Phase II Non-Randomized Three Arm Trial of Induction Chemotherapy With Nab-Paclitaxel and Cisplatin (AP: Arms 1 and 3) or Single Agent Nab-paclitaxel (A: Arm 2) as Induction Therapy Followed by Definitive Concurrent Chemoradiation for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (HNSCC): "The APA Trial".
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of the Head and Neck, Carcinoma, Squamous Cell of the Head and Neck, Cancer of Head and Neck, Cancer of the Head and Neck, Head and Neck Cancer, Neoplasms, Head and Neck
Sponsor: Washington University School of Medicine

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Phase II Non-Randomized Three Arm Trial of Induction Chemotherapy with nab-Paclitaxel and 
Cisplatin (AP: Arms 1 and 3)  or Single Agent nab-Paclitaxel (A: Arm 2) as Induction Therapy 
followed by Definitive Concurrent Chemoradiation for Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck (HNSCC): “The APA Trial” 
 
HRPO #: 201510013 
Version date: 3/25/2020 
 
PRINCIPAL INVESTIGATOR 
Douglas Adkins, M.D. 
Washington University School of Medicine 
Campus Box 8056, 660 South Euclid Ave. 
St Louis, MO 63110 
Office Phone: 314-747-8475 
dadkins@wustl.edu 
 
Sub-Investigators 
 
 
Institution 
 
 
Modality 
Mackenzie Daly, M.D. 
 
 
Washington University 
Radiation Oncology 
Hiram Gay, M.D.   
 
 
Washington University 
Radiation Oncology 
Ryan Jackson, M.D. 
 
 
Washington University 
ENT 
Jose Zevallos, M.D. 
 
 
Washington University 
ENT 
Peter Oppelt, M.D. 
 
 
Washington University 
Medical Oncology 
Randall Paniello, M.D. 
 
 
Washington University 
ENT 
Patrik Pipkorn, M.D. 
 
 
Washington University 
ENT 
Jason Rich, M.D.  
 
 
Washington University 
ENT 
Wade Thorstad, M.D.  
 
 
Washington University 
Radiation Oncology 
Esther Lu, PhD 
 
 
 
Washington University 
Biostatistics 
Kevin Palka, M.D. 
 
 
Washington University 
Medical Oncology 
Sid Puram, M.D.  
 
 
Washington University 
ENT 
 
 
Study Drugs: 
 
nab-Paclitaxel 
 
 
 
 
Cisplatin 
                                          Cetuximab 
ClinicalTrials.gov #: 
NCT02573493 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to another party unless law or regulations require 
such disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 

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Phase II Non-Randomized Three Arm Trial of Induction Chemotherapy with nab-Paclitaxel and 
Cisplatin (AP: Arms 1 and 3)  or Single Agent nab-Paclitaxel (A: Arm 2) as Induction Therapy 
followed by Definitive Concurrent Chemoradiation for Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck (HNSCC): “The APA Trial” 
 
 
 Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
09/02/15 
Amendment #1 Version 
 
 
 
 
 
 
11/24/15 
Amendment #2 Version 
 
 
 
 
 
 
08/24/16 
Amendment #3 Version 
 
 
 
 
 
 
11/23/16 
Amendment #4 Version 
 
 
 
 
 
 
04/24/17 
Amendment #5 Version 
 
 
 
 
 
 
07/02/18 
Amendment #6 Version 
 
 
 
 
 
 
01/29/19 
Amendment #7 Version 
 
 
 
 
 
 
03/18/19 
Amendment #8 Version 
 
 
 
 
 
 
04/29/19 
Amendment #9 Version 
 
 
 
 
 
 
10/04/19 
Amendment #10 Version 
 
 
 
 
 
 
03/25/2020

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Phase II Non-Randomized Three Arm Trial of Induction Chemotherapy with nab-Paclitaxel and 
Cisplatin (AP: Arms 1 and 3)  or Single Agent nab-Paclitaxel (A: Arm 2) as Induction Therapy 
followed by Definitive Concurrent Chemoradiation for Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck (HNSCC): “The APA Trial” 
 
 
Principal Investigator Signature Page 
 
 
Site Principal 
Investigator: 
 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the 
conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, 
IRB/HRPO procedures, the Declaration of Helsinki, ICH 
Good Clinical Practices guidelines, and the applicable 
parts of the United States Code of Federal Regulations or 
local regulations governing the conduct of clinical 
studies. 
 
