Clinical trial NCT02126969
Conditions: Head and Neck Cancer Larynx
Keywords: Cancer Low dose radiation
Sponsor: Susanne Arnold
Start date: 2014-10-01; Completion date: 2021-06-15
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary hypothesis of this study is that hyper-radiosensitivity (HRS) seen at extremely low doses of radiation can be exploited to enhance the effect of chemotherapy, and that this effect differs from the cellular effect of higher, standard fractions of radiation used in traditional radiation treatment paradigms.

Detailed description:

Arms: arm 1: Low dose fractionated radiation - 80cGy with chemotherapy arm 2: Chemotherapy only
Interventions: intervention 1: Low dose fractionated radiation - 80cGy with chemotherapy intervention 2: Docetaxel and Carboplatin AUC 6
Intervention descriptions: intervention 1: Chemotherapy + 80 cGy of RT intervention 2: Docetaxel 75 mg/m2 and Carboplatin AUC 6 without Radiation

Protocol documents:
Prot_SAP_000.pdf: 
0 
 
Local Protocol #: 
13-H&N-24 
 
 
TITLE:  A PHASE II STUDY OF DOCETAXEL, CARBOPLATIN WITH AND WITHOUT LOW DOSE 
RADIATION AS INDUCTION THERAPY IN LOCALLY ADVANCED HEAD AND NECK CANCER  
 
Coordinating Center: 
 
 
Markey Cancer Center 
 
Principal Investigator: 
 
NAME  
Susanne M. Arnold, MD 
DEPARTMENT/DIVISION 
Internal Medicine/Medical Oncology 
OFFICE ADDRESS 
Cc457, Markey Cancer Center; 0893 
EMAIL ADDRESS 
Smarno0@uky.edu 
PHONE 
859-323-8043 
 
Co-Investigators: 
 
NAME  
Mahesh Kudrimoti, MD 
DEPARTMENT/DIVISION 
Radiation Medicine 
OFFICE ADDRESS 
N13 A B Chandler Medical Center 40536-0293 
PHONE 
859-323-6486 
EMAIL ADDRESS 
Mkudr0@uky.edu 
 
 
NAME  
Stacey Slone, PhD 
DEPARTMENT/DIVISION 
Division of Cancer Biostatistics 
OFFICE ADDRESS 
800 Rose Street, Roach Building, CC437 
PHONE 
859-323--1723 
EMAIL ADDRESS 
Stacey.slone@uky.edu 
 
 
NAME  
Tadahide Izumi, PhD 
DEPARTMENT/DIVISION 
Graduate Center for Toxicology 
OFFICE ADDRESS 
336 Health Sciences Research Building 40536-0305 
PHONE 
859-257-6472 
EMAIL ADDRESS 
t.izumi@uky.edu 
 
 
NAME  
David Orren, PhD 
DEPARTMENT/DIVISION 
Graduate Center for Toxicology 
OFFICE ADDRESS 
356 Health Sciences Research Building 40536-0305 
PHONE 
859-323-3612 
EMAIL ADDRESS 
david.orren@uky.edu 
 
Study Coordinator: 
 
Responsible Data Manager: 
Cynthia A. Leedham, PhD 
Jennifer Land 
MCC-CRO 
Cancer Research Informatics 
CC140 Pavilion C 
2365 Harrodsburg Rd, Ste A230 
Telephone: 859-257-4470  
Telephone 859-323-9964 
Fax: 859-257-4550 
fax: 859-257-4177 
 
Commercially Supplied Agent(s):  Docetaxel and Carboplatin 
 
Protocol Type / Version # / Version Date: Revised / Version 8.0 / March 1, 2018 


Protocol # 13-H&N-24 
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SCHEMA: Randomized Phase II study 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
Prior to Rx 
 
 
 
 
 
 
 
 
 
Day 1, 22 
 
 
 
 
  Day 1, 22 
 
 
Day 2, 23 
 
 
 
 
                
 
                          
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          = 80 cGy of RT, given BID 
 
           = In-port radiation biopsy 
Docetaxel 75 mg/m2 
Carboplatin AUC 6 
 
 
Docetaxel 75 mg/m2 
Carboplatin AUC 6 
Locally advanced squamous cell carcinoma 
of the head and neck (SCCHN) 
Repeat biopsy and 
evaluation by 
Multidisciplinary H&N 
oncology team 
Definitive surgery or 
chemoradiation 
Day 3-5 of Week 1 
SOC restaging after induction by 
same method at screening 
Repeat biopsy and 
evaluation by 
Multidisciplinary H&N 
oncology team  
 
 
Bx 
Bx 
Bx 
  
Bx 
  


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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ...................................................................................................................... 4 
1.1 
Primary Objectives .................................................................................................. 4 
2. 
BACKGROUND ................................................................................................................. 4 
2.1 
Squamous cell carcinoma of the head and neck (SCCHN) ..................................... 4 
2.2 
Preclinical Studies using LDFRT ............................................................................ 5 
2.3 
Clinical Studies using LDFRT................................................................................. 5 
2.4 
Rationale for Docetaxel and Carboplatin ................................................................ 6 
2.5 
Correlative Studies ................................................................................................... 6 
2.6 
Rationale .................................................................................................................. 7 
3. 
PATIENT SELECTION ...................................................................................................... 7 
3.1 
Eligibility Criteria .................................................................................................... 7 
3.2 
Exclusion Criteria .................................................................................................... 8 
3.3 
Inclusion of Women and Minorities ........................................................................ 9 
4. 
REGISTRATION PROCEDURES ................................................................................... 10 
4.1 
Protocol Review and Monitoring Committee and Institutional Review Board Review
 ............................................................................................................................... 10 
4.2 
Enrollment Guidelines ........................................................................................... 10 
4.3 
Informed Consent .................................................................................................. 10 
4.4 
Compliance with Laws and Regulations ............................................................... 11 
5. 
TREATMENT PLAN ........................................................................................................ 11 
5.1 
Pre-treatment Studies ............................................................................................. 11 
5.2 
Agent Administration ............................................................................................ 11 
5.3 
Chemotherapy Premedication and Dosing: ............................................................. 12 
5.4 
Pre- and Post-Induction Treatment Tissue sampling ............................................. 12 
5.5 
Post-Induction Reassessment ................................................................................. 12 
5.6 
Dosage and fields Low-Dose Fractionated Radiation (LDFRT) ........................... 13 
5.7 
Dosage and fields for Standard Fraction Radiation post-Induction ....................... 13 
5.8 
General Concomitant Medication and Supportive Care Guidelines ...................... 13 
5.9 
Duration of Therapy .............................................................................................. 13 
5.10 
Duration of Follow Up ........................................................................................... 14 
5.11 
Criteria for Removal from Study ........................................................................... 14 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 14 
6.1 
Dose Modifications ................................................................................................ 14 
6.2 
Hematologic Toxicity ............................................................................................ 15 
6.3 
Non-hematologic Toxicity ..................................................................................... 15 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................ 16 
7.1 
Adverse Events and Potential Risks ...................................................................... 16 
7.2 
Adverse Event Characteristics ............................................................................... 17 
7.3 
Expedited Adverse Event Reporting ..................................................................... 17 
7.4 
Expedited Reporting to External Agencies ............................................................ 18 
7.5 
Routine Adverse Event Reporting ......................................................................... 19 


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8. 
PHARMACEUTICAL INFORMATION ......................................................................... 19 
8.1 
Commercial Agent:  Docetaxel ............................................................................. 19 
8.2 
Commercial Agent: Carboplatin ............................................................................ 21 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 23 
9.1 
Biomarker Studies ................................................................................................. 23 
9.2 
Correlative Studies (Tumor Biopsy and Radiation Port Images) .......................... 25 
10. 
STUDY CALENDAR ....................................................................................................... 26 
11. 
MEASUREMENT OF EFFECT ....................................................................................... 27 
11.1 
Antitumor Effect – Solid Tumors .......................................................................... 27 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ........................................... 32 
12.1 
Data Reporting ....................................................................................................... 32 
13. 
STATISTICAL CONSIDERATIONS .............................................................................. 32 
13.1 
Experimental Design ............................................................................................. 32 
13.2 
Accrual and Power Considerations ........................................................................ 33 
13.3 
Interim Analyses .................................................................................................... 33 
13.4 
Details for Interim Analyses with O'Brien-Fleming Boundaries .......................... 33 
13.5 
Analysis Plan ......................................................................................................... 33 
13.6 
Data Management .................................................................................................. 34 
13.7 
Reporting and Exclusions ...................................................................................... 34 
14. 
REFERENCES .................................................................................................................. 35 
APPENDIX A. 
PERFORMANCE STATUS CRITERIA .................................................. 37 
APPENDIX B.  
STAGING FOR HEAD AND NECK CANCER ...................................... 38 
APPENDIX C.            FACT-H&N V4......................................................................................... 39 
APPENDIX D.  
BIOASSAY PROCEDURES .................................................................... 43 
 
 
 


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1. OBJECTIVES 
 
The primary hypothesis of this study is that hyper-radiosensitivity (HRS) seen at extremely low doses of 
radiation (80 cGy) can be exploited to enhance the effect of chemotherapy, and that this effect differs from the 
cellular effect of higher, standard fractions of radiation used in traditional radiation treatment paradigms.   
 
1.1 
Primary Objectives 
 
Primary: 
 
1.1 
To assess the primary site complete response rate of patients treated with 2 cycles of induction 
Docetaxel and Carboplatin with low dose fractionated radiation therapy (LDFRT) compared to 
those treated with chemotherapy alone.  
Secondary: 
 
1.2 
To assess overall response rate of patients to 2 cycles of induction Docetaxel and Carboplatin 
with or without LDFRT  
1.3 
To assess the toxicity and quality of life (QOL) of LDFRT with chemotherapy compared to 
chemotherapy alone in this patient population 
1.4 
To assess the 3-year overall survival of patients treated with this regimen. 
1.5 
To assess measures of DNA repair (gamma-H2AX levels, PARP activation) and DNA repair 
kinetics (Comet assay) in serial mucosal cell samples obtained from the irradiated region of the 
head and neck (i.e. buccal, tongue, pharyngeal wall, etc.) of subjects on this trial. These will be 
collected:  
1.5.1 Prior to therapy 
1.5.2 During induction therapy and LDFRT 
1.5.3 During the first week of full-dose radiation in both groups. 
The outcomes of the proposed research will provide direct validation of the hypothesis that LDFRT improves 
response rates of patients with SCCHN to induction chemotherapy, through a different mechanism than standard 
fractions of radiation.   
 
2. BACKGROUND 
 
2.1 
Squamous cell carcinoma of the head and neck (SCCHN) 
 
Squamous cell cancer of the head and neck (SCCHN) comprise 5% of all cancers, with 40,000 new cases 
diagnosed annually.1 The age-adjusted incidence of squamous cell carcinoma of the head and neck (SCCHN) 
is 13.07 per 100,000 individuals in Kentucky, placing Kentucky third in incidence rate in the United States.1 
Treatment of locally advanced SCCHN consists of aggressive regimens of chemotherapy and radiation with an 
approximate 5-year survival of 50%.2 There are substantial opportunities to improve survival in this disease, 
and one paradigm that has received extensive study is induction therapy, given prior to definitive treatment 
with radiation or chemoradiation.3  This has shown a survival advantage in SCCHN in recent years,4-7 but 
with the potential for increased toxicity which has kept this promising therapy from wide adoption by clinical 


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oncologists.  
 
In addition, it is difficult to tease out the effect of induction because its pairing with concomitant 
chemotherapy and radiation in all of these studies, with response rate (RR) as a surrogate for that effect The 
synergy between radiation and chemotherapy is well established in vitro and in the field of SCCHN 
treatment.8,9 and has become the standard of care for locally advanced SCCHN since initial studies in the 
1980’s. In general, standard doses of radiation cause single- and double-strand DNA damage, which 
accumulates unrepaired and cause global cellular catastrophe and rapid cell death. Radiation recruits more 
cells into active cell cycle, which, in theory, allows a higher percentage of cells to be susceptible to 
chemotherapy agents. The addition of chemotherapy to radiation, in turn, is thought to alter the intrinsic 
radioresistance of tumor cells. By killing a percentage of cancer cells, chemotherapy also allows 
reoxygenation of previously hypoxic areas thus enhancing radiotherapy.  
 
Because low doses of radiation (1-100 cGy) do not cause such global cellular injury, the initial slope of the 
radiation cell-survival curve was presumed to be an ineffective dose range for human tumor therapy. 
However, Joiner and colleagues were the first to describe techniques to adequately study low dose radiation 
and demonstrated an initial phase of hypersensitivity to radiation at doses less than 100 cGy (Figure 1).10,11 
Termed hyper-radiosensitivity (HRS), this phenomenon was postulated to be exploitable over 20 years ago.  
 
This proposal investigates the role of low-dose fractionated radiation (LDFRT) combined with chemotherapy 
as induction therapy in a phase II randomized clinical trial in locally advanced squamous cell carcinoma of the 
head and neck. Correlative studies will evaluate the level of DNA repair and DNA repair kinetics in subjects 
prior to and after exposure to low-dose (<100 cGy) and standard dose (> 180 cGy) fractions of radiation 
throughout the course of this treatment. This evaluation of DNA damage will help to elucidate the mechanism 
of cell death that occurs when cells are exposed to radiation doses of less than 100 cGy. The outcomes of the 
proposed research will provide direct validation of the clinical hypothesis that LDFRT improves response 
rates in patients with SCCHN to induction chemotherapy, and will evaluate and elucidate the level of DNA 
damage and repair kinetics in response to different doses of radiation. This phase II trial will provide the 
evidence needed to test this treatment paradigm in a phase III trial at the national level and will provide 
preliminary data for independent funding to study the molecular effects of low-dose radiation.   
 
