Clinical secondary endpoints in phase II include adverse events, in-field and out-field, objective 
response rate, distant PFS, overall PFS, and overall survival. 
 
11.3 
Accrual 
 
The study will be conducted at the CTRC at UTHSCSA. We anticipate that 42 evaluable patients 
(11 in the first stage and 31 in the second stage) will be accrued over two years, and that the 
monthly accrual rate will be approximately 1-2 patients per month. 
 
11.4 
Safety Evaluation During the Second Stage 
 
In the phase II component of study, safety will be monitored continuously using Bayesian methods. 
The toxicities of the combination of RT and cetuximab have been characterized by a randomized 
study by Bonner et al 18 in which 208 patients treated with RT and cetuximab were evaluated for 
toxicity. Grade 3/4 radiation mucositis and radiation dermatitis were common toxicities occurring 
with high frequencies. The proportion of grade 3/4 events in the RT+cetuximab arm were 56% for 
mucositis and 23% for radiation dermatitis. While the intratumoral injection of EGFR AS is not 
expected to increase the rate of SAEs, we will nonetheless monitor patients for unexpected 
increases in mucositis and radiation dermatitis that may be attributable (possibly, probably, 
definitely) to the addition of EGFR AS, and will suspend the trial if there is evidence that the 
occurrences of these toxicities are greater than what would be expected from radiation and 
cetuximab without EGFR AS. 
 
We use informative prior distributions of SAEs to conform in part to the reported SAE frequencies 
in Bonner – probabilities of grade 3/4 mucositis of 56% and grade 3/4 radiation dermatitis of 23%. 
Our assumed prior probabilities are not as concentrated as the nominal uncertainty in the 

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estimates from the Bonner study of 208 patients, but instead allow for greater variability, which can 
arise from different treatment populations. Specifically, we specify a 90% credibility interval for the 
probability of mucositis as 56% 15%, and 23% 10% for the probability of radiation dermatitis; these 
are wider intervals than suggested by the results of the study by Bonner et al. 
 
Assuming that the prior probability of an SAE follows a beta distribution, the stopping rule is based 
on the updated posterior probability of an SAE. As each patient is observed for SAEs, the posterior 
probability, which follows a beta distribution, of SAE can be calculated. If at any time during the  
trial the posterior probability is ≥ 0.80 that the rate of treatment-related grade 3/4 mucositis 
exceeds 56%, the study will be suspended pending review by Data and Safety Monitoring 
Committee (DMSC). Similarly, if the posterior probability is greater than 0.80 that the rate of 
treatment-related grade 3/4 radiation dermatitis exceeds 23%, the study will be suspended for 
review by the DSMC. To permit continuous monitoring of SAEs, a table (see below) based on the 
cumulative number of patients experiencing SAEs at any point during the trial can be used to  
signal when the study should be suspended and reviewed by the DSMC. 
 
Table 6 Number of Patients Observed to Have Treatment-Related SAEs and Corresponding Posterior 
  
Probabilities Needed to Suspend the Study in Phase II 
 
Treatment-Related 
 
 
Grade 3/4 Mucositis 
Treatment-Related 
Grade 3/4 Radiation Dermatitis 
 
Patients 
SAEs 
Pr( ≥0.56)* 
SAEs 
Pr ( ≥ 0.23) 
4 
--- 
--- 
4 
.825 
5 
--- 
--- 
4 
.804 
6 
6 
.814 
5 
.861 
7 
7 
.848 
5 
.843 
8 
8 
.877 
5 
.823 
9 
8 
.832 
5 
.802 
10 
9 
.862 
6 
.858 
11 
9 
.815 
6 
.840 
12 
10 
.848 
6 
.821 
13 
11 
.875 
6 
.801 
14 
11 
.833 
7 
.856 
15 
12 
.862 
7 
.838 
16 
12 
.818 
7 
.820 
17 
13 
.848 
7 
.800 
18 
13 
.803 
8 
.854 
19 
14 
.834 
8 
.837 
20 
15 
.862 
8 
.819 
21 
15 
.821 
9 
.868 
22 
16 
.849 
9 
.852 
23 
16 
.807 
9 
.835 
24 
17 
.837 
9 
.818 
25 
18 
.863 
10 
.866 
26 
18 
.824 
10 
.850 
27 
19 
.851 
10 
.834 
28 
19 
.811 
10 
.817 
29 
20 
.839 
11 
.864 
30 
21 
.864 
11 
.849 
31 
21 
.827 
11 
.833 
* π is the posterior probability of a treatment-related SAE. For example, given the observed number of patients treated and 
the number of patients observed with SAEs, Pr(π ≥0.56) is the posterior probability that treatment-related grade 3/4 
mucositis exceeds 0.56, the expected value prior to study. 

