Phase I Dose Escalation Study of Stereotactic Body Radiotherapy for Carcinoma of the Head and Neck in High Risk Patients Who Are Ineligible/Refuse Standard of Care Therapy
Phase: NA
Conditions: Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Recurrent Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Recurrent Oral Cavity Squamous Cell Carcinoma, Recurrent Oropharyngeal Squamous Cell Carcinoma, Stage II Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage III Hypopharyngeal Squamous Cell Carcinoma, Stage III Laryngeal Squamous Cell Carcinoma, Stage III Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage III Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage III Oral Cavity Squamous Cell Carcinoma, Stage III Oropharyngeal Squamous Cell Carcinoma, Stage IVA Hypopharyngeal Squamous Cell Carcinoma, Stage IVA Laryngeal Squamous Cell Carcinoma, Stage IVA Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage IVA Oral Cavity Squamous Cell Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma, Stage IVB Hypopharyngeal Squamous Cell Carcinoma, Stage IVB Laryngeal Squamous Cell Carcinoma, Stage IVB Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage IVB Oral Cavity Squamous Cell Carcinoma, Stage IVB Oropharyngeal Squamous Cell Carcinoma, Stage IVC Hypopharyngeal Squamous Cell Carcinoma, Stage IVC Laryngeal Squamous Cell Carcinoma, Stage IVC Nasopharyngeal Keratinizing Squamous Cell Carcinoma, Stage IVC Oral Cavity Squamous Cell Carcinoma, Stage IVC Oropharyngeal Squamous Cell Carcinoma
Sponsor: Case Comprehensive Cancer Center

 
Protocol version 09/30/2016 
Includes Amendment 3 
1 
CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
STUDY NUMBER:  CASE 8314 
 
STUDY TITLE:  
Phase I Dose Escalation Study of Stereotactic Body 
Radiotherapy for Carcinoma of the Head and Neck in High Risk Patients Who are 
Ineligible/Refuse Standard of Care Therapy 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: Shlomo A. Koyfman, MD 
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic  
Department of Radiation Oncology & Bioethics 
9500 Euclid Avenue  
 
 
 
Cleveland, OH   44195 
216-444-7552  
 
 
koyfmas@ccf.org 
 
CO- INVESTIGATORS:              
 
 
 
 
 
David Adelstein, MD 
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic  
Department of Solid Tumor Oncology 
9500 Euclid Avenue  
 
 
 
Cleveland, OH   44195 
216-444-9310  
 
 
adelstd@ccf.org 
 
 
 
 
 
Nikhil Joshi, MD 
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic  
Department of Solid Tumor Oncology 
9500 Euclid Avenue  
 
 
 
Cleveland, OH  44195 
216-444-6630 
joshin@ccf.org 
 
 
 
 
 
Neil Woody, MD 
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic  
Department of Solid Tumor Oncology 
9500 Euclid Avenue  
 
 
 
Cleveland, OH  44195 
216-445-6940 

 
Protocol version 09/30/2016 
Includes Amendment 3 
2 
woodyn@ccf.org 
 
 
 
 
 
Jessica Geiger, MD 
 
 
 
 
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic  
Department of Solid Tumor Oncology 
9500 Euclid Avenue  
 
 
 
Cleveland, OH  44195 
 
 
 
 
216-444-0888 
 
 
 
 
geigerj@ccf.org 
 
 
 
 
 
 
 
 
 
 
Min Yao, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals 
Department of Radiation Oncology 
11100 Euclid Ave   
Cleveland, OH 44106 
216-844-3951  
 
 
 
 
 
 
min.yao@uhhospitals.org 
 
 
 
 
 
 
Mitchell Machtay, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals 
Department of Radiation Oncology 
11100 Euclid Ave  
Cleveland, OH 44106 
 
 
 
 
216-844-2530  
 
 
 
 
 
Mitchell.Machtay@UHhospitals.org 
 
 
 
 
 
 
Michael Gibson, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals 
Department of Radiation Oncology 
11100 Euclid Ave  
Cleveland, OH 44106 
216-844-5586 
Michael.Gibson@UHhospitals.org 
 
 
 
 
 
Ping Xia, PhD 
Cleveland Clinic  
Department of Radiation Oncology 
9500 Euclid Avenue  
 
 
 
Cleveland, OH   44195 

 
Protocol version 09/30/2016 
Includes Amendment 3 
3 
216-444-1938  
 
xiap@ccf.org 
 
 
 
 
 
Bridgett Harr, CNP 
Cleveland Clinic  
Department of Radiation Oncology 
9500 Euclid Avenue  
 
 
 
Cleveland, OH   44195 
216-444-3787  
 
harrb@ccf.org 
 
 
 
 
 
 
 
STATISTICIAN:  
 
Chandana Reddy, MS 
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic  
Taussig Cancer Center 
 
9500 Euclid Avenue  
 
 
 
Cleveland, OH   44195 
 
216-444-9446 
 
 
 
 
reddyc@ccf.org 
 
SPONSORS:  
 
 
Case Comprehensive Cancer Center   
 
 
 
 
 
 
 
 
SUPPORT: 
 
 
2014 EPCRS grant    
 
 
 
 
 
SUPPLIED AGENT(S):  
N/A 
 
 
 
 
  
 
OTHER AGENT(S): 
 
N/A 

 
Protocol version 09/30/2016 
Includes Amendment 3 
4 
SCHEMA 
 
 
 
 
 
Informed Consent Provided 
 
REGISTRATION 
 
 
SBRT - DOSING SCHEMA 
 
 
Dose Level 
 
 
SBRT Dose  
 
Level   1 
 
40 Gray in 5 fractions 
 
Level  2 
 
45 Gray in 5 fractions 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
5 
  
TABLE OF CONTENTS 
 
SCHEMA 
 
1.0  
INTRODUCTION  
 
1.1 
HPV/p16 negative SCC-HN 
1.2 
High Risk Patients ineligible for standard therapy 
1.3  
Stereotactic Body Radiation Therapy (SBRT) in head and neck cancer 
1.4  
Proposal 
 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
 
3.0 
STUDY DESIGN 
3.1       Dose Escalation 
3.2       Patient Enrollment 
3.3       Expected Duration of Participation 
 
4.0  
PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
       
 
5.0 
REGISTRATION 
 
6.0  
TREATMENT PLAN  
6.1 
Simulation/Planning CT 
6.2  
Radiation Planning 
6.3  
Treatment 
6.4 
Duration of Follow Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
8.1 
Adverse Events and Potential Risk List  
 
