The Quarterback Trial: A Randomized Phase III Clinical Trial Comparing Reduced and Standard Radiation Therapy Doses for Locally Advanced HPV Positive Oropharynx Cancer
Phase: PHASE3
Conditions: Squamous Cell Carcinomas
Sponsor: Icahn School of Medicine at Mount Sinai

The Quarterback Trial:A Randomized Phase III Clinical Trial Comparing Reduced and Standard 
Radiation Therapy Doses for Locally Advanced HPV16 Positive Oropharynx Cancer
PI: Marshall Posner, MD
NCT01706939
Document Date: 2-21-2020

1 
The Quarterback Trial:A Randomized Phase III 
Clinical Trial Comparing Reduced and Standard 
Radiation Therapy Doses for Locally Advanced 
HPV16 Positive Oropharynx Cancer 
Principal Investigator: Marshall Posner, MD 
 Mount Sinai Medical Center 
   One Gustave. L. Levy Place, 
   New York, NY-10029 
   marshall.posner@mssm.edu 
 212 659 5461 
Funding Sponsor: Mount Sinai Medical Center 
IND Sponsor: Not applicable 
Version: 1.1 
Version Date: May 02, 2012 
IRB Approved: June 28, 2012 
Version:  2.0 
Version Date: March 11, 2013 
IRB Approved: April 2, 2013 
Version: 2.1 
Version Date: April 15, 2013 
IRB Approved: May 28, 2013 
Version: 3.0 

2 
Version Date: September 8, 2013 
IRB Approved: November 5, 2013 
Version: 4.0 
Version Date: December 23, 2013 
IRB Approved: February 3, 2014 
Version: 4.1 
Version Date: January 9, 2020 
IRB Approved: February 21, 2020 

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Site #1 
Robert Alter, M.D. 
The John Theurer Cancer Center at Hackensack University Medical Center 
 
Hackensack, NJ 07601 
Phone: 551-996-5865 
Phone2: 551-996-5072 
E-mail: RAlter@HackensackUMC.org 
 
Contact Person: 
Seana Krauss, R.N. 
Phone: 551-996-8612 
Fax: 551-996-0747 
E-mail: skrauss@hackensackUMC.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

4 
 
 
 
 
Investigators/Study Staff 
 
Vishal Gupta, MD  
Co-Investigator 
Chairman, Radiation Oncology 
212-241-7818 
vishal.gupta@mountsinai.org 
 
Richard Bakst, MD 
Co-Investigator 
Radiation Oncology 
212-241-7818 
richard.bakst@mountsinai.org 
 
Andrew Sikora, MD/PhD 
Co-Investigator 
Chairman, Translational Studies 
212-241-7063 
andrew.sikora@mssm.edu 
 
Kenneth Rosenzweig, MD 
Co-Investigator 
Radiation Oncology 
212-241-5095 
kenneth.rosenzweig@mountsinai.org 
 
Marcelo Bonomi, MD 
Co-Investigator 
Chairman, Quality of Life Committee 
336-716-0477 
mbonomi@wakehealth.edu 
 
Krzysztof Misiukiewicz, MD 
Co-Investigator 
Medical Oncology 
212-241-0288 
kryzstof.misiukiwiecz@mssm.edu 
 
James Godbold, PhD 
Co-Investigator 
Biostatistics 
212-241-4808 
james.godbold@mssm.edu 
 
Karen S Anderson, PhD 
The Biodesign Institute,Arizona State University 
POB 876401, 1001 S Mcallister Avenue 
Tempe, AZ 85287 
Chairman, Immune Correlates 
kander22@asu.edu  
480-965-6982 
 
Tamar Kotz 
Co-Investigator 
Speech and Swallowing Group 
212-241-8452 
tamar.kotz@mountsinai.org 
 
 
Seunghee Kim-Schulze, PhD 
Co-Investigator 
Immune Monitoring, Biorepository 
212-659-8264 
seunghee.kim-schulze@mssm.edu 
 
 
David Zhang, MD 
Co-Investigator 
Chairman, Pathology Committee 
212-659-8173 
zhangd01@mssm.edu 
 
 
Peter Som, MD 
Co-Investigator 
Chairman, Radiology Committee 
212-241-7420 
peter.som@mountsinai.org 
 
Hoda Badr, PhD 
Co-Investigator 
Quality of Life Committee 
212-659-5547 
hoda.badr@mssm.edu 
 
 
Eric Genden, MD 
Co-Investigator 
Chairman, Surgical Oncology 
212-241-7063 
eric.genden@mountsinai.org 
 
Brett Miles, DDS/MD 
Co-Investigator 
Surgery 
212-241-9410 
brett.miles@mountsinai.org 
 
 

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Table of Contents 
        INVESTIGATORS/STUDY STAFF ....................................................................................................................... 4 
1.0   INTRODUCTION .................................................................................................................................................... 5 
1.1    Study Design .......................................................................................................................................................... 5 
1.2   Primary Objectives ................................................................................................................................................. 5 
1.3   Secondary Objectives ............................................................................................................................................. 5 
1.4  Treatment Schema ................................................................................................................................................... 6 
2.0   BACKGROUND ....................................................................................................................................................... 6 
2.1   HPV – Related Oropharynx  ................................................................................................................................... 6 
2.2  TPF and  HPV Oropharynx Cancer  ....................................................................................................................... 9 
2.3  Rationale for Dose Reduction of Radiotherapy and Trial Design ......................................................................... 13 
2.4  Smoking History and Histological Requirements .................................................................................................. 15 
2.5  Correlative Studies Background ............................................................................................................................ 15 
3.0   PARTICIPANT SELECTION .............................................................................................................................. 16 
3.1   Inclusion Criteria ................................................................................................................................................. 16 
3.2  Exclusion Criteria ................................................................................................................................................. 17 
3.3  Inclusion of Women, Minorities and Other Underrepresented Populations ......................................................... 18 
4.0   REGISTRATION PROCEDURES ....................................................................................................................... 18 
4.1  General Guidelines................................................................................................................................................ 18 
4.2  Registration Process.............................................................................................................................................. 19 
5.0   TREATMENT PLAN ............................................................................................................................................. 19 
5.1   Induction Chemotherapy Pre-treatment Criteria ................................................................................................. 21 
5.2   Induction Chemotherapy Agent Administration ................................................................................................... 21 
5.3  Chemoradiotherapy Pre-Treatment Criteria ......................................................................................................... 22 
5.4  Chemoradiotherapy Agent Administration ............................................................................................................ 24 
6.0   ASSESSMENT OF RESPONSE AND ASSIGNMENT OF RADIATION ARM ............................................. 24 
6.1  Paragraph w/o heading ......................................................................................................................................... 24 
6.2  Randomization ....................................................................................................................................................... 25 
7.0   (XRT) DELIVERY OF RADIATION .................................................................................................................. 25 
7.1  Paragraph w/o heading ......................................................................................................................................... 25 
7.2 Technical Factors ................................................................................................................................................... 25 

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8.0  SURGICAL INTERVENTIONS ............................................................................................................................ 28 
8.1  Determination of Stage .......................................................................................................................................... 28 
8.2  Examination and EUA/biopsy for Post Induction Response Assessment .............................................................. 28 
8.3  Post-radiation Neck Dissection ............................................................................................................................. 29 
9.0   GENERAL CONCOMITANT MEDICATION AND SUPPORTIGE CARE GUIDELINES ........................ 29 
9.1   Hydration ............................................................................................................................................................. 29 
9.2   
10.0  DURATION OF THERAPY................................................................................................................................. 30 
10.1  Duration of Follow Up ........................................................................................................................................ 31 
10.2  Criteria for Removal from Study ......................................................................................................................... 31 
11.0  EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ......................................... 31 
11.1  Anticipated Toxicities .......................................................................................................................................... 31 
11.2  Dose Modifications/Delays ................................................................................................................................. 32 
12.0  DRUG FORMULATION AND ADMINISTRATION ....................................................................................... 43 
13.0  CORRELATIVE/SPECIAL STUDIES ............................................................................................................... 43 
13.1 Probable Laboratory Correlative Studies ............................................................................................................ 43 
13.2  Specific Study Plans ............................................................................................................................................ 43 
13.3 Blood and Tissue Collection and Preparation  .................................................................................................... 44 
14.0  STUDY CALENDARS .......................................................................................................................................... 46 
15.0  MEASUREMENT OF EFFECT .......................................................................................................................... 48 
15.1  Antitumor Effect—Solid Tumors .......................................................................................................................... 53 
15.2  Other Response Parameters ................................................................................................................................ 53 
16.0  ASSESSMENT OF QUALITY OF LIFE AND PATIENT REPORTED SYMPTOMS ................................. 53 
17.0  ADVERSE EVENT REPORTING REQUIREMENTS ..................................................................................... 55 
17.1  Definitions ........................................................................................................................................................... 55 
17.2  Procedures for AE and SAE Recording and Reporting ....................................................................................... 56 
17.3  Reporting Requirements ...................................................................................................................................... 57 
17.4  Reporting to the Study Center ............................................................................................................................. 57 
17.5  Reporting to the Institutional Review Board (IRB) ............................................................................................. 58 
17.6  Reporting to Hospital Risk Management ............................................................................................................. 58 
17.7  Monitoring of Adverse Events and Period of Observation .................................................................................. 58 

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18.0  DATA AND SAFETY MONITORING ............................................................................................................... 58 
18.1  Data Reporting .................................................................................................................................................... 58 
18.2  Safety Meetings.................................................................................................................................................... 59 
18.3  Non-MSSM Site Monitoring ................................................................................................................................ 60 
19.0  REGULATORY CONSIDERATIONS ............................................................................................................... 60 
19.1  Protocol Review and Amendments ...................................................................................................................... 60 
19.2  Informed Consent ................................................................................................................................................ 60 
19.3  Ethics and Good Clinical Practice (GCP) .......................................................................................................... 61 
19.4  Study Documentation .......................................................................................................................................... 61 
19.5  Records Retention................................................................................................................................................ 61 
19.6  Multi-center Guidelines ....................................................................................................................................... 62 
20.0  STATISTICAL CONSIDERATIONS ................................................................................................................. 62 
20.1 Study Design/Endpoints ....................................................................................................................................... 62 
20.2 Sample Size/Accrual Rate ..................................................................................................................................... 62 
20.3 Stratification Factors ........................................................................................................................................... 63 
20.4 Randomization Process ........................................................................................................................................ 63 
20.5 Analysis of Primary Endpoints ............................................................................................................................. 63 
20.6 Analysis of Secondary Endpoints ......................................................................................................................... 63 
21.0  PUBLICATION PLAN ......................................................................................................................................... 63 
22.0  REFERENCES ...................................................................................................................................................... 64 
23.0  APPENDICES ........................................................................................................................................................ 67 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 INTRODUCTION  
 
 
____ 
 
 
 
 
 
_________ 
1.1 
Study Design 
 
This is a randomized Phase III study comparing two doses of definitive radiation therapy given with 
induction and concurrent chemotherapy in HPV-positive oropharynx, unknown primary or nasopharynx 
cancer.  Eligible, consented and registered patients will receive three cycles of Docetaxel Cisplatin and 5-FU 
(TPF) induction chemotherapy. After 3 cycles, the patients will be assessed for clinical, radiographic and 
pathologic response to TPF. Patients with a clinical or radiographic CR or  PR will be randomized on the 
second phase of this study, where patients with HPV 16 or with another strain of HPV will undergo a 2:1 
randomization or 1:1 randomization, respectively, to reduced (5600 cGy) or standard (7000 cGy)  dose 
radiotherapy with weekly Carboplatin .  Patients not meeting the response criteria will be treated with 
standard dose CRT. Patients not completing 3 cycles TPF for reasons of toxicity, progressive disease, choice, 
or other medical necessity will be treated with standard dose CRT or surgery depending on their primary site 
and overall medical condition and followed for survival. Any adverse events occurring thereafter in these 
patients will not be considered related to the study and will not be tracked or reported.  
  
1.2 
Primary Objectives 
1.2.1 
To determine the comparative rate of progression free survival (PFS) at 3 years in patients with 
advanced HPV related oropharynx cancer, nasopharynx cancer or unknown primary treated with 
reduced or standard dose CRT. 
1.2.2 
To determine the comparative rate of local-regional control (LRC) at 3 years in patients with 
advanced HPV related oropharynx cancer or unknown primary treated with reduced or standard 
dose CRT. 
 
1.3 
Secondary Objectives 
1.3.1 
To determine the comparative rate of local-regional control (LRC) over 5 years in patients with 
advanced HPV related oropharynx cancer or unknown primary treated with reduced or standard 
dose CRT. 
1.3.2 
To determine the comparative rate of progression free survival (PFS) over 5 years in patients with 
advanced HPV related oropharynx cancer or unknown primary treated with reduced or standard 
dose CRT. 
1.3.3 
To determine Overall Survival (OS) at 3 and 5 years treated with reduced or standard dose CRT. 
1.3.4 
To compare acute toxicity in patients treated with reduced or standard dose CRT. 
1.3.5 
To compare long term toxicity of patients treated with reduced or standard dose CRT at 2, 3 and 5 
years. 
1.3.6 
To determine biomarkers predictive of failure with either reduced or standard dose radiotherapy. 
1.3.7 
To establish a tumor tissue, germline DNA and plasma bank for future studies of the protocol 
selected and treated populations. 
 

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1.4 
Treatment Schema 
 
Consent and Screen (n=365)
Operable Patients –
Offer Surgery (n=35)
Induction 
Chemotherapy(n=3
30)
Toxicity Dropouts 
(n=30)
Standard 
Chemoradiation
Surgery
Complete Induction 
chemotherapy (n=300)
90%
Non-responders (n=60)
Standard Chemoradiation 
with Carboplatin, Erbitux, 
Paclitaxel weekly
Responders (n=240)
Re-Register and 
Randomize
ARM A: Reduced Dose Radiation +  
Carboplatin (n=160)
ARM B: Standard Dose Radiation + 
Carboplatin (n=80)
Follow Up
Follow Up
80%
Treatment Schema
(n= approx. # of subjects)
Equivocal Response.  
Reassess biopsy
 
2.0 
BACKGROUND 
2.1 
HPV – Related Oropharynx Cancer 
 
The demographics and prognosis of locally advanced head and neck squamous cell cancer (HNC) has 
changed dramatically over the last two decades. Epidemiologic evidence has revealed a significant increase 
in the incidence of oropharynx cancer (OPC) in North America and Europe. Molecular studies of 
oropharyngeal tumors have revealed that this increase is due to an increase in the incidence of tumors which 
contain Human Papillomavirus (HPV), most specifically HPV16 and for which there is direct evidence that 
HPV16 is the molecular cause mechanistically driving the development and viability of the cancer cells. 
HPV-related oropharynx cancer (HPVOPC) now accounts for almost 60% of OPC seen in the USA and an 
increasing fraction of these malignancies in Europe (1-3).   
 
Based on the existing data from clinical trials and patient material through retrospective analysis, it is now 
understood that there are two dominant carcinogenic and biologic pathways where oropharynx cancer 
develops: Environmentally related OPC (EROPC), caused by smoking and alcohol, and HPV related OPC 
(HPVOPC).  The relative paucity of genetic changes in HPV-positive head and neck cancer is in sharp 

6 
 
contrast to what is observed in HPV-negative head and neck cancer and is mechanistically related to the 
direct effects of viral proteins in inactivating regulators of key cellular processes(4-7). In the typical EROPC, 
mutations and deletions of p53 have very frequently been demonstrated. In contrast, HPVOPC do not 
contain p53 mutations. Similarly, p16 in the Rb pathway of cell growth is frequently mutated, deleted or 
silenced in EROPC but is often up-regulated in HPVOPC as a consequence of viral alterations in Rb 
function. Up regulation of p16 can be seen in up to 20% of non-HPV related cancers including other sites in 
the head and neck, however, p16 appears to be up-regulated in >95% of HPVOPC making it a good 
screening tool(8). 
 
Studies in unselected patients suggest that patients with HPVOPC have a better prognosis than patients with 
HPV-negative, predominantly environmentally related OPC (EROPC) (9-11).  In one retrospective study of 
radiotherapy as sole therapy from Denmark, p16 was used as a surrogate for HPV. In this randomized study 
of a radiation sensitizer, the control arm of radiotherapy only was analyzed for p16 expression. There was 
62% 5-year survival among p16+ patients compared to 26% in p16 -patients. LRC was 58% vs. 28%, 
respectively (Figure 1). A significant fraction of p16+ tumors were not of oropharyngeal origin (12). 
 
 
Figure 1: p16 Status, Local Regional 
Control and Survival: Radiotherapy Only
Lassen et al, JCO  2009
 
 
 
A second trial, Licitra et al retrospectively evaluated surgery in the HPV positive and negative cases. Surgery 
alone was effective therapy for a small group of patients.  The surgery only patients were spared the long 
term consequences of radiation. However, selection for surgery only was not well explained(13). 
 

7 
 
Licitra et al, JCO  2006
Figure 2: Surgery and HPV in Oropharynx Cancer
 
 
 
ECOG (E) 2399, a Phase II study of operable patients treated with an aggressive Sequential Therapy (ST) 
regimen of induction chemotherapy followed by chemoradiotherapy for organ preservation, prospectively 
evaluated HPV status and reported a significant difference in survival for patients with HPVOPC compared 
to EROPC. Sixty two OPC cases were treated and all of the 38 of the HPVOPC cases were HPV 16 positive. 
Even among this small group of less the 65 patients, overall survival was significantly better for the 
HPVOPC. An analysis of failure in this population revealed several important features. First, LRC was much 
better in the HPVOPC patients.  Additionally, co-morbidities and non-cancer deaths were much reduced. 
The impact of therapy on LRC was most striking however; 5% versus 33% Local Regional Failure (LRF) in 
HPVOPC vs. EROPC, respectively (14, 15).  

8 
 
Figure 3: Oropharynx Tumor HPV Status And Survival 
in ECOG 2399 
Time in Months
Probability
0
10
20
30
40
50
60
0.0
0.2
0.4
0.6
0.8
1.0
Negative
Positive
Log-rank test, p=0.004
Two-year Overall Survival
Fakhry, JNCI, 2008
 
 
The University Michigan used a single cycle of induction chemotherapy to select operable OPC patients for 
radiotherapy or surgery. They analyzed 42 informative cases for HPV and HPV copy number and found 
responses to induction chemotherapy correlated with HPV status as did disease specific survival.  The 
relationship to copy number of HPV in the tumors was less clear although there was a suggestion that 
increasing copy number was associated with a better prognosis(16). 
 