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The table above presents the minimum number of patients experiencing treatment-related SAEs 
(i.e., those SAEs judged to be possibly, probably, or definitely related to the study regimen) that 
would dictate suspension of the trial in accordance with the stopping rule. For example, after the 
first 10 patients have completed treatment and been observed for toxicity, 9 patients experiencing 
treatment-related grade 3/4 mucositis, or 6 patients experiencing treatment-related grade 3/4 
radiation dermatitis, would trigger trial suspension pending review by the DSMC. 
 
11.5 
Hypothesis Testing and Operating Characteristics for Correlative-Study Endpoints 
 
Correlative studies will assess antitumor activity measured by levels of biomarker expression. This 
will involve measurement of the following biomarkers from tumor tissue using RPPA: EGFR, 
pEGFR, Src, pMAPK, STAT3, pSTAT3, pSTAT5, pSTAT1, pAKT, p38, p21, p27, PARP, E- 
cadherin, p-ErbB3, and Ki67. In some instances immunohistochemical staining of selected 
proteins will be performed to verify or validate RPPA results. Biomarkers will be tested for 
treatment-associated modulation (i,e., change from baseline) as well as for association with 1-year 
locoregional PFS (primary endpoint), and other efficacy parameters, such as objective response 
rate, PFS, and overall survival. These analyses will be exploratory in nature. 
 
To estimate the power of our study to assess whether significant modulation of biomarkers occurs 
from therapy, we assume that 80% of patients in phase II will have a 2nd biopsy after 2 doses of 
cetuximab with EGFR AS, thereby providing paired tumor tissue samples in 24 patients total. 
Based on data from a prior phase I clinical trial, the standard deviation was 0.7 on average for 
paired differences (log2[post/baseline]) in proteins measured pre and post therapy. Assuming this 
standard deviation will apply, a two-tailed signed rank test at α = 0.01 (to control the false-positive 
rate) in 24 patients will provide 80% power to detect a change of 0.55 (log2 scale), which 
corresponds to a change of 46% from the baseline-expression level. Although the search for 
individual biomarkers that change with treatment is exploratory and hypothesis generating, we will 
report all nominal p-values along with those that remain significant using a 10% false discovery 
rate. 
 
It is also of interest to assess whether biomarker modulation within the treatment window is 
associated with PFS. To estimate power for these analyses, we use Cox proportional hazards 
regression to evaluate whether PFS depends on change in biomarker expression, considered for 
each biomarker individually. We assume that 25% of treated patients will have loco-regional 
progression within 1 year, i.e., PFS = 0.75, based on expectation averaged over the null and 
alternative hypotheses. We also assume that among 31 patients enrolled in phase II, 24 will have 
adequate tissue and biomarker assessments before and after therapy. We further assume that 
accrual in phase II will take 18 months, with 12 months of follow-up beyond the last patient 
enrolled. Under exponential survival, these assumptions imply that 9 of the 24 patients with pre- 
post biomarker measurements will have loco-regional progression within our study time frame. A 
two-tailed Cox-regression test of trend at α = .05 will therefore have 80% power to detect a hazard 
ratio of 3.8, which corresponds to a one-unit change (i.e., 2-fold increase or decrease) in the 
biomarker tested. 
 
With respect to assessing PFS in relation to baseline measurements of biomarkers, we assume 
that all 31 patients enrolled in study will have tissue available for analysis, in which case 12 
patients are expected to have loco-regional progression within the study time frame. For this 

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situation, the minimum detectable hazard ratio would be 3.2 under the conservative assumption 
that variability in biomarker expression among patients is no greater than that within patients 
(greater variability would provide increased opportunity to detect biomarker effects). 
 
The analyses of the correlative data are exploratory. A less restrictive test (α = .05) is used for 
PFS to avoid missing important leads. Nominal p-values for all biomarkers associated positively or 
negatively with PFS will be reported along with a designation of those that fall within a 10% false 
discovery rate. 
 
11.6 
Additional Analyses 
 
The data from all evaluable patients will be used in the analyses of safety (phase I and 
phase II), tumor response (phase II), and survival (phase II). 
 
Baseline Characteristics 
 
Baseline descriptive statistics on all evaluable patients will be provided on 
demographic variables (age, sex, and race/ethnicity), performance status, 
laboratory parameters, treatment regimens that were previously used, and disease 
characteristics, including tumor size, number of nodes involved, and metastatic 
sites. 
 
Safety Profile 
Using NCI CTCAE (v4.0), the number of patients experiencing AEs over their 
course of treatment, and for 30 days beyond the last protocol treatment 
administered, will be characterized by type of AE and grade, and by the time of 
onset in relation to the first day of therapy. Attribution of AEs to treatment 
(unrelated, unlikely, possible, probable, or definite) will be recorded, and the details 
of all treatment-related toxicities will be reported. 
 