8.1.1 SBRT 
8.2 
Definitions 
 
8.2.1 Adverse Events 
 
8.2.2 Significance of an Adverse Event 
 
8.2.3 Serious Adverse Events 
 
8.2.4 Expectedness 
 
8.2.5 Attribution 
8.3 
Reporting Procedures for All Adverse Events 

 
Protocol version 09/30/2016 
Includes Amendment 3 
6 
8.4 
Serious Adverse Event Reporting Procedures 
8.5 
Data Safety Toxicity Committee    
 
9.0  
STUDY PARAMETERS AND CALENDAR 
   9.1  
Study Parameters 
   9.2  
Calendar 
 
 10.0 
MEASUREMENT OF EFFECT  
 10.1 
Response Criteria  
   
 11.0 
DATA REPORTING/REGULATORY CONSIDERATIONS 
 11.1 
Data Reporting 
 11.2 
Regulatory Considerations  
 
 
 12.0 
STATISTICAL CONSIDERATIONS 
 
  
REFERENCES 
 
 
 
APPENDICES        
 
 
 
APPENDIX A 
 
FACT H&N (Short Form) 
 
  
APPENDIX B 
 
Targeted/Planned Enrollment Table 
 
 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
7 
1.0 
INTRODUCTION 
 
 
1.1 
HPV/p16 negative SCC-HN 
 
There are well studied standard treatment approaches, both operative based, and non-
operative based, for patients with squamous cell cancer of the head and neck (SCC-
HN).1-3  The great majority of patients who present with locally advanced SCC-HN are 
treated with definitive chemoradiotherapy (CRT).4  Recent studies have emerged 
indicating that human papillomavirus (HPV) and/or p16 associated SCC of the 
oropharynx is increasing in incidence and has a biologically distinct pathogenesis and 
response to treatment than other head and neck cancers.5,6  These patients have superior 
disease control rates and overall survival compared to the more traditional non-viral 
associated cancers.  Patients with HPV/p16 negative disease, however, have inferior 
locoregional control rates when treated with standard chemoradiotherapy and clinical 
trials are currently investigating the addition of transoral robotic surgery or targeted 
systemic agents in an effort to intensify the current standard of care and improve 
outcomes.7,8   
 
 
1.2 
High risk patients ineligible for standard therapy 
 
Among the HPV/p16 negative population, there is a subset of patients who are high risk 
for poor outcomes as they are ineligible for standard of care chemoradiotherapy, either 
due to advanced age, co-morbid illnesses, or because of patient refusal.  These patients 
present a clinical challenge as their disease calls for very aggressive therapy, but patient 
factors precludes this possibility and often relegates them to substandard treatment 
options.  In our practice, some of these high risk patients are treated with full course 
radiation, potentially with a targeted agent, some with a split course radiation approach 
and simply offered palliative treatment approaches.  For those who undergo conventional 
6-7 weeks of radiotherapy, treatment can be difficult to complete and be associated with 
significant morbidity.  Loco-regional control outcomes are also inferior at 30-60%.9-11  

 
Protocol version 09/30/2016 
Includes Amendment 3 
8 
As such, shorter, more tolerable, and potentially more effective treatments are needed in 
this high risk patient population with HPV/p16 negative SCC-HN.   
 
1.3  
Stereotactic Body Radiation Therapy (SBRT) in head and neck cancer 
 
Stereotactic body radiotherapy (SBRT) is a technique that employs highly focused 
external beam radiation delivered in large doses over 1-5 treatments and has become a 
standard treatment approach for a variety of tumor types and clinical scenarios (e.g. 
medically inoperable lung cancer).12  SBRT has become increasingly utilized in SCC-HN 
in patients who have recurrent previously irradiated disease.  Doses most commonly 
employed range from 30-50 Gray (Gy) in 5 fractions (fx), with locoregional disease 
recurrence rates of 30-50%.  Grade 3-5 toxicity can be significant including soft tissue or 
bone necrosis, fibrosis, dysphagia, carotid blowouts, and fistulization, and range from 3-
18% among several series.13  The University of Pittsburgh has the most extensive 
experience with this technique and has performed the only phase I dose escalation study 
testing the safety of SBRT in previously irradiated SCC-HN.  They successfully escalated 
doses up to 44Gy in 5 fx without encountering grade 3-5 toxicity.14  They have went on 
to treat >150 patients with ≥40Gy, without excessive morbidity.15  We have treated 12 
patients with SBRT in the reirradiation setting with varying doses of 35Gy in 5 fractions 
up to 45Gy in 5 fractions.  Our preliminary experience suggests that it is feasible, 
planning according to traditional constraints is achievable and the short term toxicities are 
quite mild.  We are awaiting maturity of our experience to assess long term severe late 
effects. 
 
A summary of SBRT reirradiation studies in head and neck cancer are depicted in the 
following table: 
 
Efficacy and Toxicity of Definitive Head and Neck SBRT Re-irradiation 
Study 
Number 
of 
Patients 
SBRT 
Dose/ 
#fractions 
Median 
f/u 
(months) 
Median 
Survival/ 
1y OS 
Response 
Rate 
(CR+PR) 
Local-
Regional 
Progression 
Toxicity 

 
Protocol version 09/30/2016 
Includes Amendment 3 
9 
Siddiqui, et al 
(2009)16  
29 
36-48Gy 
5-8fx 
36 
7 mths 
38% 
69 
4% 
14% grade ≥3 
(dysphagia, cataract, 
pain); 14% grade 4 
(fistula/ulceration)† 
Roh, et al. 
(2009)17  
44 (35 
evaluable) 
18-40Gy 
3-5fx 
17  
16 mths 
52% 
80% 
 
11% 
10% grade ≥4 (soft 
tissue/bone 
necrosis/death) 
Unger, et al. 
(2010)18  
38  
 21-35Gy 
2-5fx 
16 
20 mths 
40% 
80% 
32% 
12% grade 4/5 (arterial 
bleed, death, fistula, soft 
tissue necrosis, 
dysphagia, trismus, 
cranial neuropathy) 
Kodani, et al. 
(2011)19  
21* 
20-42Gy 
3-8fx 
28 
16 mths 
70% 
62% 
 
14% 
28% late ≥ grade 3 
(hemorrhage and death X 
2 , mucositis, skin 
necrosis, chronic ulcer) 
Cengiz, et al. 
(2011)20  
 
46 (37 
evaluable) 
18-35Gy 
1-5fx 
7 
12 mths 
46% 
57% 
 
13.5% 
13% carotid blowout (7/8 
died)‡ 
13% late ≥ grade 2(Soft 
tissue/bone  necrosis, 
dysphagia) 
Comet, et al. 
(2012)21  
40 
36Gy 
6fx 
26 
14 mths 
58% 
79 
 
23% 
10% grade 3  (mucositis, 
dysphagia, fibrosis).  
Vargo, et al. 
(2014)22  
132 
35-50Gy 
5fx 
6 
7 mths 
49% 
75%** 
44% 
7% grade 3 (Dysphagia, 
Pain and Skin). No grade 
4/5 
OS = overall survival; † All fistulas occurred in the setting of tumor recurrence/progression rather than due to SBRT toxicity.  ‡ All 
pts with carotid blowout had tumor completely surrounding carotid arteries, with no constraints applied to avoid the vessels.  No 
patient with carotid artery dose <100% had CBO and only patients with >180 degrees of CA involved had CBO. * Includes only 
those patients with prior radiation. ** While not reported in this series, this rate was culled from several previous published reports 
from the UPitt experience. 
 