2.2 
 Preclinical Studies using LDFRT 
 
Until recently, the initial slope of the radiation cell-survival curve (doses of 0-100 cGy) was presumed to be 
an ineffective dose range for human tumor therapy. However, as techniques to adequately study low dose 
radiation have improved, quite the opposite effect has been described. Joiner revolutionized thinking about 
low doses of radiation (<100 cGy) by demonstrating an initial phase of hypersensitivity to radiation using 
doses from 0 to 50 cGy.10,11 In work from the University of Kentucky, Ahmed and colleagues12-14 have 
expanded our understanding of this synergy by combining LDFRT and various chemotherapeutic agents. 
Using very low doses of radiation in combination with chemotherapy, they have demonstrated enhanced cell 
death compared to chemotherapy or radiation alone. More importantly, in cell culture, pro-apoptotic 
pathways were enhanced without the induction of pro-survival pathways; both in p53 mutant and wild-type 
cell lines. Significantly, LDFRT avoids the development of one type of radiation resistance (the upregulation 
of pro-survival pathways) seen with higher dose radiation. This may provide one way to overcome radiation 
resistance, a major cause of treatment failure in SCCHN, while still enhancing cell death.  
 
2.3 
Clinical Studies using LDFRT 
 
These pre-clinical studies suggest a unique synergistic effect between LDFRT and taxane-based 


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chemotherapy. While Joiner and colleagues were the first to describe the potential of LDRFT as a therapeutic 
modality, our investigative team has explored the synergy of LDFRT and various chemotherapeutic agents 
in vitro.12,14 We found that chemotherapy followed by LDFRT enhanced cell death compared to 
chemotherapy alone. Based on this preclinical work, we designed a strategy to capitalize on this synergy, 
using LDFRT as a chemotherapy potentiator in the setting of induction chemotherapy in SCCHN.13  Our 
novel induction strategy was successfully translated into two phase II clinical trials,13,15 and showed less 
toxicity than other induction chemotherapy regimens and similar efficacy. Using four to eight fractions of 
50 to 80 cGy of LDFRT in combination with chemotherapy provided excellent response rates (85%) and 
favorable long-term survival compared to historical controls.15  Our initial trials were the first in humans 
using this approach, but lacked a comparator arm, which is needed to accurately examine the true effect of 
LDRFT with chemotherapy. This randomized phase II trial design, seeks to prove the hypothesis that 
LDFRT can enhance the effect of induction chemotherapy in SCCHN, through the phenomenon of HRS that 
exists at very low doses of radiation.  
The application of HRS and LDFRT to clinical cancer treatment was pioneered by our group, who published 
the first human trials of this novel paradigm. Potentiating the effect of chemotherapy with the lowest doses 
of radiation had never been shown to be effective in humans prior to our studies. In addition, work by 
University of Kentucky investigators and colleagues at other institutions has advanced the field of 
knowledge of LDFRT’s a) interactions with a variety of chemotherapies,12-15 b) mechanisms of cellular 
injury, and c) role in phase I and II studies in other tumor types.16 
 
2.4 
Rationale for Docetaxel and Carboplatin 
 
Docetaxel is an inhibitor of microtubule function and is well established as a radiosensitizer of cancer cell 
lines in vitro.17,18 Combination therapies utilizing Carboplatin and Docetaxel have become the standard for 
induction regimens in SCCHN.6,7,19 Taxanes induce G2/M arrest, the most radiosensitive phase of the cell 
cycle, through inhibition of microtubule function,17,18,20 within two hours after administration and this effect 
peaks between 8 and 12 hours.21,22 Multiple in-vitro studies in head and neck cancer cell lines show supra-
additive effect of taxanes and radiation when cells were exposed to taxanes prior to irradiation.17 In vitro 
data with Carboplatin also indicates an additive effect when given prior to irradiation using various cell 
lines.23 Additionally, the pharmacokinetics of carboplatin is not altered by pretreatment with taxanes at 
standard doses. The combination of Docetaxel and Carboplatin was chosen because of the proof of its 
efficacy in induction therapy in head and neck cancer, as well as the ability to complete chemotherapy 
infusion in a timely manner to allow for two fractions of LDFRT to be delivered on Day 1. We propose to 
expand our understanding of LDFRT and chemotherapy in a randomized phase II study of Docetaxel and 
Carboplatin with LDFRT as induction therapy in patients with bulky Stage II, Stage III and IV H&N cancer.  
 
2.5 
Correlative Studies 
 
In preclinical studies, low dose radiation is thought to exert its influence in the early G2/M checkpoint 
through the damage response of G2-phase cells. Radiation induces DNA double strand breaks with cellular 
response including phosphorylation of ATM, followed by activation of downstream targets with gamma-
H2AX operating as a damage sensor 24. In preclinical studies, Krueger and colleagues 25 demonstrated that 
low-dose hyper-radiosensitivity caused a predictable increase in gamma-H2AX within 1-2 hours after each 
low dose fraction, but this has not been studied in humans to date. To determine the effect of low-dose 
radiation, we will measure the time dependent expression of gamma-H2AX in serial mucosal sampling 
from the irradiated mucosa of these patients. Tissues will be collected pre-therapy and after the first dose 
of induction chemotherapy and LDFRT, as well as within the first week of definitive, full-dose radiation, 
as listed in section 5.4. In addition, assessment of DNA repair kinetics through the use of Comet assays 


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will allow an estimation of DNA repair when human cells are exposed to low doses and full doses of 
radiation. Planned investigation will include the analysis of markers of DNA damage: including 
immunohistochemical staining for PARP (single-strand breaks) gamma-H2AX (double-strand breaks) and 
DNA repair kinetics (Comet assay) analyzed at multiple time points to assess radiosensitization of cancer 
cells by different doses of ionizing radiation. Correlative endpoints will provide intra-patient assessment of 
response to DNA damage by low-dose and standard dose radiation, by direct evaluation within the 
radiation port. This avenue of study is unique and sampling at different time points will help define the 
different cellular responses to low-dose (<100 cGy) radiation and standard dose radiation (>180 cGy).   
 
2.6 
Rationale 
 
The primary hypothesis of this study is that hyper-radiosensitivity (HRS) seen at low doses of radiation 
(80 cGy) can be exploited to potentiate the effect of chemotherapy, and that this hrs results in DNA 
damage response that is distinct from the DNA damage response caused by traditional doses of 
radiation (> 180 cGy) used in cancer treatment. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed locally advanced head and neck cancer 
of squamous type stage III, IVA and IV B (larynx, oral cavity, oropharynx and hypopharynx or unknown 
primary isolated to the head and neck region) and select Stage II tumors of the BOT (size more than 3 
cm), who are appropriate for potentially curative therapy with chemoradiotherapy or surgical resection, 
as determined by the Multidisciplinary Head and Neck Cancer Clinical Care and Research Team. 
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be accurately measured 
in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for 
nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or 
calipers by clinical exam. See Section 11 for the evaluation of measurable disease. All disease must 
be assessed within 28 days prior to registration.   
 
3.1.3 ECOG performance status of 0, 1 or 2 (see Appendix A). 
 
3.1.4 No prior chemotherapy for the current locally advanced SCCHN. Prior radiation or chemotherapy for a 
previous head and neck cancer is allowed provided full dose radiation can be delivered to the current 
treatment and provided the patient remains in remission for greater than 3 years from prior diagnosis. 
 
3.1.5 Age ≥18 years.  
 
3.1.6 Life expectancy of greater than 3 months 
 
3.1.7 Patients must have normal organ and marrow function measured within 14 days of registration as 
defined below: 
 
− absolute neutrophil count 
≥ 1,000/mcL 
− platelets 
≥ 100,000/mcL 
− total bilirubin 
≤ institutional upper limit of normal 
− AST(SGOT 
 
 
 
≤ 1.5 × institutional upper limit of normal 


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− Alkaline phosphatase  
≤ 2.5 × institutional upper limit of normal 
− creatinine 
within normal institutional limits 
OR 
− Creatinine clearance 
≥ 60 mL/min/1.73 m2 for patients with creatinine levels above 
institutional normal. 
 
3.1.8 The effects of Docetaxel, Carboplatin, and LDFRT are known teratogens. For this reason, women of 
child-bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, throughout the duration of active treatment 
and for 4 months after completion of chemotherapy and radiation. Should a woman become pregnant 
or suspect she is pregnant while she or her partner is participating in this study, she should inform 
her treating physician immediately. Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of active study treatment, and for 4 months 
after completion of chemotherapy and radiation (both induction and definitive) administration. 
 
3.1.9 ity to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Prior chemotherapy for the current SCCHN will not be allowed. Patients with second primary cancers 
of the head and neck who remain in remission for 3 years from the prior diagnosis are eligible for 
this study, provided they may receive full dose radiation to the current SCCHN cancer. 
 
3.2.2 Patients who are receiving any other investigational agents. 
 
3.2.3 Patients with known brain metastases should be excluded from this clinical trial because of their poor 
prognosis and because they often develop progressive neurologic dysfunction that would confound 
the evaluation of neurologic and other adverse events. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
Carboplatin or Docetaxel. 
 
3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
3.2.6 Pregnant women are excluded from this study because Docetaxel, Carboplatin, and radiation are 
agents with 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 
Docetaxel, Carboplatin and radiation, breastfeeding should be discontinued if the mother is treated 
with these agents and/or radiation. These potential risks may also apply to other agents used in this 
study. 
 


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3.2.7 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential 
for pharmacokinetic interactions with Docetaxel, Carboplatin and radiation. In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. 
Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when 
indicated. 
 
3.2.8 No other prior malignancy is allowed except for the following: adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, adequately treated previous Stage I or II cancer 
from which the patient is currently in complete remission or other cancer from which the patient has 
been disease-free for 3 years.  
 
3.2.9 Patients with nasopharynx or salivary gland primary site will be excluded from this trial. 
 
3.2.10 Patients with distant metastatic disease (M1c) will not be eligible for this study. 
 
3.2.11 Patients with grade II or greater peripheral neuropathy will be excluded from study. 
 
Note: In calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later would be considered Day 28. 
If Day 28 falls on a weekend or holiday, the test or measurement may be performed on the next working day 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. The required table below shows 
estimated accrual targets of the anticipated patient population based on the catchment area of the MCC and 
are not a limitation to accrual by category. 
 
Accrual Targets  
Ethnic Category 
Sex/Gender 
Females 
 Males 
 Total 
Hispanic or Latino 
1 
+ 
2 
= 
3 
Not Hispanic or Latino 
32 
+ 
37 
= 
69 
Ethnic Category: Total of all  subjects 
33 
+ 
39 
= 
72 
Racial Category 
 
American Indian or Alaskan  
Native 
0 
+ 
0 
= 
0 
Asian 
2 
+ 
2 
= 
4 
Black or African American 
5 
+ 
6 
= 
11 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
26 
+ 
31 
= 
57 
Racial Category: Total of all subjects 
33 
+ 
39 
= 
72 
 
 
 
 
 
 
 
 


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4. REGISTRATION PROCEDURES 
 
4.1 
Protocol Review and Monitoring Committee and Institutional Review Board Review 
 
Before implementing this study, the protocol, the proposed informed consent form, and other information 
to subjects must be reviewed by the Markey Cancer Center’s Protocol Review and Monitoring Committee 
and the University of Kentucky Institutional Review Board (IRB). A signed and dated statement that the 
protocol and informed consent have been approved by the IRB must be maintained in the Markey Cancer 
Center Clinical Research and Data Management Shared Resource Facility (MCC CRDM SRF) regulatory 
binder. Any amendments to the protocol, other than administrative ones, must be reviewed and approved 
by the PRMC and the UK IRB.   
 
4.2 
Enrollment Guidelines 
 
Eligible patients will be identified by the principal investigator and co-investigators of this study. Potentially 
eligible patients will be screened in the University of Kentucky Markey Cancer Center clinics by the 
investigators, study personnel, and the Principal Investigator (PI). Upon obtaining proper consent, patients 
will be enrolled into the study.   
 
4.3 
Informed Consent 
 
The goal of the informed consent process is to provide people with sufficient information so they can make 
informed choices about whether to begin or continue participation in clinical research. The process involves 
a dynamic and continuing exchange of information between the research team and the participant throughout 
the research experience. It includes discussion of the study's purpose, research procedures, risks, and 
potential benefits, and the voluntary nature of participation. The informed consent document provides a 
summary of the clinical study and the individual's rights as a research participant. The document acts as a 
starting point for the necessary exchange of information between the investigator and potential research 
participant. Also, research participants and their families may use the consent document as an information 
resource and reference throughout participation in the trial. The informed consent document is often 
considered the foundation of the informed consent process; it does not, however, represent the entirety of 
the process. Nor is the informed consent document a risk-management tool for the investigator and/or 
institution. 
 
The investigator must explain to each subject (or legally authorized representative) the nature of the study, 
its purpose, the procedures involved, the expected duration, the potential risks, and benefits involved and 
any discomfort it may entail. Each subject must be informed that participation in the study is voluntary and 
that he/she may withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
 
This informed consent should be given by means of a standard written statement, written in non-technical 
language. The subject should read and consider the statement before signing and dating it, and should be 
given a copy of the signed document. If the subject cannot read or sign the documents, oral presentation may 
be made or signature given by the subject’s legally appointed representative, if witnessed by a person not 
involved in the study, mentioning that the patient could not read or sign the documents. No patient can enter 
the study before his/her informed consent has been obtained. The informed consent form is considered part 
of the protocol, and must be submitted by the investigator with the protocol at the time of IRB review. 
 