Survival 
PFS will be measured from the initial date of treatment to the date of documented 
progression, or the date of death (in the absence of progression). 
 
Overall survival will be measured from the initial date of treatment to the recorded 
date of death or for a total of 5 years follow up (See Section 12.3). 
 
PFS and overall survival will be estimated by the Kaplan-Meier method. The 
corresponding median survival times (with 90% confidence limits) will be 
determined, as will the cumulative percentage of patients remaining progression- 
free at selected time points after initial treatment. 
 
Tumor Response 
Response rates will be estimated by the proportion of patients with a best  
response of complete response (CR), partial response (PR), or stable disease (SD) 
by RECIST criteria, with corresponding exact 90% confidence limits being  
reported. The distribution of response duration (time to progression among patients 

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achieving CR, PR, or SD) will be characterized by median and quartiles, with the 
corresponding Kaplan-Meier estimate being made of PFS among patients 
responding to treatment. 
 
12. 
RECORDS TO BE KEPT 
 
12.1 
In addition to the regular hospital or clinic chart, a separate patient folder will be kept which 
includes: 
 
▪ The patient’s signed, dated and witnessed consent 
 
▪ Pathologic documentation of squamous cell carcinoma of the head and neck 
 
▪ The Completed Patient Registration Form and all other study forms 
 
12.2 
Within 7 days after patient’s entry on study, copies of the following must be received by the 
coordinating nurse at the CTRC at the UTHSCSA: 
 
Ofelia Romero, RN 
Clinical Research Nurse III 
Department of Clinical Investigations 
Institute for Drug Development 
Cancer Therapy and Research Center at UTHSCSA 
Mail Code 8229 
7979 Wurzbach Road, Suite Z413 
San Antonio, Texas 78229 
Office: (210) 450-1810 
Fax: (210) 614-4418 
Email: romeroo@uthscsa.edu 
 
12.2.1 Completed Patient Registration Form. Eligibility criteria will be clearly stated. 
Baseline information will include: age, gender, race, feeding tube placement, smoking and 
alcohol history, performance status, TNM staging, and sites of disease involvement. 
 
12.2.2 Flow Sheet reflecting pretreatment test results and the first therapy. 
 
12.2.3 Measurement Form showing baseline measurement (measurable disease 
patients). 
 
12.2.4 Pathology Report (pathologic confirmation of disease.) 
 
 
12.3 
Thereafter, while the patient is on study, forms will be completed according to the following 
schedule: 
 
12.3.1 Evaluation forms after completion of radiation. Clinical and radiographic response 
will be reported. Also, response in the primary and lymph nodes will be reported 

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separately. Measurement forms must give serial measurements or evaluations as required 
by protocol to assess disease response to therapy. Follow-up forms will report the 
presence of feeding tube and late toxicities. 
 
12.3.2 A final Treatment Summary Form is to be submitted when the patient progresses, 
dies, or goes off study for any other reason. Any subsequent head and neck surgery will 
be reported. 
 
12.3.3 Follow-Up Form is submitted at the time the patient goes off study at any time 
prior to treatment completion as scheduled and thereafter, every 3 months for the first 2 
years, then every 6 months for the next 3 years, and subsequently annually at the 
discretion of the treating physician. 
 
12.3.4 Death must be reported, using the Follow-Up Form 
 
 
13. 
CORRELATIVE STUDIES 
 
13.1 
Reverse Phase Protein Microarrays (RPPA) 
 
The last decade has witnessed a relative explosion in the development and availability of 
therapeutic reagents that block specific signaling pathways. While gene microarrays and 
transcriptional profiling can provide information regarding coordinate gene expression and 
transcriptional control mechanisms, they cannot capture fluctuating signaling events that occur at 
the protein and particular the post translational level. In addition, mRNA levels do not necessarily 
correlate with protein abundance. To fully realize the potential of molecular targeted therapy, it is 
critical to apply tools that can profile the cancer cell proteome in terms of both total levels and 
functional modifications. Only recently has technology been developed to measure the activation 
state of kinase driven signal transduction networks. Using antibodies that specifically recognize the 
phosphorylated and total isoforms of kinase substrates, reverse phase protein microarrays (RPPA) 
can multiplex and quantify a large array of activated proteins.37 The amount of target is determined 
by comparison to standard curves of peptide and phosphopeptide target. Approaches that rely on 
immobilized antibodies to capture their analytes from solution (forward phase approach) are limited 
by the lack of antibodies that can function in this format and the need for a relatively large amount 
of starting material as well as using a single condition for multiple antibodies. In contrast, the 
reverse phase approach (RPPA) is accomplished by depositing small volumes of cell lysates onto 
a high protein-binding substratum such as a nitrocellulose slide using a robotic microarrayer 
requiring small amounts of input protein which has been boiled in SDS mimicking the rigorous 
conditions of western blotting. Each slide can accommodate up to 160 different samples with 
titration curves and peptide controls. Arrays are then probed with signal generating detection 
antibodies, which can be dependent or independent of the phosphorylation state. Hierarchical 
clustering analysis facilitates the determination of distinct molecular subgroups according to their 
protein signature. New antisera continue to be validated and over 100 different signaling related 
antibodies to date have been validated for their use in RPPA. 
 