 
 

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Phase II Non-Randomized Three Arm Trial of Induction Chemotherapy with nab-Paclitaxel and 
Cisplatin (AP: Arms 1 and 3)  or Single Agent nab-Paclitaxel (A: Arm 2) as Induction Therapy 
followed by Definitive Concurrent Chemoradiation for Locally Advanced Squamous Cell 
Carcinoma of the Head and Neck (HNSCC): “The APA Trial” 
 
SCHEMA 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1.0 
INTRODUCTION AND BACKGROUND .................................................................................. 8 
1.1 
Introduction ............................................................................................................................... 8 
1.2 
Rationale for Adding Nab-Paclitaxel to IC in HNSCC............................................................. 9 
1.3 
APF-C as Induction Chemotherapy followed by CRT ........................................................... 10 
1.4 
ACF as Induction Chemotherapy followed by CRT ............................................................... 13 
1.5 
A Comparison of Four Taxane-based IC Regimens ............................................................... 15 
1.6 
“The APA Trial” ..................................................................................................................... 15 
1.7 
Amendment to Add Arm 3: .................................................................................................... 16 
2.0 
STUDY ENDPOINTS ................................................................................................................ 19 
2.1 
Primary Objectives .................................................................................................................. 19 
2.2 
Secondary Objectives .............................................................................................................. 19 
3.0 
PATIENT ELIGIBILITY ........................................................................................................... 20 
3.1 
Inclusion Criteria..................................................................................................................... 20 
3.2 
Exclusion Criteria ................................................................................................................... 21 
3.3 
Inclusion of Women and Minorities ....................................................................................... 22 
4.0 
REGISTRATION PROCEDURES............................................................................................. 22 
4.1 
Confirmation of Patient Eligibility ......................................................................................... 22 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database .................................... 23 
4.3 
Assignment of UPN ................................................................................................................ 23 
5.0 
TREATMENT PLAN AND SCHEDULED ASSESSMENTS .................................................. 24 
5.1 
Summary of Treatment Plan ................................................................................................... 24 
5.2 
Evaluations for Toxicity and Response................................................................................... 25 
5.3 
General Concomitant Medication and Supportive Care Guidelines ....................................... 25 
5.4 
Women of Childbearing Potential ........................................................................................... 25 
5.5 
Duration of Therapy ................................................................................................................ 26 
5.6 
Duration of Follow-up ............................................................................................................ 27 
5.7 
Baseline Assessment ............................................................................................................... 27 
5.8 
Induction Chemotherapy Regimen ......................................................................................... 28 
5.9 
Definitive Radiation and Concurrent Chemotherapy .............................................................. 30 
5.10 Definitive Radiation Therapy (Arms 1 and 2 Only) ............................................................... 33 
5.11 Definitive Radiation Therapy (Arm 3 Only) ........................................................................... 37 
5.12 Follow-Up Assessments .......................................................................................................... 41 
6.0 
PHARMACEUTICAL INFORMATION ................................................................................... 43 
6.1 
nab-Paclitaxel (Abraxane) ...................................................................................................... 43 
6.2 
Cisplatin (CDDP, Platinol-AQ®) ........................................................................................... 46 
6.3 
Cetuximab (Erbitux) – with Radiation ARM 2 and selected ARM 1 or 3 patients ................ 48 
7.0 
DOSE MODIFICATIONS .......................................................................................................... 51 
7.1 
nab-Paclitaxel Dose Modifications ......................................................................................... 52 
7.2 
Cisplatin Dose Modifications .................................................................................................. 54 
7.3 
Cetuximab Dose Modifications............................................................................................... 55 
8.0 
CORRELATIVE STUDIES ....................................................................................................... 58 
8.1 
Genomic Analysis ................................................................................................................... 58 
8.2 
Immunologic Analysis ............................................................................................................ 58 
8.3 
Quality of Life Assessments ................................................................................................... 58 
9.0 
DEFINITION OF TUMOR RESPONSE CRITERIA ................................................................ 59 