Recently, results of retrospective analyses of survival and HPV status were reported from two International 
Phase III trials comparing chemoradiotherapy (CRT) regimens in locally advanced HNC. In both trials there 
were insufficient patient numbers to report a treatment effect; however the impact of HPV on survival, 
regardless of therapeutic assignment, was highly significant (8, 17). The RTOG (R) 01-29 has the most 
extensive data and retrospectively analyzed on 323 out of 433 OPC cases.  In RTOG 01-29, patients were 
randomized between CRT with accelerated fractionation with cisplatin versus regular fractionation and 
cisplatin. The overall survival (OS) and progression free survival (PFS) at three years were 82%and 74% in 
HPVOPC compared to 57% and 43% for EROPC, respectively. A careful analysis of failure and death 
revealed a LRF rate of 14% versus 35% for HPVOPC versus EROPC and a second primary tumor rate of 6% 
versus 15% respectively. Non-cancer deaths also occurred in 9% and 19% respectively. All these data 
support a better outcome for HPVOPC, much of which is found in improved LRC, some of which is 
explained by less co-morbidity. 
 
2.2 
TPF and HPV Oropharynx Cancer 
 
We retrospectively evaluated tumor HPV16 status, survival and demographics in subjects with OPC treated 
in TAX324, a large international randomized Phase III clinical trial. TAX 324 compared survival between 
ST with TPF or PF followed by chemoradiotherapy with weekly carboplatin in patients with locally 
advanced HNC (18, 19).  The data demonstrate a significant difference in survival outcome and patterns of 
failure between patients with HPVOPC and EROPC and significant differences in demographic 
characteristics in the populations.  
 

9 
 
Demographic Differences between HPVOPC and EROPC Patients Of the 501 patients entered on TAX 324, 
264 (53%) were identified as having oropharynx cancer (OPC). Of these 264 subjects, 119 had tissue 
prospectively collected and 111, or 42% of all OPC cases, were analyzable for HPV 16 status and constitute 
the study population.   The demographic data and test results for group comparisons are shown in Table 1. 
Comparisons of the cases with analyzable tissue to those without such tissue are also shown. There are 56 
(50%) patients identified as HPV positive (HPVOPC) and 55 (50%) as HPV negative (EROPC).  Both 
HPVOPC and EROPC cases are evenly divided with regard to treatment assignment and sex.  HPVOPC 
cases are significantly younger, 54 compared to 58 years (P=.02), than the EROPC cases, despite a highly 
selected population for a phase III trial. Performance status (PS) was also significantly different between the 
two populations, despite selection for good PS in patients for enrollment in this trial. Thus, 77% of HPVOPC 
patients were PS 0 compared to 49% of the EROPC patients (P=.003). 
 
Table 1: TAX 324 Demographics By HPV Status 
HPV+
N=56 (50%)
HPV-
N=55 (50%)
P-value
Treatment 
TPF
PF 
28 (50%)
28 (50%)
26 (47%)
29 (53%)
0.85
Age Yrs
Median (Range)
54 (39-71)
58 (41-78)
0.02
Nodal Stage
N0-N1
N2-N3 
13 (23%)
43 (77%)
18 (33%)
37 (67%)
0.30
T stage
T1-T2
T3-T4
28 (50%)
28 (50%) 
11 (20%)
44 (80%)
0.001
PS WHO
0
1
43 (77%)
13 (23%)
27 (49%)
28 (51%)
0.003
Posner et al, ASCO, 2010
 
 
Outcome Differences between HPVOPC and EROPC Patients. Results for OS, PFS and site of failure for the 
111 patients analyzed for HPV16 status, independent of treatment arm, are shown in Table 2. HPVOPC and 
EROPC surviving patients were followed for a median of 83 months and 82 months respectively. At the time 
of analysis 79% of HPVOPC patients were still alive, and their PFS rate was 73% compared to the 31% OS 
and 29% PFS, for the EROPC patients (both P<.0001).   
 
OS and PFS are shown in Figure 4, respectively. The median overall survival time for the EROPC patients is 
21 mo (95% CI: 13-49 mo), while median survival has not been reached in the HPVOPC group after almost 
7 years median follow-up. There is an 80% reduction in mortality in HPVOPC compared to EROPC 
(HR=0.2, 95% CI: 0.10-0.38; P<.0001). 
  
Analysis of the site of failure, as shown in Table 2, reveals a significant reduction in local-regional failure 
(13% vs. 42%, p = .0006) and slightly reduced distant failure in the HPVOPC patients compared to the 
EROPC patients. There was also a significant difference in total disease failures (16% vs. 49%, p = .0002) 
and a borderline improvement in deaths without recurrence (p = .07). These data indicate that local-regional 

10 
 
control is the major parameter contributing to improved survival and that PS and co-morbidities among 
EROPC patients account for another fraction of mortality. 
 
 
Table 2: TAX 324 Analysis of Failure By HPV Status 
HPV+
N=56
HPV-
n=55
P-value#
Median Follow Up
Months (95% CI)
83 (77-93)
82(68-86)
NS
Survival Status
Alive
Dead 
44 (79%)
12 (21%)
17 (31%)
38 (69%)
<0.0001
PFS Status
No Progression/Death
Progression/Death
41 (73%)
15 (27%)
16 (29%)
39 (71%)
<0.0001
Local-Regional Failure
7 (13%)
23 (42%)
0.0006
Distant Metastases
3 (5%)
6 (11%)
NS
Both
1 (2%)
2 (4%)
NS
Total Disease Failures
9 (16%)
27 (49%)
0.0002
Died Without 
Recurrence
5 (9%)
12 (22%)
0.07
Posner et al, ASCO, 2010
 
 
OS and PFS rate-over-time data - as a yearly analysis of events over 5 years - are shown in Table 3. 
These data are informative in aligning information on OS and PFS for qualitative comparisons 
among trials focusing on OPC. As can be seen, early PFS at 2 and 3 years predicts later survival for 
HPVOPC and EROPC patients when treated with Sequential Therapy. PFS is a potential indicator of 
the durability of survival in both populations of oropharynx cancer compared to other head and neck 
sites and the slope of PFS in ST trials can be used to inform long-term survival estimates in a 
qualitative manner for future studies. 
 

11 
 
Table 3: TAX324 Oropharynx Cancer, HPV, Survival and PFS
OS (95% CI)
HPV+
HPV-
All
1- yr
0.93  (0.82-0.97)
0.69  (0.54-0.79)
0.81  (0.72-0.87)
2- yr
0.89  (0.78-0.95)
0.48  (0.34-0.61)
0.69  (0.60-0.77)
3 -yr
0.87  (0.75-0.94)
0.41  (0.28-0.53)
0.65  (0.55-0.73)
5 -yr
0.82  (0.69-0.90)
0.35  (0.23-0.48)
0.59  (0.49-0.67)
PFS (95% CI)
1- yr
0.85  (0.73-0.92)
0.52  (0.38-0.64)
0.69 (0.59-0.76)
2- yr
0.83  (0.70-0.91)
0.35  (0.23-0.48)
0.59 (0.49-0.68)
3 -yr
0.81  (0.68-0.90)
0.33  (0.21-0.46)
0.57 (0.48-0.66)
5 -yr
0.78  (0.64-0.87)
0.28  (0.17-0.40)
0.53 (0.43-0.62)
 
 
It is apparent from the data presented here from TAX 324 as well as other trials that survival is significantly 
better for HPVOPC compared to EROPC. In Table 4, comparable data on OS and PFS for TAX 324, R01-29 
and OS data from the HeadStart trial are shown for a qualitative comparison(8, 17, 19).  
 
Table 4: The Impact of HPV on Survival in Protocol 
Driven Large Phase III Trials
Study
GeoLocation
Patients 
Tested
Therapeutic
Regimens
HPV+/HPV-
(%HPV+)
Time
Interval
Survival
HPV+/HPV-
01-29
USA
323/433 (75%)
CRT vs. RT
206/323 (65%)
3 year OS
3 Year PFS
82% vs. 57%
74% vs. 43%
HeadStart
International
195/465 (42%)
CRT vs. CRT
54/141   (28%)
2 Year OS
2 Year PFS
94% vs. 77%
NA
TAX324
International
111/264 (42%)
ST vs. ST
56/55     (50%)
3 Year OS
3 Year PFS
5 Year OS
5 Year PFS
87% vs. 41%
81% vs. 33%
82% vs. 35%
78% vs. 28%
Ang, NEJM, 2010; Rischin; JCO, 2010
 
 
As can be seen, survival in all three trials is similar at the 3-year analysis time point. PFS is different 
between R01-29 and TAX 324 in the first 3 years by as much as 7%, in favor of TAX324. Importantly, in 

12 
 
assessing outcomes, CRT trials may also have greater rates of late distant metastases and/or late fatal 
morbidity not captured in the early analysis of the CRT trial.  Data from this 5-year minimum follow-up 
analysis indicate that the 2- and 3-year actuarial PFS rates in this Sequential Therapy plan predict 5-year 
actuarial overall survival in HPVOPC and, therefore, can be used to predict long-term survival in Sequential 
Therapy studies. The data from R01-29 has been limited to the 3-year survival data reported. Longer-term 
survival and PFS in R01-29 are not available yet, and thus, data on the impact of the lower 3-year PFS in 
HPVOPC, late toxicity and the risk for delayed distant metastases on 5-year OS in the CRT regimen are not 
available.  
 
2.3 
Rationale for Dose Reduction of Radiotherapy and Trial Design  
 
In general, patients with HPVOPC are young and will live for prolonged periods. They are at high risk for 
long-term toxicity and mortality from therapy(20). While the long-term consequences of chemotherapy for 
head and neck cancer are relatively constrained, high-dose radiotherapy (RT) and chemoradiotherapy 
substantially impact on local tissues and organ function and result in a significant rate of late mortality and 
morbidity in patients(21-25). Studies are now being designed to reduce the impact of RT and CRT for 
patients. Identifying appropriate endpoints and study arms which will allow an early assessment of outcomes 
will be problematic, particularly for equivalence studies wherein survival differences are small, and where 
prolonged time periods and large patient numbers are necessary to accurately assess outcomes. For 
Sequential Therapy as given with TAX 324, 3-year PFS may be an appropriate endpoint. The same may not 
be possible for CRT. The best example of changing outcomes in CRT trials would be R91-11, in which a 
premature negative conclusion regarding the efficacy of induction therapy was published with the early 
analysis. Late toxicity and morbidity, a hallmark of upfront cisplatin-based CRT trials, led to equivalence 
between induction therapy and CRT for laryngectomy-free survival at 5 years, and more importantly a non-
significant relative 10% improvement in overall survival in the PF induction arm compared to the CRT arm 
which included an every 3-week bolus cisplatin for 3 cycles during radiotherapy(8, 19, 22).  
 
The survival results in HPVOPC achieved in TAX 324 strongly suggest that it might be possible to reduce 
long-term morbidity in HPVOPC and preserve survival perhaps by better selection and by reducing 
radiotherapy intensity in the context of ST for more advanced cases. We might best approach HPV-negative 
disease with novel therapies and more aggressive ST or CRT.  
 
Current radiation dose reduction trials are under way in ECOG and at Dana Farber Cancer Institute (DFCI). 
ECOG 1308 is a Phase II trial treating patients with p16 positive resectable OPC with an aggressive regimen 
of induction chemotherapy using weekly Paclitaxel, cisplatin every 3 weeks, and Cetuximab weekly for 3 
cycles, followed by Cetuximab plus radiotherapy to a total radiation dose of 5400 cGy for responders. Non-
responders receive standard radiotherapy with Cetuximab. The DFCI is conducting a Phase II trial of TPF 
induction followed by radiotherapy with Carboplatin and Cetuximab to a total radiotherapy dose of 6000 
cGy in HPV16 positive patients. There are currently no other trials that are active, although a randomized 
trial is planned at Johns Hopkins. The RTOG plans a randomized trial to compare cisplatin CRT to erbitux 
CRT, with full dose radiotherapy in both arms. 
 
The data from TAX 324 suggest that it is possible to reduce the radiation dose because of the superior 
progression free survival and the ability to select risk based CRT.  Data from the randomized Bonner trial of 
radiotherapy +/- Cetuximab suggest that Cetuximab might be an effective radiotherapy sensitizer for 
oropharynx cancer on the basis of a significant survival advantage for the Cetuximab arm in oropharyngeal 
cancer patients(26). In that trial, as with TAX 324, oropharynx cases fared significantly better for survival 
with Cetuximab compared with radiotherapy alone.  Furthermore, late toxicity was not adversely affected by 
adding Cetuximab to radiotherapy although acute toxicity was enhanced. In the setting of a reduced dose 
trial there are pros and cons to cetuximab including non-cross resistance (pro) and enhanced toxicity (con). 

13 
 
Because of the uncertainty around the relative value of a platinum sensitizer and cetuximab there is no clear 
advantage and perhaps enhanced toxicity to adding erbitux. 
 
 
For the Quarterback Trial TPF will be modified to reduce the 5-fluorouracil dose by 25% to reduce the rates 
and duration of grade 3 and 4 mucositis and eliminate febrile neutropenia. Neulasta and G-CSF will not be 
allowed during induction chemotherapy to enhance recovery from neutropenia due to ambiguous data 
regarding tumor protection in one randomized trial.  Based on the plan by ECOG to test a radiation dosage of 
5400 cGy and DFCI to test 6000 cGy, we feel a dose of 5600 cGy is a reasonable therapy endpoint 
representing an approximate 20-25% dose reduction from the standard 6900-7200 cGy of definitive 
radiotherapy and a proportional decrease in radiation toxicity. Both arms will receive weekly carboplatin as a 
radiation senstizer.  We will compare the reduced dose experimental arm to the established therapy in 
TAX324.  
 
There are currently no active randomized trials of radiation dose reduction for HPVOPC. The current trials 
by DFCI and ECOG are non-randomized Phase II trials and will not realistically provide data that would 
lead to a change of practice. The RTOG trial compares standard dose radiotherapy with cisplatin or 
cetuximab and will not reduce long term morbidity. This trial aims to directly compare a reduced radiation 
dose to the standard of care in HPVOPC for non-inferiority, thus allowing for direct comparison of outcomes 
between the two groups. 
 
2.4 
Smoking History and Histological Requirements 
 
Patient selection for the Quarterback Trial will include squamous cell carcinomas of head and neck classified 
as oropharynx, unknown primary (cervical lymph nodes) or nasopharynx primary that are both HPV16 
positive by PCR and p16 positive(1, 27-29). Tissue for confirmation of HPV and p16 status will be required 
and analyzed at a central laboratory. Although p16 has been found to be a potential independent risk factor 
for prognosis, and a negative p16 is highly predictive of a negative HPV test, about 10-20% of HNC tumors 
are p16 positive independent of HPV presence. Because the biologic behavior of this population may be 
heterogeneous and is less well understood, p16+ HPV16- patients will be excluded from the second phase of 
the trial – randomization to radiotherapy. Similarly, 95% of HPV positive oropharynx cancer is HPV16+, 
and the behavior of other serotypes is unknown. Hence this study will be limited to HPV16+ cancers and 
HPV other strains will be analyzed separately. In addition, smoking has been shown to be a prognostic factor 
and prospective smoking and tobacco utilization data will be collected for this study(30). In the original 
analysis of RTOG 0129, a history of smoking above and below 20 pack years correlated to meaningfully 
different populations(8).  We have therefore chosen to retain this as a stratification factor.  Patients will be 
stratified based on smoking history of 20 pack years or greater versus less than 20 pack years. Correlative 
science studies will be performed and all patients entered will be asked to provide plasma and germ line 
DNA as well as additional slides from diagnostic biopsies. 
 
2.5 
Correlative Studies Background 
 
It is still not well understood as to what biological factors influence the growth and response to treatment of 
HPVOPC tumors.  Current research strongly suggests that there are multiple pathways that may account for 
the difference in growth and treatment response between HPVOPC and non-HPVOPC tumors.  Furthermore, 
there are several mechanisms reported in the literature that may account for differences in survival within the 
HPVOPC subset of patients.   
 
This study will collect blood and tumor samples in order to further quantify such mechanisms.  It will be 
difficult to predict what studies will be most likely to be valuable and informative given the rapid advances 
in technology and knowledge that we will be refining the translational components of this study as we 

14 
 
proceed. At present we plan several potential research studies: we plan to analyze expression of p16, p53, 
cMET in tumor, and quantify HPV copy number. Serial blood samples will be collected to measure 
sequential plasma anti-HPV antibody titers to HPV16 proteins, cytokines and growth factors (eg HGF) and 
quantify of circulating tumor cells, whole blood HPV DNA, MDSC, and other immune function cells.  
Additionally, studies will be performed to quantify tumor EGFR copy number and Bcl-xL expression, in 
order to further study the relationship between these proteins and survival of HPVOPC patients.  Finally, 
HPV related signaling pathways will be analyzed possibly using such markers as NFĸβ and STAT3 in 
tissues or a high throughput screening system. Antibodies the HPV16 early antigens are elevated in 
HPVOPC and may prove to be a useful biomarker for assessing risk of recurrence and  response to 
therapy(31).  
 
Kumar, et. al. reported that low EGFR and high p16 expression are markers of good response to treatment 
(32).  Other studies have also shown HPV copy number to be linked to better response to treatment and 
improved OS(7).  p16 will be measured as a marker for HPV status, as it is a cyclin-dependent kinase 
inhibitor which acts to inhibit pRb phosphorylation, thus blocking cell cycle progression.  The inactivation of 
pRb by HPV leads to overexpression of p16, making it a good marker for HPV status.  Additionally, high 
EGFR expression, low p53, as well as high Bcl-xL (an antiapoptotic protein) expression are factors that may 
indicate poor response to treatment and poor outcomes.  This study will seek to analyze these factors, as well 
as proteins that are often mutated in cell signaling pathways, such as cMET, in order to further correlate 
these proteins with treatment response. Having a robust, protocol driven study with tissue and blood 
collection will be a valuable resource to establish predictive markers of response and understand the biology 
of HPVOPC. 
 
3.0 
PARTICIPANT SELECTION 
 
All patients will be evaluated in the multidisciplinary head and neck cancer clinic where eligibility criteria, 
entry and disease parameters will be evaluated and documented. Subjects who enroll on this study must be 
diagnosed with squamous cell carcinoma in the oropharynx, nasopharynx, or cervical nodal unknown 
primary as documented in the medical record, and must not have received any prior chemotherapy, 
radiotherapy or surgery for their cancer. Potential participants will be screened based on their past medical 
history, the results of their radiological scans, blood work, as well as a number of other required studies that 
will determine their eligibility.  To enroll on this study, tumor tissue must be available and  p16 must be 
assessed and proven to be positive by IHC in a lab verified by the central laboratory or with slides that can 
be reviewed in the central laboratory (28, 29).  To be randomized into a radiotherapy arm in cohort 1, HPV 
16 status must be assessed and proven to be positive by PCR.  If the HPV status is a HPV oncogenic type 
other than 16, the patient will be randomized 1:1 separately into cohort 2.  If the patient is HPV negative, the 
patient will not be randomized into a radiotherapy arm, but instead will be transferred to standard of care 
treatment. 
 