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4.4 
Compliance with Laws and Regulations 
 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and International 
Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), the Declaration of 
Helsinki, any applicable local health authority, and Institutional Review Board (IRB) requirements. The PI 
or designee will be responsible for obtaining continuing and not less than annual IRB re-approval throughout 
the duration of the study. Copies of the Investigator’s annual report to the IRB and copies of the IRB 
continuance of approval must maintained by the MCC CRDM SRF. The PI or designee is also responsible 
for notifying the Data and Safety Monitoring Committee of the MCC and the UK IRB of any significant 
adverse events that are serious and/or unexpected, as per SOP’s of those entities. DSMC will review all 
adverse events of this IIT as per its SOP. 
 
5. TREATMENT PLAN 
 
5.1 
Pre-treatment Studies 
  
Prior to any study-required tests, subjects must first provide written informed consent to participate in this 
study. Within 6 weeks, all patients will undergo a direct laryngoscopy (DL) or indirect laryngoscopy (IDL) 
(if the primary tumor is easily and completely evaluable by IDL). Within 4 weeks of registration, all patients 
will undergo a history and physical exam, ECOG performance status evaluation,, a CT or MRI scan of the 
involved area of the head and neck and a CT of the Chest or chest X-ray.  Within 2 weeks of registration, all 
patients will undergo a complete blood count with differential and platelets, and serum chemistries 
(including sodium, potassium, chloride, bicarbonate, calcium, total protein, albumin, BUN, creatinine, AST, 
alkaline phosphatase, and total bilirubin).  
 
5.2 
Agent Administration 
 
Treatment will be administered on an outpatient or inpatient basis. Appropriate dose modifications are 
described in Section 6. No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. Carboplatin and Docetaxel are 
FDA approved for this indication and will be administered as below on Day 1 and 22. Radiation will be 
given on Days 1, 2, 22, and 23 of chemotherapy. The first fraction will be given within 1 hour after 
completion of Carboplatin while the remaining fractions of each cycle will have at least a 3-hr interfraction 
interval.  
 
Induction Regimen Description 
Agent 
Premedications / 
Precautions 
Dose (solution and 
volume) 
Route 
Schedule 
Cycle 
Length 
Docetaxel  
Dexamethasone  
8 mg BID PO or IV 
Day prior, day of and 
day after Docetaxel 
75 mg/m2 
(250 cc NS) 
IV over 60 minutes 
per institutional 
guidelines 
Day 1 
every 21 
days 
 
Carboplatin  
 
Ondansetron 8 mg PO 
or IV 
AUC = 6 
(250 cc NS)  
GFR calculation by 
Cockcroft-Gault 
equation; AUC by 
Calvert formula: 
IV over 30 minutes 
after completion of 
Docetaxel per 
institutional 
guidelines 
Day 1 
Low dose 
fractionated 
None 
 
80 cGy 
BID with at least 3 
hours between doses 
Days 1 and 2 


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12 
 
radiation 
(total of four 
fractions per cycle) 
**Anti-emetic regimen per NCCN and institutional guidelines  
 
5.3 
Chemotherapy Premedication and Dosing: 
 
All chemotherapy will use actual body weight and will be administered as an i.v. infusion. Docetaxel will be 
given at a dose of 75 mg/m2 intravenously over one hour on Days 1 and 22. Docetaxel will be dosed to the 
nearest 5mg using a standard body surface area chart. Carboplatin infusion will follow Docetaxel and will be 
given at a dose of Area under the Curve of 6 (using Cockcroft-Gault calculation) intravenously over one hour 
on Days 1 and 22. 
 
To avoid allergic reactions associated with Docetaxel, the following premedications are recommended:  
 
• Dexamethasone 8mg PO BID 1 day prior to, day of and day after chemotherapy. If a patient fails to 
premedicate on the day prior to chemotherapy, then give dexamethasone 12mg IV 
 
Other anti-emetics are per institutional standard and at the discretion of the treating physician.  
 
5.4 
Pre- and Post-Induction Treatment Tissue sampling 
 
Prior to chemotherapy and radiation and as outlined below, patients will undergo buccal swab sampling in 
the mouth. Wherever possible this sampling will be in the area of the radiation delivery. See Appendix D 
for sampling instructions 
 
Buccal sampling: 
Subjects will first rinse their mouth with water. The mucosa will be swabbed with a cytology brush (which 
is then discarded), subjects will rinse again and the same area will be scraped gently with a wooden spatula 
10 times. Specimens are fixed onto uncharged slides and spray fixed.  A second cytology brush is then 
applied to the area and placed in media for storage as per sample collection instructions (see correlative 
section 9.0 and Appendix D). These samples will be collected with a mandatory pre-treatment sample and a 
minimum of 3 samples during induction, and a minimum of 3 samples during definitive radiation as 
described in Appendix D.   
 
5.5 
Post-Induction Reassessment 
 
Following two cycles of induction therapy and at least 2 weeks after the last LDFRT dose, subjects will have 
reassessment by radiographic and clinical evaluation (DL or IDL) to assess primary site and complete RR. 
A panendoscopy will only be performed, if the primary tumor is not easily and completely assessable by 
indirect laryngoscopy. The assessment of tumor response will be made by the otolaryngologist or oncologist 
performing the procedure. In the case of apparent progressive disease, biopsies of the primary tumor area 
will be taken. This is considered part of routine care of patients undergoing neoadjuvant therapy. If a subject 
has biopsy or surgical removal, those tissues will also be collected for correlative study (although no surgical 
removal is planned in these patients). Following induction, all subjects will undergo definitive radiation and 
chemotherapy or surgery, as per standard of care, as pre-determined by a multidisciplinary review of cases. 
Subjects must have recovered from all study related (possible, probable or definite) toxicities to < grade 2 
(CTCAE v4.0) as determined by the treating physician prior to initiation of definite treatment.  Definite 
therapy should occur on or after Day 43 and prior to Day 64 from the start of induction (Day 1). Definitive 
radiation will incorporate the dose of radiation used during induction into the final dose calculation, with 
dose adjustments of definitive radiation made at the discretion of the treating radiation oncologist.  Definitive 


Protocol # 13-H&N-24 
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13 
 
surgery will incorporate standard of care surgical removal.  
 
5.6 
Dosage and fields Low-Dose Fractionated Radiation (LDFRT) 
 
Doses of 80 cGy per fraction will be administered (to a total of 640 cGy for the entire induction scheme). 
The patient will be treated with shaped fields encompassing gross disease only (including the primary and 
gross nodal disease) with a maximum 2cm margin. The spinal cord will be excluded from the radiation field 
and CT based treatment planning will be used as needed and as appropriate.  
 
5.7 
Dosage and fields for Standard Fraction Radiation post-Induction 
 
Following induction, dosage and fields for definitive standard fractionation will be determined by the 
treating radiation oncologist. The accepted standard total dose of radiation used for definitive therapy ranges 
from 66-72Gy when once-daily RT is used at 1.8-2.0Gy/fraction and from 74.4-81.6Gy when twice-daily 
RT is used at 1.2Gy/fraction. In calculating the planned total dose of radiation to be used for subsequent, 
definitive therapy the radiation oncologist will incorporate the induction dose used into the final calculation 
for a maximum total dose of approximately 74Gy if once-daily fractionation is used or approximately 
82.4Gy if twice-daily fractionation is used. Since the 640 cGy used in the induction regimen is delivered at 
a very low dose/fraction (i.e. 80cGy), it is expected that the incorporation of this dose into the calculated 
total doses should not be associated with any significant increase in late radiation damage/effect, as 
previously described in our non-randomized phase II trials. 
 
Management and dose modifications associated with the above adverse events are outlined in Section 6. 
Performance status will be evaluated based on the ECOG Performance Status Criteria (Appendix A). 
Toxicities will be graded as per section 7.0.   
 
5.8 
General Concomitant Medication and Supportive Care Guidelines 
 
The use of concomitant bisphosphanates, and other supportive medications determined necessary for the 
health of subjects are allowed, but concurrent cancer therapies other than the treatment regimen of this trial 
are not allowed. Caution should be taken when administering supportive medications that are metabolized 
through the cytochrome P450 system, although this study does not specifically exclude agents known to 
affect or with the potential to affect selected CYP450 is enzymes.  
 
5.9 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 2 cycles or until one 
of the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 


Protocol # 13-H&N-24 
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14 
 
 
 
 
5.10 
Duration of Follow Up 
 
Patients will be followed by study team until resolution of side effects from induction therapy to less than 
or equal to grade 1 toxicity (excluding previously existing conditions, which must return to baseline) AND 
until the patient has completed their definitive chemotherapy and radiation or definitive surgery with follow-
up scans (per institutional guidelines be usually performed within 8 weeks of last dose of radiation). Patients 
will be followed for 3 years after completion of the study by the Kentucky Cancer Registry which is required 
by law to follow all cancer patients diagnosed in Kentucky for their lifetime from the time of diagnosis until 
death. KCR routinely records overall survival, as well as time of first recurrence and sites of recurrence, 
therefore, is uniquely qualified to follow these patients long-term. At the point three years from completion 
of final subject, and at interim analysis, the KCR will search the database for survival, both overall and 
progression-free. 
 
5.11 
Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 5.9 applies. The reason for 
study removal and the date the patient was removed must be documented in the Case Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modifications 
 
Cycle 2 of therapy may be administered provided the subject meets all of the following criteria within 2 days 
of Cycle 2 Day 1: 
 
• 
ANC ≥ 1,000/µL. 
• 
Platelet count ≥ 75,000/µL. 
• 
total bilirubin ≤institutional upper limit of normal 
• 
AST(SGOT ≤ 1.5 × institutional upper limit of normal 
• 
Alkaline phosphatase ≤ 2.5 × institutional upper limit of normal 
• 
All other Grade 2, 3 or 4 non-hematological toxicities listed in section 6.3 have resolved. 
• 
Serum creatinine ≤ 1.5 x ULN OR measured or calculated creatinine clearance ≥ 60 mL/min 
using the Cockcroft-Gault. 
 
Assessment for dose modification will be conducted prior to each dose. Dose escalation will not be allowed 
during this study. Chemotherapy doses may be reduced or held for hematological and non-hematological 
effects. If chemotherapy is held, radiotherapy will be held and will restart on the same day as 
chemotherapy based on the parameters for alteration due to toxicity listed below. Radiation doses are 
not decreased. Treatment may be delayed no more than three weeks to allow recovery from toxicity. A 
patient will be allowed a maximum of two dose reductions. Dose adjustments will be made according to the 
following guidelines: 
 
Dose Modification Table 
Modification Episode 
Carboplatin (AUC) 
Docetaxel (mg/m2) 
0 
6 
75 
-1 
5 
65 


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15 
 
-2 
4 
55 
 
 
6.2 
Hematologic Toxicity 
The following table outlines the dose reduction guidelines for docetaxel and carboplatin for 
thrombocytopenia and neutropenia that occurs at any point during the prior cycle.   
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neutropenia 
No change 
No Change 
Hold until < grade 
2, then reduce 
Carboplatin and 
Docetaxel by 1 
dose level 
Hold until < grade 2, 
then reduce 
Carboplatin and 
Docetaxel by 1 dose 
level 
Febrile 
Neutropenia 
No change 
No Change 
Hold until < grade 
2, then reduce 
Carboplatin and 
Docetaxel by 1 
dose level 
Hold until < grade 2, 
then reduce 
Carboplatin and 
Docetaxel by 1 dose 
level 
Thrombocytopenia 
No change 
Hold until < grade 1, 
then resume at same 
dose of Carboplatin 
and Docetaxel  
Hold until < grade 
1, then reduce 
Carboplatin and 
Docetaxel by 1 
dose 
Hold until < grade 1, 
then reduce 
Carboplatin and 
Docetaxel by 1 dose 
level 
 
6.3 
Non-hematologic Toxicity 
The following table outlines the dose reduction guidelines for docetaxel and carboplatin for non-hematologic 
toxicities that occur at any point during the prior cycle.  
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucositis 
No change 
No change 
No change 
Hold until < grade 2, 
then reduce Docetaxel 
and Carboplatin by 1 
dose level 
Motor and Sensory 
Neuropathy 
 
No change 
No change 
Hold until< grade 
2, then reduce 
Docetaxel 1 dose 
level  
Off study 
Arthralgias 
Myalgias 
No Change 
No Change 
Hold until< grade 
2, then reduce 
Docetaxel by 1 
dose level  
Off study 
Elevated Bilirubin 
Hold until< 
IULN, then 
reduce Docetaxel 
by 1 dose level 
Hold until< IULN, 
then reduce 
Docetaxel by 1 
dose level 
Hold until< IULN, 
then reduce 
Docetaxel by 1 
dose level 
Off Study 
Elevated AST or 
ALT 
No Change 
Hold until< 1.5 x 
ULN, then reduce 
Docetaxel by 1 
dose level 
Hold until< 1.5 x 
ULN, then reduce 
Docetaxel by 1 
dose level 
Off study 
Elevated serum 
creatinine  
No Change 
Hold until < grade 
1, then resume at 
same dose of 
Carboplatin  
Hold until < grade 
1, then reduce 
Carboplatin by 1 
dose level 
Off Study 


Protocol # 13-H&N-24 
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16 
 
Nausea and/or 
Vomiting 
No change 
No Change 
No Change 
Hold until< grade 2, 
then reduce Docetaxel  
and Carboplatin by 1 
dose level 
 
For any grade 3 or 4 toxicity not mentioned above (excluding alopecia), and considered possibly, probably 
or definitely related to treatment, treatment should be withheld until resolution to grade < 2. Treatment 
should resume at a one dose level reduction. For grade 1 or 2 toxicities not mentioned above, no dose 
reductions will occur. Chemotherapy will be discontinued if irreversible, symptomatic cardiac 
arrhythmia/dysfunction occurs. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of 
AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event 
requires expedited reporting (via Medwatch form 3500A) in addition to routine reporting. 
 