We have acquired experience with RPPA in collaboration with Dr. Gordon Mills at MD Anderson 
Cancer Center (MDACC). Using RPPA, we are currently analyzing biomarker expression levels in 

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tumor biopsies obtained before, during and after intratumoral gene therapy treatment using an 
EGFR antisense gene in patients with recurrent HNSCC. As shown in Figure 1, this technique 
provides quantitative information on the expression of critical proteins. 
 
 
A 
B 
 
 
 
 
Figure 1. Validation and sensitivity of tissue lysate arrays. Panel A. Serial dilutions of activated 
purified AKT, Phospho-AKT peptide were arrayed in duplicate and quantitated. The linearity and 
sensitivity (femtograms of purified protein) is represented in the plot. Panel B. Tissue lysate arrays are 
compared to Western blots of the same cell lysate treated with the KP86328 (AKT inhibitor) and 
LY294002 (PI3 kinase inhibitor). The squares highlight the detection of phospho-AKT upon EGF 
stimulation by tissue lysate arrays. Quantitative results from tissue lysate arrays and Western Blot 
demonstrated remarkable concordance. 
 
Preliminary results from tumor biopsies collected from SCCHN patients treated on the first two dose 
tiers of a phase I clinical trial to determine the toxicity and biologic efficacy of EGFR AS demonstrates 
that expression of the target gene (EGFR) as well as its phosphorylated form and downstream targets 
can be measured using RPPA (Figure 2). 

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Figure 2. Detection of total EGFR and phosphorylated forms of EGFR (p-EGFR 992, p-EGFR 
1173) in SCCHN tissues by RPPA. Tissue lysates are prepared from SCCHN patients treated on an 
EGFR antisense gene therapy trial. Tissue is harvested before (Pre), during (Dur) and after (Post) 
treatment. Each sample is analyzed in duplicate serial dilutions. The RPPA panels represent results 
from two patients (patients A and B) treated on the first 2 dose tiers. 
 
To date, over 100 monospecific antibodies have been validated for use in RPPA (see 
http://home.ccr.cancer.gov/ncifdaproteomics). MDACC and NCI/FDA maintain a joint database of 
validated antibodies for RPPA. These antibodies detect a variety of proteins involved in 
phosphorylation, apoptosis (activated and cleaved proteins) and cell cycle progression (cyclins, 
phosphohistones p21, p27). Although up to 100 antibodies have been validated, we will prioritize 
pathways and antibodies for analysis. Blockade of EGFR in head and neck cancer cell lines leads 
to downregulation of several downstream signaling proteins including pSrc, pMAPK, pSTAT3, 
pSTAT5, pSTAT1, and pAKT. The first tier of proteins/phosphoproteins would include EGFR, 
pEGFR, Src, pMAPK, STAT3, pSTAT3, pSTAT5, pSTAT1, pAKT, p38, p21, p27, PARP, E- 
cadherin, p-ErbB3, and Ki67. Additional pathways/proteins can be evaluated as other antisera are 
validated and/or new hypotheses emerge from ongoing experiments. 
 
Frozen tumor will be homogenized with lysis buffer. Lysates will be boiled with 1% SDS, mimicking 
the stringent conditions used in immunoblotting. After centrifuging, the protein-rich supernatant can 
be stored at –80°C and transferred to the Mills laboratory at MDACC for RPPA. The cost of setting 
up a RPPA facility (~$500,000) requires that the lysates be arrayed in the Mills lab. Serial dilutions 
with additional lysis buffer are generated from each lysate immediately prior to array preparation 
using a Tecan liquid handling robot. A robotic arrayer then creates a 640 spot array on 
nitrocellulose-coated glass slides where each spot on the array represents a precise dilution of a 
particular sample lysate. As many as 160 different samples with 4 serial dilutions can be studies  
on a single slide and with robotics, 24 identical slides can be printed at a time. The Mills lab has 
successfully transferred lysates from center to center with retention of signals. Each slide is then 
probed with a specific validated primary antibody under optimal blocking conditions to minimize 

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background noise. Multiple controls are placed on each slide to facilitate quantitation. The signal is 
amplified using a DAKO catalyzed system and antibody to -actin and GAPDH can be used as 
controls. Slides are then scanned and analyzed by ImageQuant software (Molecular Dynamics). 
The serial dilution “dot” intensities are quantitated using Microvigene software (VigeneTech, Inc.) 
The Mills lab has demonstrated that this technique is sensitive (to femtograms of protein) and 
reproducible. Serial dilutions allow an accurate determination of protein quantity using 
concentration curves of synthetic phospho- and non-phosphopeptides of the antibody-binding site 
for each antibody. 
 