3.1 
Inclusion Criteria 
 
Participants must meet the following criteria to be eligible to participate in the study. Patients may enroll in 
the study if they are p16+ and not yet tested for HPV by PCR and if they meet the other eligibility criteria. 
They will enter the experimental post-Induction portion of the study if the surgical specimens or biopsies are 
proven to be HPV+ on PCR testing: 
 
3.1.1  Participants must have histologically or cytologically confirmed squamous cell carcinoma of the 
oropharynx, unknown primary, or nasopharynx that is  p16 positive as determined by IHC. Tissue 
from the primary site must be available for biomarker studies and for PCR testing. IHC must be 

15 
 
performed in a lab verified by the central laboratory or the sldies must be available for review by the 
central laboratory (Zhang, MSSM) and PCR must be done in the central laboratory prior to 
randomization. See section 13.3 for exception regarding urgency of therapy. HPV16 PCR must be 
performed and results available for randomization after induction. 
3.1.2 
Stage 3 or 4 disease without evidence of distant metastases. 
3.1.3   At least one clinically evaluable or uni- or bi-dimensionally measurable lesion by RECIST 1.1 
criteria. 
3.1.4 
 Age > 18 years. 
3.1.5 
No previous surgery, radiation therapy or chemotherapy for SSCHN (other than biopsy  
or tonsillectomy) is allowed at time of study entry. 
 
3.1.6 
ECOG performance status of 0 or 1.  
 
3.1.7 
No active alcohol addiction (as assessed by medical caregiverand defined as at 
least 6 months without activity). 
• 
 
3.1.8 
Participants must have adequate bone marrow, hepatic and renal functions as defined below: 
 
 
Hematology: 
 
 
Neutrophil count > 1.5 x 109/l. 
 
Platelet count > 100 x 109/l. 
 
Hemoglobin > 10 g/dl. 
 
Renal function: > 60 ml/min (actual or calculated by the Cockcroft-Gault method) as 
follows: 
CrCl (mL/min) =      (140-age) (weight kg) 
                                         72 x serum creatinine (mg/dL) 
 
N.B. For females, use 85% of calculated CrCl value.  
 
Or a Creatinine < the upper limites of normal 
 
 
Women of childbearing potential must have a negative pregnancy test within 7 days 
of starting treatment. 
 
 
Hepatic:     
 
Total Bilirubin  institutional upper level of normal (ULN)  
 
AST or ALT and Alkaline Phosphatase must be within the range allowing 
for eligibility, as in the table below: 

16 
 
                          
 
3.1.9 
Ability to understand and the willingness to sign a written informed consent document. 
3.1.10 Patients with Gilbert’s Disease and absent hepatic pathology by history and clinical 
assessment maybe treated on study with bilirubins > the ULN for the institution if other liver 
function studies are within the nmormal range 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for admission into 
the study. 
3.2.1  Pregnant or breast feeding women, or women and men of childbearing potential not willing to 
use adequate contraception while on treatment and for at least 3 months thereafter. 
3.2.2  Previous or current malignancies at other sites, with the exception of adequately treated in situ 
carcinoma of the cervix, basal or squamous cell carcinoma of the skin, thyroid cancer, or other 
cancer curatively treated by surgery and with no current evidence of disease for at least 5 
years. 
3.2.3  Symptomatic peripheral neuropathy ≥ grade 2 by NCI Common Terminology Criteria (NCI-
CTC) version 4. 
3.2.4  Symptomatic altered hearing > grade 2 by NCI-CTCv4 criteria. 
3.2.5  Other serious illnesses or medical conditions including but not limited to: 
 
 
 
Unstable cardiac disease despite treatment, myocardial infarction within 6 months 
 prior to study entry 
 
History of significant neurologic or psychiatric disorders including dementia or  
 seizures 
 
Active clinically significant uncontrolled infection 
 
Active peptic ulcer disease defined as unhealed or clinically active 
 
Hypercalcemia  
 
Active drug addiction including alcohol, cocaine or intravenous drug use defined as 
 occurring within the 6 months preceding diagnosis 
 
Chronic Obstructive Pulmonary Disease, defined as being associated with a 
 hospitalization for pneumonia or respiratory decompensation within 12 months of 
 diagnosis. This does not include obstruction from tumor 

17 
 
 
Autoimmune disease requiring therapy, prior organ transplant, or HIV infection  
 
Interstitial lung disease 
 
Hepatitis C by history 
3.2.6 
Patients that have experienced an involuntary weight loss of more than 25% of their body weight 
in the 2 months preceding study entry. 
3.2.7 
Concurrent treatment with any other anticancer therapy. 
3.2.8 
Participation in an investigational therapeutic drug trial within 30 days of study entry. 
3.2.9 
Active smoking within the past 20 years with a cumulative Pack Year history of > 20 Pack Years 
or active smoking (Defined as > 1 cigarette per day) within the last 5 years. 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
The inclusion and exclusion criteria do not affect enrollment of women, minorities, or other under-
represented populations. 
 
4.0 
REGISTRATION PROCEDURES  
 
After the patient signs the informed consent the patient will be registered for screening and once the 
investigator has verified that the patient meets all inclusion/exclusion criteria, the patient will be registered 
for and started on therapy. Patients who only have p16 testing and lack HPV PCR may proceed to induction 
however they will not be assigned to an experimental group until HPV PCR is completed and the results are 
available. The verification of patient’s eligibility will be performed centrally after the receipt of the patient 
registration form.  It is mandatory not to exceed 14 days between the date of registration for therapy and the 
start of the study treatment.  p16 testing in a lab verified by the central lab or slides must be available to be 
reviewed by the central laboratory must be confirmed prior to registration for therapy, unless there is an 
urgency of therapy. External sites can utilize their own Pathology Department for p16 testing if they submit 
their standard operating procedures (SOP) for p16 testing to the central lab prior to their first enrollment, 
along with slides and pathological material for 10 test cases for verification (see SOP). In any case, all events 
occurring after the registration must be recorded in the case report form and will be taken into account in the 
analysis, whether the patient received the study treatment or not.  Patient must receive a treatment to be 
included in the intent to treat analysis. 
4.1 
General Guidelines 
 
Institutions will register eligible participants with the Mount Sinai Cancer Clinical Trials Office. 
Registration must occur prior to the initiation of therapy. Any participant not registered to the protocol 
before treatment begins will be considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist. A registration form will be faxed to the CRC prior to the start of therapy. 
  
Following registration, participants may begin protocol treatment. Issues that would cause treatment 
delays should be discussed with the Principal Investigator. If a participant does not receive protocol 
therapy following registration, the participant’s protocol status must be changed. Notify the registrar of 
participant status changes as soon as possible. 
 

18 
 
 
4.2 
Registration Process  
   
The registration procedures are as follows: 
 
1. Obtain written informed consent from the participant prior to the performance of any study related 
procedures or assessments and register consent. 
 
2. Complete the protocol-specific eligibility checklist using the eligibility assessment documented in the 
participant’s medical/research record. To be eligible for registration to the therapeutic study, the 
participant must meet each inclusion and exclusion criteria listed on the eligibility checklist 
including p16, however HPV PCR results need not be necessary. 
 
3. Patients will be re-registered for post-induction treatment assignment as per the protocol design and will 
require final HPV PCR for this. Pathologic and radiologic criteria as outlined in the protocol will 
determine the post-induction arm assignment. 
  
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for the treatment 
study. Registration to both treatment and ancillary studies will not be completed if eligibility 
requirements are not met for all studies. 
  
5.0 
TREATMENT PLAN  
 
Treatment should generally be administered on an outpatient basis. Expected toxicities and potential 
risks as well as dose modifications for Docetaxel, Cisplatin, 5-Fluorouracil, and Carboplatin are described 
in Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). Patients will initially be treated 
with cisplatin during TPF induction therapy, as not carboplatin. Carboplatin will only be substituted for 
cisplatin during TPF if toxicity precludes continuing with cisplatin ans described below. No investigational 
or commercial agents or therapies other than those described below may be administered with the intent to 
treat the participant's malignancy. All therapy and clinical studies are Standard of Care for SCCHN and 
require no special handling. 
 
In the first phase of the study, three cycles of TPF induction chemotherapy will be delivered. TPF 
chemotherapy will be given every 21 days starting on days 1, 22 and 43 (+ 2 days).  All patients, if possible, 
will have a port-a-cath placed prior to initiating chemotherapy so that chemotherapy may be given efficiently 
and completely. Patients who refuse a port or have an infection that necessitates removing the port should be 
treated in the inpatient setting or with a PICC line.  Following the first phase of treatment with induction 
chemotherapy, patients will be re-assessed for response to treatment.  Those who do not respond to treatment 
will not be  randomized to the second phase of treatment.  Rather, they will be treated with more intensive 
chemoradiotherapy in a non-responder treatment arm (treatment and follow up data will still be collected on 
these patients.)  Those who respond with a CR or PR (see section 5.4.4 for PR specific criteria) will be 
continue on the second phase of the trial, which will include randomization to standard or reduced radiation 
dose chemoradiotherapy.  Concurrent chemoradiotherapy with weekly Carboplatin for the experimental and 
standard arms respectively should start 4-6 weeks after day 1, cycle 3 of induction chemotherapy for all 
patients, regardless of their phase two treatment arm. 
 
 
 

19 
 
Induction Chemotherapy Treatment Plan Overview* 
Agent 
Pre-
medications; 
Precautions 
Dose 
Route 
Schedule 
Docetaxel 
Refer to 
Section 5.2.1 
75 mg/m² 
Intravenous infusion 
over 60 minutes, 
mixed in 250 mL 
normal saline 
Day 1, every 
21 days 
( + 2 days) 
Cisplatin 
Refer to 
Section 5.2.2 
100 mg/m² 
Intravenous infusion 
over 60 minutes to 3 
hours, mixed in 1000 
ml of normal saline 
Day 1, every 
21 days  
(+ 2 days) 
5-FU 
Refer to Section 
5.2.4 
750 mg/m2/day 
24-hour continuous 
infusion over 4 days 
Days 1, 2, 3 
and 4 of 
Cycles 1, 2 
and 3, every 
21 days 
( + 2 days) 
Carboplatin  
(as a substitute 
for cisplatin in 
response to 
cisplatin 
toxicity) 
Refer to Section 
5.2.3 
AUC 6, 
calculated by 
the Calvert 
formula 
IV over 
approximately 30 to 
45 minutes, mixed in 
normal saline or D5W 
per pharmacy 
standards 
Day 1, every 
21 days  
( + 2 days) 
 
Chemoradiotherapy Treatment Plan Overview* 
Carboplatin 
Refer to Section 
5.4.3 
AUC 1.5, 
calculated by 
the Calvert 
formula 
IV over 
approximately 30 
minutes, mixed in 
250ml normal saline 
or D5W 
Weekly on 
Monday or 
Tuesday 
anytime, or 
Wednesday 
prior to 
radiation 
*Please refer to section 5.2 Induction Chemotherapy Agent Administration and 5.4 
Chemotherapy Agent Administration for additional agent administration specifications. 
 
 
5.1       Induction Chemotherapy Pre-treatment Criteria 
   
5.1.1 
Cycle 1, Day 1:  All eligibility criteria must be met   
5.1.2 
Subsequent Cycles: 
 
ANC > 1500 mm3 
Platelets > 100,000 mm3 
Bilirubin < institutional ULN 
 
5.2 
 Recommendations for Induction Chemotherapy Agent Administration 

20 
 
 
5.2.1 
Docetaxel 
Dose: 
 
75 mg/m²  
Route:  
Intravenous infusion over 60 minutes, mixed in 250 mL normal saline  
Schedule: 
Day 1, every 21days (+ 2 days) 
Recommended premedication for docetaxel is as follows: dexamethasone 8 mg by mouth  twice daily for 6 
doses, starting the evening before chemotherapy, plus 10 mg PO or IV 30 to 60 minutes before docetaxel (or 
solumedrol 80 mg IV bolus), ranitidine 50 mg IV bolus (or equivalent).  After premeds, Docetaxel 75 mg/m² 
will be mixed in 250 ml of normal saline and infused over 1 hour. 
 
5.2.2 
Cisplatin 
Dose: 
 
100 mg/m² 
Route:  
Intravenous infusion over 60 minutes to 3 hours, mixed in 1000 ml of normal saline 
Schedule: 
Day 1, every 21 days (+ 2 days) 
Day 1  
One liter of normal saline solution containing KCl (20 mEq/L) and MgSO4 (2g/L) will be infused as 
prehydration for cisplatin prior to beginning cisplatin infusion. An oral equivalent dose of KCl may replace 
the KCl contained in the saline solution. 
The antiemetic regimen may be chosen by the treating physician.  In general, the antiemetics should include 
a 5-HT3 antagonist (i.e.  Ondansetron 8-24 mg IV or orally) and fosaprepitant. Additional antiemetics may 
include, but are not limited to, lorazepam and metoclopramide. 
Furosemide 10 mg IV bolus will be given as premedication for cisplatin, then cisplatin 100 mg/m² in 1000 
ml of normal saline will be given over 60 minutes to 3 hours. Mannitol 12.5 g will be mixed in the bag with 
cisplatin, or given immediately after completion of cisplatin. If mannitol is given after cisplatin, mannitol 
may be mixed in one liter of post-cisplatin IV fluids, and the cisplatin may then be mixed with 250 ml of 
normal saline.  One liter of normal saline solution containing KCL (20 mEq/L) and MgSO4 (2g/L) will be 
infused as post-hydration for cisplatin. An oral equivalent dose of KCl may replace the KCl contained in the 
saline solution.  
 
5.2.3 
Carboplatin (as a substitute for cisplatin) 
 
Dose: 
 
AUC 6, calculated by the Calvert formula  
 
Route:  
IV over approximately 30 to 45 minutes, mixed in normal saline or D5W  
Schedule: 
Day 1, every 21 days ( + 2 days) 
 
5.2.4 
5- Fluorouracil 
Dose: 
          750 mg/m2/day 
Route:  
24-hour continuous infusion over 4 days  
Schedule: 
Days 1, 2, 3 and 4 of Cycles 1, 2 and 3 (every 21 days)  ( + 2 days) 
5-FU continuous infusion is for each of days 1-4 and should be delivered as one total infusion. 

21 
 
 
5.2.5 
Days 2-5  
Day 2  Patients receiving cisplatin should receive a minimum of 2 liters of normal saline with or 
without MgSO4 and KCL on Day 2, either in a local clinical area, at home or in their main clinic 
treatment facility, with anti-emetic therapy as necessary. 
 
Days 2, 3, 4, 5 
Patients should be able to tolerate a minimum oral fluid intake ( 2 L oral intake/day) day 3 and after. If 
inadequate oral intake of fluids is observed, the patient should return to a treatment facility for additional IV 
hydration, or receive home hydration as clinically indicated. If the patient is unable to return to the treatment 
facility, they will be instructed to visit a local medical facility for IV hydration. With a disconnection on Day 
5 consider giving at least an additional liter of NS with or without MgSO4 and KCL and antiemetic therapy. 
Patients will be given ciprofloxacin, levoquin or a suitable substitute immediately after the termination of the 
5-FU infusion on day 5, and no later than day 6 through day 15 of each cycle for prophylaxis. 
 
5.3 
Chemoradiotherapy Pre-Treatment Criteria 
5.3.1 
All eligibility criteria must be met 
5.3.2 
Subsequent cycles: 
 
ANC > 1500 mm3 
Platelets > 100,000 mm3 
 
5.4 
Recommendations for Chemoradiotherapy Agent Administration 
 
5.4.1 
Carboplatin 
 
Dose: 
AUC 1.5, calculated by the Calvert formula 
 
Route: 
IV over approximately 30 minutes, mixed in 250ml normal saline or D5W  
 
Schedule: 
Weekly on Monday or Tuesday any time, or Wednesday prior to radiation 
 
Carboplatin will be given at a low dose of AUC 1.5 per TAX 324 study (Posner et al NEJM 2007).   
 
Prehydration: 
Prehydration IV fluids are not required, but once patients develop treatment-induced 
mucositis that affects their comfort when eating and drinking, at least 500 mL of normal saline prehydration 
is recommended weekly. Additional IV fluids may be given anytime at the discretion of the treating 
physician. 
5.4.2 
Other Modality(ies) or Procedures: 
A PEG will not be placed prior to chemoradiotherapy for patients.  
 

22 
 
 
6.0 
ASSESSMENT OF RESPONSE AND ASSIGNMENT OF RADIATION ARM 
 
6.1   
Patients will all have a clinical examination, a PET/CT and a high resolution contrast enhanced 
(when possible)  neck CT or MRI prior to initiating induction therapy and will have these repeated shortly on 
week 9, 10 or after completing their 3rd cycle of induction. After repeat scans following induction, all 
patients determined to have a CR, and eligible patients with a PR (as outlined below), who continue to meet 
eligibility criteria will then be randomized in a 2:1 ratio to the experimental reduced dose or to the control 
standard dose radiation therapy.  Patients with no response, or with progressive disease will receive CRT. 
We recommend standard radiation dosing plus carboplatin (AUC 1.5), Paclitaxel (40 mg/M2) and Erbitux 
(with loading when feasible) weekly for these patients. 
 
 
 
The following guidelines have been developed specifically to identify subjects with a Partial Response:  
 
Partial Response:  If patients do not have a CR to induction, the partial response will need to be further 
assessed to determine subsequent radiation dosing. Clinical response of nodal disease is important and 
informs the overall response assessment. Clinical response will be recorded Slightly different criteria will be 
applied to the primary or nodal site. 
 