7.1 
Adverse Events and Potential Risks 
 
7.1.1 Adverse Event List for Docetaxel  
 
Incidence rates of all adverse events associated with Docetaxel are provided in the product package insert. 
Side effects include: 
Cardiac: arrhythmias, pericardial effusions.  
Hematologic: dose-related neutropenia, leukopenia, thrombocytopenia, anemia, hypoglycemia, 
hypernatremia.  
Gastrointestinal: nausea and vomiting, diarrhea, oral mucositis, pancreatitis, esophagitis.  
Neurologic: reversible dysthesias or paresthesias, peripheral neuropathy, mild or moderate 
lethargy or somnolence, headache, seizures.  
Hypersensitivity: hypersensitivity (local or general skin rash, flushing, pruritus, drug-fever, chills 
and rigors, low back pain), severe anaphylactoid reactions (flushing with hypo- or hypertension, 
with or without dyspnea).  
Dermatologic: alopecia, desquamation following localized pruriginous maculopapular eruption, 
skin erythema with edema, extravasation reaction (erythema, swelling, tenderness, pustules), 
reversible peripheral phlebitis, nail changes.  
Hepatic: increased transaminase, alkaline phosphatase, bilirubin; hepatic failure; hepatic drug 
reaction.  
Pulmonary: dyspnea with restrictive pulmonary syndrome, pleural effusions.  
Other: asthenia, dysgeusia, anorexia, conjunctivitis, arthralgia, muscle aches, myopathy, 
peripheral edema, fluid retention syndrome, ascites.  
 
7.1.2 Adverse Event List for Carboplatin 
 
Incidence rates of all adverse events associated with Carboplatin are provided in the product package insert. 
Side effects include: 
Hematologic: Thrombocytopenia (dose limiting), neutropenia, leukopenia, anemia.  
GI: Nausea and vomiting (frequent but less severe than with cisplatin), treatable with appropriate 
antiemetic prophylaxis. Anorexia, diarrhea, and constipation have also been reported.  
Dermatologic: Rash, urticaria. Rarer reactions include alopecia, mucositis, and hypersensitivity 


Protocol # 13-H&N-24 
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17 
 
reactions.  
Hepatic: Abnormal liver function tests, usually reversible with standard doses.  
Neurologic: Rarely peripheral neuropathy is seen. May be more common in patients greater than 
65 years of age. May also be cumulative, especially in patients with prior cisplatin treatment. 
Ototoxicity (rare).  
Renal: Elevations in serum creatinine, BUN; electrolyte loss (Mg, K, Na, Ca).  
Miscellaneous: Pain, asthenia, flu-like syndrome.  
 
7.1.3 Adverse Event List for Low-dose Radiation 
 
 
Reversible skin changes and mucositis are expected side effects of radiotherapy. Combined modality therapy 
increases the risk for acute toxicities, but with low doses of radiation (640 cGy total) minimal toxicity is 
expected, as reported in our prior studies (14-16). The total dose of radiation given as definitive therapy after 
completion of induction will take into account this initial dose of radiation, and will be at the discretion of 
the attending radiation oncologist. 
 
7.1.4 Other Adverse Event List for Low-dose Radiation 
 
There is estimated to be a 1% risk per year of second primary cancers in this population of patients, which 
is unrelated to treatment.  
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version4.0 will be utilized 
for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE 
version4.0. A copy of the CTCAE version4.0 can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs should be reported using a Medwatch form only if required by the reporting chart below. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 For MCC Investigator-Initiated Trials (IITs), investigators must report to the Overall PI any 
serious adverse event (SAE) that occurs after the initial dose of study treatment, during treatment, 
or within 30 days of the last dose of treatment on the local institutional SAE form. This applies to 
the following categories: 
• Grade 3 (severe) Events – Only events that are Unexpected and Possibly, Probably or 
definitely related / Associated with the Intervention. 


Protocol # 13-H&N-24 
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18 
 
• ALL Grade 4 (life threatening or disabling) Events – Unless expected AND 
specifically listed in protocol as not requiring reporting. 
• ALL Grade 5 (fatal) Events regardless of study phase or attribution 
 
Note: If subject is in Long Term Follow Up, death is reported at continuing review.  
 
7.3.2 The following table outlines the required forms and reporting structure for clinical trials. 
 
Study type 
Expedited reporting 
to MCC 
Expedited 
reporting to 
External Agency 
Non-
expedited 
AE 
Form 
IRB 
IIT by MCC 
investigator of 
commercially 
available agent 
(non-IND and 
non-IDE)  
• 
Grade 3 –
Unexpected AE 
PLUS Possibly, 
Probably or 
Definitely 
Related  
• 
ALL Grade 4 
unless expected 
AND listed in 
protocol as not 
requiring 
reporting. 
• 
ALL Grade 5 
(fatal) Events 
FDA: 
Suspected AE 
that is serious 
and 
Unanticipated 
(not listed in IDB 
or consent) 
OnCore  and 
DSMC 
reporting 
only 
Voluntary 
Medwatch 
3500 for 
Serious and 
unanticipated 
 
OnCore for all 
AEs, including 
SAEs 
 
 
 
7.3.3 MCC Expedited Reporting Guidelines for MCC IITs 
 
Investigators within MCC will report SAEs directly to the MCC DSMC per the MCC DSMC SOP 
and the University of Kentucky IRB reporting policy.  
 
 
 
 
Attribution 
MCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event. 
 
 
7.4 
Expedited Reporting to External Agencies 
 
The Overall PI will comply with the policies of all external funding agencies and the UK IRB regarding 


Protocol # 13-H&N-24 
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19 
 
expedited reporting, as per the UK IRB’s SOP: http://www.research.uky.edu/ori/SOPs_Policies/C4-0150-
Mandated_Reporting_to_External_Agencies_SOP.pdf. 
 
7.4.1  Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall PI 
will report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the 
FDA’s criteria for expedited reporting following the reporting requirements and timelines set by the FDA.   
 
7.4.2 Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to the UK Office of Risk Management any participant safety reports 
or sentinel events that require reporting according to institutional policy.  
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the OnCore 
case report forms. The exception to this is that all grade 1 and 2 lab AEs that are not clinically significant, 
are not required to be recorded in OnCore or reported to DSMC but will be recorded as source 
documentation AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must 
also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the commercial agents administered in this 
study can be found in Section 7.1. 
 
8.1 
Commercial Agent:  Docetaxel 
 
(Please refer to the package insert for further information)  
 
8.1.1 Other Names  
Taxotere, RP 56976, NSC #628503.  
 
8.1.2 Classification  
 
Anti-microtubule agent.  
 
8.1.3  Mode of Action  
 
Docetaxel, a semisynthetic analog of taxol, promotes the assembly of tubulin and inhibits microtubule 
depolymerization. Bundles of microtubules accumulate and interfere with cell division.  
 
8.1.4 Storage and Stability  
 
Docetaxel infusion solution, if stored between 2 and 25ºC (36 and 77ºF) is stable for 4 hours. Fully prepared 
docetaxel infusion solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be 
used within 4 hours (including the administration time). Store between 2 and 25°C (36 and 77ºF). Retain in 


Protocol # 13-H&N-24 
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20 
 
the original package to protect from bright light. Freezing does not adversely affect the product.  
 
8.1.5 Dose Specifics  
 
Docetaxel will be administered as a 60 minute intravenous infusion. Dose will be calculated based on the 
patient’s actual body weight.  
 
8.1.6 Preparation  
 
Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be 
exercised when handling and preparing docetaxel solutions. The use of gloves is recommended.  
 
If docetaxel concentrate, initial diluted solution, or final dilution for infusion should come into contact with 
the skin, immediately and thoroughly wash with soap and water. If docetaxel concentrate, initial diluted 
solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly 
wash with water.  
 
Docetaxel for Injection Concentrate requires two dilutions prior to administration. Please follow the 
preparation instructions provided below. NOTE: Both the docetaxel for Injection Concentrate and the 
diluent vials contain an overfill.  
 
A. Preparation of the Initial Diluted Solution  
 
1. Gather the appropriate number of vials of docetaxel for Injection Concentrate and diluent (13% Ethanol 
in Water for Injection). If the vials were refrigerated, allow them to stand at room temperature for 
approximately 5 minutes.  
 
2. Aseptically withdraw the contents of the appropriate diluent vial into a syringe and transfer it to the 
appropriate vial of docetaxel for Injection Concentrate. If the procedure is followed as described, an initial 
diluted solution of 10mg docetaxel/mL will result.  
 
3. Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixture of the 
concentrate and diluent. Do not shake.  
 
4. The initial diluted docetaxel solution (10 mg docetaxel/mL) should be clear; however, there may be some 
foam on top of the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow 
any foam to dissipate. It is not required that all foam dissipate prior to continuing the preparation process. 
The initial diluted solution may be used immediately or stored either in the refrigerator or at room 
temperature for a maximum of 8 hours.  
B. Preparation of the Final Dilution for Infusion  
 
1. Aseptically withdraw the required amount of initial diluted docetaxel solution (10mg docetaxel/mL) with 
a calibrated syringe and inject into an infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% 
Dextrose solution to produce a final concentration of 0.3 to 0.74mg/mL. Thoroughly mix the infusion by 
manual rotation.  
 
2. As with all parenteral products, docetaxel should be inspected visually for particulate matter or 
discoloration prior to administration whenever the solution and container permit. If the docetaxel for 
Injection, initial diluted solution, or final dilution for infusion is not clear or appears to have precipitation, 


Protocol # 13-H&N-24 
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21 
 
these should be discarded.  
 
The final docetaxel dilution for infusion should be administered intravenously as per protocol under ambient 
room temperature and lighting conditions.  
Contact of the docetaxel concentrate with plasticized PVC equipment or devices used to prepare solutions 
for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2-
ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final docetaxel dilution for 
infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and 
administered through polyethylene-lined administration sets.  
 
8.1.7 Route of Administration  
 
Docetaxel will be administered as a 60 minute infusion in saline or D5W through an administration set that 
does not contain phthalate plasticizers along the fluid pathway that is connected to the patient’s vascular 
access catheter.  
 
8.1.8 Incompatibilities  
 
Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions 
for infusion should be avoided. Diluted docetaxel solution should be stored in bottles (glass, polypropylene) 
or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. 
(See Sec. 8.2.6.b).  
 
The metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, 
inhibit, or are metabolized by cytochrome P450 3A4, such as cyclosporine, terfenadine, ketoconazole, 
erythromycin, and troleandomycin. Caution should be exercised with these drugs when treating patients 
receiving docetaxel as there is a potential for a significant interaction.  
 
8.1.9 Availability  
 
Docetaxel (Taxotere®) is commercially available.  
Docetaxel for Injection Concentrate is supplied in a single-dose vial as a sterile, pyrogen-free, non-aqueous, 
viscous solution with an accompanying sterile, non-pyrogenic, diluent (13% ethanol in Water for Injection) 
vial. The following strengths are available: 80 mg, 20 mg. 
 
8.2 
Commercial Agent: Carboplatin  
 
(Please refer to the package insert for further information) 
 
8.2.1 Other Names  
 
CBDCA, Paraplatin, JM-8, NSC-241240  
 
8.2.2 Classification  
 
Second-generation tetravalent organic platinum compound  
 
 


Protocol # 13-H&N-24 
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22 
 
8.2.3 Mode of Action  
 
Like cisplatin, carboplatin binds to DNA, thereby inhibiting DNA synthesis, in a cell cycle nonspecific 
manner. Carboplatin must first undergo activation to produce antineoplastic activity. Bidentate carboxylate 
ligands of carboplatin are displaced by water forming (aquation) positively charged platinum complexes 
which bind to nucleophilic sites in DNA, such as the O-6 position on guanine. Carboplatin produces 
predominantly interstrand DNA crosslinks rather than DNA-protein crosslinks. Intrastrand crosslinks result 
from the formation of adducts between the activated platinum complexes of the drug and the N-7 atom (not 
exclusively) atom on guanine to produce 1, 2 intrastrand links between adjacent guanine molecules, between 
neighboring guanine and adenosine molecules, or between neighboring guanine molecules. Interstrand 
cross-linking within the DNA helix also occurs. Platinum adducts may inhibit DNA replication, transcription 
and ultimately cell division.  
 
8.2.4 Storage and Stability  
 
Intact vials are stored at room temperature protected from light. The reconstituted solution is stable for at 
least 24 hours. When further diluted in glass or polyvinyl plastic to a concentration of 10mg/mL with normal 
saline or 5% dextrose carboplatin is stable for 8 hours at 25 degrees C. Stability with further dilution to 
0.5mg/mL has been reported for up to 8 hours. Other stability data indicate that carboplatin is stable for up 
to 24 hours and may be refrigerated; however, the manufacturer recommends that reconstituted solutions be 
discarded after 8 hours due to the lack of preservative in drug formulation.  
 
8.2.5 Dose Specifics  
 
Carboplatin will be given by IV at an area under the curve (AUC) dose of 6. Routine premedication should 
include at least a 5-HT antagonist and dexamethasone. The dose of carboplatin based on target AUC is 
calculated using the Calvert equation:  
Dose (total mg) = Target AUC X (GFR + 25). The patient’s creatinine clearance (GFR) in mL/minute is 
calculated by the Cockcroft Gault equation.  
NOTE: When using the Calvert equation, GFR should not exceed 125 mL/min. Thus, the maximum 
carboplatin dose is 6 x (125 + 25), or 900 mg.  
 