13.2 
IHC Analysis of Tissue Microarrays 
 
Because RPPA is an emerging technology, which cannot identify the cells expressing the target 
protein, we will also carry out IHC analysis of the proteins identified by RPPA of TMA generated 
from the biopsy samples. For high throughput immunohistochemical analysis and standardization 
of staining conditions, tissue microarrays (TMAs) will be constructed from formalin fixed paraffin 
embedded tissue blocks from the tumor biopsies. Using a manual tissue arrayer (MTA-1, Beecher 
Instruments, Sun Prairie, WI) 0.6 mm tissue cores will be extracted from each pre and post 
treatment tumor in triplicate and arrayed on 1-2 recipient paraffin blocks along with normal tonsillar 
controls. The newly constructed array block will then be warmed to 35-37°C for 10 minutes to 
allow annealing of donor cores to the paraffin wax of the recipient block and minimize core loss. 
Donor cores will range from 2-4 mm in length. Hence each TMA will yield an estimated 100 to 200 
tissue sections (4 μm thickness). For TMA quality assessment morphologic confirmation of tumor, 
throughout the entire thickness of the block, one hematoxylin and eosin stained slide will be 
prepared from every five tissue sections. Immunohistochemical staining will be performed to 
assess various biomarkers in the EGFR signaling pathway including EGFR, pEGFR, Src, pMAPK, 
STAT3, pSTAT3, pSTAT5, pSTAT1, pAKT, p38, p21, p27, PARP, E-cadherin, p-ErbB3, and Ki67 
on paraffin sections cut from the TMAs using standard methods. Sections will be deparaffinized 
with successive ethanol and xylene baths. These sections were then subjected to an optimized 
antigen retrieval method individualized to each antibody. Signal amplification will be performed 
using a proprietary micropolymer peroxidase (ImmPRESS™, Vector, Burlingame, CA) conjugated 
to an anti mouse antibody. Immunoreactive cells will be visualized with the brown color resulting 
from incubation with diaminobenzidine (DAB) chromogenic substrate at room temperature for 5 
minutes. Sections will be counterstained blue with hematoxylin for 15 seconds and lithium 
carbonate for 5 seconds to provide morphologic detail on paraffin sections cut from the TMAs 
using commercially available antibodies and standard methods. Sections will be deparaffinized 
with successive ethanol and xylene baths. These sections will then be subjected to an optimized 
antigen retrieval method individualized to each antibody. Signal amplification will be performed 
using a proprietary micropolymer peroxidase (ImmPRESS™, Vecto 
 
 
r, Burlingame, CA) conjugated to an anti mouse antibody. Immunoreactive cells will be visualized 
with the brown color resulting from incubation with diaminobenzidine (DAB) chromogenic substrate 
at room temperature for 5 minutes. Sections will be counterstained blue with hematoxylin for 15 
seconds and lithium carbonate for 5 seconds to provide morphologic detail. Immunohistochemical 
staining will be scored semiquantitatively for each core. The percentage of immunoreactive cells 
will be recorded, rounded to the nearest 10 percentile. Additionally, intensity will be scored as 

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follows: 0 (none), 1+ (weak), 2+ (moderate) 3+ (strong). A composite score will be derived from the 
product of the percentage and intensity of staining. When appropriate, separate scores for each 
case will be assigned for cytoplasmic and nuclear staining. 
 