 
While SBRT in the re-irradiation setting has been shown to be safe with reasonable 
control rates, this technique has not been formally studied in the radiation naïve patient.   
As such, we propose a phase I dose escalation study in high risk patients who are 
ineligible/refuse standard of care therapy as a means of assessing the safety of such 
treatment in patients who may have prolonged survival compared to re-irradation 

 
Protocol version 09/30/2016 
Includes Amendment 3 
10 
patients.  We will also evaluate the efficacy of this far more tolerable and convenient 
regimen than our current commonly used approaches for these patients. 
 
1.4  
 Proposal 
 
 
 
We propose to  conduct a phase I dose escalation trial of SBRT in high risk patients with 
locally advanced head and neck cancer who are ineligible/refuse standard 
chemoradiotherapy. 
 
2.0  
OBJECTIVES 
 
2.1  
Primary Objective: To explore the maximum tolerated dose of head and neck SBRT in 
a high risk patient population ineligible for standard chemoradiotherapy.  Two dose levels will 
be used  40Gy, 45Gy all in 5 fractions.       
2.2       Secondary Objectives:  
2.2.1    Assess profiles of SBRT toxicity and examine patient (including co-morbidities),  
tumor and treatment related factors that are associated with SBRT related toxicity  
2.2.2 identify any dose volume parameters that are associated with SBRT related toxicity  
2.2.3 explore potential dose response relationships between higher SBRT dosing and 
radiographic response 
2.2.4 assess impact of SBRT on patients quality of life 
 
 
3.0  
STUDY DESIGN 
 
3.1 
 
Dose Escalation 
 
3.1.1  
This is a phase I SBRT dose escalation study consisting of three dose levels: 
40Gy and 45Gy all in 5 fractions.   
 
3.1.2  
Each dose level will have 6 patients allocated to them.  We chose this number 
as twice the usual number of patients in a phase I chemotherapy related dose 
escalation protocol as a means of being conservative to ensure adequate 
capture of potential toxicities.   
 
3.1.3  
After all six planned patients are enrolled to the initial dose level, the study 
will be placed on temporary hold until all patients in that cohort are assessed 
at their 3 month post SBRT visit for DLTs.  If ≤1 patient experiences a DLT, 
patients will be enrolled at the next dose level.  If ≥3 patients experience a 
DLT, further accrual will be permanently halted and the study stopped.  If 2 
patients experience a DLT, then an additional 6 patients will be enrolled at the 
same dose level.  In this setting, if ≤ 3/12 patients have a DLT, patients will be 
enrolled at the next dose level. If ≥ 4/12 patients have a DLT, further accrual 

 
Protocol version 09/30/2016 
Includes Amendment 3 
11 
will be permanently halted and the study stopped and 35 Gy will not be 
recommended as safe. 
3.1.4      
The dosing strategy for the 2nd (45Gy) cohort will be identical to the first as 
outlined in 3.1.3.  If ≤ 3/12 patients have a DLT in this 2nd cohort, then this will 
be the recommended phase II dose.  If ≥ 4/12 patients have a DLT, then this dose 
level will be deemed unacceptably toxic and the 1st dose level will be considered 
the recommended phase II dose. 
 3.1.5    
All patients will have ongoing assessments of DLTs, which can be delayed after  
SBRT and occur beyond 3 months.  If a given dose is deemed safe and subsequent 
patients are entered into a higher dosing cohort and in continued follow up, 
additional DLTs are noted in the previously completed dosing cohort such that 2/6 
patients experience DLTs, then accrual to the next higher dosing cohort will be 
halted and 6 additional patients will be accrued to the previously completed lower 
dosing level following the guidelines detailed above in section 3.1.3. 
3.1.6  
All toxicities will be scored per CTCAE v4.0 criteria.  In our institutional 
experience of split course radiotherapy to 60-66Gy in a similar patient population, 
we encountered no grade 4/5 toxicities.  However, given that this is SBRT and 
novel in this patient population, we are doing this study to assess the incidence of 
these grade 4/5 toxicities.   
 
Dose limiting toxicities in this study will be defined as grade 4/5 toxicity: 
 - soft tissue or bone necrosis 
 - carotid blowout or other treatment related bleed 
 - aspiration 
 - infection  
 - fistula that is deemed as life threatening.   
 
While grade 3 toxicities will be recorded as SAEs and reported as per IRB 
guidelines, they will not be considered DLTs or influence the dose escalation 
component of the study, given the high risk nature of the disease and the 
associated morbidities of uncontrolled disease. 
3.1.7  
All grade 3 toxicities will be recorded as serious adverse events but will not be  
scored as DLT, as these are somewhat expected and most often reversible 
complications associated with radiotherapy.  Grade 1/2 events will be recorded, 
but will not be considered serious adverse events. 
3.1.8 
Symptoms and morbidity attributed to disease progression, as determined by the  
treating physician, and another co-investigator of the study, will not be considered 
a toxicity that will influence the dosing schema. 
 
    
3.2   
Patient Enrollment 
 
We plan on enrolling a maximum of 18 patients to this study.  This relies on the 
traditional 3+3 approach used in many chemotherapy phase I studies, but we have 
doubled the number in each arm to ensure we capture potential toxicities which can be 
delayed. 

 
Protocol version 09/30/2016 
Includes Amendment 3 
12 
 
3.3  
Expected Duration of Subject Participation  
 
3.3.1   PreSBRT visits for dental evaluation (if indicated) and simulation. 5 visits for 
treatment over a 1.5 to 3 week time period.   
 
3.3.2 Patients will be followed for one year after SBRT.  All patients will be seen at least at 
0.5, 3, 6, 9 and 12 months post SBRT.  Additional visits will be made if clinically indicated 
based on patient symptomatology. 
 
4.0 
PATIENT SELECTION 
 
Patients with cancer of the head and neck who are deemed unfit for continuous course standard 
cisplatin based chemoradiotherapy will be eligible.  Patients with squamous cell cancer (mucosal 
or cutaneous; p16 positive or negative), adenocarcinoma, or salivary gland cancer are eligible. 
A completed patient eligibility checklist is required following the approved standard 
operating procedure of the enrolling institution. 
 