8.2.6 Preparation  
 
Add 5, 15, or 45 mL sterile water, normal saline, or 5% dextrose to the 50, 150, or 450 mg vial, respectively. 
The resulting solution contains 10 mg/mL. The desired dose is further diluted, usually in 5% dextrose.  
 
8.2.7 Administration  
 
Infuse over 30 minutes 
 
8.2.8 Incompatibilities  
 
Aluminum displaces platinum from the carboplatin molecule, resulting in the formation of a black precipitate 
and loss of potency. Carboplatin solutions should not be prepared or administered with needles, syringes, 
catheters, or IV administration sets containing aluminum parts that might be in contact with the drug.  
 
 


Protocol # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
23 
 
8.2.9 Drug Interactions  
 
Concomitant myelosuppressive drugs or radiation therapy may potentiate the hematologic toxicity of 
carboplatin.  
Concomitant nephrotoxic drugs may potentiate the nephrotoxicity of carboplatin, particularly when 
carboplatin is given in high-dose chemotherapy regimens.  
 
8.2.10 Compatibilities  
 
Carboplatin (0.3 mg/mL) is chemically compatible in normal saline or 5% dextrose for 24 hours at room 
temperature.  
 
 
8.2.11 Availability  
 
Carboplatin is commercially available as a lyophilized powder in 50, 150, or 450 mg vials.  
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
It is well established that radiation doses > 180 cGy causes DNA damage in the form of double-strand and 
single-strand breaks,8,9 which accumulate unrepaired and cause global cellular catastrophe and rapid cell 
death.8,26 In contrast, DNA damage caused by LDFRT is proposed to differ from higher-dose radiation 
through enhancement of, pro-apoptotic pathways without induction of pro-survival pathways.12,14  We 
propose to explore whether these in vitro findings are replicated in humans, through the study of the effect 
of LDFRT and chemotherapy on human samples obtained during this clinical trial.  This will be 
accomplished by evaluating intra-patient variation in DNA damage responses to different doses of radiation 
via: a) markers of DNA damage responses, PARP (DNA single-strand breaks) and γ-H2AX (DNA double-
strand breaks), and b) DNA repair kinetics measured by Comet assay. The γ-H2AX foci formation is the 
most frequently used marker for cellular DNA damage response to ionizing radiation. However, the benefit 
of using the extent of γH2AX foci as a measure of biodosimetry (or dose-dependent radiation-induced DNA 
damage) during radiation therapy has only recently been described.27,28  PARP (poly(ADP-ribose) 
polymerase) is a marker more specific to DNA single-strand breaks, and PARP activity has been linked to 
both beneficial (DNA repair) and harmful 
(inflammation 
caused 
by 
PARP 
over-
activation) 
pathophysiologic 
effects. 
Therefore, monitoring both biomarkers will 
provide us a unique capability to assess key 
responses to varying doses of radiation in 
patients.  
 
Using buccal swab sampling 29 30,31  of the 
involved-field of radiation to study DNA 
repair, is novel. In Fig. 2, we assessed the 
immunostaining procedure with intact buccal 
cells collected from normal volunteers (Fig. 2a&b). As expected, γ-H2AX foci were absent (Fig. 2a) from 
unexposed buccal cells and normal oral keratinocytes OKF4 (Fig. 2c, compare to cells exposed to H2O2 in 
Fig. 2 Immunocytochemistry of human oral cells. (a&b) normal
oral keratinocyte (OKF4) stained with γH2AX (green) without
(a) or with (b) 50 µM H2O2 30 min treatment. Note the γH2AX
foci that is intensified in nuclei in (b) compared to (a) and 
(c).(c&d) intact human buccal cells stained with (c) anti-γH2AX
or (d) anti-APE1 antibody.  


Protocol # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
24 
 
Fig. 2d). However, buccal cells successfully stained with anti-APE1 antibody, which detected APE1 
localized in nuclei, demonstrating that the proposed procedure is feasible in human cells.  
 
(c) Approach  
Sample collection:  
Subjects will rinse their mouth, and the mucosa will be swabbed with a cytology brush,  subjects will rinse 
again and the same area will be swabbed gently with a wooden spatula 10 times. Cytology brush will be 
placed in media and transported to research lab, and spatula specimens are fixed onto uncharged slides and 
spray fixed.  A second cytology brush is then applied to the area and placed in media for storage and/or 
subsequent processing for Comet assays (see above).  Following collection, fixed slides are then stable until 
staining. Following collection, fixed slides are then stable until staining.  Prior to staining, slides are placed 
in 95% alcohol for removal of the coating fixative. To enable multiple immunostaining experiment on a 
glass plates, the buccal spread will be separated by hydrophobic (wax) pen. The samples will be blocked in 
1% BSA solution for 1 h, and then antibodies for γ-H2AX and poly(ADP-ribose) will be applied and 
incubated for 2 h. After washing with 1% BSA, secondary antibodies conjugated to AlexaFluora488 will be 
applied and incubated for 1 h. If necessary, a positive control (e.g., APE1 antibody) for the staining will be 
used. The samples will then be washed in 1% BSA, stained with DAPI solution, then mounted on anti-fading 
reagent and sandwiched on coverslips. Cells will be analyzed using an inverted fluorescence microscope in 
Izumi lab with x40 objective. Cells will be analyzed using an inverted fluorescence microscope in Izumi lab 
with x40 objective. For counting foci numbers, an analytical software Image-J (NIH) will be used. 
 
In  
 
 
preclinical 
studies, 
Krueger and 
colleagues25 
demonstrated that low-dose HRS caused a predictable increase in γ-H2AX within 1-2 hours after each low 
dose fraction.  To determine the effect of LDFRT and full-dose RT, we will measure the time dependent 
expression of γ-H2AX as well as direct DNA damage in serial mucosal sampling from the irradiated mucosa 
of these patients.  We expect that LDFRT-mediated DNA damage will increase the expression of γ-H2AX, 
but not to the extent seen in full-dose radiation. Preliminary experiments have shown the feasibility of using 
γ-H2AX antibody for damage specific foci detection (Fig. 2a&b), including immunostaining procedure for 
buccal cell staining from normal human volunteers (Fig. 2a&b). APE1, an essential DNA repair protein, was 
detected predominantly in the nuclei of the buccal cells when stained with an APE1 antibody (Fig. 2d), 
indicating our immunostaining protocol can effectively probe for damage/repair proteins.  In this setting, no 
γH2AX foci were detected because the specimen was unirradiated. The result in Fig. 2c is still informative 
as it sets the background intensity of γH2AX, and we will elucidate how the signal changes after LDFRT 
and full-dose radiation. 
Comet assays will determine both damage induction on samples collected immediately after radiation and 
repair kinetics on samples collected serially from the same subjects during LDFRT and full-dose radiation. 
After collection or upon removal from storage, buccal cells are washed in PBS, collected by centrifugation, 
resuspended in low-melting agarose solution, and then immobilized on slides. Immobilized cells are lysed 
and resulting nucleoids (nuclear DNA spheres) are subject to electrophoresis. Subsequently, DNA in these 
samples is stained with SYBR Gold and visualized by fluorescence microscopy to assess DNA damage, 
Sampling schedule for buccal collection (minimum of 3 times points needed for 
kinetics of radiation) 
Pre-treatment 
Induction Day 1 (both arms) 
& 2 (in LDFRT arm) 
Definitive Radiation week 1 
1 sample 
Sample after each dose of 
LDFRT (4 samples) or during 
chemotherapy in non-LDFRT 
arm (2 samples) 
Sample after each dose of radiation 
(3-4 samples) 


Protocol # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
25 
 
evidenced by migration of DNA away from the nucleoid (head) to form a comet-like tail. DNA damage 
levels are quantified from signal intensity in comet tails relative to the head, from ≥50 cells per sample. 
Electrophoresis under neutral conditions is used to measure radiation-induced DNA double-strand breaks 
while alkaline conditions reveal the sum of abasic sites, single- and double-strand breaks. Fig. 3 shows 
alkaline Comet images of buccal cells untreated or treated ex vivo with H2O2; note the prominent tail 
produced by H2O2 treatment that induces types of damage similar to that of radiation. Our correlative studies 
(by Orren/Izumi) will be compared to the 
clinical 
assessment of treatment to assess response 
to 
treatment, time to progression and survival.  
These 
correlations will be exploratory in nature. 
9.2 
Correlative 
Studies 
(Tumor 
Biopsy 
and Radiation Port Images) 
Subjects who have previously collected 
tumor 
tissue will be asked to give permission for correlative studies on these biopsies.  Participants will not have 
to undergo any additional biopsies of their tumor to be on this study, only buccal mucosal samples as 
described in section of the protocol.  De-identified images from radiation treatment planning will also be 
available to investigators for correlation with DNA repair findings and location of the buccal swab in 
relation to radiation fields.  No identifiers will be given to investigators.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. Representative Comet images on freshly collected 
buccal cells, either untreated (a) or treated ex vivo with H2O2 
(b) as indicated.


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26 
 
10. STUDY CALENDAR 
Within 6 weeks, all patients will undergo a direct laryngoscopy (DL) or indirect laryngoscopy (IDL) (if the 
primary tumor is easily and completely evaluable by IDL). Within 4 weeks of registration, all patients will 
undergo a history and physical exam, ECOG performance status evaluation, a CT or MRI scan of the 
involved area of the head and neck and a CT of the Chest or chest X-ray. Within 2 weeks of registration, all 
patients will undergo a complete blood count with differential and platelets, and serum chemistries. Once 
informed consent and enrollment have been completed, subjects will be randomized to one of two treatment 
arms: a) chemotherapy alone or b) chemotherapy plus LDFRT. Treatment will be administered on an 
outpatient or inpatient basis.  
 
Evaluation 
Pre-
Study 
Day 
1 
Day 
2 
Day 
22 
Day 
23 
Day 
38-
50(c) 
Week 
1 of 
definiti
ve 
RT/CT
(d) 
4-6 
weeks 
post 
definitive 
Radiatio
n or 
surgery 
STUDY COMPLETE 
LTFU by 
KCR at 
interim 
and at 3 
years 
H&P* 
PS assessment 
X 
 
 
X 
 
X 
 
X 
 
Vital signs and 
height and weight 
X 
 
 
X 
 
 
 
 
 
CBC w/ differential 
X 
 
 
X 
 
X 
 
 
 
Electrolytes (a) 
X 
 
 
X 
 
X 
 
 
 
b-HCG (b) 
X 
 
 
 
 
 
 
 
 
Chest X-ray or CT 
scan Chest 
X 
 
 
 
 
 
 
X 
 
MRI or CT scan of 
Neck (e) 
X 
 
 
 
 
X 
 
X 
 
Panendoscopy or 
Indirect 
laryngoscopy 
X 
 
 
 
 
X 
 
 
 
Mucosal sampling 
(f) 
X 
X 
X 
 
 
 
X 
 
 
QOL form 
X 
 
 
 
 
X 
 
 
 
Chemotherapy 
 
X 
 
X 
 
 
 
 
 
80 cGy RT 
 
X   X 
X   X 
X   X 
X   X 
 
 
 
 
OS and PFS survival 
assessment 
 
 
 
 
 
 
 
 
X 
 
*:  Day 22 H&P should be within 2 days of chemotherapy cycle 2 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b: Serum pregnancy test (women of childbearing potential). 
c:     Off-study evaluation.   
d:  Definite radiation should occur on or after Day 43 and prior to Day 64 from initiation of induction (Day 
1). Definitive surgery should occur on or after Day 43.  
e: Using same form of radiographic assessment pre-treatment and post-induction 
f: Pre dose (1 sample), day 1 and 2 post radiation, cycle 1 induction (4 samples in LDFRT arm 2 samples in 
non-LDFRT arm) and Day 1-5 full dose radiation (3-4 samples) 
 
 
 


Protocol # 13-H&N-24 
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27 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be evaluated for response to induction after 2 cycles of 
therapy.  
 
Response and progression will be evaluated in this study using the new international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) (34). Changes 
in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with Docetaxel, Carboplatin, and LDFRT. 
 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified according 
to the definitions stated below. (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression of 
the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm with 
CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 


Protocol # 13-H&N-24 
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28 
 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next largest 
lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 to 6 weeks before the beginning of the treatment (see study calendar). 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin 
nodules). In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 


Protocol # 13-H&N-24 
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29 
 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review later and, because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there 
is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor markers Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 


Protocol # 13-H&N-24 
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30 
 
of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on 
a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT  scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum 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. (Note:  the appearance of one or more new lesions is also 
considered progressions). 
 
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. 
 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 


Protocol # 13-H&N-24 
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31 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
 


Protocol # 13-H&N-24 
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32 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
This study will require data submission and reporting via the OnCore Database, which is the official 
database of the Markey Cancer Center Clinical Research and Data Management Shared Resource Facility 
(CRDM SRF). Instructions for submitting data is listed in Study-Specific Data Management Plans created 
by CRDM SRF staff. 
 
12.1.2 Responsibility for Data Submission 
 
Study staff is responsible for submitting study data and/or data forms to OnCore as per the Markey Cancer 
Center CRDM SRF SOP’s. This trial will be monitored by the MCC Data and Safety Monitoring 
Committee (DSMC) on a schedule determined by the Protocol Review and Monitoring Committee at the 
initial PRMC review. The CRDM SRF staff is responsible for compiling and submitting data for all 
participants and for providing the data to the Principal Investigator for review.   
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Experimental Design 
 
This is a randomized phase II trial of chemotherapy with or without low-dose radiation in locally advanced 
SCCHN.   