Primary Site:   The patient can be considered for randomization and potential reduced radiation dosing if the 
primary site demonstrates significantly decreased FDG avidity, such that the pattern and/or intensity is more 
suggestive of, or at least consistent with, physiologic or inflammatory uptake, as opposed to oncologic 
uptake.  Altered anatomy at the site of the primary after treatment can be present, as the initial tumor mass 
may have destroyed normal tissue, distorted normal contours and eliminated normal tissue planes.  However, 
if the primary site has a residual PET positive mass lesion an EUA should be strongly recommended and 
even if biopsy is negative, careful consideration with agreement by the multi-disciplinary team as to whether 
there is a partial response should  occur and be documented before assignment to randomization. 
Nodal Disease:  If a lymph node was PET avid at presentation and has no, or only minimal uptake after 
induction and the residual node is < 2 cm in maximal diameter, randomization for potential reduced dosing is 
acceptable.  If the residual disease is greater than 2 cm and there is considerable PET avidity consistent with 
tumor present in the lymph node rather than inflammation and post-radiation nodal dissection is not feasible, 
randomization should not occur.  For Nodes > 2 cm which are not PET avid the degree of shrinkage must be 
considered and the possibility of post-radiotherapy neck dissection raised prior to randomization. Special 
cases need to be considered as well: 
 
Cystic Lymph Nodes:  These are frequently seen in HPV positive tumors and have distinct behavior from 
solid nodal metastases.  They may not take up FDG at presentation due to the large component of fluid 
present and they may not demonstrate a size decrease, although ultimately they are almost uniformly  shown 
to negative post-treatment.  Thus, these lymph nodes will not have the same size criteria applied to them as 
for solid nodes and can be randomized for potential reduced doses if there has been a decrease in PET 
avidity even if there has not been a change in their size. 
 
In order for the patient to be considered for randomization, both the primary and the nodal site need to have 
had a response as outlined above. There must be agreement between the surgical, medical and radiation 
oncologists as to the extent of final response prior to movemnegt to the next phase. If either the primary or 
nodes do not achieve an adequate response, standard radiation doses must be used. We recommend standard 
radiation dosing plus carboplatin (AUC 1.5), Paclitaxel (40 mg/M2) and Erbitux (with loading when 

23 
 
feasible) 250 mg/M2 weekly during radiotherapy for these patients. Patient receiving this treatment will be 
followed as a separate cohort. 
 
6.2 
Randomization 
 
Randomization will be accomplished through eRAP by the clinical research coordinator and the registration 
center. Eligibility and HPV status will be reviewed and confirmed by the team. Once the patient has passed 
the eligibility criteria and the eligibility checklist has been sent to central registration, central registration will 
query the eRAP randomization module and obtain a radiation assignment. This will be communicated by 
email and fax to the site Clinical Research Coordinator and by email to the site radiation oncologist of 
record, the treating medical oncologist and the site principal investigator (see Section 20.4 for randomization 
process).  
 
 
7.0   
RECOMMENDATIONS FOR DELIVERY OF RADIATION (XRT)   
 
7.1  
 All patients will receive daily radiation treatment with intensity-modulated radiotherapy 
(IMRT).  Treatment will be given 5 days per week and will not routinely be delivered on Saturday, 
Sunday or major holidays unless a treatment is missed during the week due to technical and/or 
medical reasons.  No more than 5 treatments should be given per week.  Radiotherapy will be 
administered according to the guidelines below: 
 
7.2 Technical Factors 
Photon beams of >4 MV are required.  Intensity Modulated Radiotherapy (IMRT) is 
required for all cases. IMRT via dynamically moving leaves, step-and-shoot with a multileaf 
collimator, Rapid Arc, binary multileaf collimator and tomotherapy are allowed.  Three-
dimensional conformal radiotherapy (3D-CRT) and proton therapy are not allowed. 
 
Immobilization, Simulation, and Localization 
A thermoplastic head mask (or similar immobilization device) is required for IMRT.  Bite 
blocks, dental rolls and other set-up techniques may be used at the discretion of the treating 
radiation oncologist.  A treatment planning CT scan is mandatory for defining target 
volumes.  IV contrast is not required for the treatment planning CT as long as a pre-
induction CT, MRI and/or PET/CT scan with contrast is available and is fused to the 
treatment planning CT.  CT scan thickness should be <0.3 cm.  The treatment planning CT 
scan should be acquired with the patient in the same position and using the same 
immobilization device as for treatment.  Volumes for all structures must be contoured on 
each relevant CT slice.  
 
 
 
Treatment Planning/Target Volumes 
 
Gross Tumor Volume (GTV) 
GTV consists of gross tumor at the primary site and gross nodal disease.  The volumes will 
be defined based on imaging studies (CT, MRI, and/or PET/CT) in conjunction with 
information from clinical examination.  All of the information utilized for target volume 
delineation must be obtained prior to the initiation of induction chemotherapy.  Therefore, it 
is essential that all patients need to be seen by a radiation oncologist prior to enrollment on 
the trial. 
 
As this is an induction trial, in many cases, definition of the “GTV” is not a straightforward 
exercise, since it may have decreased in size or not be visible after IC and prior to initiating 

24 
 
radiation.  The goal is to reconstruct the pre-IC GTV volume on the post induction, pre-
radiation, planning CT scans.  This can be done using the pre-treatment imaging as a guide 
or preferably using image fusion, at the discretion of the treating physician.  It is critical that 
the volume defined for radiation treatment is the initial volume of disease and not only the 
residual found after IC. 
 
Clinical Target Volume (CTV) – Standard Dose Arm 
The clinical target volume (CTV) is generated to account for microscopic disease. The 
CTVs should not include bone (unless involved) or air. There will be two CTVs for the 
Standard Dose Arm. CTV70 will include the primary tumor and involved nodal GTVs with 
a 0.5 cm margin to account for microscopic extension.  The second CTV will be the bilateral 
elective neck, and there are two options for treating this region:   
 
CTV56 can be delineated if the radiation oncologist prefers to utilize a simultaneous 
integrated boost (SIB) IMRT technique which allows for one treatment plan. This 
region would receive 1.6 Gy per fraction x 35 fractions while the CTV70 received 
2.0 Gy per fraction x 35 fractions.   
 
CTV50 can be delineated if the radiation oncologist prefers to utilize a sequential 
boost technique which allows the elective neck to receive a higher dose per fraction. 
The CTV50 will receive 2 Gy per fraction x 25 fractions concurrently with the 
CTV70.  At 50 Gy (25 fractions), a second plan would provide a 20 Gy boost to the 
CTV70 region only (2 Gy x 10 fractions). 
 
Clinical Target Volume (CTV) – Reduced Dose Arm 
There will be two CTVs for the Reduced Dose Arm.  The CTVs should not include bone 
(unless involved) or air.  CTV56 will include the primary tumor and involved nodal GTVs 
with a 0.5 cm margin to account for microscopic extension. CTV50.4 will include the 
bilateral elective neck.  The CTV56 and CTV50.4 will be treated with an SIB technique 
where the CTV56 will receive 2 Gy per fraction x 28 fractions and the CTV50.4 will receive 
1.8 Gy per fraction x 28 fractions. 
 
Planning Target Volume (PTV) 
PTV incorporates a margin that accounts for daily set up variation. The PTV should be a 
0.3-0.5 cm expansion of all CTVs depending on the treating physician’s comfort level. 
Modification of PTV is allowed at the discretion of the treating radiation oncologist for 
sparing of normal tissues, or if it is needed to facilitate the planning process, e.g. if the PTV 
overlaps a critical structure that must be spared. Each CTV will have an individual PTV 
designed for set-up uncertainty. No PTV expansion will be done for the GTV, as these will 
be included within the volume of their respective CTV. 
 
Avoidance Structures 
The following normal tissue structures will be defined.  The dose constraints are listed for 
each structure. 
 
A. Spinal cord: Maximum dose <45 Gy 
B. Expanded spinal cord (5 mm expansion around spinal cord): Maximum dose <50 Gy 
C. Brainstem: Maximum dose <54 Gy 
D. Parotid glands: Mean dose <26 Gy. If this is not possible due to adjacent disease, 
then the volume of one parotid gland receiving 30 Gy or more (V30) should be 
<50%. 
E. Larynx: Mean dose <45 Gy 
F. Mandible:  Maximum dose <70 Gy 

25 
 
G. Oral cavity: Mean dose <40 Gy 
  
 
For cases in which treatment volumes approach the base of skull, the following avoidance 
structures will be added: 
A. Inner ear: Mean dose <30 Gy 
B. Optic nerves: Maximum dose <50 Gy 
C. Optic chiasm: Maximum dose <50 Gy 
D. Expanded optic nerve and chiasm (2 mm expansion around these structures): 
Maximum dose <54 Gy 
E. Retina: Maximum dose <45 Gy 
F. Brain: Maximum dose <60 Gy 
 
 
Target Dose Prescriptions 
To accommodate for tissue heterogeneity, density corrections are required, and will be 
applied to all plans, unless contraindicated, for example, by significant amounts of scatter on 
the planning CT scan.    Patients whose tumors that respond to induction chemotherapy as 
outlined above will be randomized to either standard dose (70 Gy) or reduced dose (56 Gy) 
as follows: 
 
Standard Radiation Dosing  
 
Option 1 via Simultaneous Integrated Boost 
(a) PTV70 will be treated to a total dose of 70 Gy in 2.0 Gy/fraction x 35 fractions. 
(b) PTV56 will be treated to a total dose of 56 Gy in 1.6 Gy/fraction x 35 fractions. 
 
 
Option 2 via Sequential Boost 
(a) PTV70 will be treated to a total dose of 70 Gy in 2.0 Gy/fraction x 35 fractions. 
(b) PTV50 will be treated to a total dose of 50 Gy in 2.0 Gy/fraction x 25 fractions. 
 
Reduced Radiation Dosing (via Simultaneous Integrated Boost) 
(a)  PTV56 will be treated to a total dose of 56 Gy in 2.0 Gy/fraction x 28 fractions. 
(b)  PTV50.4 will be treated to a total dose of 50.4 Gy in 1.8 Gy /fraction x 28 fractions. 
 
PTV coverage 
All plans must be normalized such that 95% of the PTV is covered with the prescription 
dose.  No more than 10% of the PTV may receive > 105 % of the prescription dose.  No 
more than 1cc of the PTV may receive >110% of the prescription dose.  No more than 1% of 
the PTV may receive < 93% of the prescription dose.  No more than 1cc of tissue outside the 
PTV may receive > 110% of the prescription dose.  
 
 
 
 
Note: in any case with a conflict/overlap between target and normal tissue, target dose 
considerations will take priority, with the exception of the spinal cord limits. 
 
Treatment Breaks 
There are no planned treatment breaks on this study; any breaks in planned radiotherapy are 
strongly discouraged. Radiotherapy interruptions will be permitted for unavoidable 
mechanical malfunction or serious illness requiring hospitalization, such as sepsis, delirium, 
severe respiratory compromise or hemodynamic instability, at the discretion of the Principal 
Investigator. Treatment breaks should be as short as possible. The reason for any 
interruption in treatment must be documented in the treatment chart. 

26 
 
 
7.3 Quality Assurance 
 
Initial:  Prior to the first radiation treatment, the standard quality assurance procedures will 
be followed. The monitor units required to deliver the prescribed dose shall be calculated. 
The monitor units generated by the IMRT planning system must be independently checked 
prior to the patient’s first treatment.  Measurements in a quality assurance phantom will be 
done for each patient that will be treated. An ion chamber measurement, to assess absolute 
dose, in addition to a film or matrix measurement will be taken during the QA period.   
 
On the first day of treatment each patient will have electronic portal images taken that 
localize the isocenter placement, which will be approved by a radiation oncologist prior to 
delivery of the first treatment, per standard practice. 
 
Weekly:  Verification portal images will be taken at least twice per week and approved by a 
radiation oncologist prior to continuation of treatment per standard practice.  During 
treatment, patients may lose a significant amount of weight and the RT plan may need to be 
adjusted.  It is at the discretion of the treating radiation oncologist to re-simulate and re-plan 
a patient’s radiation treatment due to significant weight loss, though this is  not mandatory.  
If the patient is re-planned, the PTV coverage and dose constraints for normal tissues, as 
specified above, need to be met for the combined plan. 
 
 
Isodose Distribution  
All plans will have complete documentation in the patient’s chart, including representative 
CT slices with treatment isodoses. A DVH with all PTV and CTV structures and all normal 
tissue structures will be generated for each patient and documented in the patient’s 
radiotherapy chart. 
 
Quality Assurance 
Each treatment plan will be reviewed by at least one non-treating radiation oncologist prior 
to therapy to assure that the appropriate fields and doses will be delivered.  The Radiation 
oncologist will review the plan according to the checklist provided in Appendix x, which 
will be included in the record. 
  
 
8.0 
SURGICAL INTERVENTIONS 
 
8.1 
Determination of Stage 
 
Clinical stage will be based on clinical exam, and office based endoscopic evaluation with flexible 
endoscopy of the upper aerodigestive tract as well as radiographic evaluation with CT and/or MRI  in 
conjunction with  CT/PET. Formal operative endoscopy with biopsy under general anesthesia will be 
performed as indicated when diagnostic or staging dilemma occurs. When the primary tumor is identifiable, 
a preoperative tissue biopsy will be taken and used for histopathological analysis and assignment of HPV 
status. Biopsies performed outside the institution will be internally reviewed by pathology department 
according to protocol guidelines and repeat biopsies will be obtained if there is inadequate tissue for 
analysis. In the case of unknown  primary tumors, a needle biopsy of the metastatic lymph node will be 
performed for these purposes. Final staging will be performed according to standard AJCC TNM criteria.  
 
8.2 
Examination and  EUA/biopsy for Post Induction Response Assessment 
 

27 
 
The treating team (Medical Oncology, Radiation Oncology and Surgical Oncology) will determine whether 
an EUA is required after three cycles of chemotherapy to adequately assess response primary site and 
possible post-radiation neck dissection.  Study subjects may undergo a repeat endoscopy and biopsy to 
determine response, if in question. Both a superficial and a deep biopsy, if possible, will be obtained from 
the primary site to determine tumor status. In partial response patients, biopsies will be directed at the 
visible/palpable mucosal abnormality or submucosal mass. In patients with clear evidence of persistent 
disease at the primary site (By clinical exam and office fiberoptics), a repeat biopsy is not mandatory and is 
at the discretion of the treating team.  Patients with an unknown primary carcinoma should not undergo an 
examination under anesthesia (EUA) after induction chemotherapy unless it is clinically indicated and only 
after discussion with overall PI.  Patients who have had tonsillectomy prior to treatment will not undergo 
EUA or biopsy post induction chemotherapy.  
 
 
  
8.3 
Post-radiation Neck Dissection 
 
At the completion of the radiation  residual cervical disease will be assessed clinically and with CT/PET at 
12-16 weeks after therapy (33). Patients with residual cervical metastases >2cm, or any size in conjunction 
with PET positivity (SUV >3.0) will be treated with planned neck dissection and pathologic evaluation of  
the residual lymph node. PET negative nodes <2cm will be observed and repeat PET/CT will be obtained in 
6 months after completion of therapy to determine complete resolution of disease unless, in the opinion of 
the radiologist there is indication of persistent cancer. PET negative cystic nodes will be followed and a 
repeat scan performed at 6 months.  All patients undergoing salvage neck dissection will also undergo EUA 
and, if indicated,  biopsy of the primary site at the time of the neck dissection. 
 
9.0 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Recommended premedication for docetaxel is as follows: dexamethasone 8 mg by mouth twice daily for 3 
days, starting the night before chemotherapy.  Patients will  automatically receive prophylactic antibiotic 
therapy. 
9.1 
Hydration 
Patients receiving cisplatin should receive a minimum of 2 liters of normal saline with or without MgSO4 on 
Day 2, either in a local clinical area, at home or in their main clinic treatment facility, with anti-emetic 
therapy as necessary.   
Patients should be able to tolerate a minimum oral fluid intake ( 2 L oral intake/day) day 3 of TPF and after. 
If inadequate oral intake of fluids is observed, the patient should return to a treatment facility for additional 
IV hydration, or receive home hydration as clinically indicated. If the patient is unable to return to the 
treatment facility, they will be instructed to visit a local medical facility for IV hydration. 
 
 
 
10.0 
DURATION OF THERAPY 
Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In 
the absence of treatment delays due to adverse events, induction chemotherapy will continue for 3 cycles 
followed by 6 or 7 weeks of chemoradiation or until one of the following criteria applies: 
 
 
Patient withdraws consent 
 
Patient is removed early from protocol therapy at PI’s discretion 

28 
 
 
Patient is found ineligible 
 
Patient completion of  protocol requirements 
 
Unacceptable toxicity 
 
Pregnancy 
 
Adverse Event 
 
Progressive disease/ relapse 
 
Lost to follow-up 
 
Non-Compliance with therapy and protocol procedures 
 
Death 
 
Other 
 
10.1 
Duration of Follow Up  
Participants will be followed with a physical examination every 1-2 months during the first year of 
follow up, every 2-3 months in the second year and every 3-4 months in the third year. Thereafter 
participants will be followed biannually. Routine PET/CT scans should be performed at 12, 24, and 
36  months after therapy  has been completed in the absence of prior progression and then according 
to local practice. Participants will be followed for minimum of 5 years after completion of study 
treatment or until death, whichever occurs first through standard of care treatment after therapy as 
prescribed by the Investigator which can include clinic visits or other follow-up by other means.  
Participants removed from study for unacceptable adverse events will also be followed until resolution or 
stabilization of the adverse event. 
  
10.2 
Criteria for Removal from Study  
Participants will be removed from study when any of the criteria listed in Section 10.0 applies. The reason for 
study removal and the date the participant was removed must be documented in the study-specific case 
report form (CRF). Alternative care options will be discussed with the participant. 
In the event of unusual or life-threatening complications, participating investigators must immediately 
notify the Principal Investigator, Marshall Posner, MD at 212-659-5461. 
 
11.0 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity assessments 
will be done using the CTEP Active Version v.4 of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) which is identified and located on the CTEP website at: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  as incorporated into the eRAP 
Case Report Forms.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate medical 
treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All Severe or unexpected adverse events and selected adverse events (non-severe) experienced by 
participants will be collected from the time of the first dose of study treatment, through the study and until 
the final study visit. Participants continuing to experience toxicity at the off study visit may be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible. 
  
11.1 
Anticipated Toxicities 

29 
 
 
A list of the adverse events and potential risks associated with the agents administered in this study appear 
below and will determine whether dose delays and modifications will be made or whether the event requires 
expedited reporting in addition to routine reporting. 
 
11.1.1 Adverse Event Lists(s) for Docetaxel 
 
When used as single agent, the prominent dose-limiting effects of Docetaxel are neutropenia, 
anaphylactoid type reactions, fluid retention, digestive tract toxicities (nausea, vomiting, oral 
mucositis, and diarrhea) and reversible paresthesias. 
 
11.1.2 Adverse Event List(s) for Cisplatin 
  
The major dose limiting toxicities observed with Cisplatin single agent are nausea and vomiting, 
peripheral neuropathy, nephrotoxicity and ototoxicity. 
 