4.1 
Inclusion Criteria 
 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
_____ 4.1.1  The patient must have squamous cell carcinoma, adenocarcinoma or malignant 
salivary gland cancer (e.g. acinic cell, adenoid cystic, mucoepidermoid, salivary duct 
carcinoma) proven by histologic diagnosis.  Both mucosal and cutaneous cancers are eligible. 
 
_____ 4.1.2  The patient must have clinical stage T1-4, N0-3, M0-1, stage II-IVC carcinoma 
as per the 7th edition of the AJCC staging manual.  Patients with T1N0M0 will be ineligible.  
Patients with metastatic disease with a limited metastatic burden are eligible if obtaining 
local control is determined by their treating oncologist to be an important therapeutic goal. 
 
 _____4.1.3  The patient must have imaging documenting a primary tumor, or involved 
lymph node, ≥2.5cm in greatest dimension. 
 
_____4.1.4  PET/CT is required for all patients, unless contraindicated.  This may be 
acquired prior to study entry or after enrollment prior to SBRT planning. 
 
_____ 4.1.5   The patient must have a history and physical documented within four weeks of 
registration and be deemed by a medical oncologist to be ineligible for standard continuous 
course chemoradiotherapy with Cisplatin, or refuse treatment with Cisplatin. 
 
 
 
 
_____ 4.1.6  Performance status - Karnofsky PS ≥ 40 
 
_____ 4.1.7  Age >18 years.   
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
13 
_____ 4.1.8  Female patients can not be of childbearing age, or if they are, must have a 
negative pregnancy test prior to enrollment and be willing to  use 
contraceptives during treatment and continue for 6 additional months. 
 
_____ 4.1.9  Patients must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a patient from study enrollment. 
 
_____ 4.2.1   Patients with T1N0M0 stage I disease. 
 
_____ 4.2.2 
Patients who are receiving any other investigational agents.   
 
_____ 4.2.3 
Patients with non-malignant histology. 
 
 
_____ 4.2.4 
Patients with life expectancy <6 months.  
 
______4.2.5 Patients who cannot lie flat for 20 minutes. 
 
______4.2.6 Patients with prior history of head and neck radiotherapy (>40Gy) with 
significant areas of anticipated overlap 
 
 
4.3    Inclusion of Women and Minorities   
 
 Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 5.0 
Registration 
 
All subjects who have been consented are to be registered in the OnCore Database.  
  
 
6.0  
TREATMENT PLAN  
 
6.1 
Simulation/Planning CT and Co-registration 
 
The patient will undergo a CT simulation for treatment planning with a recommended slice 
thickness of 1.5 mm, and a maximum allowed slice thickness of 3 mm.   Patients will be 
immobilized using a 5pt aquaplast mask during the simulation.  IV contrast should be used 
unless there is a contraindication (e.g. allergy or elevated creatinine).  These images should 
be co-registered with the diagnostic PET/CT for planning purposes.  If an MRI has been 
obtained, it should also be co-registered to aid in target delineation.    
 
6.2       Radiation Planning 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
14 
Radiation planning will utilize tissue heterogeneity corrections. The gross target volume (GTV) 
should be contoured and include all radiographically apparent areas of disease.  There will be no 
clinical target volume (CTV) expansion on this volume.  A planning target volume (PTV) will 
then be generated with a 2-3.5mm expansion of the GTV.  A 2.5mm expansion is recommended 
but some variability is allowed for based on tumor location and motion and setup variability 
from patient to patient. 
An optional elective CTV can be contoured and include areas thought to be at high risk of 
microscopic disease.  This volume will be treated with 30Gy concurrently using a simultaneous 
integrated planning technique.  While this will generally not be used for most patients, some 
patients with multifocal nodal disease may require more comprehensive lower dose coverage of 
their other nodal stations.  The use of this target volume is at the discretion of the treating 
radiation oncologist.   
 
The radiation dose will be prescribed to cover 95% of the PTV.  Thus >95% of the PTV should 
receive the prescription dose (e.g. 35Gy in 5 fx).  >99% of the GTV must also receive 
prescription dose.  Rapid dose falloff outside the PTV is the priority and heterogeneity within the 
target is allowed.   <0.03cc of tissue inside the PTV should receive >110% of the prescription 
dose. 
Normal structures to be contoured include the brainstem, brainstem planning risk volume 
(PRV=brainstem +3mm) brain, spinal cord, spinal cord PRV (spinal cord +5mm) eyes, optic 
nerves, optic chiasm, cochlea, parotids, submandibular glands, oral cavity, lips, larynx, 
supraglottis, constrictors, esophagus, trachea, carotid arteries, brachial plexus.   
 Effort should be made to minimize the dose to these structures as much as possible.  Any normal 
structure involved with disease should be treated fully.  However, the following constraints are 
considered hard constraints and cannot be violated, even if this compromises tumor coverage. 
 
x Spinal cord – <0.03cc ≥ 25Gy 
x Brainstem - <0.03cc ≥ 25Gy 
x Optic nerves - <0.03cc ≥ 20Gy 
x Optic chiasm - <0.03cc ≥ 20Gy 
x Eyes - <0.03cc ≥ 25Gy 
x Brachial Plexus - <0.03cc ≥ 30Gy 
 
For patients that would require inclusion of >180 degrees of involvement of the carotid 
artery, PTV can be contracted to allow for more aggressive carotid sparing at the discretion 
of the treating radiation oncologist. 
 
 
Representative SBRT treatment planning images and dose volume histogram plots 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
15 
 
 
 
 
 
 
 
 
 
6.3  
Treatment 
 
Patients will be treated on a linear accelerator equipped with cone beam CT image-guidance, 
or on a Cyberknife platform.  Daily image guidance must be performed and confirmed by a 
physician or medical physicist before each treatment. If the shift exceeds 7mm, a second 
confirmatory image acquisition using the image guidance platform will need to be performed 
to confirm that residual error is <3mm.  Residual error >3mm requires repositioning of the 
patient.  Radiation fractions will be given with at least 40 hours between fractions and 
typically be delivered every other day (e.g. M, W, F, M, W).  Twice weekly fractions are also 
acceptable (e.g. M, Th, M, Th, M).  Total treatment time should be between 10-18 days.   
 
6.4 
Duration of Follow Up 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
16 
Patients will be followed for toxicity for 1 year after treatment has been discontinued or until 
death, whichever occurs first.  Following completion of this period of follow-up on-study 
patients will then be followed per standard of care as detailed below.    
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause. Serious adverse 
events that are still ongoing at the end of the study period will necessitate follow-up to 
determine the final outcome.  
 