Protocol # 13-H&N-24 
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33 
 
 
13.2 
Accrual and Power Considerations 
The primary endpoint is primary site CR rate, which in our previous study was 60% using LDFRT + 
chemotherapy. We will assume that the control arm of this trial (chemotherapy alone) will provide only a 
30% primary site CR rate. Using a binomial test of two independent proportions with 2 planned interim 
analyses (after 25% and 50% of total patient accrual) with O’Brien-Fleming stopping boundaries for futility, 
34 subjects per group are needed for this phase II based on a two-sided type I error rate of at most 10% and 
80% power. Conservatively allowing 5% drop out or loss to follow up, we plan to enroll 72 total patients. 
All sample size calculations with corresponding interim analysis rules were conducted using PASS 11.0.32  
  
13.3 
Interim Analyses  
 
Using a binomial test of two independent proportions with 2 planned interim analyses (after 25% and 50% 
of total patient accrual) with O’Brien-Fleming stopping boundaries for futility, 34 subjects per group are 
needed for this phase II based on a two-side type I error rate of at most 10% and 80% power. The O’Brien-
Fleming boundaries and alpha spending details are listed in the table and figure below.   
 
13.4 
Details for Interim Analyses with O'Brien-Fleming Boundaries 
  
% of 
Accruals 
Lower 
Upper 
Nominal 
Inc 
Total 
Inc 
Total 
Look 
Boundary Boundary 
Alpha 
Alpha 
Alpha 
Power 
Power 
1 
25% 
-3.750 
3.750 
0.00018 0.00018 0.00018 
0.006 
0.006 
2 
50% 
-2.540 
2.540 
0.011 
0.011 
0.011 
0.219 
0.225 
3 
100% 
-1.662 
1.662 
0.096 
0.089 
0.100 
0.582 
0.807 
 
 
 
13.5 
Analysis Plan 
 
Following study completion, the percentage of subjects achieving primary site CR in each group will be 
estimated along with exact 90% binomial confidence intervals. A binomial test or Fisher’s exact test will 
also be employed to test for a difference in primary site CR rates between treatment and control groups, with 
p-values < 0.10 considered significant.. All correlative endpoints and secondary endpoints are exploratory 


Protocol # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
34 
 
in nature and will be primarily descriptive; however, strategies will include safety incidence tables, 
differences in QOL scores from baseline to completion of treatment between groups using 2-sample t-test 
or Wilcoxon Rank Sum tests depending on parametric assumptions and, and Kaplan-Meier curves for overall 
survival with corresponding log rank tests for comparisons between groups. 
 
13.6 
Data Management 
 
All data will be stored in the OnCore Data Management System of the Markey Cancer Center. Case report 
forms will record all study endpoints and data will be accessed in a secure manner using this password 
protected, encrypted software. The study statistician, along with staff from the Biostatistics Shared 
Resource Facility (BSRF), will work closely with the study PI and the CRDM SRF staff on the 
development of eCRFs for the study. Instructions for data entry will be listed in Study-Specific Data 
Management Plan created by CRDM SRF staff in conjunction with the study statistician. The OnCore 
database is housed on secure servers maintained by the Cancer Research Informatics Shared Resource 
Facility (CRISRF) of Markey Cancer Center. The database is backed up daily. Data will be accessed by 
the study statistician via OnCore on a regularly scheduled basis to perform statistical programming to 
assess data quality control, study recruitment and to generate interim reports and analyses. In collaboration 
with the study team, procedures and timelines will be developed for data quality control, resolution of data 
queries, interim reporting, and final data analysis. 
 
13.7 
Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with Docetaxel, 
Carboplatin, and LDFRT. 
 
13.7.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). [Note:  By arbitrary convention, category 9 usually designates 
the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who received no 
study medication) should be included in the main analysis of the response rate. Patients in response 
categories 4-9 should be considered to have a treatment failure (disease progression). Thus, an incorrect 
treatment schedule or drug administration does not result in exclusion from the analysis of the response 
rate. Precise definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on the basis 
of a subset of patients, excluding those for whom major protocol deviations have been identified (e.g., 
early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.). 
However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly reported. The 95% 
confidence intervals should also be provided.  
 
 


Protocol # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
35 
 
14. REFERENCES 
 
 
1. 
CINA+. (2013). Cancer Incidence Rates in North America., 2006-2010 
 
2. 
Pignon J-P, Maître Al, Maillard E, et al: 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 92:4-14, 2009 
 
3. 
Vokes EE: Induction Chemotherapy for Head and Neck Cancer: Recent Data. The 
Oncologist 15:3-7, 2010 
 
4. 
Haddad R, O'Neill A, Rabinowits G, et al: Induction chemotherapy followed by 
concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone 
in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. The Lancet 
Oncology 14:257-264, 2013 
 
5. 
Posner MR, Haddad RI, Wirth L, et al: Induction chemotherapy in locally advanced 
squamous cell cancer of the head and neck: Evolution of the sequential treatment approach. Seminars in 
oncology 31:778-785, 2004 
 
6. 
Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, Fluorouracil, and Docetaxel 
in Unresectable Head and Neck Cancer. New England Journal of Medicine 357:1695-1704, 2007 
 
7. 
Hitt R, López-Pousa A, Martínez-Trufero J, et al: Phase III Study Comparing Cisplatin 
Plus Fluorouracil to Paclitaxel, Cisplatin, and Fluorouracil Induction Chemotherapy Followed by 
Chemoradiotherapy in Locally Advanced Head and Neck Cancer. Journal of Clinical Oncology 23:8636-
8645, 2005 
 
8. 
RL S: Biochemical pharmacology of chemotherapeutic drugs used as radiation 
enhancers. . Semin Oncol 19:2-7, 1992 
 
9. 
Milas L MM, Mason KA.: Combination of taxanes with radiation: preclinical studies. 
Semin Radiat Oncol 9(2 Suppl 1):12-26., 1999 
 
10. 
Marples B JM: The response of Chinese hampster V79 cells to low radiation doses.  
Evidence of enhanced sensitization of the whole cell population. Radiat Res 133:41-51, 1993 
 
11. 
Joiner MC, Marples B, Lambin P, et al: Low-dose hypersensitivity: current status and 
possible mechanisms. International journal of radiation oncology, biology, physics 49:379-389, 2001 
 
12. 
Dey S, Spring PM, Arnold S, et al: Low-Dose Fractionated Radiation Potentiates the 
Effects of Paclitaxel in Wild-type and Mutant p53 Head and Neck Tumor Cell Lines. Clinical Cancer 
Research 9:1557-1565, 2003 
 
13. 
Arnold SM, Regine WF, Ahmed MM, et al: Low-dose fractionated radiation as a 
chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma 
of the head and neck: results of a new treatment paradigm. International journal of radiation oncology, 
biology, physics 58:1411-1417, 2004 
 
14. 
Chendil D OR, Alcock RA, Patel N, Mayhew C, Mohiuddin M, Gallicchio VS, Ahmed 
MM.: Low dose fractionated radiation enhances the radiosensitization effect of paclitaxel in colorectal 
tumor cells with mutant p53. Cancer 89:1893-1900, 2000 
 
15. 
Gleason J KM, Van Meter E, Mohiuddin M, Regine WF, Valentino J, Kenady D, 
Arnold SM.  : Low-dose fractionated radiation with induction chemotherapy for locally advanced head and 
neck cancer: 5 year results of a prospective phase II trial. International Journal of Radiation Oncology  
Biology  Physics 81:S502-S503, 2012 
 
16. 
Regine WF, Hanna N, Garofalo MC, et al: Low-Dose Radiotherapy as a 
Chemopotentiator of Gemcitabine in Tumors of the Pancreas or Small Bowel: A Phase I Study Exploring a 
New Treatment Paradigm. International journal of radiation oncology, biology, physics 68:172-177, 2007 
 
17. 
Creane M SC, Mothersill C. : Effect of docetaxel (Taxotere) on expression of 
radiation-induced lethal mutations in human cell lines.  . Int J Radiat Biol 75:725-730, 1999 
 
18. 
Dunphy F BJaDT: Paclitaxel and carboplatin in head and neck cancer. . Semin Oncol 


Protocol # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
36 
 
24:S19-27, 1997 
 
19. 
Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and Fluorouracil Alone or 
with Docetaxel in Head and Neck Cancer. New England Journal of Medicine 357:1705-1715, 2007 
 
20. 
Hennequin C GN, Favaudon V: Interaction of ionizing radiation with Paclitaxel 
(Taxol) and docetaxel (Taxotere) in HeLa and SQ20B cells. . Cancer Res 56:1842-1850, 1996 
 
21. 
Chougule PB AM, Akerley W, et al. : Chemoradiotherapy for advanced inoperable 
head and neck cancer: a phase II study. . Semin Radiat Oncol 9:58-63, 1999 
 
22. 
Zanelli GD QM, Robiuex I, et al: Paclitaxel as a radiosensitizer: A proposed schedule 
of administration based on in-vitro data and pharmcokinetic calculations. Eur J Cancer . 33:486-492, 1997 
 
23. 
S. SKM: Interaction of platinum drugs with clinically relevant x-ray doses in 
mammalian cells: a comparison of Carboplatin, carboplatin, iproplatin, and tetraplatin. Int J Radiat Oncol 
Biol Phys 20:221-225, 1991 
 
24. 
Löbrich M JP: Harmonising the response to DSBs: a new string in the ATM bow. . 
DNA Repair (Amst). 4:749-759, 2005 
 
25. 
Krueger SA, Wilson GD, Piasentin E, et al: The Effects of G2-Phase Enrichment and 
Checkpoint Abrogation on Low-Dose Hyper-Radiosensitivity. International journal of radiation oncology, 
biology, physics 77:1509-1517, 2010 
 
26. 
Chua MLK, Rothkamm K: Biomarkers of Radiation Exposure: Can They Predict 
Normal Tissue Radiosensitivity? Clinical Oncology 25:610-616, 2013 
 
27. 
Gonzalez J, Roch-Lefevre S, Mandina T, et al: Induction of gamma-H2AX foci in 
human exfoliated buccal cells after in vitro exposure to ionising radiation. Int J Radiat Biol 86:752 - 759, 
2010 
 
28. 
Yoon AJ, Shen J, Wu H-C, et al: Expression of Activated Checkpoint Kinase 2 and 
Histone 2AX in Exfoliative Oral Cells after Exposure to Ionizing Radiation. Radiation Research 171:771-
775, 2009 
 
29. 
Loprevite M, Tiseo M, Chiaramondia M, et al: Buccal Mucosa Cells as In vivo Model 
to Evaluate Gefitinib Activity in Patients with Advanced Non–Small Cell Lung Cancer. Clinical Cancer 
Research 13:6518-6526, 2007 
 
30. 
Szeto YT, Benzie, I.F., Collins, A.R., Choi, S.W., Cheng, C.Y., Yow, C.M. and Tse, 
M.M: A buccal cell model comet assay: development and evaluation for human biomonitoring and 
nutritional studies. Mutation Research 578:371-381, 2005 
 
31. 
Izumi and Orren Personal Communication, 2013 
 
32. 
Hintze J: PASS 11. NCSS, LLC. Kaysville, Utah, USA www.ncss.com., 2011 
 
 


Protocol # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
37 
 
APPENDIX A. 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 


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38 
 
APPENDIX B.  
STAGING FOR HEAD AND NECK CANCER 
 
Please see www.nccn.org for complete staging system for H&N cancer 
 
 
 


Protocol # 13-H&N-24 
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39 
 
APPENDIX C. FACT-H&N V4.  
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 
 
 
 
 
 


Protocol # 13-H&N-24 
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40 
 
 
 
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 
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. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
 ..........................................................................................  
0 
1 
2 
3 
4 


Protocol # 13-H&N-24 
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41 
 
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 
 
 
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 


Protocol # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
42 
 
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 # 13-H&N-24 
Version Date: 2018 March 1st 
 
 
 
 
 
 
43 
 
APPENDIX D.  
BIOASSAY PROCEDURES 
Buccal Swab Procedure 
Use positively charged slides (ex. Snowcoat Leica 3800299) white with frosted end. 
1. Rinse mouth 
2. Using PurFybr cytology brushes, twirl brush against inner cheek or oropharynx as near as possible to  
radiation port, gently but firmly to dislodge cellular materials.  Save brush #. Transfer to 15 ml centrifuge  
tubes containing 2 ml ice-cold Phosphate-Buffered Saline (PBS) solution and using sharp scissors, cut  
(just enough of) the shaft of the brush and re-cap the tube.  Refrigerate tube in preparation for transport.   
3. Scrape buccal mucosa 10 times firmly, but gently in same region, with wooden spatula  
4. Smear the cells onto slide 1, then gently spread with slide 2 
5. Immediately spray fix with Fisher Scientific* PROTOCOL* Cytologic Fixative - 50mL (245688)1 
6. Allow slide to dry (can leave like this) and then label slides with subject ID and sample letter once slide  
has dried (i.e. “001-B”), label conical tube with same label number  
7. Place slides in slide box and transport to cc419 for pickup by Izumi lab 
8. Using a second PurFybr cytology brush, twirl brush in same region of the mouth gently but firmly to  
dislodge cellular materials.  
9. Transfer 2nd brush to 15 ml centrifuge tubes containing 2 ml ice-cold Phosphate-Buffered Saline (PBS)  
solution and Using sharp scissors, cut (just enough of) the shaft of the brush and re-cap the tube. Keep  
tubes on ice for transport to Orren lab.  Call contact number in Orren lab, and if no answer, leave in  
refrigerator in cc419 for pickup. 
1 Coating fixatives are substitutes for wet fixatives. They are either aerosols applied by spraying the cellular samples or a liquid base,  
which is dropped onto the slide. They are composed of an alcohol base, which fixes the cells and wax like substance, which forms a thin 
protective coating over the cells e.g. Carbowax (Polyethylene Glycol) fixative. Most of these agents have a dual action in that they fix the  
cells and, when dry, form a thin protective coating over the smear. The coating fixative should be applied immediately on fresh smears.  
The distance from which the slides are sprayed 10 to 12 inches (25-30 cm) is the optimum distance. Prior to staining, the slides have to be  
kept for 15 minutes in 95% alcohol for removal of the coating fixative. 
Time Points for the study: 
Buccal Sampling Schedule 
Treatment 
Day 
Buccal sample 
Pre-treatment 
(
d t
)
Pre-treatment 
Prior to all radiation/chemotherapy   
Induction Therapy 
(minimum 3 samples) 
Cycle 1 Day 1* 
After LDFRT fraction 1 
After LDFRT fraction 2 
Cycle 1 Day 2** 
Pre-treatment 
After LDFRT fraction 3 
Definitive Radiation 
(minimum 3 samples) 
Definitive Radiation 
Week 1 
Days 1-5*** 
Pretreatment Day 1 
After radiation fraction Day 1 
After Cisplatin Day 1 
After radiation fraction (preferably Day 4 or 5) 
* non-LDFRT arm will have two samples obtained during chemotherapy 
** non-LDFRT arm will not have sampling on Day 2 
*** surgical patients will not undergo definitive radiation sampling  
 