11.1.3 Adverse Event List(s) for 5-Fluorouracil 
 
The major dose limiting toxicities observed with 5-fluorouracil single agent are mucositis, 
myelosuppression and diarrhea. 
 
 
11.1.4 Adverse Event List(s) for Carboplatin 
 
The major dose limiting toxicities observed with Carboplatin single agent are myelosuppression and renal 
toxicity. 
 
11.2 
Dose Modifications/Delays 
11.2.1   Docetaxel 
Neutropenia and/or Its Complications 
Fever should be graded using the NCI-CTC v.4 grading system. The reported temperature should be 
the oral or equivalent temperature. In case of grade 2 fever [temperature > 38.1°C (100.6°F)] 
concomitant with grade 4 neutropenia (ANC < 0.5 x 109/L), the following approach is 
recommended:  
 
 
Hospital admission except where outpatient care may be indicated 
 
Pre-antibiotic evaluation 
 
Complete Blood Count with differential and blood culture should be performed 
 
Start of an empirical antibiotic therapy 
 
In case of febrile neutropenia [grade 2 fever (temp. > 38.1°C)] with grade 4 neutropenia (ANC 
< 0.5 x 109/L)] requiring I.V. antibiotics, the blood counts must be done every 2 days until 
recovery of ANC > 0.5 x 109/L. This must be documented on the Case Report Form for Febrile 
Neutropenia. 
 

30 
 
Action Taken for Febrile 
Neutropenia or 
Documented Neutropenic 
Infection:Adverse event 
Action to be taken for subsequent cycles 
 
 Febrile neutropenia 
 Documented infection 
1.    The first episode of febrile neutropenia or documented grade 3 
/4 neutropenia with documented infection will result in a 
reduction of docetaxel to 60 mg/m2. 
 
2.    If there is a second episode, the patient will remain on study and 
additionally, the cisplatin dose will be reduced to 75 mg/m² 
 
 
Action Taken 
Following Results 
of Neutrophil 
Counts On  Day 
21:   ANC 
(x109/L) 
 
Action to be taken 
 1.5 
 Treat on time and at full dose 
 
< 1.5 
1. 
Delay 1-7 days and repeat complete blood count on every other day on 
days 21- 28 
2. 
If ANC > 1.5 x 109/L, then proceed with full dose chemotherapy 
3. 
If ANC < 1.5 x 109/L on Day 28, then consider GM-CSF for 7 days 
 
On day 35, perform complete blood count with differential 
 
Proceed with full dose chemotherapy if ANC > 1.5 
4. 
If there is no recovery by day 35, (ANC < 1.5 x 109/L), the patient will 
go off drug therapy 
 
Stomatitis 
 
If stomatitis is present on day 1 of any cycle, treatment should be withheld until 
stomatitis has resolved.   
Thrombocytopenia 
 
Grade 4 thrombocytopenia requires a dose reduction of docetaxel from 75 to 60 
mg/m2.  The drug will be held to resolution for up to 2 weeks and must resolve to 
≥100,000. 
Cutaneous Reactions  
 
Grade 0, 
1 and 2: No change 
 
 
Gra
de 3: Delay until < grade 1 and retreat with a dose reduction of Docetaxel from 75 to 

31 
 
60 mg/m². If no recovery to < grade 1 within 2 weeks delay, patient will go off 
protocol therapy 
 
 
Grade 4: 
The patient will go off all drug therapy 
 
 
Nail 
changes will not motivate dose-modification 
 
Nausea and/or Vomiting 
 
Prop
hylactic antiemetic regimen with 5-HT3 antagonists and aprepitant should be 
administered from the first cycle. In addition, the corticosteroids used during 3 days 
for the prophylaxis of fluid retention should also reduce the incidence and severity of 
emesis.  
 
 
Pati
ents with nausea and vomiting despite these measures may be treated with another 
antiemetic regimen (i.e. high dose metoclopramide) as appropriate. 
Bilirubin and Impaired Liver Function 
 
In the event that bilirubin levels are above institutional ULN on Day 1 of cycles 2 
and/or 3, the cycle will be delayed by a maximum of 2 weeks. If no recovery, the 
patient should be taken off chemotherapy. 
 
 
In the event that AST and/or ALT and/or alkaline phosphatase levels are abnormal in 
the absence of progressive disease, on Day 1 of cycles 2 and/or 3 the following dose 
modifications will apply: 
  
Dose Modifications for Abnormal Liver Function (Docetaxel) 
 
                                              AST or ALT: 
ALK PHOS: 
 ULN 
>1x but 1.5x 
>1.5x but 5x 
>5x ULN 
 ULN 
75 mg/m² 
75 mg/m² 
75 mg/m² 
Hold* 
>1x but  2.5x 
75 mg/m² 
75 mg/m² 
65 mg/m²** 
Hold* 
>2.5x but  5x 
75 mg/m² 
60 mg/m²** 
Hold* 
Hold* 
>5x ULN 
Hold* 
Hold* 
Hold* 
Hold* 
 
*Hold until recovered, maximum 2 weeks, then re-treat at a reduced dose.  “Recovered” is 
defined as meeting the study baseline eligibility criteria. 
 

32 
 
Bilirubin: Docetaxel should not be administered to patients with serum total bilirubin >ULN.  
If serum total bilirubin is > institutional ULN on treatment day, hold Docetaxel until serum 
total bilirubin is  institutional ULN (maximum 2 weeks), then re-treat at a reduced dose.  
 
**Reduced doses of Docetaxel will be at 60mg/m2. After Docetaxel is dose is reduced, there 
will be no re-escalation. There will be only one dose reduction. 
Guidelines for the Management of Other Docetaxel-Specific Toxicities (No Dose Modification 
Required) 
Anaphylactoid Type Reactions, Hypersensitivity Reactions 
 
During the 1st and the 2nd infusions, a careful evaluation of general 
sense of well being and whenever possible blood pressure and heart rate monitoring 
will be performed for at least the first 10 minutes, so that immediate intervention 
would occur in response to symptoms of an untoward reaction.  The frequency of 
monitoring blood pressure and heart rate is per nursing standard. 
 
 
Facilities, care provider and equipment for resuscitation have to be immediately 
available: antihistamine, steroids, and epinephrine. 
 
 
In case anaphylactoid or hypersensitivity reaction occurs, the following will 
apply: 
 
 
Management of Hypersensitivity Reactions 
 
Mild symptoms: 
 
 
Localized cutaneous reaction, such as 
pruritus, flushing, rash. 
 Decrease the rate of infusion until recovery of 
symptoms, stay at bedside.  The time allowed is per  
the physician’s assessment at bedside. 
 Then, complete Docetaxel infusion at the initial 
planned rate. 
 At subsequent cycles use the same pre medication 
guidelines. Section 5.2.1 

33 
 
Moderate symptoms: 
 
 
Any symptom not listed above (mild 
symptoms) or below (severe symptoms), 
such as generalized pruritus, flushing, 
rash, dyspnea, hypotension with systolic 
blood pressure > 80 mmHg 
 Stop Docetaxel infusion. 
 Give i.v. antihistamine and i.v. corticosteroids**  
  After recovery of symptoms; depending on the 
physician’s assessment of the patient, Docetaxel 
infusion should be resumed at a slower rate, then 
increased incrementally to the initial planned rate, 
(e.g. infuse at an 8 hour rate for 5 minutes, then at a 
4-h rate for 5 minutes, then at a 2-h rate for 5 
minutes, then finally, resume at the initial planned 
rate).  The time allowed to hold the drug is per the 
physician’s assessment at bedside. 
 For the next cycle of treatment the rate of infusion 
should be decreased initially and then increased 
back to initial planned rate, (e.g. infuse at an 8 hour 
rate for 5 minutes, then at a 4-h rate for 5 minutes, 
then at a 2-h rate for 5 minutes, and finally, 
administer at the initial planned rate.) For all 
subsequent cycles, antihistamines* and steroids** 
will be given intra-venous one hour before infusion 
in addition to the premedication planned. Section 
5.2.1 
Severe symptoms: 
 
Such as bronchospasm, generalized urticaria, 
hypotension with systolic blood pressure < 80 
mmHg, angioedema 
 
Stop Docetaxel infusion. 
 
Give i.v. antihistamine and steroids**. 
 
Add epinephrine*** or bronchodilators and/or i.v. 
fluids, if indicated. 
 
Once all signs and/or symptoms of hypersensitivity 
reaction disappear, Docetaxel may be reinfused the 
same treatment guidelines outlined under moderate 
symptoms. At the subsequent cycles, Dexamethasone 
will be given at 20 mg orally the evening before 
chemotherapy, the morning of chemotherapy and one 
hour before Docetaxel infusion. 
 
Additionally diphenhydramine (or equivalent) will be 
given at 50 mg intra-venous 1 hour before Docetaxel 
infusion.  
 
If a severe reaction recurs, patient will go off protocol 
chemotherapy. 
NCI-CTC Grade 4 reaction 
 
 
Patient will go off therapy. 
* 
antihistamines: 
 
 
dexchlorpheniramine                            (*) i.v. 5-10 mg 
 
or 
clemastine  
(*) i.v. 2 mg 
 
or 
diphenhydramine  
(*) i.v. 25-50 mg 
 
or 
promethazine  
(*) i.m. 50-100 mg 
 
** corticosteroids:  dexamethasone or equivalent 
(*) i.v. 5-10 mg of dexamethasone 
 
*** epinephrine: administered at a 1:1000 dilution (0.01 mg per kilogram with a maximum dose of  
0.5 mg  subcutaneously repeated every 20 minutes as necessary). 

34 
 
 
Fluid Retention 
 
 
There are no dose reductions for fluid retention. 
 
 
Patients developing new onset edema, progression of existing edema, or another sign 
of fluid retention (e.g. 2 pound weight gain) are to be treated with oral diuretics.  
Regimens found to be effective in the management of fluid retention due to Docetaxel are 
listed below. 
 
 
Triamterene/hydrochlorothiazide one capsule orally once daily up to three times daily. 
 
 
Furosemide 40 mg orally daily if edema progresses despite Triamterene/ 
hydrochlorothiazide therapy.  Potassium supplementation should be given as needed. 
 
 
If after a two-week trial, furosemide 40 mg once orally per day is ineffective, the patient 
may be treated with furosemide 20 mg orally per day plus metolazone 2.5 mg orally per 
day with potassium supplementation as needed. 
 
 
Further therapy should be customized depending upon the clinical situation.  The 
clinical tolerance of the patient, the overall tumor response and the medical judgment of 
the investigator will determine if it is in the patient’s best interest to continue or 
discontinue treatment.  
 
11.2.2 Cisplatin 
 
Peripheral Neuropathy 
 
 
A neurological examination must be performed at least before entry into 
the study and then once every cycle and when the patient goes off chemotherapy. In case 
of symptoms or signs experienced by the patient, more frequent examinations should be 
performed and dose modification will be as follows: 
 
 
Grade 0, 1:  No change 
 
 
Grade > 2: Carboplatin at an AUC of 6 may be substituted for Cisplatin during 
induction TPF 
 
 
Ototoxicity 
 
 
Cisplatin is known to cause high frequency hearing loss.  If grade 1 or 2 hearing loss occurs, the 
risk of additional hearing loss versus the potential benefit of continuing Cisplatin chemotherapy 
should be made.  Grade 3 and 4 hearing loss is an indication to discontinue the drug however 
this decision can be made with the patient and after a formal hearing tests. 
 
 
In cases of grade 
3 or 4 toxicity, or risk decision made for grade 1 or 2 hearing loss, Carboplatin (at dosage 
of AUC 6) may be used to replace Cisplatin in the remaining Induction chemotherapy 
cycles. The dose of Carboplatin AUC 6 will be calculated based on the Calvert formula. 
 

35 
 
Thrombocytopenia 
Dose Modification for Thrombocytopenia 
 
Nadir of last course 
< 100,000 
Dose of Cisplatin 
Platelets (day 1 of each cycle) 
 
<100,000 
>100,000 
> 50,000 
Hold 
Cisplatin = 100% 
< 50,000 (1st occurrence) 
 
Hold 
Cisplatin = 80% 
<50,000 (2nd occurrence) 
Hold 
Cisplatin = 60% 
** Please note that dose reduction percentage is calculated by taking off from the original 
dose and not the previous dose. 
 
Dose Modification of Cisplatin in Kidney Impairment 
Calculated Creatinine 
Clearance (mL/min) 
 
Percent Dose to Give 
 
 60 
100% 
< 60 
0% (withhold treatment for a maximum of 1 weeks and repeat serum 
creatinine weekly after additional hydration), then 
 
If CCl was < 60 mL/min and is now:  
** The percent dose to give 
is:  
 
> 50 but < 60 
80% 
 
 40 but  50 
 Carboplatin should be 
substituted at an AUC of 6 
 
< 40 
 Carboplatin should be 
substituted at an AUC of 6 
**Please note that dose reduction percentage is calculated by taking off from the original 
dose and not the previous dose. 
 
If creatinine clearance recovers, and in the opinion of the treating physician the patient can 
tolerate it, cisplatin should be reinstituted and the dose of Cisplatin for the  last cycle should 
be re-escalated to  100 mg/M2 dose level.  
 
Carboplatin Dose Adjustments (as substitute for Cisplatin in induction Chemotherapy)  
 
Formula to calculate Creatinine Clearance: 
CrCl (mL/min) =     (140-age) (weight kg)_____ 
                               72 x serum creatinine (mg/dL) 
 

36 
 
N.B. For females, use 85% of calculated CrCl value.  
 
Ototoxicity, Nausea and Vomiting 
Cisplatin is the preferred therapy for TPF and chemoradiotherapy, Carboplatin may be 
substituted for Cisplatin if a patient develops grade 3 ototoxicity, or an unacceptable Cisplatin 
associated nausea and vomiting, after receiving 1 or 2 doses of Cisplatin. 
Dose alteration for toxicity is to be based on single worst toxicity. Once Carboplatin dose is 
reduced, there will be no re-escalation. 
 
Hematologic Toxicity 
Absolute Neutrophil Count (Reduce doses only for febrile neutropenia or if ANC is < 
500/mm3 for > 5 days.  ANC must be > 1,500/mm3 and platelet count must be > 
100,000/mm3 on day 1 of each cycle). 
 
 
 
Dose Modification for Hematologic Toxicity 
 
 
Absolute Neutrophil Count (ANC) 
 
Nadir of 
last course 
Dose of Carboplatin 
ANC (day 1 of each cycle) 
<1500 
> 1500 
Febrile neutropenia 
(regardless of duration) 
Hold 
Carboplatin = AUC 4 
< 500 for < 5 days 
Hold 
Carboplatin = AUC 6 
< 500 for > 5 days 
Hold 
Carboplatin = AUC 4 
 
Platelets 
 
 
Nadir of last course 
< 100,000 
Dose of Carboplatin 
Platelets (day 1 of each cycle) 
<100,000 
>100,000 
> 50,000 
Hold 
Carboplatin = AUC 5 
< 50,000 
Hold 
Carboplatin = AUC 4 
 
 
In the event that dose adjustments are needed for both Absolute Neutrophil Count (ANC) 
and platelets, patients are to receive the lower dose. 

37 
 
 
 
Treatment should be delayed for up to 2 weeks until ANC is > 1500/mm3 and the platelet 
count is > 100,000/mm3.  However, if the counts have not recovered in 2 weeks, the 
patient should go off chemotherapy. 
 
 
Dose reductions for reduced ANC are NOT based on a single nadir count.  The ANC 
must remain < 500 for > 5 days before a dose reduction is made.  If the results of the 
scheduled weekly Complete Blood Count documents an ANC of < 500, repeat counts are 
to be obtained every other day until the ANC recovers to a level of > 500. 
 
 
If chemotherapy must be withheld due to hematologic toxicity, Complete Blood Count 
and platelet counts should be obtained weekly until the counts reach the lower limits for 
treatment as outlined. 
 
 
No dose reduction will be made for anemia. 
Neurotoxicity 
 
In the event of neurotoxicity (> grade 3), Carboplatin therapy is discontinued. 
 
Nephrotoxicity 
If, despite adequate rehydration, serum creatinine increases to Formula to calculate Creatinine 
Clearance using real weight: 
 
CrCl (mL/min) =      (140-age) (weight kg)_____ 
                               72 x serum creatinine (mg/dL) 
 
N.B. for females, use 85% of calculated CrCl value.  
 
  
 
Grade 0, 1:  No change 
 
Grade > 2: Carboplatin at an AUC of 6 may be substituted for  Cisplatin 
 
11.2.3 
5- Fluorouracil 
 
Mucositis 
 
In case of grade 3 mucositis lasting more than 96 hours , 5-fluorouracil dose will be 
reduced by 10%.  A mouth rinse, such as Magic Mouthwash (Maalox, Benadryl, and 
Lidocaine) should always be allowed. 
 
 
In case of grade 3 mucositis lasting more than 96 hours as a second occurrence or grade 4 
mucositis, the patient will have 5-fluorouracil reduced a total of  20% from baseline and 
will continue on docetaxel and cisplatin. 
• 
 
 
Other dose adjustments to 5-fluorouracil may be made at the discretion of the local PI 
based on a given patient’s clinical profile to preserve patient safety.  The rationale for 
such decisions are to be clearly documented in the relevant clinic note. 

38 
 
• 
 
Diarrhea 
 
For the first episode of grade 3 diarrhea lasting 3 or more days, reduce dose of 5-FU by 
10%. For the second episode of grade 3 diarrhea lasting 3 or more days, we will reduce 
the dose of docetaxel by an additional 10 %. For the first episode of grade 4 diarrhea, we 
will reduce both 5-FU and Docetaxel by 10%. For the second episode of grade 4 diarrhea, 
we will discontinue cisplatin, 5-FU and Docetaxel and move to standard 
chemoradiotherapy. Anti-diarrheals and other supportive measures, such as IV fluids, 
should be used, as deemed clinically indicated. Octreotide is recommended for severe 
diarrhea. If the patient has a significant diarrhea occurrence again (> 3 loose stools/24 hr), 
the patient should be treated prophylactically in the subsequent cycles with 2 tablets of 
loperamide or atropine atropine/diphenoxylate in addition to 1 or 2 tablets after each 
loose stool. The maximum daily dose of loperamide is 16mg and diphenoxylate is 
20mg/day.  
 
Skin 
 
In case of rash or moist desquamation of grade 3 lasting > 7 days, the dose of 5-
fluorouracil will be reduced by 10 % in the subsequent cycle. For second occurrence of 
grade 3 toxicity or grade 4 skin toxicity, 5-Fu will be discontinued. 
 