 
 
Table 7. Summary Table Of Material To Be Collected And Timepoints 
Method 
Specimen Type 
Timepoints 
Baseline biopsy 
Week 2 biopsy 
(after week 2 of cetuximab and EGFR AS 
but prior to radiation) 
RPPA 
Tumor Tissue, fresh 
frozen and/or paraffin- 
embedded 
X 
X 
IHC 
Tumor Tissue, paraffin- 
embedded 
X 
X 

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14. 
REFERENCES 
 
1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54(1):8-29. 
2. Kotwall C, Sako K, Razack M, et al. Metastatic patterns in squamous cell cancer of the head and neck. 
Am J Surg 1987;154:439. 
3. Zbaeren P, Lehmann W. Frequency and sites of distant metastases in head and neck squamous cell 
carcinoma. Arch Otolaryngol Head Neck Surg 1987;113:762-4. 
4. Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for 
head and neck squamous- cell carcinoma: three meta-analyses of updated individual data. MACH-NC 
Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 
2000;355(9208):949-55. 
5. Brizel D, Albers M, Fisher S, et al. Hyperfractionated irradiation with or without concurrent 
chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998;338(25):1798-804. 
6. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant 
chemotherapy and radiation therapy for advanced-stage orophaynx carcinoma. J Natl Cancer Inst 
1999;91(24):2081-6. 
7. Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy 
alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 
1998;16(4):1318-24. 
8. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with 
advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 
1998;16(4):1310-7. 
9. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy 
and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head 
and neck cancer. J Clin Oncol 2003;21(1):92-8. 
10. Forastiere AA, Berkey B, Maor M, et al. Phase III Trial to Preserve the Larynx: Induction 
Chemotherapy and Radiotherapy Versus Concomitant Chemoradiotherapy Versus Radiotherapy 
Alone, Intergroup Trial R91-11. Proc Am Soc Clin Oncol 2001;20:A4. 
11. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the 
head and neck. N Engl J Med 2006;354(6):567-78. 
12. Vokes EE, Weichselbaum RR, Lippman S, Hong WK. Head and neck cancer. N Engl J Med 
1993;328:184-94. 
13. Argiris A, Brockstein BE, Haraf DJ, et al. Competing causes of death and second primary tumors in 
patients with locoregionally advanced head and neck cancer treated with chemoradiotherapy. Clin 
Cancer Res 2004;10(6):1956-62. 
14. Yancik R, Havlik RJ, Wesley MN, et al. Cancer and comorbidity in older patients: a descriptive profile. 
Ann Epidemiol 1996;6(5):399-412. 
15. Hong W, Lippman S, Itri M, et al. Prevention of second primary tumors with isotretinoin in squamous- 
cell carcinoma of the head and neck. N Engl J Med 1990;3223:795-801. 
16. Khuri FR, Lee JJ, Lippman SM, et al. Randomized phase III trial of low-dose isotretinoin for prevention 
of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst 
2006;98(7):441-50. 
17. Mendelsohn J, Baird A, Fan Z, Markowitz SD. Growth factors and their receptors in epithelial 
malignancies. In: Mendelsohn J, Howley PM, Israel MA, Liotta LA, eds. The Molecular Basis of 
Cancer. Philadelphia: W.B. Saunders Company; 2001:137-44. 
18. Huang SM, Harari PM. Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale 
and preliminary clinical results. Invest New Drugs 1999;17(3):259-69. 

CTRC# 11-47 
Version date January 13, 2015 
54 of 53 
Confidential 
 
 
 
 
19. Tzahar E, Waterman H, Chen X, et al. A hierarchical network of interreceptor interactions determines 
signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 
1996;16(10):5276-87. 
20. Lenferink AE, Pinkas-Kramarski R, van de Poll ML, et al. Differential endocytic routing of homo- and 
hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. Embo J 
1998;17(12):3385-97. 
21. Karunagaran D, Tzahar E, Beerli RR, et al. ErbB-2 is a common auxiliary subunit of NDF and EGF 
receptors: implications for breast cancer. Embo J 1996;15(2):254-64. 
22. ERBITUX. ImClone Systems Incorporated and Bristol-Myers Squibb Company. 2004;ER-Boool. 
23. Robert F, Ezekiel MP, Spencer SA, et al. Phase I study of anti--epidermal growth factor receptor 
antibody cetuximab in combination with radiation therapy in patients with advanced head and neck 
cancer. J Clin Oncol 2001;19(13):3234-43. 
24. Bonner JA, Giralt J, Harari PM, et al. Cetuximab prolongs survival in patients with locoregionally 
advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy 
with or without cetuximab. Proc Am Soc Clin Oncol 2004;22(14S):A5507. 
25. Argiris A. Update on chemoradiotherapy for head and neck cancer. Curr Opin Oncol 2002;14(3):323-9. 
26. Nabel GJ, Nabel EG, Yang ZY, et al. Direct gene transfer with DNA-liposome complexes in melanoma: 
expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci U S A 
1993;90(23):11307-11. 
27. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth 
factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer 
Res 1993;53(15):3579-84. 
28. Rubin Grandis J, Melhem MF, Barnes EL, Tweardy DJ. Quantitative immunohistochemical analysis of 
transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell 
carcinoma of the head and neck. Cancer 1996;78(6):1284-92. 
29. Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF-alpha and EGFR protein in head and 
neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 1998;90(11):824-32. 
30. Rubin Grandis J, Chakraborty A, Melhem MF, Zeng Q, Tweardy DJ. Inhibition of epidermal growth 
factor receptor gene expression and function decreases proliferation of head and neck squamous 
carcinoma but not normal mucosal epithelial cells. Oncogene 1997;15(4):409-16. 
31. Noonberg SB, Scott GK, Garovoy MR, Benz CC, Hunt CA. In vivo generation of highly abundant 
sequence-specific oligonucleotides for antisense and triplex gene regulation. Nucleic Acids Res 
1994;22(14):2830-6. 
32. Kunkel GR. RNA polymerase III transcription of genes that lack internal control regions. Biochim 
Biophys Acta 1991;1088(1):1-9. 
33. He Y, Zeng Q, Drenning SD, et al. Inhibition of human squamous cell carcinoma growth in vivo by 
epidermal growth factor receptor antisense RNA transcribed from the U6 promoter. J Natl Cancer Inst 
1998;90(14):1080-7. 
34. Hui KM, Ang PT, Huang L, Tay SK. Phase I study of immunotherapy of cutaneous metastases of 
human carcinoma using allogeneic and xenogeneic MHC DNA-liposome complexes. Gene Ther 
1997;4(8):783-90. 
35. Lai S, Lui V, Koppikar P, et al. Intratumoral epidermal growth factor receptor (EGFR) antisense (AS) 
DNA in recurrent squamous cell carcinoma of the head and neck (SCCHN): A phase I trial. J Clin 
Oncol 2007;25(June 20 supplement):6009. 
36. Eisenhauer, EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009; 45(2): 228-47. 
37. Sheenan K, et al. Use of reverse phase protein microarrays and reference standard development for 