 
 

ICF_001.pdf: 
IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 1 of 14
HN-24 Consent-HIPAA v5 vd 03/01/18
COMBINED CONSENT AND AUTHORIZATION TO
PARTICIPATE IN A RESEARCH STUDY 
UNIVERSITY OF KENTUCKY
CHANDLER MEDICAL CENTER
MARKEY CANCER CENTER
Study Title: 13-HN-24: A Phase II Study of Docetaxel, Carboplatin With and Without Low Dose 
Radiation as Induction Therapy in Locally Advanced Head and Neck Cancer
INVESTIGATOR INFORMATION:
Susanne Arnold, M.D.
Hematology/Oncology
Markey Cancer Center
(859) 323-8043 (Day)
(859) 323-5321 (Evenings and Weekends)
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS RESEARCH?
You are being invited to take part in a research study about the treatment of head and neck cancer using 
a standard chemotherapy combination (Docetaxel/Carboplatin) with or without low dose radiation 
therapy (LDFRT). You are being invited to take part in this research study because you have locally 
advanced cancer of the head and neck. If you volunteer to take part in this study, you will be one of 
about 72 people to do so.
WHO IS DOING THE STUDY?
The person in charge of this study is Susanne M. Arnold, MD of the University of Kentucky,
Department of Internal Medicine.  There may be other people on the research team assisting at different 
times during the study. 
WHAT IS THE PURPOSE OF THIS STUDY?
The purpose(s) of this study is to evaluate the effects (good and bad) of standard chemotherapy 
(Docetaxel/Carboplatin) with and without low dose radiation. Docetaxel and Carboplatin are approved 
for the treatment of locally advanced squamous cell carcinoma of the head and neck.
The results of this study will be shared with the Kentucky Lung Cancer Research Program (KCLRP) 
who is providing financial support for the study, the Food and Drug Administration and other federal 
agencies, if required.
ARE THERE REASONS WHY YOU SHOULD NOT TAKE PART IN THIS STUDY?
You should not take part in the study if:
x
You are under the age of 18
x
You are pregnant or nursing a child
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 2 of 14
HN-24 Consent-HIPAA v5 vd 03/01/18
x
You are currently taking any other investigational agents
x
You have had an allergic reaction to the drugs used in this study (Carboplatin or Docetaxel) or 
similar compounds 
x
You currently have illnesses that would keep you from being in this study and following the 
study requirements such as: an active infection, congestive heart failure, unstable angina, cardiac 
arrhythmia, or psychiatric illness/social situations
x
You are HIV-positive and receiving combination antiretroviral therapy
WHERE IS THE STUDY GOING TO TAKE PLACE AND HOW LONG WILL IT LAST?
The research procedures will be conducted at the University of Kentucky’s Markey Cancer Center.
Treatment may be given on an inpatient or outpatient basis, and will last for 2 cycles (normally 21 days 
each).
You will need to come to the Markey Cancer Center for a pre-study visit and on Days 1, 2, 22, and 23 during 
treatment and at the end of treatment, usually between day 38 and 50. After that visit, you will begin 
definitive radiation or surgery between day 43 and 64, and after receiving definitive radiation treatment you 
will need to come in for an assessment. You will be asked to come in 4 to 6 weeks after definitive radiation 
or surgery for additional assessments. You will then be followed by your doctor for return of your cancer.  If 
you agree to be in this study, you will be asked to volunteer for a total of about 3 and a half years.
WHAT WILL YOU BE ASKED TO DO?
Before you begin treatment (Pre-study visit)…
If not already completed within 6 weeks of starting the study: 
x
You will have a direct laryngoscopy or an indirect laryngoscopy, where a surgeon uses a camera or a 
small mirror to look down your throat at your cancer. 
If not already completed within 4 weeks of starting the study: 
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs, height and weight.
x
You will have a Chest X-ray or CT scan of your chest.
x
You will have a CT scan or MRI of your head and neck.
If not already completed within 2 weeks of starting the study:
x
You will have a blood sample drawn for routine laboratory tests including complete blood count and 
blood chemistries.  
x
If you are a female who is able to have children you will have a serum (blood) pregnancy test 
performed. 
You will also be asked to fill out a form that helps us understand your quality of life during this study
and to provide a mucosal sample of mouth cells.
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 3 of 14
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If the exams, tests and procedures above show that you are able to participate in the study, and you 
choose to take part, then you will be randomized (assigned by chance like flipping a coin) to one of two 
treatment arms: a) chemotherapy alone or b) chemotherapy plus LDFRT. 
After you have been randomized to the study and before you start treatment, you will be asked to 
provide a mucosal sample. Mucosa refers to the lining of the cheeks. To provide a mucosal sample, you 
will be asked to rinse your mouth and a brush will be twirled against your inner cheek to dislodge cells.
Next, your cheek will be gently scraped in the same region with a wooden spatula 10 times. Then your 
inner cheek will be swirled with a brush a second time. These mouth samples are for research purposes 
only, and will be sent to the research lab of Dr. David Orren and Dr. Tadahide Izumi for study of your 
cells’ reaction to radiation. Your samples will be used for these studies and any leftover cells will be 
stored in this lab indefinitely.  Only approved members of the research team will have access to your 
samples, and your samples will have a code number to protect your identity.  Your samples will not be 
used for genetic testing.
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
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If you are selected in the group that has chemotherapy only:
On Day 1
You will undergo the following procedures that are part of regular cancer care:
x
You will receive the standard chemotherapy combination Docetaxel and Carboplatin.
You will also undergo the following tests and procedures that are for research purposes only: 
x
You will be asked to provide a mucosal sample. 
On Day 22
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs, height and weight.
x
You will have a blood sample drawn for routine laboratory tests including complete blood count 
and blood chemistries.  
x
You will receive a standard chemotherapy combination Docetaxel and Carboplatin.
If you are in the group that has chemotherapy plus LDFRT: 
On Day 1
You will undergo the following procedures that are part of regular cancer care:
x
You will receive a standard chemotherapy combination Docetaxel and Carboplatin with two 
small doses of radiation.
You will also undergo the following tests and procedures that are for research purposes only: 
x
You will be asked to provide a mucosal sample.
On Day 2
x
You will be asked to provide a mucosal sample. 
x
You will receive two small doses of radiation.
On Day 22
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs, height and weight.
x
You will have a blood sample drawn for routine laboratory tests including complete blood count 
and blood chemistries.  
x
You will receive chemotherapy using a standard chemotherapy combination 
(Docetaxel/Carboplatin) with LDFRT. 
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 5 of 14
HN-24 Consent-HIPAA v5 vd 03/01/18
On Day 23
x
You will receive LDFRT. 
All subjects in both groups will undergo the following procedures after two cycles of induction 
treatment:
Day 38-50
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs, height and weight.
x
You will have a blood sample drawn for routine laboratory tests including complete blood count 
and blood chemistries.  
x
You will receive an MRI or CT scan of your head and neck.
x
You will receive a re-evaluation of your cancer by a surgeon (which may include a surgery 
called panendoscopy or indirect laryngoscopy, if needed).
x
You will be asked complete a quality of life form.
You will then undergo definitive radiation therapy or surgery. 
During Week 1 of definitive radiation therapy:
x
You will be asked to provide a mucosal sample. 
Within 4 to 6 weeks of definitive radiation therapy: 
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs, height and weight.
x
You will receive a Chest X-ray or CT scan of your chest.
x
You will undergo a CT scan or MRI of your head and neck.
Long term follow up visit: 
x
You will receive a final assessment by the study doctor. 
All procedures are being done as part of standard care except for the following procedures which are 
being done for research purposes: 
x
Mucosal samples
x
Quality of life form administration
x
We also will request a sample of your cancer tissue that was taken when you had your biopsy or 
surgery (if extra tissue is available) from the pathology laboratory that made your diagnosis.
You will not have to undergo any additional biopsies or surgery to participate in this trial. This 
information and these samples will help researchers understand the effects of radiation and 
chemotherapy on your cancer and will be compared to your mucosal samples. These samples 
will not be stored long-term or used for other investigations other than this study. No identifiers 
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 6 of 14
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or private health information will be given to investigators who study your tumor and the 
investigators will not be able to identify you.
x
We will also request the radiation treatment planning pictures (CT scans) of your head and neck 
to study the region of the throat that received radiation to better understand how your cells react 
to radiation.  No identifiers will be given to investigators that study these images, and the 
investigators will not be able to identify you.  
Women who can become pregnant and men must agree to use adequate contraception (hormonal or 
barrier method of birth control or abstinence) prior to study entry, through the duration of active 
treatment and for 4 months after completion of chemotherapy and radiation administration, both 
induction and definitive, if applicable. Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating physician 
immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception 
prior to the study, for the duration of active study treatment, and for 4 months after completion of 
chemotherapy and radiation (both induction and definitive) administration.
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS?
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  Side 
effects may be mild or very serious. Your health care team may give you medicines to help lessen side 
effects. In some cases, side effects can be serious, long lasting, or may never go away. There also is a 
risk of death.
Risks and side effects related to the radiation include those which are:
Likely
x
Tanning, redness, or darkening of skin in treatment area
x
Rash, itching or peeling of skin
x
Temporary hair loss in the treatment area
x
Temporary fatigue
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 7 of 14
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Possible Side Effects of Carboplatin:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Carboplatin, more than 20 and up to 100 may have:
x Hair loss
x Vomiting, nausea
x Infection, especially when white blood cell count is low
x Anemia which may cause tiredness, or may require blood transfusions
x Bruising, bleeding
x Belly pain
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Carboplatin, from 4 to 20 may have:
x Diarrhea, Constipation
x Numbness and tingling in fingers and toes
x Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat
RARE, AND SERIOUS
In 100 people receiving Carboplatin, 3 or fewer may have:
x Changes in vision
x Changes in taste
x Damage to organs which may cause hearing and balance problems
Possible Side Effects of Docetaxel
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Docetaxel, more than 20 and up to 100 may have:
x Swelling of the body
x Hair loss
x Change in nails
x Rash, itching
x Vomiting, diarrhea, nausea
x Sores in mouth which may cause difficulty swallowing
x Infection, especially when white blood cell count is low
x Anemia which may require blood transfusions
x Tiredness
x Numbness and tingling of the arms and legs
x Fever
x Absence of menstrual period
x Swelling and redness of the arms, leg or face
x Pain
x Watering, itchy eyes
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 8 of 14
HN-24 Consent-HIPAA v5 vd 03/01/18
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Docetaxel, from 4 to 20 may have:
x Severe skin rash with blisters and peeling which can involve inside of mouth and other parts of the 
body
x Belly pain
x Bruising, bleeding
x Liver damage which may cause yellowing of eyes and skin
x Kidney damage which may require dialysis
x Scarring of the lungs
x Blood clot which may cause swelling, pain, shortness of breath
x Abnormal heart rate
x Shortness of breath, wheezing
x Chest pain
RARE, AND SERIOUS
In 100 people receiving Docetaxel, 3 or fewer may have:
x Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat
x Liver damage which may cause yellowing of the eyes and skin
Blood Draw: soreness, bruising, pain, infection, possible fainting, bleeding.
CT Scans: Each CT scan will give a radiation dose greater than that from typical natural background 
exposure, but less than the limit for radiation workers and well below the levels that are considered to be 
a significant risk of any harmful effects. 
MRI exam:
LIKELY:
•
Anxiety/stress
•
Claustrophobia
•
Discomfort
•
Discomfort of noise level when having the MRI
RARE, BUT SERIOUS:
•
Injury related to the presence of metallic or surgical implants or metal pieces in the body and the 
MR magnet; it is important that you let the MRI team know about whether you have these before 
the MRI procedure. 
Possible Risks of Infusions:
You will receive study drug intravenously, which means you will receive it directly into your vein.  This 
may cause the following problems:
•
irritation of the vein; your skin near the vein could become warm, swell, hurt, or get red
•
damage to your vein
•
damage to the skin or tissue around the injection site
•
increase or decrease in electrolyte levels (the amount of certain salts and other chemicals in your 
blood), causing health problems
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 9 of 14
HN-24 Consent-HIPAA v5 vd 03/01/18
•
a blood clot or an air bubble could form, which could block a blood vessel in another part of your 
body
Reproductive risks:
You should not become pregnant or father a baby while on this study because the treatment used in this 
study may involve a risks to you (or your embryo or fetus if you become pregnant) which are currently 
unforeseeable. Women should not breastfeed a baby while on this study.  It is important that you 
understand that you need to use birth control while on this study and for 4 months after your last 
treatment.  Check with your study doctor about what kind of birth control methods to use and how long 
to use them. Some methods might not be approved for use in this study.  Some of the drugs used in the 
study may make you unable to have children in the future. 
If you or your partner becomes pregnant anytime during the study or within 4 months after stopping the 
study drug, you MUST immediately tell your study doctor. The study doctor must then report the 
outcome of the pregnancy to the Sponsor (and/or the FDA).
For more information about risks and side effects, ask your study doctor.
There is always a chance that any medical treatment can harm you, and the investigational treatment in 
this study is no different.  In addition to the risks listed above, you may experience a previously 
unknown risk or side effect.
WILL YOU BENEFIT FROM TAKING PART IN THIS STUDY?
There may be no direct benefit to you for participating in this study.  The growth of your cancer may be 
slowed as a result of your participation in this study; however, that result cannot be guaranteed. Your 
participation in this study could help advance medical research and the information from this research 
may help other people with cancer.
DO YOU HAVE TO TAKE PART IN THE STUDY?
If you decide to take part in the study, it should be because you really want to volunteer.  You will not 
lose any benefits or rights you would normally have if you choose not to volunteer.  You can stop at any 
time during the study and still keep the benefits and rights you had before volunteering. If you decide 
not to take part in this study, your decision will have no effect on the quality of medical care you 
receive.
IF YOU DON’T WANT TO TAKE PART IN THE STUDY, ARE THERE OTHER CHOICES?
If you do not want to be in the study, the following types of alternative therapy are available: other 
chemotherapy, radiation or palliative therapy, which is therapy that provides relief of symptoms of your 
cancer. You do not need to participate in this study to receive treatment for your cancer.
You may talk with your study doctor about these and other options before you agree to enter the study, 
and about other options that may become available during the study.
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 10 of 14
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WHAT WILL IT COST YOU TO PARTICIPATE?
You and/or your insurance company, Medicare or Medicaid will be responsible for the costs of all care 
and treatment you receive during this study that you would normally receive for your condition. These 
are costs that are considered medically reasonable and necessary and will be part of the care you receive 
if you do not take part in this study.
Medicare, or Medicaid will pay medically necessary costs (if you have any questions regarding 
Medicare/Medicaid coverage you should contact Medicare by calling 1-800-Medicare (1-800-633-4227) 
or Medicaid at 1-800-635-2570.
A co-payment/deductible from you may be required by your 
insurer or Medicare/Medicaid even if your insurer or Medicare/Medicaid has agreed to pay the 
costs. Some health plans will not pay for some costs of people taking part in clinical trials. Check with 
your health plan or insurance company to find out what they will pay for. Taking part in this study may 
or may not cost your insurance company more than the cost of getting regular cancer treatment.  
The University of Kentucky may not be allowed to bill your insurance company, Medicare or Medicaid 
for the medical procedures done strictly for research. Neither you nor your insurance company will be
billed for the collection of mucosal samples, the quality of life assessments or the 3 year follow up 
assessment. These costs will be paid by the sponsor KCLRP. 
WHO WILL SEE THE INFORMATION THAT YOU GIVE?
We will make every effort to keep confidential all research records that identify you to the extent 
allowed by law.
Your information will be combined with information from other people taking part in the study. When 
we write about the study to share it with other researchers, we will write about the combined information 
we have gathered. You will not be personally identified in these written materials. We may publish the 
results of this study; however, we will keep your name and other identifying information private.
We will make every effort to prevent anyone who is not on the research team from knowing that you 
gave us information, or what that information is. At the University of Kentucky, data is stored at the 
Markey Cancer Center in locked facilities, and with limited access to records by designated research 
staff.
You should know, however, that there are some circumstances in which we may have to show your 
information to other people. For example, the law may require us to show your information to a court or 
to tell authorities if you report information about a child being abused or if you pose a danger to yourself 
or someone else.
Organizations that may look at and/or copy your medical records for research, quality assurance and 
data analysis include:
x
The University of Kentucky Institutional Review Board
x
Representatives of the U.S. Food and Drug Administration as required by law
x
Representatives of the National Cancer Institute (NCI)
x
Representatives of the Kentucky Cancer Registry
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 11 of 14
HN-24 Consent-HIPAA v5 vd 03/01/18
x
Authorized representatives of the University of Kentucky, UK Hospital, and Markey Cancer
Center and the Kentucky Lung Cancer Research Program (KCLRP)
CAN YOUR TAKING PART IN THE STUDY END EARLY?
If you decide to take part in the study you still have the right to decide at any time that you no longer 
want to continue. You will not be treated differently if you decide to stop taking part in the study.
The individuals conducting the study may need to withdraw you from the study, and the study 
medication will no longer be provided by the investigator. This may occur if you are not able to follow 
the directions they give you, if they find that your being in the study is more risk than benefit to you, or 
if the agency funding the study decides to stop the study early for a variety of scientific reasons. 
If you are a female of childbearing potential, your participation in this study may be discontinued if you 
become pregnant or suspect you may have become pregnant.
If you decide to leave the study, please contact Susanne Arnold, MD or one of the study associates who 
will tell you what you should do before leaving.  You may be asked to return to the clinic for follow-up
care, if necessary.  You may be asked to have any laboratory tests, or physical examinations that the 
study doctor feels are necessary.  Until your permission is withdrawn, additional information may 
continue to be taken from your medical records for study follow-up purposes.
ARE YOU PARTICIPATING OR CAN YOU PARTICIPATE IN ANOTHER RESEARCH 
STUDY AT THE SAME TIME AS PARTICIPATING IN THIS ONE?
You may not be allowed to take part in this study if you are currently involved in another research study.  
It is important to let the investigator/your doctor know if you are in another research study.  You should 
also discuss with the investigator before you agree to participate in another research study while you are 
enrolled in this study.
WHAT HAPPENS IF YOU GET HURT OR SICK DURING THE STUDY?
If you believe you are hurt or if you get sick because of something that is due to the study, you should 
call Susanne Arnold, M.D. at (859) 323-8043 immediately. If you should have an emergency after 5pm 
during the week or on the weekend, please contact the UK Paging Operator at (859) 323-5321 and ask 
to page Susanne Arnold, MD. She will determine what type of treatment, if any, that is best for you at 
that time.
It is important for you to understand that the University of Kentucky does not have funds set aside to 
pay for the cost of any care or treatment that might be necessary because you get hurt or sick while 
taking part in this study. Also, the University of Kentucky will not pay for any wages you may lose if 
you are harmed by this study.  
The medical costs related to your care and treatment because of research related harm will be your 
responsibility.  It is possible that these costs may be paid by your insurer if you are insured by a health 
insurance company (you should ask your insurer if you have any questions regarding your insurer’s 
willingness to pay under these circumstances); or may be paid by Medicare or Medicaid if you are 
covered by Medicare, or Medicaid (if you have any questions regarding Medicare/Medicaid coverage 
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 12 of 14
HN-24 Consent-HIPAA v5 vd 03/01/18
you should contact Medicare by calling 1-800-Medicare (1-800-633-4227) or Medicaid 1-800-635-
2570.
A co-payment/deductible from you may be required by your insurer or Medicare/Medicaid even if your 
insurer or Medicare/Medicaid has agreed to pay the costs).  The amount of this co-payment/deductible 
may be substantial.
You do not give up your legal rights by signing this form.
WILL YOU RECEIVE ANY REWARDS FOR TAKING PART IN THIS STUDY?
You will not receive any rewards or payment for taking part in the study.  There is a chance that the 
mucosal samples that you are donating under this study may be used and may have some commercial 
value. Should your donated mucosal sample(s) lead to the development of a commercial product, the 
University of Kentucky will own it and may take action to patent and license the product. The 
University of Kentucky does not intend to provide you with any compensation for your mucosal sample 
donation nor for any future value that the mucosal samples you have given may be found to have. You 
will not receive any notice of future uses of your mucosal sample(s).
WHAT IF YOU HAVE QUESTIONS, SUGGESTIONS, CONCERNS, OR COMPLAINTS?
Before you decide whether to accept this invitation to take part in the study, please ask any questions 
that might come to mind now.  Later, if you have questions, suggestions, concerns, or complaints about 
the study, you can contact the investigator, Susanne Arnold, M.D. at (859) 323-8043 or your study 
coordinator at (859)257-3379.  If you have any questions about your rights as a volunteer in this 
research, contact the staff in the Office of Research Integrity at the University of Kentucky at 859-257-
9428 or toll free at 1-866-400-9428. We will give you a signed copy of this consent form to take with 
you.
WHAT IF NEW INFORMATION IS LEARNED DURING THE STUDY THAT MIGHT 
AFFECT YOUR DECISION TO PARTICIPATE?
If the researcher learns of new information in regards to this study, and it might change your willingness 
to stay in this study, the information will be provided to you.  You may be asked to sign a new informed 
consent form if the information is provided to you after you have joined the study. 
WHAT ELSE DO YOU NEED TO KNOW?
There is a possibility that the data/tissue/specimens/blood collected from you may be shared with other 
investigators in the future.  If that is the case the data/tissue/specimen/blood will not contain information 
that can identify you unless you give your consent/authorization or the UK Institutional Review Board 
(IRB) approves the research.  The IRB is a committee that reviews ethical issues, according to federal, 
state and local regulations on research with human subjects, to make sure the study complies with these 
before approval of a research study is issued.
The Kentucky Lung Cancer Research Program (KCLRP) is providing financial support and/or material 
for this study.
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 13 of 14
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A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by U.S. 
Law. This website will not include information that can identify you.  At most, the website will include 
a summary of the results.  You can search this website at any time.
AUTHORIZATION TO USE OR DISCLOSE YOUR IDENTIFIABLE HEALTH 
INFORMATION 
The privacy law, HIPAA (Health Insurance Portability and Accountability Act), requires researchers to 
protect your health information.  The following sections of the form describe how researchers may use 
your health information.  
Your health information that may be accessed, used and/or released includes:
x
Demographic Information (Example:  Sex, race & age, etc.)
x
History and diagnosis of your disease
x
Specific information about treatments you have received
x
Past and present medical records pertaining to your health condition
x
Your entire research record
x
Information about other medical conditions that may affect your treatment
x
Medical data, including physical examinations, laboratory test results, tumor measurements, 
CT scans, MRIs, X-rays, photographs of radiation therapy target areas, and pathology results
x
Information on side effects (adverse events) you may experience, and how these were treated
x
Long-term information about your general health status and the status of your disease
x
Mucosal, tissue and/or blood samples, associated data related to the analysis of the samples
The Researchers may use and share your health information with:
x
The University of Kentucky’s Institutional Review Board/Office of Research Integrity.
x
Law enforcement agencies when required by law.
x
Authorized representatives of the University of Kentucky, UK Hospital, and Markey Cancer 
Center
x
Representatives of the Kentucky Cancer Registry
x
Representatives of the U.S. Food and Drug Administration (FDA)
x
Kentucky Lung Cancer Research Program (KCLRP) and their representatives 
x
The National Institutes of Health and its affiliates including the for Human Research 
Protections (OHRP) and the NCI (National Cancer Institute) and their affiliates
The researchers agree to only share your health information with the people listed in this document.  
Should your health information be released to anyone that is not regulated by the privacy law, your
health information may be shared with others without your permission; however, the use of your health 
information would still be regulated by applicable federal and state laws, which were made to protect 
you.
You will not be allowed to participate in the research study if you do not sign this form.   If you decide 
not to sign the form, it will not affect your:
x
Current or future healthcare at the University of Kentucky
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19