Patients will be followed for one year after SBRT.  All patients will be seen at 0.5, 3, 6, 9, 12 
months after SBRT. At the three month visit, a post-SBRT PET/CT will be obtained to assess for 
disease response.  CT of the neck and chest (preferably with contrast barring allergies or renal 
insufficiency) will be obtained at the 6 and 12 month visits.  At each visit, patients will be 
assessed for Head and Neck toxicity using the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.  While no other toxicities are expected, any additional toxicity 
should also be scored by CTCAE version 4.0.  In addition they will complete the FACT-H&N 
questionnaire (validated questionnaires to assess treatment related quality of life).  When study 
follow-up is completed at 12 months, the patient will transition to standard follow-up off 
protocol with physician visits and head and neck exam every 3 months for year 2, every 4 
months for year 3, every 6 months for year 4 and annually thereafter.     
 
 
7.0   
DOSING DELAYS / DOSE MODIFICATIONS 
 
 
7.1 Modifications to the treatment schedule due to changes in patient condition are at the 
discretion of the treating physician.  Such modifications are not expected as the expected 
acute toxicity of the treatment is minimal.  If any patient requires dosing delay such that the 
total duration of the radiation course is greater than 18 days due to a clinical factor this will 
be reported.   
 
7.2 There will be no dosing modifications made to the three predefined dosing cohorts.  
Accrual to the predefined dose cohorts will be performed according to Section 3.1.  
 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS    
 
The following is a list of AEs (Section 8.1) and the reporting requirements associated with 
observed AEs (Sections 8.3 and 8.4).  
 
Adverse events will be followed until resolution or for a maximum of 30 days post study 
discontinuation.   Serious adverse events that are still ongoing at the end of the study period will 
necessitate further follow-up to determine the final outcome.  
 
8.1 
Adverse Events and Potential Risks  
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
17 
8.1.1 SBRT 
 
Treatment related head and neck toxicity will be monitored using the CTCAE version 4.0 
instrument. Toxicity data will be continually assessed by the treating radiation oncologist each 
time a patient comes for a clinical visit, and the data will be entered into the database.  Excessive 
toxicity that would lead to termination of the study includes the requisite number of grade 4 or 5 
toxicities as detailed in 3.0 above.    
 
8.2 
Definitions  
 
8.2.1 
Adverse Events   
 
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments. 
 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research or 
any underlying disease, disorder, or condition of the subject. In general, adverse events that 
are at least partially the result of (a) or (b) would be considered related to the research, 
whereas adverse events solely related to (c) or (d) would be considered unrelated to the 
research.  
 
8.2.2 The significance of an adverse event is used to describe the patient/event outcome or 
action criteria associated with events that pose a threat to a patient’s life or functioning (i.e., 
moderate, severe or life threatening).  Based on the National Cancer Institute Guidelines for 
the Cancer Therapy Evaluation Program, severity can be defined by the following grades of 
events: 
 
 
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance) 
 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; non-
invasive intervention or elective interventional radiological procedure; transfusion;). 
 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring 
hospitalization or invasive intervention; transfusion; therapeutic endoscopy or operation). 
 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life-
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis; life–threatening physiologic consequences; need for intensive care or 

 
Protocol version 09/30/2016 
Includes Amendment 3 
18 
emergent invasive procedure; emergent interventional radiological procedure, therapeutic 
endoscopy or operation). 
 
Grades 5 are fatal adverse event resulting in death.     
 
8.2.3   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes:  
x Results in death.  
x Is a life-threatening adverse experience.  The term life-threatening in the definition 
of serious refers to an adverse event in which the subject was at risk of death at the 
time of the event.  It does not refer to an adverse event which hypothetically might 
have caused death if it were more severe.  
x Requires inpatient hospitalization or prolongation of existing hospitalization.  
Any adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 12 hours OR 
o The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care). 
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a serious 
adverse event dependant on clinical judgment.  In addition where local regulatory 
authorities specifically require a more stringent definition, the local regulation takes 
precedent.  
x Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
x Is a congenital anomaly/birth defect.  
x Is an important medical event.  Important medical events that may not result death, 
be life-threatening, or require hospitalization may be considered a serious adverse 
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.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood disease or disorders, or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
 
8.2.4 Expectedness 
Adverse Events can be Expected or Unexpected. 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
19 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
8.2.5 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 
x Definite – The AE is clearly related to the study drug/procedure. 
x Probable – The AE is likely related to the study drug/procedure. 
x Possible – The AE may be related to the study drug/procedure. 
x Unlikely – The AE is doubtfully related to the study drug/procedure. 
x Unrelated – The AE is clearly NOT related to the study drug/procedure. 
 
 
8.3  
Reporting Procedures for All Adverse Events 
 
All participating investigators will assess the occurrence of any treatment related AEs throughout 
the subject’s participation in the study.  Subjects will be followed for toxicity one year after 
treatment has been discontinued or until death, whichever occurs first.  The clinical course of 
each event will be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause.   
 
The investigator is responsible for ensuring that all treatment related AEs observed by the 
investigator or reported by the subject which occur after the subject has signed the informed 
consent are fully recorded in the subject’s case report form, subject’s medical records, and/or any 
other institutional requirement. Source documentation must be available to support all adverse 
events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.   
 
The study team will provide the following for all adverse events: 
x Description of the event 
x Date of onset and resolution 
x Grade of toxicity  
x Attribution of relatedness to the investigational agent 
x Action taken as a result of the event 
x Outcome of event 
 
In this study, descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 available at http://ctep.cancer.gov will be utilized for 

 
Protocol version 09/30/2016 
Includes Amendment 3 
20 
AE reporting.  
 
Adverse events will be reported to the IRB according to the IRB policies and procedures in 
reporting adverse events. 
 
8.4  
Serious Adverse Event Reporting Procedures 
 
Serious adverse events that occur beginning with the signing of the informed consent form, 
during treatment, or within thirty days of the last dose of treatment must be reported to the 
Cleveland Clinic Principal Investigator. 
 
 
8.5  
Data Safety Toxicity Committee 
 
It is the Case Comprehensive Cancer Center’s Principal Investigator’s responsibility to ensure 
that ALL serious adverse events are reported to the Case Comprehensive Cancer Center’s Data 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
Sponsor or other Regulatory body.  
 