Other Guidelines: 
 
Doses will be modified in cases of severe hematological and/or non-  hematological 
toxicities. Dose adjustments are to be made according to the NCI-CTC criteria showing 
the greatest degree of toxicity. Toxicities will be graded using the NCI-CTC criteria 
version 4.0.  
 
 
Cutaneous toxicity can be caused by Docetaxel or 5-fluorouracil.   Palmar and plantar rash 
and scrotal or vulvar dermatitis are examples of 5-fluorouracil toxicity, but plantar and 
palmar rash has also been reported with Docetaxel. Rash with Docetaxel may occur on 
arms, face and thorax and can be associated with pruritus.  The investigator should 
consider the agent causing the rash and modify the appropriate agent accordingly. 
   
 
After dose reduction for toxicity, 5-FU will not be re-escalated. 
 
 
For > grade 3 toxicities, chemotherapy should be held for a maximum of two weeks from 
the planned date of reinfusion until resolution to < grade 1. 
 
If a patient experiences several toxicities and there are conflicting recommendations, you 
must follow the most conservative dose adjustment recommended (dose reduction 
appropriate to the most serious toxicity). 
 
Note that the doses, which have been reduced for toxicity, must not be re-escalated 
(except for nephrotoxicity of Cisplatin). 
 
In case of dose delay >2 weeks, the patient will go off all protocol therapy and will be 
immediately referred to the radiation oncologist or surgical oncologist for treatment 
depending on each situation.  However he/she will remain on study and be evaluated and 
followed for survival accordingly. 

39 
 
11.2.4 
Carboplatin (AUC 1.5) 
 
The carboplatin dose for weekly concurrent chemoradiotherapy is an AUC of 1.5.  Thereafter, the AUC will 
be changed only in case of hematological toxicity.  
 
See the tables below for approach to myelosuppression. 
 
Table: Carboplatin dose modification based on ANC 
ANC 
(x109/L) within 24 hrs 
of therapy 
Action to be taken 
 1.5 
Treat at current dose 
 1.0, < 1.5 
Treat at AUC of 1.0 
< 1.0 
Hold treatment, and resume therapy at AUC of 1.0 at the next weekly 
therapy planned when ANC  1.0. If neutropenia requiring further 
chemotherapy break occurs, carboplatin will be discontinued for the 
remainder of the therapy.  
 
**For febrile neutropenia, instructions for ANC <1.0 will be followed.  In addition, 
prophylactic antibiotics and growth factor support may be administered as clinically 
indicated. 
 
 
Table: Carboplatin dose modification based on platelet count 
Platelet count within 24 hrs of 
therapy 
Action to be taken 
> 100,000 
Treat at current dose 
< 100,000 
Hold treatment, and resume therapy at AUC of 1.0 at the 
next weekly therapy planned when platelets  100,000. 
If thrombocytopenia requiring further chemotherapy 
break occurs, carboplatin will be discontinued for the 
remainder of the therapy.  
 
 
 
Renal toxicity: Serum creatinine will be measured weekly within 24 hours of carboplatin 
dosing.  If the serum creatinine has not changed more than 25% relative to the serum 
creatinine at baseline, the creatinine clearance and carboplatin dose need not to be 
recalculated.  If there is a rise or fall greater than 25% relative to baseline serum 
creatinine values, then the creatinine clearance and carboplatin dose must be recalculated.  
 
12 
DRUG FORMULATION AND ADMINISTRATION  
Drug formulation and administration are in accordance with commercially available product guidelines 
for all agents listed in Section 5.0.  
13 
CORRELATIVE/SPECIAL STUDIES  
 

40 
 
13.1 
Probable Laboratory Correlative Studies 
 
This clinical trial aims to investigate a reduction in radiation intensity in patients with HPVOC. The goals of 
these exploratory translational studies are to understand the tumor biology, immunology, and epidemiology; 
and to develop predictive biomarkers to be examined in a larger prospectively randomized trial. Tissue and 
unstained slides will be stored in the tissue biorepository. Plasma, sera, Whole blood DNA, and cells will be 
stored in the Posner Laboratory.  
 
The following projects may be carried out with specimens from study participants with collaborators:  
 
1. Tumor tissue will be evaluated for the biomarkers (this is a preliminary list which may 
change and expand as new technology and biomarkers become available): HPV copy 
number, c-Met expression, BCL-x, EGFr copy number, EGFr expression and EGFr 
phosphorylation. (Zhang Laboratory) 
2. CTC assessment: The number of circulating tumor cells may be evaluated as a possible 
prognostic indicator. (Investigator TBD) 
3. Cytokine profiling of the patients plasma will be assessed with baseline samples obtained 
prior to therapy (Sikora Lab). 
4. Circulating immune cells will be assessed including MDSC, T regulatory and T cell 
subsets. (Sikora and Posner lab) 
5. The immunologic function and specificity of patient’s T lymphocyte responses to HPV 
epitopes will be studied and targeted epitopes identified (Posner Lab). 
6. Serologic responses to HPV proteins will be investigated in patients over time in response 
to therapy. (Anderson Lab) 
7. Tissue microarrays and IHC will be used to establish differences between primary tumors 
with and without distant spread Zhang, Anderson, and Posner Labs. 
8. Whole blood DNA will be collected for future analysis (Zhang lab).  
 
13.2 
Specific Study Plans 
 
The following studies are given a brief description okf current plans, which may change as technology 
will change and samples will not be accessed until the study is complete uinless approved by the tissue 
committee for pilot analyses. 
 
1) 
T Cell specificity and Function in HPV Oropharynx Cancer 
 
It is possible that preserved or improved immune responses in HPVOC patients may 
protect against distant metastases, second primaries or recurrence or may mediate some 
portion of the responsiveness. We have identified immunogenic HLA-A2-restricted 
peptides derived from HPV16E6 and E7(34) . Here, we will evaluate pre and post therapy 
T cell function towards HPV peptides by ELISPOT in vitro and correlate responses with 
stage, clinical response and tumor control. We hypothesize that cured patients will have a 
more robust response after therapy has completed and we may identify preferred peptide 
epitopes associated with improved survival and/or response. 
 
2) Serologic assessments 
 
We have developed a novel multiplex antibody assay using the Luminex system that 
allows us to establish the titers of complex and seemingly heterogeneous antibody 
responses to the full genome of HPV16. Using this system we will monitor the antibody 
response of the HPVOC prior to, and 6 months after therapy has completed  and then at 6 

41 
 
month intervals for 2 years to determine if response are maintained, can predict tumor 
control, and can establish patterns that might be useful in predicting the development of 
cancers. 
 
3) 
Tissue microarrays 
 
There will be distinct differences between primary tumors and metastatic, nodal and 
persistent disease in patients. We will use TMA to evaluate biomarkers and tumor 
differences that can be used to predict metastatic behavior and response. While tumor 
control is frequently a process related to tumor volume, those cells that can metastasize 
may have a distinct signature that can point to a pathway that can be exploited for better 
anti-tumor therapy, could be identified in small numbers of tumor cells, might be present 
in CTC, etc. This is exploratory study data set. 
 
 
 
 
13.3 
Blood and Tissue Collection and Preparation  
 
Blood will be collected to measure plasma and serum factors such as antibodies, cytokines, DNA, 
etc and cells for immune studies and germ line DNA. The target amount to be collected from each 
subject will be less than 200 mls of whole blood (46 ml at baseline; 36 ml at 12, 24 and 36 months 
post-CRT; 6 ml at post-induction and 3, 6, 9 and 18 months post-CRT).  Blood will be collected in 
10ml green top tubes (only at MSSM), 6ml red top tubes and  10 ml EDTA Tubes (EDTA only 
collected at baseline).   Processing and labeling of the blood will be done according to the “Blood 
Handling” section outlined below.  Lag time between collection and the start of processing will be as 
brief a spossible, preferably not overnight and this time will be recorded for each sample.  
Components will be stored from these tubes including plasma and buffy coat.  If collected and 
handled properly, each of the tubes should yield approximately 3mls of plasma, buffly coat and 
PBMCs.  Plasma will be maintained as 1ml aliquots and frozen and stored at –80C and buffy coat 
will be stored from green tubes, at local institutional temperature guidelines.  A portion of each of 
these samples will be stored at the biospecimen repository, and a portion maintained at this facility, 
until exhausted.  Samples will be labeled a code linked to the patient case report form. All patients 
will have tumor testing for HPV16 and p16 in a central laboratory as part of their screening. Slides 
and microarrays from tumor tissues will be labeled similarly as blood samples above.  
 

42 
 
Blood Handling 
 
Blood collection will be performed before surgery (if necessary) and in the absence of any systemic 
anesthesia. Blood will be obtained at each visit, according to the table below: 
 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
  
Baseline 
Post 
Induction 
pre XRT 
3 Mo 
Post 
CRT 
6 Mo 
Post 
CRT 
9 Mo 
Post 
CRT 
12 
Mo 
Post 
CRT 
18 Mo 
Post 
CRT 
24 Mo 
Post 
CRT 
36 Mo 
Post 
CRT 
Window 
Period 
n/a 
n/a 
+ 1 
month 
+ 1 
month 
+ 1 
month 
+ 1 
month 
+ 2 
months 
+ 2 
months 
+ 2 
months 
*Green 
Top 
30 ml 
n/a 
n/a 
n/a 
n/a 
30 ml 
n/a 
30 ml 
30 ml 
Red Top 
6 ml 
6 ml 
6 ml 
6 ml 
6 ml 
6 ml 
6 ml 
6 ml 
6 ml 
EDTA 
lavender 
10 ml 
n/a 
n/a 
n/a 
n/a 
n/a 
n/a 
n/a 
n/a 
KEY:  
  
*Green Top: 10 ml tube; collected ONLY at MSSM 
 
Red Top: 6 ml tube; to be processed, frozen at each site and batch shipment on dry ice 
 
EDTA: 10 ml tube to be shipped at ambient temperature by next day priority mail 
 
n/a: not applicable 
 
 
Viable lymphocytes will be processed from green top tubes using standard ficoll-hypaque density 
gradient separation.  Buffy coat layers will be stored as viable cells in DMSO-containing media at  
-80C to -170C.  
 
Blood for plasma will be spun within 5 hours of collection.  Blood tubes will be spun at 3000 x g for 
10’ at 4C and the plasma and buffy coat removed by pipetting.  Plasma will be stored in 1ml 
aliquots.  All samples will be stored at -80C.  White blood cell fraction will be stored in a single 
tube at local institutional temperature guidelines and kept locally.  
 
Blood for whole blood DNA extraction will be delivered to the Zhang Laboratory for processing. 
 
Tissue Collection 
 
All patients will have their tumors tested for HPV and p16 in the central laboratory of David Zhang, 
MD or by a laboratory verified by the central lab, respectively. p16 test slides from other outside 
laboratories must be avaialable for review and may be reviewed post registration if there is an 
urgency og therapy. If the external site is relying on the central lab to conduct p16 testing, paraffin 
embedded and formalin fixed blocks from the original and subsequent biopsy specimens will be sent 

43 
 
to Dr. Zhang’s laboratory and will be cut in his laboratory for PCR testing and IHC. If the external 
site is conducting p16 testing using its own Pathology Department, the site must submit their 
standard operating procedures to the central lab before their first enrollment, along with the slides 
and archived pathological material for 10 test cases for verification purposes.  p16 testing can only 
be done at the external site if the central lab has cleared it.  In the event that there is an urgency to 
initiate therapy, and there is a delay in receiving requested pathological material from an outside 
laboratory, results from p16 testing done at the outside laboratory can be used for screening the 
study candidate.  However, the Overall PI must be informed of this exception and subsequently 
provided with a copy of the p16 testing repeated at the laboratory verified by the central lab.  If there 
is a discrepancy in the results of the outside laboratory and the laboratory verified by the central lab, 
the Overall PI will advise on how to address and document the difference.  HPV testing must be 
done by the central lab of David Zhang.  The primary untreated tumor will be tested for p16 prior to 
the start of induction chemotherapy and for HPV 16 prior to the start of chemoradiotherapy.  
 
The p16 slides will be sent for review by the central lab. Additional slides, from 5-20, and tissue 
microarrays will be cut from the blocks and stored in Dr. Michael Donovan’s Biorepository before 
they are returned to the site. Any additional biopsies from the primary tumor or a recurrence will be 
obtained and handled in the same fashion. 
 
Specimen Management Committee 
 
A Specimen Management team will decide priority and allocation of samples not included in the 
original plan. The team will consist of the Overall study PI, and the Site PIs and Chairmen of the 
Pathology, Radiation Oncology, ENT, and Medical Oncology for the study and for the teams at each 
site, and Dr. Karen Anderson. Proposals will be reviewed and upon a majority agreement, samples 
will be allocated for each study. A quorum for decisions would include at least one member from 
each site and one of the Study chairmen of Radiation Oncology, ENT. Pathology, and Medical 
Oncology.  
 
 
 

44 
 
 
14 
STUDY CALENDAR (History, Exam and Lab) 
                                                 
*Many of these tests and procedures are likely to be part of regular cancer care. If some of these tests or procedures 
were done recently, they may or may not have to be repeated. 
1 Evaluations after chemotherapy 
2 Ht, Wt, Performance status, neurologic examination, vital signs (heart/blood pressure/temperature). Height is only 
required at baseline. 
3 CBC with differential:  WBC, neutrophils and platelets count, hemoglobin 
4 Alkaline phosphatase, AST (SGOT), ALT (SGPT), bilirubin, creatinine clearance, electrolytes, calcium, protein, 
albumin, magnesium, urinalysis (dipstick) 
 
Pre-Study* 
Induction Chemotherapy 
Chemo/RT 
Reassessment1 
(Week 8-10) 
Post-Study 
Follow-up 
Informed Consent 
To be obtained 
before enrollment 
 
 
 
 
Tissue - HPV 
Status and p16 by 
Central 
Labortaory 
P16 done prior to 
Induction; HPV16  
prior to CRT 
 
 
 
 
Medical History 
Within 10 days 
before 
registration 
Every 3 weeks  
(Day 1 of each cycle before 
treatment) 
Weekly 
 
1-2 months and 
3-4 months 
post-CRT 
Smoking History 
Within 10 days 
before 
registration 
 
 
 
 
Concurrent meds 
At Screening 
Every 3 weeks (Day 1 of each 
cycle before treatment) 
Weekly 
 
 
Physical Exam2 
Within 10 days 
before 
registration 
Every 3 weeks  
(Day 1 of each cycle before 
treatment) 
Weekly 
X 
 
1-2 months in 
first year, 2-3 
months in second 
year , 3-4 months 
in third year and 
every 6 months 
through year 5. 
 
 
Hematology3 
Within 10 days before 
registration 
Day 1 of each dose (before 
treatment) and during Week 2 
of cycle 
Weekly 
 
1-2 months and 
3-4 months 
post-CRT  
Urinalysis  
Within 10 days before 
registration 
 
 
 
 
Serum chemistry4 
Within 10 days 
before 
registration 
Day 1 and 5 of each 
treatment cycle  
(Day 1 of each dose before 
treatment ) 
Weekly 
 
1-2 months and 
3-4 months 
post-CRT  

45 
 
STUDY CALENDAR (Tumor Assessment) 
 
MDADI-HN 
(Dysphagia 
Assessment 
Questionnaire) 
Within 10 days 
before 
registration 
 
 
X 
3, 6, 12,  24, 60 
and 120 months 
Electrocardiogram 
Within 28 days before 
registration 
 
 
 
 
Adverse Event 
evaluation 
 
Every 3 weeks  
(Day 1 of each 
cycle before 
treatment) 
Weekly 
 
At every study 
visit until 
resolved or stable 
B-HC (for WOCP) 
Within 7 days before 
registration 
 
 
 
 
Tumor Assessment 
 
Pre-Study 
Induction 
Chemotherapy 
Chemo/RT 
Reassessment 
(Week 8-10) 
Post-Study 
Follow-up 
Physical tumor 
Examination 
Within 10 days 
registration 
Prior to every cycle 
 
X 
 
TNM Staging  
Within 10 days 
before registration 
 
 
 
 
Nasopharyngoscopy/ 
Laryngoscopy 
 
At end of 
Cycle 2, if 
clinically 
indicated; 
Mandatory at 
end of cycle 
3 (if no 
EUA)  
 
X 
 
Examination under 
anesthesia (EUA) 
Within 8 weeks 
before registration if 
possible. (Does not 
need to be repeated 
if time period 
exceeds 8 weeks) 
May be done if 
investigator deems it 
necessary 
 
 
 
PET/CT  and 
CT/MRI of the neck 
(base of skull 
clavicles) 
A PET/CT and 
CT/MRI of the neck; 
or only a PET/CT 
(Within 28 days 
before registration) 
At Week 9, 
10, or 
completion 
of Cycle 3 
 
A PET CT and High 
resolution CT scan or 
MRI should be 
performed at 12-16 
weeks to assess 
complete response 
 
 
12, 24 and 36 
months (only 
PET/CT) 
 

46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING/PRE-STUDY/BASELINE – Prior to start of Induction Chemotherapy   
Note: All standard of care procedures done prior to consent during the window period are valid. 
 
 
Signed informed consent form 
 
Eligibility (Inclusion/Exclusion) Checklist 
 
Medical history (within 10 days before registration) 
• 
TNM staging (within 10 days before registration) 
• 
Smoking history and questionnaire (within 10 days before registration) 
• 
Questionnaires (within 10 days before registration): 
o EORTC QLQ-C30  
o EORTC QLQ H&N35  
o MDASI-HN  
o MDADI-HN (Dysphagia) 
o Xersotomia  
• 
Physical examination, including height, weight, and vital signs (within 10 days before registration), 
• 
Neurological examination (within 10 days before registration) 
• 
ECOG Performance Status (within 10 days before registration) 
• 
Electrocardiogram (ECG) (within 28 days before registration) 
 
Tumor assessment  
 
Adverse Events 
 
Concomitant medications 
CORRELATIVE STUDIES CALENDAR (See Section 16.0 for QOL) 
 
Pre-Study 
Induction 
Chemotherapy 
Chemo/RT 
Reassessment 
(Week 8-10) 
Post-Study 
Follow-up 
Tissue Microarray 
X 
 
 
 
 
CTC’s  (cell Save 
tube) 
X 
 
 
 
 
T Cell Specificity 
and Function 
Whole Bood DNA 
4-5 large green top 
tubes, 1 EDTA 
X 
 
 
X 
 
3, 12, and 24, 
36  months 
Serologic 
Assessments 
(1 Green  Top) 
X 
 
 
X 
3, 6, 9, 12, 18, 
and 24, 36 
months 
Swallowing 
Function 
 
 
 
 
6, 12, 24,  and 
36 months 

47 
 
 
Examination under anesthesia (EUA) and biopsy (within 8 weeks before registration, if possible; 
does not need to be repeated if time period exceeds 8 weeks)  
 
HPV and p16 tests by central lab or by a lab verified by the central lab, respectively – Pathological 
material is required for both tests.  However, only p16 results are required for entry into the study.  
HPV 16 results are not required until randomization. 
 