CTRC# 11-47 
Version date January 13, 2015 
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molecular network analysis of metastatic ovarian carcinoma. Molecular and Cellular Proteomics 
2005:In Press. 
38. Fazzari M, Heller G, Scher HI. The phase II/III transition. Toward the proof of efficacy in cancer clinical 
trials. Control Clin Trials 2000;21(4):360-8. 

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APPENDIX I 
 
 
ECOG PERFORMANCE STATUS 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 

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APPENDIX II 
 
Template for Reporting Adverse Events 
In Human Gene Transfer Trials 
This template is intended to facilitate the reporting of adverse events in human gene transfer trials. You may 
download this as a Word document and the fields will expand according to the amount of text entered. Use of this 
template is not required and other formats (e.g. AdEERS reports, MedWatch forms) may be acceptable provided that 
they include all the information specified in M-I-C-4-a of the NIH Guidelines for Research Involving Recombinant 
DNA Molecules. (http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html) 
 
Submitting this completed template to the NIH Office of Biotechnology Activities alone does NOT fulfill the 
reporting requirements of other agencies. However, some agencies may accept submission of a duplicate copy of this 
completed template. You should verify with the other parties to whom you report whether the use of this template is 
acceptable. 
Completed reports may be sent via U.S. mail, courier service, e-mail, or facsimile to: 
NIH Office of Biotechnology Activities 
6705 Rockledge Drive, Suite 750 
Bethesda, Maryland 20892-7985 
(For all non-USPS deliveries use Zip Code 20817) 
Telephone 301-496-9838 
Fax 301-496-9839 
E-mail address for Reporting Adverse Events: GeMCRIS@od.nih.gov 
General E-mail: oba@od.nih.gov 
 
Website: www4.od.nih.gov/oba/ Gene Transfer Adverse Event Reporting Template Version 4.29.05 
PROTOCOL AND EVENT TYPE 
NIH/OBA (RAC) Protocol Number 
FDA IND number 
Date this report completed: 
Seriousness of the AE (choose one) 
Death 
Life-threatening 
Initial or prolonged hospitalization 
Disability 
Congenital anomaly 
Required intervention to prevent permanent 
impairment/damage 
Other medically important condition 
Non-serious 
Severity of Event 
Minimal Moderate Severe 
Life- Threatening Fatal 
Was this event expected in terms of its severity? 
Yes No 
Was this event expected in terms of its specificity? 
Yes No 
Relationship of Event to gene transfer product 
Unrelated 
Unlikely 
Possible Probable 
Definite 
Attribution of AE 
Attribution of AE, continued 
Concomitant medication 
Product 
Intervention 
Underlying disease 
Route of administration 