9.0  
STUDY PARAMETERS AND CALENDAR  
 
9.1 
Study Parameters 
 
9.1.1 Screening Evaluation   
 
Patients will complete the FACT H&N quality of life questionnaires at baseline.  
 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
21 
9.2 
Calendar    
 
 
  
  
Assessment 
Months Since Treatment 
Baseline 
0  
Post 
Treatment 
 (Last OTR 
Visit) 
0.5  
(1-3wks) 
3 
 
 
9 
6, 
12 
Informed Consent 
X 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
Vitals1 
X 
X 
X 
X 
X 
X 
Physical Exam2 
X 
X 
X 
X 
X 
X 
PET/CT3  
X 
 
 
X 
 
 
CT neck and chest4 
 
 
 
 
 
X 
FACT-H&N survey  
X 
 
X 
X 
X 
X 
CTCAE Toxicity Assessment 
 
X 
X 
X 
X 
X 
1 Height not required 
2 Focused head and neck exam at each visit with optional pharyngolaryngoscopy 
3 An additional PET/CT may be done after the 3 month time point to help clarify the etiology 
of abnormalities that are found clinically or radiographically to suggest potential 
recurrence/progression 
4 With contrast unless contraindicated 
 
 
10.0  MEASUREMENT OF EFFECT  
 
10.1  The primary endpoint of this dose finding study is safety and to assess the toxicity 
associated with escalating doses of SBRT.  Secondary endpoints include disease response, as 
measured by clinical examination and the accompanying imaging studies obtained at 3, 6, 
and 12 months post SBRT.  Response will be measured according to standard RECIST 
criteria as follows: 
 
Response 
Evaluation of Target Lesions 
Complete Response 
(CR) 
Disappearance of all targeted lesion(s), or significant 
shrinkage of disease and metabolic response with 
SUV <4. Residual tissue fullness, asymmetry or 
fibrosis that continues to improve on serial CT 
imaging after an initial decline (>50%) in SUV will be 
considered treatment effect. 
Partial Response  
         (PR) 
At least a 30% decrease in the sum of diameters of 
targeted lesion(s), taking as reference the baseline sum 
of diameters, and or a >50% decrease in tumor SUV. 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of diameters of 
targeted lesions, taking as reference the smallest sum 

 
Protocol version 09/30/2016 
Includes Amendment 3 
22 
on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.   
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
  
 
 
11.0 
DATA REPORTING/REGULATORY CONSIDERATIONS   
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
11.1 
Data Reporting  
 
The OnCore Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management.  OnCore 
is a Clinical Trials Management System housed on secure servers maintained at Case 
Western Reserve University.  OnCore properly used is compliant with Title 21 CFR Part 11.  
Access to data through OnCore is restricted by user accounts and assigned roles.  Once 
logged into the OnCore system with a user ID and password, OnCore defines roles for each 
user which limits access to appropriate data. User information and password can be obtained 
by contacting the OnCore Administrator at oncore-registration@case.edu. 
 
OnCore is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification. This study will utilize electronic Case 
Report Form completion in the OnCore database.  A calendar of events and required forms 
are available in OnCore. 
 
11.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws.  
11.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures.  
The Principal Investigator or Co investigators will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits of 
the study as well as the subject’s financial responsibility.  Subjects must also be notified that they 
are free to discontinue from the study at any time.  The subject should be given the opportunity 
to ask questions and allowed time to consider the information provided.  

 
Protocol version 09/30/2016 
Includes Amendment 3 
23 
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 
11.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow the 
sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 
information that includes all hospital records relevant to the study, including subjects’ medical 
history. 
 
11.2.3  Retention of records 
 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with national and international regulations. No 
records will be destroyed until the Principal Investigator confirms destruction is permitted.  
 
11.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits 
or inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.   
11.2.5 Data Safety and Monitoring Plan 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI regulations.  
 
12.0     STATISTICAL CONSIDERATIONS 
 
The main endpoint of this dose finding study is safety and to identify the maximum tolerated 
dose of SBRT in this patient population.  Dose escalation studies typically involve a “3+3” 
design. However, as SBRT is a powerful treatment tool, and toxicities can be delayed, we erred 
on the conservative side and doubled our dose level population.  As such, we have planned for 
accrual of 6 patients to each dose level.  If sufficient DLTs are not seen in the third dose level 
(45Gy in 5 fraction), then an additional 6 patients will be accrued to this dose level to provide 
more robust safety information on this dose, which would become the recommended dose for 
future study.   We also performed probability analysis using binomial distribution analysis to 
calculate the probability of escalating to each dose level, as demonstrated in the following table: 
p of 
Dose 1- p of <=1 DLT in 
Dose 1- p of 2 DLT in 1st 
Dose 1- p of <=1 DLT in 
p for Next 

 
Protocol version 09/30/2016 
Includes Amendment 3 
24 
DLT 
1st 6 pts 
6 pts 
2nd 6 pts 
Dose 
0.15 
0.78 
0.18 
0.78 
0.91 
0.2 
0.66 
0.25 
0.66 
0.82 
0.25 
0.53 
0.30 
0.53 
0.69 
0.3 
0.42 
0.32 
0.42 
0.56 
0.4 
0.23 
0.31 
0.23 
0.31 
 
For our secondary endpoints, we will also use Kaplan-Meier estimates to plot overall survival 
and local progression free survival.  We will conduct trend tests to investigate the relationship 
between SBRT dose and response.  Non-parametric methods, including but not limited to the 
Mann-Whitney test and Fisher’s exact test, will be used to analyze patient, tumor and treatment 
related factors associated with SBRT related morbidity, including DLTs as well as grade 3 acute 
and late events. We will use repeated ANOVA measures to analyze the quality of life data.   
 
REFERENCES 
1. 
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. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology 2003;21:92-8. 
2. 
Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and 
neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy 
trials of the EORTC (#22931) and RTOG (# 9501). Head & neck 2005;27:843-50. 
3. 
Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy 
for organ preservation in advanced laryngeal cancer. The New England journal of medicine 
2003;349:2091-8. 
4. 
Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head 
and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. 
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and 
Oncology 2009;92:4-14. 
5. 
Allen CT, Lewis JS, Jr., El-Mofty SK, Haughey BH, Nussenbaum B. Human 
papillomavirus and oropharynx cancer: biology, detection and clinical implications. 
Laryngoscope 2010;120:1756-72. 
6. 
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 
oropharyngeal cancer. N Engl J Med 2010;363:24-35. 
7. 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1221. 
8. 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1216. 
9. 
Stevens CM, Huang SH, Fung S, et al. Retrospective study of palliative radiotherapy in 
newly diagnosed head and neck carcinoma. Int J Radiat Oncol Biol Phys 2011;81:958-63. 
10. 
Agarwal JP, Nemade B, Murthy V, et al. Hypofractionated, palliative radiotherapy for 
advanced head and neck cancer. Radiother Oncol 2008;89:51-6. 
11. 
Minatel E, Gigante M, Franchin G, et al. Combined radiotherapy and bleomycin in 
patients with inoperable head and neck cancer with unfavourable prognostic factors and severe 
symptoms. Oral Oncol 1998;34:119-22. 