IRB#: 14-0404-F2L
Protocol - PI Initiated\13-HN-24 (Arnold)
Page 14 of 14
HN-24 Consent-HIPAA v5 vd 03/01/18
x
Current or future payments to the University of Kentucky  
x
Ability to enroll in any health plans (if applicable)
x
Eligibility for benefits (if applicable)
After signing the form, you can change your mind and NOT let the researcher(s) release or use 
your health information (revoke the Authorization). If you revoke the authorization:
x
You must send a written letter to: Susanne Arnold, M.D. c/o Markey Cancer Center Clinical 
Research Organization, cc140 Markey Cancer Center, 800 Rose Street, Lexington, KY. 40536-
0093 to inform her of your decision. In that letter you should describe what you want to revoke:
x
If you do not want to participate in future follow-up
x
If you do not want to allow the use of your current information
x
If you want to have samples that have not already been used destroyed 
x
Researchers may use and release your health information already collected for this research 
study.
x
Your protected health information may still be used and released should you have a bad reaction 
(adverse event).
x
You may not be allowed to participate in the study.
If you become pregnant anytime during the study or within 4 months after stopping the study 
drug, you must inform the study doctor. The study doctor must then report the outcome of the 
pregnancy to the sponsor and the FDA. 
The use and sharing of your information has no time limit.
If you have not already received a copy of the Privacy Notice, you may request one.  If you have 
any questions about your privacy rights, you should contact the University of Kentucky’s Privacy 
Officer between the business hours of 8am and 5pm EST, Mon-Fri at: (859) 323-1184.
You are the subject or are authorized to act on behalf of the subject.  You have read this 
information, and you will receive a copy of this form after it is signed.
_____________________________________________                ____________
Signature of person agreeing to take part in the study
          Date
_____________________________________________
Printed name of person agreeing to take part in the study
_____________________________________________
____________
Name of [authorized] person obtaining informed consent
          Date
_________________________________________
Signature of Principal Investigator or Sub/Co-Investigator
Approval of IRB #14-0404 
Valid from 3/19/18 - 5/1/19