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Other suspected cause (describe) 
Type of report 
Initial 
Follow-up 
DEMOGRAPHICS 
PI Name 
Name of Clinical Trial Site/Organization 
PI Telephone Number 
PI E-mail Address 
Reporter name 
Reporter Telephone number 
Reporter E-mail address 
Research Participant’s study identification number 
Research Participant’s gender 
Research Participant’s date of birth 
Research Participant’s date of death 
Research Participant’s weight in kgs 
Research Participant’s height in cms 
Which Arm/Cohort/treatment group was the subject assigned to? 
Was subject dosed? 
Yes No Information Not Available 
What study agent was received: 
IND agent Placebo Blinded Study Agent 
Were there any Protocol Deviations/Violations/Exceptions 
for this participant? 
Yes:  
 
No 
DETAILED ADVERSE EVENT INFORMATION 
Adverse Event Date 
Description of Event 
Relevant tests (e.g. x-rays) and results 
Treatment (s) of Adverse Event (Include medications used to treat this event.) 
Name of Concomitant Medications 
(Do not include medications used to treat this event.) 
Pre-existing conditions/ relevant clinical history 
(if this is an oncology trial, please designate primary disease, e.g. ovarian cancer) 
Date(s) of treatment(s) of the adverse event 
Was autopsy performed? 
Yes No 
Date of autopsy 
or Not Applicable   
 
Outcome of the event 
Recovered/resolved 
Recovering/resolving 
Not recovered/not resolved 

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Recovered/resolved with sequelae 
Fatal 
Unknown 
Documentation accompanying the report 
(e.g., H& P, Progress Notes, Discharge Summary, Lab or Autopsy Reports, Other, etc.) 
Description of any “other” documentation 
PRODUCT AND DOSING INFORMATION 
Name of gene transfer product 
Vector type (e.g. adenovirus) 
Vector sub-type (e.g. type 5, also include relevant deletions) 
Lot number 
Was the agent manufactured at an NGVL? 
Route of administration 
Site of administration 
Did subject receive the dose specified in the protocol? 
If not, what dose was given? 
Date of first exposure to study agent? 
Date of most recent exposure to study agent? 
Total dose received prior to this event? 
Total dose quantity administered to subject to date 
Unit of measure for a single dose 
Dose quantity in a single administration 
If courses used, how many were given prior to this event? 
How many doses on the last course were given? 
Was the administration of this product stopped because of this adverse event? 
Name of other treatment (s) (medications, radiation, surgery) received by research participant as required by 
the protocol 

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APPENDIX III 
 
Supplemental Efficiency and Distribution Data 
 
We performed tumor volume studies in our athymic nude mouse xenograft model using the same EGFR antisense 
construct that will we are proposing to admiminister to the head and neck cancer patients. This construct was 
administered either by intratumoral inoculation (Figure 1A) or by intravenous administration (Figure 1B). In each 
case, tumor growth inhibition was observed compared with treatment using the control EGFR sense DNA construct. 
 
 
 
 
6 
 
5 
 
4 
 
3 
 
2 
 
1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Day 
 
 
 
Sense control 
Antisense EGFR 
 
50 
 
 
 
25 
 
 
 
0 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Day 
 
Each time point plotted indicates days on which i.v. injections 
(25 g of DNA) were administered 
Control Sense 
EGFR antisense 
Figure 1. Tumor growth inhibiton of SCCHN xenografts treated with (A) intratumoral (left above) or (B) intravenous 
administration of EGFR antisense DNA (pNGVL-EGFR-AS) compared with administration of the control EGFR sense 
DNA. The intratumoral DNA (25 g) was given three times a week and the intravenous DNA (25 g) was 
administered daily after the formation of palpable tumor nodules (~10-14 days) (right above). 
 
In addition to the efficacy data, we performed DNA distribution studies using the pNGVL-EGFR AS construct. As 
shown in the summary Table and figures below, the DNA was less widely distributed without co-administration of 
liposomes.38 
 
Table: Summary of EGFR antisense DNA tissue distribution at each time point 
 
O r g a n  
D a y 2 
D a y 7 
D a y 1 4  
D a y 2 1  
D a y 2 8 
B l o o d  
- 
- 
- 
- 
0 
B r a in  
3 
0 
- 
- 
- 
H e a r t 
2 
2 
0 
- 
- 
L u n g 
0 
- 
- 
- 
- 
L iv e r 
0 
- 
- 
- 
- 
K id n e y 
0 
- 
- 
- 
- 
G o n a d  
0 
- 
- 
- 
- 
L e f t m u s c l e 
3 
3 
0 
- 
- 
R ig h t m u s c le ( I n j) 2 
1 
0 
- 
- 
L e f t L y m p h n od e 
1 
2 
2 
1 
0 
R i g h t l y m p h n od e 2 
0 
- 
- 
- 

CTRC# 11-47 
Confidential 
Version January 13, 2015 
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CTRC# 11-47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version January 13, 2015 
A3 
Confidential