 
Protocol version 09/30/2016 
Includes Amendment 3 
25 
12. 
Timmerman RD, Herman J, Cho LC. Emergence of Stereotactic Body Radiation Therapy 
and Its Impact on Current and Future Clinical Practice. J Clin Oncol 2014;32:2847-54. 
13. 
Lim CM, Clump DA, Heron DE, Ferris RL. Stereotactic Body Radiotherapy (SBRT) for 
primary and recurrent head and neck tumors. Oral Oncol 2013;49:401-6. 
14. 
Heron DE, Ferris RL, Karamouzis M, et al. Stereotactic body radiotherapy for recurrent 
squamous cell carcinoma of the head and neck: results of a phase I dose-escalation trial. Int J 
Radiat Oncol Biol Phys 2009;75:1493-500. 
15. 
Vargo JA, Heron DE, Ferris RL, et al. Prospective evaluation of patient-reported quality-
of-life outcomes following SBRT +/- cetuximab for locally-recurrent, previously-irradiated head 
and neck cancer. Radiother Oncol 2012;104:91-5. 
16. 
Siddiqui F, Patel M, Khan M, et al. Stereotactic body radiation therapy for primary, 
recurrent, and metastatic tumors in the head-and-neck region. Int J Radiat Oncol Biol Phys 
2009;74:1047-53. 
17. 
Roh KW, Jang JS, Kim MS, et al. Fractionated stereotactic radiotherapy as reirradiation 
for locally recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2009;74:1348-55. 
18. 
Unger KR, Lominska CE, Deeken JF, et al. Fractionated stereotactic radiosurgery for 
reirradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2010;77:1411-9. 
19. 
Kodani N, Yamazaki H, Tsubokura T, et al. Stereotactic body radiation therapy for head 
and neck tumor: disease control and morbidity outcomes. Journal of radiation research 
2011;52:24-31. 
20. 
Cengiz M, Ozyigit G, Yazici G, et al. Salvage reirradiaton with stereotactic body 
radiotherapy for locally recurrent head-and-neck tumors. Int J Radiat Oncol Biol Phys 
2011;81:104-9. 
21. 
Comet B, Kramar A, Faivre-Pierret M, et al. Salvage stereotactic reirradiation with or 
without cetuximab for locally recurrent head-and-neck cancer: a feasibility study. Int J Radiat 
Oncol Biol Phys 2012;84:203-9. 
22. 
Vargo JA, Heron DE, Ferris RL, et al. Examining tumor control and toxicity after 
stereotactic body radiotherapy in locally recurrent previously irradiated head and neck cancers: 
Implications of treatment duration and tumor volume. Head Neck 2014;36:1349-55. 
 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
26 
APPENDIX A: FACT-Head and Neck QOL Questionnaire 
 
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your response 
as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of energy ........................................................
0 
1 
2 
3 
4 
GP2 
I have nausea ......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends ....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ...............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
27 
 
 
 
GS7 
I am satisfied with my sex life .............................................
0 
1 
2 
3 
4 

 
Protocol version 09/30/2016 
Includes Amendment 3 
28 
 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad .............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness .........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ..................
0 
1 
2 
3 
4 
GE4 
I feel nervous ......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying .............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ............................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling .....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life ..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ................................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now .............
0 
1 
2 
3 
4 
 
 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
29 
 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
 
 
 
 
 
 
 
 
H&N1 
I am able to eat the foods that I like ....................................
0 
1 
2 
3 
4 
H&N2 
My mouth is dry .................................................................
0 
1 
2 
3 
4 
H&N3 
I have trouble breathing .......................................................
0 
1 
2 
3 
4 
H&N4 
My voice has its usual quality and strength.........................
0 
1 
2 
3 
4 
H&N5 
I am able to eat as much food as I want ..............................
0 
1 
2 
3 
4 
H&N6 
I am unhappy with how my face and neck look ..................
0 
1 
2 
3 
4 
H&N7 
I can swallow naturally and easily......................................
0 
1 
2 
3 
4 
H&N8 
I smoke cigarettes or other tobacco products ......................
0 
1 
2 
3 
4 
H&N9 
I drink alcohol (e.g. beer, wine, etc.) ...................................
0 
1 
2 
3 
4 
H&N 
10 
I am able to communicate with others ................................
0 
1 
2 
3 
4 
H&N 
11 
I can eat solid foods .............................................................
0 
1 
2 
3 
4 
H&N 
12 
I have pain in my mouth, throat or neck ..............................
0 
1 
2 
3 
4 
 
 

 
Protocol version 09/30/2016 
Includes Amendment 3 
30 
Appendix B Targeted/Planned Enrollment Table  
This report format should NOT be used for data collection from study participants.  
 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects  
 
 
Ethnic Category  
Females  
 
Males  
Total  
Hispanic or Latino  
1 
 
1 
2 
Not Hispanic or Latino  
2 
 
14 
16 
Ethnic Category: Total of All Subjects *  
3 
 
15 
18 
Racial Categories  
 
 
 
American Indian/Alaska Native  
0 
 
0 
0 
Asian  
0 
 
0 
0 
Native Hawaiian or Other Pacific Islander  
0 
 
0 
0 
Black or African American  
1 
 
2 
3 
White  
1 
 
14 
15 
Racial Categories: Total of All Subjects *  
2 
 
16 
18 

1 
 
Amendment Summary: 
Study Title: Phase I Dose Escalation Study of Stereotactic Body Radiotherapy for p16 Negative Squamous 
Cell Carcinoma of the Head and Neck in High Risk Patients Who are Ineligible/Refuse Standard of Care 
Therapy 
PI: Shlomo Koyfman,MD 
Study ID:  Case 8314 
 
Protocol Changes (revised on 11-26-2014 from original submission on 10-08-2014. Footer date did not 
change) 
x 
Removed HX4 and Threshold pharmaceuticals from Title page as Sponsor and Supplied Agent 
x 
Removed HX4 component from Study Schema on pg 4 
x 
Removed sections 1.4 and 1.5 from introduction describing background on HX4 
x 
Removed section 5.0 discussing all details of HX4 
x 
Removed HX4 component as second question of study in purpose section 1.6 (now 1.4) 
x 
Removed HX4 uptake characteristics as secondary objective in section 2.2.1 
x 
Removed HX4 imaging from PRE-SBRT visits in 3.3.1 
x 
Removed HX4 scans and pre/post HX4 vitals from study calendar in section 9.2 
Consent Form Changes 
x 
Added Min Yao MD as CoPI from UH 
x 
Removed discussion of HX4 as purpose #2 of the study from page 2 
x 
Removed optional preSBRT HX4 imaging from study procedures (bottom pg 2) 
x 
Removed reference to HX4 imaging in “before begin study” section top pg 3 
x 
Removed HX4 reference in study schema under “study plan” section pg 4 
x 
Removed HX4 imaging and pre/post HX4 vitals from study calendar on pg 5 
x 
Removed reference to HX4 in “cost” section 
x 
Removed “optional imaging component” and distinct signature area to agree to participate in 
HX4 component (pg 11) 