Urinalysis (dipstick) 
 
Blood tests – Hematology, Chemistry, and Research labs (within 10 days before registration) 
 
Pregnancy test, if applicable (within 7 days before registration) 
 
PET/CT and CT/MRI of the neck; or PET/CT alone (within 28 days before registration) 
 
 
INDUCTION CHEMOTHERAPY (PHASE I) – Day 1 of Each Cycle (+ 2 days) 
 
 
Medical history 
 
Physical examination, including weight, and vital signs  
• 
Neurological examination 
• 
Physical tumor examination 
• 
ECOG Performance Status  
• 
Blood tests - Hematology Chemistry. Hematology will also be performed during week 2.  Chemistry 
will also be performed on Day 5 of each cycle.  
• 
Examination under Anesthesia (EUA) – done at the discretion of the Investigator 
• 
Nasopharyngoscopy/Laryngoscopy at end of Cycle 2 (at discretion of Investigator) - if there was no 
EUA done.  
• 
Concomitant medications 
• 
Adverse events 
• 
Questionnaires – does not need to be repeated if done during Screening  
o EORTC QLQ-C30 
o EORTC QLQ H&N35 
o MDASI-HN 
o MDADI-HN (Dysphagia) 
o  Xerostomia 
• 
Induction Chemotherapy (~ 7-hr infusion) 
 
 
POST-INDUCTION (REASSESSMENT EVALUATION) – After 3 cycles but prior to CRT 
 
 
Randomization Eligibility (Inclusion/Exclusion) Checklist 
 
Blood tests – Only research labs 
 
HPV16 results by central lab 
 
PET/CT and CT/MRI of the neck (end of Cycle 3) 
 
EUA (at Investigator’s discretion) 
 
Nasopharyngoscopy/Laryngoscopy (if no EUA was done) 
 
Repeat endoscopy and biopsy (if clinically indicated) 
 
 
CHEMORADIATION THERAPY (CRT) (PHASE 2) – Weekly  
 
 
Medical History 
 
Physical examination, including weight, and vital signs   

48 
 
• 
Neurological examination 
• 
ECOG Performance Status  
• 
Concomitant medications 
• 
Blood Tests - Hematology Chemistry 
• 
Questionnaires (Bi-weekly on even weeks):  
o EORTC QLQ-C30 
o EORTC QLQ H&N35 
o MDASI-HN 
o MDADI-HN (Dysphagia) – done weekly 
o  Xerostomia – done weekly 
• 
Adverse events 
• 
Chemotherapy (once per week) 
• 
Radiotherapy (5 times per week) 
 
 
POST-CHEMORADIATION (REASSESSMENT EVALUATION) - 8-10 weeks post-CRT 
   
• 
Physical examination, including weight, and vital signs   
• 
Neurological examination 
• 
Physical tumor examination 
• 
ECOG Performance Status  
• 
Nasopharyngoscopy, if clinically indicated. 
 
PET/CT and CT/MRI of the neck – done at 12-16 weeks. 
 
 
FOLLOW-UP PERIOD: 
 
Visits will occur 1-2 months for first year, every 2-3 months for second year and then yearly for 5 yearsafter 
completion of study treatment.  Refer to grid above for the specific time points. 
 
 
Medical History 
 
Physical examination, including weight, and vital signs   
• 
Neurological examination 
• 
ECOG Performance Status  
• 
Blood Tests – Hematology, Chemistry, TSH (Q 6 months as SOC), and Research 
• 
PET/CT  
• 
Questionnaires:  
o EORTC QLQ-C30 
o EORTC QLQ H&N35 
o MDASI-HN 
o MDADI-HN (Dysphagia) 
o  Xerostomia 
• 
Adverse events 
• 
Record of relapse progression, new treatments, and new primary 
• 
Survival status 
 
15.0 
MEASUREMENT OF EFFECT 
15.1 
Antitumor Effect–Solid Tumors 

49 
 
 
Response will be reported after three cycles of induction for primary site and for neck disease (day 21-35). 
Clinical assessment, pathological assessment (primary site biopsy) and radiographic assessment will be used 
to report response to treatment. 
 
Radiologic Response Assessment 
Radiographic response will be assessed by objective response defined by Response Evaluation Criteria in 
Solid tumors (RECIST 1.1). However, the response criteria to determine eligibility for reduced 
radiation will be followed according to guidelines outlined in section 5.0. 
 
Sites of malignant disease must be documented at baseline evaluation and recorded in the source documents 
and in the patient's Case Report Form. Tumor assessments will be performed according to RECIST 1.1 
criteria (http://www3.cancer.gov/dip/RECIST.htm).Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. 
15.1.1 Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study treatment will be evaluable 
for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants 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 participants will have their response classified according to 
the definitions stated below. (Note: Participants who exhibit objective disease progression or die prior 
to the end of cycle 1 will also be considered evaluable.) 
Evaluable for Primary Outcome: Only patients who are randomized and have received one dose of  
radiation and chemotherapy  will be eligible for assessment of the  primary outcome (LRC, PFS). All 
patients who have started chemotherapy will be analyzed on an ITT for LRC,  PFS,  and survival. 
15.1.2 Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) lesion that can be 
accurately measured in at least one dimension with longest diameter  >20 millimeters (mm) using 
conventional techniques (CT, MR1, x-ray) or  >10 mm with spiral CT scan. Measurable lesions must be 
at least 2 times the slice thickness in mm. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
Target lesions. All measurable lesions up to a maximum of 5 lesions per organ and 10 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) and 
their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of 
the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. 
The baseline sum LD will be used as the reference by which to characterize the objective tumor response. 
15.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or digital 
measurement tool. All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 

50 
 
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 when both methods have been used to assess the anti-tumor effect of a treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. 
This applies to tumors of the chest, abdomen, and pelvis. Head and neck tumors and those of extremities 
usually require specific protocols. 
Ultrasound (US). When the primary endpoint of the study is objective response evaluation, US should 
not be used to measure tumor lesions. It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules. US might also be useful to 
confirm the complete disappearance of superficial lesions usually assessed by clinical examination. 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should follow the NCI 
Guidelines for using FDG PET as an indicator of therapeutic response. Patients should avoid strenuous 
exercise and be on a low carbohydrate diet for 24 hours prior to the scan. Patients should fast for 4 hours or 
longer prior to the FDG injection and should have a serum glucose of less than 200 mg/dL at the time of 
FDG injection. A 10-20 mCi dose of FDG should be injected for typical adult patients. For longitudinal 
studies with multiple scans, particular attention should be paid to ensure consistent patient preparation and 
acquisition parameters between the follow-up scan and the baseline scan. When designing a study where 
PET scans are going to be utilized as one of the modalities to evaluate efficacy, it is important to consult 
with physicians in nuclear medicine in designing the appropriate criteria to be utilized. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation has not yet 
been fully and widely validated. Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers. Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation purposes in reference centers. 
However, such techniques may be useful to confirm complete pathological response when biopsies are 
obtained. 
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 subject to be considered in complete 
clinical response. Specific additional criteria for standardized usage of prostate-specific antigen (PSA) 
and CA-125 response in support of clinical trials are being developed. 
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. 

51 
 
15.1.4  Response Criteria  
15.1.4.1 Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions. 
Partial Response (PR):  At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD. 
Progressive Disease (PD):  At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started or the appearance of 
one or more new lesions  (new lesions must be > slice thickness). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started. 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or unevaluable 
data. In this case, a concise explanation must be given. 
Note: If tumor response data is missing, an overall assessment cannot be done. However, if there is 
missing or unevaluable data for non-target lesions, but data is available for all target lesions, the 
overall response for that time point will be assigned based on the sum LD of all target lesions. 
Additionally, the assessment of CR cannot be made if there is missing or unevaluable data for non-
target lesions. In this case, the overall assessment would be PR. 
15.1.4.2  Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesions and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions* (new lesions must be > slice 
thickness) and/or unequivocal progression of existing non-target lesions. 
Unknown (UN): Assessment of non-target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
 
Note: Although a clear progression of "non-target" lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed at a later time by review of the Principal Investigator (or Protocol Chair). 
Additionally, the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment is mandatory to differentiate between stable or progressive disease. 

52 
 
15.1.4.3 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 participant'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 for 
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 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Note:   Participants 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. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target 
Lesions 
New 
Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Not evaluated 

53 
 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Non-CR/non-PD is preferred over stable disease for non-target disease since SD is 
increasingly used an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised.  
15.1.5 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 recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded since the 
treatment started. 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent 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. 
15.1.6 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time of objective 
disease progression or death.  
15.2 
Other Response Parameters 
 
Pathologic Response Assessment  
An exam under anesthesia (EUA) is sometimes needed to confirm pathological response of the primary site 
after completion of chemotherapy (cycle 3, day 21-35) in responders (complete response and partial 
response). In addition, follow-up endoscopic examination of any concerned sites other than the primary 
should also be performed, but repeat routine multiple endoscopies, per se, are not mandatory. The treating 
team (Medical oncology, Radiation oncology and Surgical Oncologist) will determine whether an EUA is 
required after three cycles of chemotherapy to adequately assess response. Both a superficial and a deep 
biopsy, if possible, can be taken from a primary site area known to have been biopsy-positive previously, 
preferably by the same surgeon.  If uncertain, 2 to 3 biopsies from the most accessible geometrical center of 
the primary site region should be performed.  In partial response patients, biopsies will be directed at the 
visible/palpable mucosal abnormality or submucosal mass. In patients with clear evidence of persistent 
disease at the primary site (By clinical exam and office fiberoptics), a repeat biopsy is not mandatory and is 
at the discretion of the treating team.  Patients with an unknown primary carcinoma should not undergo an 
examination under anesthesia (EUA) after induction chemotherapy unless it is clinically indicated and only 
after discussion with overall PI.  Patients who have had  tonsillectomy prior to treatment do not need to have 
an EUA with biopsy.  
 
Clinical Response Assessment 
This is typically and routinely done in the clinic with the use of direct visualization, fiber optic examination 
and manual palpation.  

54 
 
 
16.0 
ASSESSMENT OF QUALITY OF LIFE AND PATIENT REPORTED SYMPTOMS 
 
Head and neck cancer often arises in cosmetically or functionally important areas. Thus, the ability to eat, 
speak, and breathe easily, as well as the patient’s overall sense of comfort are frequently affected by these 
patients. In addition to these disease-specific symptoms, patients with head and neck cancer may also 
experience symptoms related to surgery (e.g. disfigurement) or to radiation therapy (e.g., dysphagia, 
xerostomia, and mucositis). These may lead to feeling of general overall sickness and can potentially result 
in social isolation. Patient-reported symptoms tend to be more severe than those recorded by physicians, 
patient reported outcome instruments are increasingly being used to measure symptom burden, functionality 
and quality of life. It can provide more comprehensive and improved toxicity data. Quality of life (QOL) 
assessment is a multi-dimensional construct that involves an individual’s subjective assessment of the impact 
of an illness or treatment on his/her physical, psychological, social, and somatic functioning and general 
well-being. The European Organization for Research and Treatment of Cancer Core measure (EORTC QLQ-
C30) is a well validated cancer-specific QOL scale that is used as a generic measurement for patients with 
cancer that in head and neck patients is used in conjunction with the site specific measurement tool EORTC 
QLQ H&N35. The M.D. Anderson Symptom Inventory-Head and Neck (MDASI-HN) module is a validated 
instrument that provides a brief measure of the symptom distress experienced by the head and neck cancer 
patients as a result of their disease and/or treatment. This symptom burden instrument was closely associated 
with the severity of radiation-induced mucositis. The MDA Xerostomia and MDADI-HN (dysphagia) 
questionnaires are radiotherapy/head and neck cancer directed questions which have a robust, validated 
assessment the specific concerns of swallowing and salivary function in head and neck cancer treated 
patients.   
 
In this study, patients will complete the EORTC QLQ-C30, EORTC QLQ H&N35, MDASI-HN, the 
MDADI-HN (dysphagia) and xerostomia questionnaires prior to therapy and then at 3, 6, 12,  24, 60 and 120  
months thereafter or in conjunction with the visits in the Follow-Up Period. During the concomitant chemo-
radiation phase of treatment, all of the above questionnaires will be assessed bi-weekly. As shown in the 
statistical plan we will use these assessments in conjunction with adverse events assessments to compare the 
experiment and control arms of this study. 
 
 
 
Pre-Study 
Induction Chemotherapy 
Chemo/RT 
Post-Study 
Follow-up 
Informed Consent 
To be obtained 
before enrollment 
 
 
 
EORTC QLQ-
C30, EORTC 
QLQ H&N35 
Within 10 days 
before 
registration,  
Or on C1D1 
before 
treatment  
Every 3 weeks  
(Day 1 of  cycles 2 
& 3 before 
treatment) 
Weeks 
2,4,6,8 
3, 6, 12,  24, 60 
and 120 
months, or in 
conjunction 
with Folllow-
up Period 
MDASI-HN 
Within 10 days 
before 
registration,  
Or on C1D1 
before 
treatment 
 
Every 3 weeks  
(Day 1 of  cycles 2 
& 3 before 
treatment) 
Weeks 
2,4,6,8 
3, 6, 12,  24, 60 
and 120 
months, or in 
conjunction 
with Folllow-
up Period 

55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
17.1 
Definitions 
17.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that develops or 
worsens in severity after starting the first dose of study treatment or any procedure specified in the protocol, 
even if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests.  
17.1.2 Serious Adverse Event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that:  
 
 
Results in death. 
 
Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have 
caused death had it occurred in a more severe form. 
 
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before the person was enrolled in the 
trial, provided that it did not deteriorate in an unexpected manner during the trial (e.g., surgery 
performed earlier than planned). 
 
Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions. 
 
Is a congenital anomaly or birth defect; or 
 
Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such medical events include allergic bronchospasm requiring intensive 
MDADI-HN 
(Dysphagia 
Assessment 
Questionnaire) 
Within 10 days 
before 
registration,  
Or on C1D1 
before 
treatment 
Every 3 weeks  
(Day 1 of  cycles 2 
& 3 before 
treatment) 
Weekly 
3, 6, 12,  24, 60 
and 120 
months, or in 
conjunction 
with Folllow-
up Period 
Xerostomia 
Within 10 days 
before 
registration,  
Or on C1D1 
before 
treatment 
Every 3 weeks  
(Day 1 of  cycles 2 
& 3 before 
treatment) 
Weekly 
3, 6, 12,  24, 60 
and 120 
months, or in 
conjunction 
with Folllow-
up Period 
Adverse Event 
evaluation 
 
Every 3 weeks  
(Day 1 of each 
cycle before 
treatment) 
Weekly 
At every study 
visit until 
resolved or stable 

56 
 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
 
 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures. 
 
Elective or pre-planned treatment for a pre-existing condition that did not worsen. 
 
Emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission. 
 
Respite care. 
 
17.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
17.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered expected 
when it appears in the current adverse event list, the Investigator’s Brochure, the package insert or 
is included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study agent(s). 
17.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, the Investigator’s 
Brochure, the package insert or when it is not included in the informed consent document as a 
potential risk.   
17.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the study treatment. 
Attribution will be assigned as follows: 
 
 
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. 
17.2 
Procedures for AE and SAE Recording and Reporting 
 
Reporting: Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 

57 
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly observed, or 
detected by physical examination, laboratory test or other means, will be recorded in the participant’s 
medical record and on the appropriate study-specific case report forms.  
 
The descriptions and grading scales found in the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. The CTEP Active Version of the 
CTCAE is identified and located on the CTEP website at:  
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
All appropriate treatment areas should have access to a copy of the CTEP Active Version of CTCAE. 
17.3 
Reporting Requirements 
 
Each participating investigator is required to abide by the reporting requirements set by the MSSM. The 
study must be conducted in compliance with FDA regulations, local safety reporting requirements, and 
reporting requirements of the principal investigator.  
 
Each investigator will be responsible to report SAEs that occur at that institution to their respective IRB. It is 
the responsibility of each participating investigator to report serious adverse events to the study sponsor 
and/or others as described below.  
17.4 
Reporting to the Study Center 
17.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, during treatment, or within 30 
days of the last dose of treatment must be reported to the MSSM Overall Principal Investigator on the local 
institutional SAE form for the local IRB and electronically on the eRAP CRF. This includes events meeting 
the criteria outlined in Section 11.1.2, as well as the following: 
 
 
Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at least possibly 
related/associated with the intervention. 
 
 
All Grade 4 (life-threatening or disabling) events that are unexpected or not specifically listed in the 
protocol as not requiring reporting. 
 
 
All Grade 5 (fatal) events while the participant is enrolled and actively participating in the trial OR when 
the event occurs within 30 days of the last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time of continuing review.  
 
Participating investigators must report each serious adverse event to the MSSM Overall Principal 
Investigator within 24 hours of learning of the occurrence by Fax and email. In the event that the 
participating investigator does not become aware of the serious adverse event immediately (e.g., participant 
sought treatment elsewhere), the participating investigator is to report the event within 24 hours after 
learning of it and document the time of his or her first awareness of the adverse event. Report serious adverse 
events by telephone, email or facsimile to: 
 
 
Marshall Posner, MD 
 
  212-659-5461      
 marshall.posner@mssm.edu 
 

58 
 
 
 
 
 
Within the following 24-48 hours, the participating investigator must provide follow-up information on the 
serious adverse event. Follow-up information should describe whether the event has resolved or continues, if 
and how the event was treated, and whether the participant will continue or discontinue study participation. 
17.4.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the MSSM Overall Principal Investigator where required on 
the toxicity Case Report Forms.   
17.5 
 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within MSSM will report all serious adverse events directly to the MSSM Office for 
Human Research Studies  
 
Other investigative sites should report serious adverse events to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted institutional SAE form 
should be forwarded to: 
 
Marshall Posner, MD 
  212-659-5461      marshall.posner@mssm.edu 
 
 
 
The MSSM Principal Investigator will submit SAE reports from outside institutions to the MSSM Office for 
Human Research Studies according to MSSM IRB policies and procedures in reporting adverse events.  
 