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9.1 
Visual Categorical Outcomes .................................................................................................. 59 
9.2 
RECIST Criteria ...................................................................................................................... 59 
9.3 
PET/CT Imaging ..................................................................................................................... 59 
10.0 REGULATORY AND REPORTING REQUIREMENTS ......................................................... 60 
10.1 Definitions ............................................................................................................................... 60 
10.2 Reporting to the Human Research Protection Office (HRPO) at Washington University ..... 62 
10.3 Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University ............................................................................................................................... 63 
10.4 Reporting Requirements for Secondary Sites ......................................................................... 63 
10.5 Reporting to Secondary Sites .................................................................................................. 63 
10.6 Reporting to Celgene .............................................................................................................. 63 
10.7 Timeframe for Reporting Required Events ............................................................................. 68 
11.0 STATISTICAL CONSIDERATIONS ........................................................................................ 69 
11.1 Study Design ........................................................................................................................... 69 
11.2 Analysis Plan and Study Power .............................................................................................. 70 
11.3 Adverse Primary Outcome Monitoring ................................................................................... 71 
12.0 DATA SUBMISSION SCHEDULE .......................................................................................... 72 
13.0 DATA AND SAFETY MONITORING ..................................................................................... 73 
14.0 AUDITING ................................................................................................................................. 74 
15.0 MULTICENTER REGULATORY REQUIREMENTS ............................................................. 74 
16.0 REFERENCES ........................................................................................................................... 76 
17.0 STUDY CALENDARS .............................................................................................................. 79 
17.1 Study Calendar 1: ARM 1 or ARM 3: Induction Chemotherapy with AP ............................. 79 
17.2 Study Calendar 2: ARM 2: Induction Chemotherapy with A ................................................. 80 
17.3 Study Calendar 3: Definitive Radiation and Concurrent Chemotherapy – Cisplatin (In 
conjunction with Arm 1) ............................................................................................................................. 81 
17.4 Study Calendar 4: Definitive Radiation and Concurrent Chemotherapy – Cetuximab (Arms 1 
{selected patients} and 2 only) ................................................................................................................... 82 
17.5 Study Calendar 5: Definitive Radiation and Concurrent Chemotherapy – Cisplatin (In 
conjunction with Arm 3) ............................................................................................................................. 83 
APPENDIX 1: ECOG Performance Status .......................................................................................... 84 
APPENDIX 2: Criteria for Response, Progression, and Relapse ......................................................... 85 
APPENDIX 3: Institutional Guidelines for IMRT ............................................................................... 89 
APPENDIX 4: Comorbidity Index ....................................................................................................... 92 
APPENDIX 5: FACT/GOG-NTX-4 (Version 4) ................................................................................. 93 
APPENDIX 6: FACT-H&N (Version 4) ............................................................................................. 94 
 
 
 

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1.0 
INTRODUCTION AND BACKGROUND 
 
1.1 
Introduction 
 
50,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed in 
the USA each year1. Most patients present with locally advanced disease and are treated 
with definitive concurrent chemoradiation therapy (CRT). We, and others, have 
investigated the addition of induction chemotherapy (IC) to complement CRT particularly 
in patients with bulky disease.  
 
TPF (docetaxel, cisplatin and 5-FU) emerged as the standard IC regimen after it was 
compared to PF and shown to be superior (TAX-323 and TAX-324 trials)2,3,4 as shown:  
 
 
 
 
 
 
 

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Cremophor-based paclitaxel appears to have similar benefit to docetaxel5.  
 
However, the relapse rate (RR) after TPF and CRT was 56% in the TAX-324 trial3,4 and 
24% in the Paradigm trial6. A complete response (CR) at the primary tumor site (PTS) 
following two cycles of IC is a surrogate prognostic marker for favorable survival free of 
disease recurrence following subsequent definitive RT-based therapy7,8. The likelihood of 
CR at the PTS after two cycles of TPF was only 14%9. The risk of grade 3-4 adverse events 
(AEs) with TPF was high (83%)6. These data establish three important endpoints (RR, PTS 
CR rate, and grade 3-4 AEs) that future clinical trials of IC should improve upon.    
 