6XPPDU\RI&KDQJHVIRU&$6(Phase I Dose Escalation Study of Stereotactic Body 
Radiotherapy for p16 Negative Squamous Cell Carcinoma of the Head and Neck in High 
Risk Patients Who are Ineligible/Refuse Standard of Care Therapy v6-2-2015


5DWLRQDOH7KHFXUUHQWSURWRFROZDVGHVLJQHGDVDSKDVH,GRVHHVFDODWLRQSURWRFROLQFOXGLQJ
DUPV*\*\DQG*\DOOLQIUDFWLRQV7KHUHLVDVXEVWDQWLDOOLWHUDWXUHRQ6%57LQ
WKHUHLUUDGLDWLRQVHWWLQJLQZKLFK*\LQIUDFWLRQVKDVEHHQXVHGDQGGHHPHGVDIHE\
QXPHURXVLQVWLWXWLRQV,DPWKHUDGLDWLRQRQFRORJ\FR3,RIDQDWLRQDO572*IRXQGDWLRQ
VWXG\WKDWLVLQYHVWLJDWLQJ6%57LQWKHUHLUUDGLDWLRQVHWWLQJIRUZKLFK*\LVWKHGRVHEHLQJ
XVHG,LQLWLDOO\HUUHGRQWKHVLGHRIEHLQJRYHUFDXWLRXVDQGVWDUWHGZLWK*\IHDULQJWKDW
SDWLHQWVZRXOGEHUHOXFWDQWWRHQUROODWKLJKHUGRVHV+RZHYHUDIWHUVFUHHQLQJQXPHURXV
HOLJLEOHSDWLHQWVWKHLPSHGLPHQWWRHQUROOPHQWLVSDWLHQWVIHDUWKDWWKHGRVHLVWRRORZWR
EHHIILFDFLRXVHVSHFLDOO\RQFHWKH\DUHDZDUHWKDWZHW\SLFDOO\XVHG*\VWDQGDUGO\LQWKH
UHLUUDGLDWLRQVHWWLQJ6HYHUDOSDWLHQWVH[SUHVVHGZLOOLQJQHVVWRHQUROOLIZHZHUHDOUHDG\
DFFUXLQJWRGRVHOHYHOEXWZHUHXQFRPIRUWDEOHZLWKGRVHOHYHOHVSHFLDOO\DVZHDUH
WHVWLQJWKLVDSSURDFKLQSDWLHQWVWKDWDUHSRWHQWLDOO\FXUDEOH

3URSRVHG$PHQGPHQWV
 $VVXFK,DPSURSRVLQJDQDPHQGPHQWWRWKHSURWRFROWRGURSWKHLQLWLDOO\SURSRVHG
GRVHOHYHODQGSURFHHGZLWK*\LQIUDFWLRQVDVRXULQLWLDOGRVH7KHUHYLVHG
SURWRFROZRXOGWKHQRQO\KDYHGRVHVJ\DQG*\LQIUDFWLRQV7KLVZLOODOVR
UHGXFHWKHQXPEHURISDWLHQWVUHTXLUHGLQVWHDGRIDQGKRSHIXOO\DPRUH
H[SHGLWLRXVFRPSOHWLRQRIWKLVWULDO,KDYHHQFORVHGWKHWUDFNHGDQGFOHDQYHUVLRQVRI
WKHUHYLVHGSURWRFRO$OOFKDQJHVZHUHPDGHPHUHO\WRUHIOHFWWKLVFKDQJHLQGRVLQJ
 7KHRQO\RWKHUFKDQJHLQWKHSURWRFROLVWKDWZHQRWLFHGDGLVFUHSDQF\LQWKH
HOLJLELOLW\FULWHULDZKHUHE\VWDJH,,ZDVGHHPHGHOLJLEOHEXW710ZDVVWDWHGWR
EHLQHOLJLEOH:HKDYHFRUUHFWHGWKHLQHOLJLELOLW\FKHFNOLVWWRVWDWHWKDW710LV
LQHOLJLEOHZKLOH6WDJH,,RU710GLVHDVHZLOOUHPDLQHOLJLEOH7KLVFODULILFDWLRQ
ZLOOUHPRYHFRQIXVLRQ

7KDQN\RXDJDLQIRU\RXUWLPHDQGUHYLHZ

6KORPR.R\IPDQ0'



6800$5<2)&+$1*(6
$PHQGPHQW9HUVLRQ'DWH6HSWHPEHU

&$6(3KDVH,'RVH(VFDODWLRQ6WXG\RI6WHUHRWDFWLF%RG\5DGLRWKHUDS\IRU
&DUFLQRPDRIWKH+HDGDQG1HFNLQ+LJK5LVN3DWLHQWV:KRDUH,QHOLJLEOH5HIXVH
6WDQGDUGRI&DUH7KHUDS\

6WXG\&KDLU6KORPR.R\IPDQ0'NR\IPDV#FFIRUJ



$GG'UV*HLJHU-RVKL:RRG\
5HPRYH'U1ZL]X
&KDQJHWLWOH
5HYLVHHOLJLELOLW\FULWHULDWRLQFOXGHRWKHUKLVWRORJLHVDGHQRFDUFLQRPDVDOLYDU\
 
JODQGFDQFHUSQHJDWLYH6&&FXWDQHRXV6&&7KLVZDVQHFHVVDU\GXH
 
WRSRRUDFFUXDO%HFDXVHWKH+39QHJDWLYH6&&SRSXODWLRQLVZDQLQJWKH
 
VWXG\WKUHDWHQVWRQRWPHHWDFFUXDODQGEHFORVHGWRGXHORZQXPEHUVRI
 
HOLJLEOHSDWLHQWV$VVXFKE\H[SDQGLQJWKHHOLJLELOLW\FULWHULDWRRWKHU
 
KLVWRORJLHVWKLVZLOOKHOSWKHDFFUXDOJRDOV$VWKLVLVSULPDULO\DQ6%57
 
VDIHW\VWXG\WKHKLVWRORJLFYDULDQWVVKRXOGQRWKDYHDQLPSDFWRQWKHVDIHW\
 
RI6%57DQGWKHUHIRUHWKHVFLHQWLILFULJRURIDVVHVVLQJWKHVDIHW\RIGRVH
 
HVFDODWLQJ6%57LQWKLVFRQWH[WUHPDLQVHYHQZLWKWKLVEURDGHQLQJRIHOLJLELOLW\
 
FULWHULD