17.6 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject safety reports or 
sentinel events that require reporting according to institutional policy. 
17.7 
Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation of study 
intervention, throughout the study, and within 30 days of the last study intervention should be followed to 
their resolution, or until the participating investigator assesses them as stable, or the participating investigator 
determines the event to be irreversible, or the participant is lost to follow-up. The presence and resolution of 
AEs and SAEs (with dates) should be documented on the appropriate case report form as required and 
recorded in the participant’s medical record to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring visit to 
obtain additional case details deemed necessary to appropriately evaluate the SAE report (e.g., hospital 
discharge summary, consultant report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably be related to 
participation in this study. Participating investigators should notify the MSSM Overall Principal Investigator 
and their respective IRB of any unanticipated death or adverse event occurring after a participant has 
discontinued or terminated study participation that may reasonably be related to the study.   
 
18 
DATA AND SAFETY MONITORING 

59 
 
18.1 
 Data Reporting 
18.1.1 Method  
The Study team and the CCTO  will collect, manage, and monitor data for this study.  
18.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or electronic) to the QACT is as 
follows: 
 
Form/eCRF 
Estimated Submission Timeline 
Eligibility Checklist 
Complete prior to registration with MSSM 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up 
visit date or call 
 
18.2 
  Independent Data Safety Monitoring Committee 
 
Because this is a Phase III trial and Independent Data Safety Monitoring  Committee (IDMC) will be 
required to review and monitor toxicity, accrual data from this trial and interim results on this trial. The 
committee will be composed of clinical specialists and a statistician with experience in oncology and who 
have no direct relationship with the study. Information that raises any questions about participant safety will 
be addressed with the Principal Investigator and study team and regular reports made to the TCI Data and 
Safety Monitoring Committee (DSMC). 
 
The IDMC will meet semi-annually and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include: up-to-date participant accrual; all grade 3 or 
higher unexpected adverse events that have been reported; summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a summary provided by the study team. 
Other information (e.g. scans, laboratory values) will be provided upon request.   
 
This trial will seek to screen and consent 365 subjects, with the anticipation that 330 of these subjects will 
undergo TPF induction chemotherapy, and 300 will successfully complete induction therapy.  Of those that 

60 
 
complete induction, it is anticipated that 80% (or approximately 240 subjects) will have a sufficient response 
to treatment as to allow for randomization in the second phase of the trial.  Blinded data on LRC and PFS 
will be reported to the DSMC after 120 patients have been followed for 12 months after completion of all 
therapy and/or 200 patients have been entered.   
 
The IDMC will include one oncologist from MSSM, unrelated to the study staff, and one each:  a medical 
oncologist, radiation oncologist and surgical oncologist from outside institutions. An independent MSSM 
statistician shall be  a member. The chairman of the DSMB will prepare minutes and report to the TCI 
DSMC. The study report will remain blinded for efficacy results unless there is sufficient reason for the 
IDMC to consider halting the trial, based on toxicity or an efficacy signal suggesting one of the arms is 
underperforming significantly. The results may then be unblinded so that a full decsion can be made using all 
the data. It is anticipated that the control arm may have more acute toxicity then the experimental arm and 
thus unblinding will be necessary if acute toxicity is significantly different. This decision cannot be made 
with less than 120 patients randomized and followed for 12 month after completion of all therapy. 
18.3 
Non-MSSM Site Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the MSSM Overall 
Principal Investigator (or Protocol Chair) or MSSM. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, institutional policy, 
Good Clinical Practice (GCP), and any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue during protocol 
performance and completion.  
 
19 
REGULATORY CONSIDERATIONS 
19.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related to the study 
(e.g., advertisements used to recruit participants) and any other necessary documents must be submitted, 
reviewed and approved by a properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be approved by the IRB 
prior to implementation. Any changes in study conduct must be reported to the IRB. The MSSM Overall 
Principal Investigator (or Protocol Chair) will disseminate protocol amendment information to all 
participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
19.2 
Informed Consent 
 
All participants must be provided a consent form describing this study and providing sufficient information 
for participants to make an informed decision about their participation in this study. The formal consent of a 
participant, using the IRB approved consent form, must be obtained before the participant is involved in any 
study-related procedure. The consent form must be signed and dated by the participant or the participant’s 
legally authorized representative, and by the person obtaining the consent. The participant must be given 

61 
 
a copy of the signed and dated consent document. The original signed copy of the consent document 
must be retained in the medical record or research file.  
 
19.3 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good and sound 
research practice: 
 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
 Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
 Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
 Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
 Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
 Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
 
State laws 
 
MSSM research policies and procedures         
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy.  
19.4 
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information enables the 
study to be fully documented and the study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not limited to hospital 
records, clinical charts, laboratory and pharmacy records, recorded data from automated instruments, 
microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.  
19.5 
Records Retention 
 

62 
 
All study-related documents must be retained for the maximum period required by applicable federal 
regulations and guidelines or institutional policies.  
 
 
19.6 
Multi-center Guidelines 
See Multi-Center SOP in Appendix 
 
20 
STATISTICAL CONSIDERATIONS  
20.1 
Study Design/Endpoints 
 
This is an open label, randomized phase III study of TPF chemotherapy followed by chemoradiotherapy. The 
primary endpoints are PFS  and the rate of local-regional control at 3 years in patients with advanced HPV 
16 and p16+ related head and neck cancer, treated with standard and reduced dose radiation.  The secondary 
objectives include Overall Survival, toxicity of reduced radiation dose, long term toxicity of reduced 
radiation dose, as well as establishing biomarkers predictive of treatment outcomes and collection of tumor 
tissue, germline DNA and a plasma bank for future studies. The study hypothesis is that LRC and PFS at 3 
years for reduced dose CRT are non-inferior to standard dose CRT. 
20.2 
Sample Size/Accrual Rate 
 
We plan to screen 365 patients and recruit a total 240 HPV16+ patients to the experimental 
chemoradiotherapy phase of this study, which will randomize 2:1 between the experimental and standard 
arms, respectively.  HR non-HPV16 patients will be sampled as an exploratory analysis and randomized 1:1. 
The plan to recruit a total of 365 patients in order to eventually randomize 240 HPV16+ responding patients 
between these two arms, will account for drop outs, HPV16 negative and non-HPV16/HRHPV+ PCR 
subjects and induction non-responders. We expect approximately 35 patients to be surgically curable, and of 
the remaining 330, approximately 10% or 30 to stop therapy due to toxicity. Of the remaining 300, 20% may 
have a poor response or be HPV16 negative and will get aggressive CRT or be randomized separately 
because of predicted poor survival or non-HPV16 status. The experimental and control groups will be 
comprised of the remaining 240 patients to be randomized 2:1 to low or standard radiotherapy. Additional 
patients will be screened and treated until a full 240 are randomized and receive their first radiation therapy. 
Patients screened and undergoing treatment with induction or assessment at the time that the first 240 have 
been randomized will also be randomized, leading to an indeterminate final number that will be greater then 
240. 
 
This minimal sample size of 240 will provide power of 74% and 78.5% to detect a differences of 10% 
between the two therapy groups in the PFS or LRC rates, respectively, at 3-years following treatment using a 
one-sided Type I error rate of 10%. (Bergstralh, 1984). These calculations are based on a 3.5-year accrual 
period with 3 more years of follow-up. The current PFS for 3 years, based on TPF is 81% and on RTOG 
0129 is 74%, hence the predicted PFS for the control arm should be 77% (average of two aggressive 
therapies with standard XRT) for the purposes of calculation. Based on PFS and  LRC recurrences in TPF 
representing approximately 80% of PFS failure, the LRC rate should be 82% for the purposes of sample size 
determination.  Power is calculated based on the log-rank test at 3-years post-therapy in all patients. 
 
Table X.  Sample size and power for 1-sided Type I error rate of 10% 

63 
 
 
Outcome 
Power 
Rate in Std 
Therapy 
Margin of  
Non-Inferiority 
Sample Size  
Std Therapy 
Sample Size  
Exp Therapy 
PFS 
74% 
77% 
10% 
80 
160 
LRC 
78.5% 
82% 
10% 
80 
160 
 
20.3 
Stratification Factors 
 
We will stratify the randomization in cohort 1 for smoking > 20 pack years and N stage N3 versus other. 
 
20.4 
Randomization Process 
 
Randomization will be performed by Central Registration within the MSSM CCTO using an eRAP based 
random assignment process. Randomization will take place once the patient has completed the eligibility 
review for randomization and will be communicated to the site study personnel as outlined in section 6.2.  
 
Lists of random treatment assignments will be generated by the Biostatistics Core working together with 
informatics personnel.  For each institution participating in the study two separate randomization lists will be 
generated for cohort 1--- one for patients with a smoking history of ≤ 20 pack years and one for patients with 
a smoking history of > 20 pack years.  In each list the probability of receiving the reduced dose of radiation 
in cohort 1 will be twice the probability of receiving the standard dose.  These lists will be generated prior to 
opening the trial for patient enrollment.  For each institution participating in the study, one randomization list 
will be generated for cohort 2, which will be separate from the list generated for cohort 1.  In the list for 
cohort 2, the probability of receiving the reduced dose of radiation will be just as likely as the probability of 
receiving the standard dose.  At the time of randomization for each patient, the eRAP system will prompt the 
person making the randomization to verify that all eligibility requirements have been satisfied and that 
informed consent has been obtained.  Each person authorized to perform randomizations will be assigned a 
unique personal code which (s)he will enter into the database at the time of randomization.  The system will 
capture the date and time the randomization is done, as well as the identity of the person obtaining the 
treatment assignment. 
20.5   Analysis of Primary Endpoints 
 
 
The primary endpoints are PFS and LRC at 3 years.  Kaplan-Meier curves will be estimated for the standard 
therapy and the experimental therapy groups.  Ninety-percent one-sided confidence intervals will be calculated 
for the differences between the cumulative PFS and between the cumulative LRC at 3 years in the standard 
therapy and experimental therapy groups.  If the lower confidence limit for the differences is less than or equal 
to 0.10, the Margin of Non-inferiority, it will be concluded that the experimental treatment is non-inferior to the 
standard therapy (da Silva et al., 2008). 
20.6 
Analysis of Secondary Endpoints 
 
The secondary endpoint of overall survival will be analyzed using Kaplan-Meier curves and a log-rank test 
for the difference between the two therapy groups. Five year OAS, PFS and LRC will be calculated using a 
log-rank test will be used to test for differences between the two treatment groups. 
 
Toxicity is another secondary endpoint. We will compute for each arm the toxicity rate and provide the 
corresponding 90% confidence intervals based on the exact binomial distribution. 
 

64 
 
Reporting and Exclusions 
Not Applicable. 
21 
PUBLICATION PLAN 
The results should be made public within 24 months of the end of data collection. If a report is planned to be 
published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements 
of the International Committee of Medical Journal Editors. A full report of the outcomes should be made 
public no later than three (3) years after the end of data collection.  
 
22 
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3. 
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Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human 
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Gillison ML. Human papillomavirus and prognosis of oropharyngeal squamous cell 
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18. 
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Hyperfractionated Accelerated Radiotherapy Limits the Additional Benefit of Simultaneous 
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25. 
Best SR, Ha PK, Blanco RG, Saunders JR, Jr., Zinreich ES, Levine MA, et al. Factors 
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Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus 
cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 
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p16(INK4a) overexpression with improved outcomes in young patients with squamous cell cancers 
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to the HPV16 proteome as biomarkers for head and neck cancer. Br J Cancer. 2011;104:1896-905. 
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Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in 
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Riemer AB, Keskin DB, Zhang G, Handley M, Anderson KS, Brusic V, et al. A conserved 
E7-derived cytotoxic T lymphocyte epitope expressed on human papillomavirus 16-transformed 
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67 
 
 
 
 
 
 
23 
APPENDICES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

68 
 
 
 
 
 
Appendix 1: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
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. 

69 
 
 
 
 
 
 
Appendix 2: Video Swallowing 
 
 
The video swallow study report will include the following information:  
 
Impressions: 
 
1. Oropharyngeal findings 
a. Penetration-Aspiration-Scale  
b. Severity rating of OP function 
i. Within Normal Limits 
ii. Mild 
iii. Mild-Moderate 
iv. Moderate 
v. Moderate-Severe 
vi. Severe 
 
2. Cervical Esophageal findings 
a. No stenosis 
b. Partial stenosis 
c. Complete stenosis 
 
Recommendations: 
 
1. Diet 
a. Regular diet 
b. Soft diet 
c. Puree diet 
d. Liquid diet 
e. G-tube w/trials 
f. G-tube, NPO 
 
2. Liquids 
a. Regular  
b. Thickened 
 
3. Therapeutic precautions/interventions 
a. Implement postures/strategies to decrease penetration/aspiration or residue 

70 
 
Consider esophageal dilation Yes or No

71 
 
Appendix 3: QOL  Questionnaires 
 
 
 
Name_______________________  Date___________  Hospital Number________ 
 
 
The M. D. Anderson Dysphagia Inventory 
 
This questionnaire asks for your views about your swallowing ability. This information will 
help us understand how you feel about swallowing. 
 
The following statements have been made by people who have problems with their 
swallowing. Some of the statements may apply to you. 
 
Please read each statement and circle the response which best reflects your experience in 
the past week. 
 
My swallowing ability limits my day-to-day activities. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
E2.  I am embarrassed by my eating habits. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
F1.  People have difficulty cooking for me. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
P2.  Swallowing is more difficult at the end of the day. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
E7.  I do not feel self-conscious when I eat. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
E4.  I am upset by my swallowing problem. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
P6.  Swallowing takes great effort. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
E5.  I do not go out because of my swallowing problem. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 

72 
 
 
F5.  My swallowing difficulty has caused me to lose income. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
P7.  It takes me longer to eat because of my swallowing problem. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
P3.  People ask me, “Why can’t you eat that?” 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
E3.  Other people are irritated by my eating problem. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
P8.  I cough when I try to drink liquids. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
F3.  My swallowing problems limit my social and personal life. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
F2.  I feel free to go out to eat with my friends, neighbors, and relatives. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
P5.  I limit my food intake because of my swallowing difficulty. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
P1.  I cannot maintain my weight because of my swallowing problem. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
E6.  I have low self-esteem because of my swallowing problem. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
P4.  I feel that I am swallowing a huge amount of food. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
 
F4.  I feel excluded because of my eating habits. 
 
Strongly Agree         Agree         No Opinion        Disagree        Strongly Disagree 
  
Thank you for completing this questionnaire! 

73 
 
 

74 
 
 

75 
 
Name_____________________  Date__________  Hospital Number__________ 
 
 
Xerostomia Questionnaire (XQ) 
 
This questionnaire asks your view about your dry mouth issue. This information will help us 
understand how you feel about dry mouth.  Please rate your response which best reflects 
your experience in the past week. The higher the score, the worse your dry mouth. 
 
1. Rate your difﬁculty in talking due to dryness 
 
0____1____2____3____4____5____6____7____8____9____10 
 
 
2. Rate your difﬁculty in chewing due to dryness 
 
0____1____2____3____4____5____6____7____8____9____10 
 
 
3. Rate your difﬁculty in swallowing solid food due to dryness 
 
0____1____2____3____4____5____6____7____8____9____10 
 
4. Rate the frequency of your sleeping problems due to dryness 
 
0____1____2____3____4____5____6____7____8____9____10 
 
5. Rate your mouth or throat dryness when eating food 
 
0____1____2____3____4____5____6____7____8____9____10 
 
6. Rate your mouth or throat dryness while not eating 
 
0____1____2____3____4____5____6____7____8____9____10 
 
7. Rate the frequency of sipping liquids to aid swallowing food 
 
0____1____2____3____4____5____6____7____8____9____10 
 
8. Rate the frequency of sipping liquids for oral comfort when 
not eating 
 
0____1____2____3____4____5____6____7____8____9____10 
 
Thank you for completing this survey. 

76 
 
 
 
 
 
 

77 
 
 
 
 
 
 
 
 
 
 
 
 

78 
 
 
 
 

79 
 
 
 
 
 
 
 
 
 
 

80 
 
Appendix 5: Smoking Questionairre for Stratification 
To be Filled out by Study Personnel 
 
Have you ever smoked?          Yes     No 
 
If yes: 
 
At what age did you begin to smoke? 
 
Are you a __ Current smoker     __Former Smoker? 
 
If you are a former smoker, how long ago did you stop smoking? _______ years 
 
What is/was the total number of cigarettes packs you use/used per Day? 
 
Do you use any other forms of tobacco?   ___ Cigars    ___Pipe      ___Other 
 
For how many years did you smoke? 
 
Have your spouse/partner ever smoked?     Yes     No 
 
 
Calculate Pack Years (Packs/day x  Years = PYR) _____________ 
 
< 20 PY               >   20 PY 
 
 
Information Obtained By: _______________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 

81 
 
Appendix 6: Inclusion Exclusion  Check List 
See Attached File

82 
 
 
Appendix 7: Randomization Check List 
See attached File 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

83 
 
Appendix 8: Multi-Center SOP 
1. Enrollment 
Bi-weekly screening/enrollment logs will be sent to MSSM coordinator via email or 
fax. 
 
2. Central Registration 
Upon consenting a patient in the trial, the external site coordinator will e-mail 
coordinator at Mt. Sinai to alert to a potential patient.  Once a patient has met the 
eligibility criteria and is ready to enroll, the external site coordinator will fax/e-mail 
the eligibility checklist with lab values provided where necessary and subject 
registration form. The following sections in the registration form should be 
completed: 
a. Subject Information 
b. Study Information 
c. Screening Information 
The PI/ research team at Mt. Sinai will confirm eligibility and  a completed and 
signed registration form with subject ID # will be sent to back to the external site 
coordinator via e-mail.  At this point, the patient can begin treatment and the 
coordinator can enter the patient into Erap.  
 
3. SAE Reporting 
The external site will complete and email Medwatch form 3500A, lab reports and 
local IRB submission to MSSM PI and MSSM Regulatory Coordinator no later than 5 
business days.  The PI will review the form and reports. If PI finds serious adverse 
event to be related to study drug it will be reported to FDA, drug sponsor, all external 
sites and MSSM IRB.  
 
 
4. Bi-weekly teleconference 
Teleconferences twice a month will be held among all the sites participating in the 
trial and will be a forum to discuss patient progress, enrollment, new risks, protocol 
amendments, and any other issues sites may be having.  
 
 
5. Off Site Monitoring 
Clinical trials conducted at a facility other than MSSM will be monitored by the OCR 
monitor– following the OCR SOP. Erap will be monitored regularly and onsite 
monitoring visits will occur quarterly depending on site’s accrual.