1.2 
Rationale for Adding Nab-Paclitaxel to IC in HNSCC  
 
Improved antitumor activity and increased intratumoral paclitaxel accumulation occurred 
with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) compared to cremophor-
based paclitaxel in nude mice bearing several human tumor xenografts10.  In contrast to 
cremophor-based paclitaxel, nab-paclitaxel resulted in higher tumor response rates in 
breast cancer11. The improved efficacy may be in part due to the high tumor expression of 
Secreted Protein Acidic and Rich in Cysteine (SPARC), a protein that plays a role in 
albumin receptor-mediated endothelial transport12,13.  
 
 

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SPARC expression is common in tumor and stromal cells of HNSCC but not in adjacent 
normal oral mucosa13,14, and is correlated with tumor response to nab-paclitaxel in patients 
with HNSCC15. Although nab-paclitaxel acts in a dose-dependent but SPARC saturable 
manner, stromal-derived SPARC does not influence accumulation of nab-paclitaxel 
delivered at therapeutic doses in a PDA mouse model16. 
 
 Nab-paclitaxel uptake by tumor cells is also mediated by macropinocytosis, in contrast to 
cremophor-based 
paclitaxel17. 
Ras 
and 
PI3K 
pathway 
activation 
stimulates 
macropinocytosis18as does EGFR activation. Ras or PI3K pathway activation occurs in the 
majority (67%) of HNSCC19-25. Based on these data, nab-paclitaxel may be a more 
effective anti-tumor agent than cremophor-based paclitaxel in the treatment of HNSCC.  
 
1.3 
APF-C as Induction Chemotherapy followed by CRT 
 
In a recent phase II trial performed at Washington University and supported by Celgene 
(protocol # ABX218/HRPO# 08-0911), we assessed the feasibility and efficacy of a novel 
induction chemotherapy regimen of nab-paclitaxel, cisplatin, 5-FU + cetuximab (APF-C) 
given to patients with locally advanced HNSCC who were subsequently treated with 
definitive CRT26Thirty patients were enrolled over 12 months. The schema for the APF-C 
regimen is shown below: 
  
 
 
 
*SD = Stable Disease; PD = Progressive Disease.  The protocol permitted resection followed by appropriate 
adjuvant (C)RT in these patients; however, no primary resections were performed because CR or PR occurred 
in all patients following ACCF. 
APF-C* 
Abraxane – 100 mg/m2  
 
         Days 1, 8 & 15 
Cetuximab – 250 mg/m2  
 
         Days 1, 8 & 15 
Cisplatin – 75 mg/m2  
 
         Day 1 
5-FU – 750 mg/m2 per day         
 
         Days 1-3 
 
*Every three week cycles 
 

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Most patients had bulky primary tumor and nodal disease (74% T3 or T4 and 79% > N2b). 
By clinical examination, 53% of patients achieved CR at the PTS following 2 cycles of 
APF-C as shown: 
 
 
The risk of serious adverse events (grades 3-4) during APF-C was 39%. The relapse rate 
with APF-C followed by CRT was only 13%, with a median follow-up of 49 months 
(range: 30-65). 
 
We then compared the outcomes of the 30 patients treated on the APF+C protocol with a 
similar historical control group of 38 patients treated at our institution with TPF + 
cetuximab as induction chemotherapy followed by definitive CRT. APF-C was superior to 
TPF-C overall (2 yr DSS 96.7% vs 77.6%, respectively, p=0.004) and in both p16 positive 
OPSCC and p16 negative HNSCC27, as shown: 
 
16
14
0
2
4
6
8
10
12
14
16
18
CR
PR

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1.4 
ACF as Induction Chemotherapy followed by CRT   
 
Compared to TPF, APF-C included two therapeutic changes: nab-paclitaxel was 
substituted for docetaxel and cetuximab was added. The second generation of this novel IC 
regimen eliminated cetuximab from the APF-C regimen to isolate the treatment effects of 
nab-paclitaxel when given with cisplatin and 5-FU (APF)28. APF (protocol # AX-HN-PI-
0005/HRPO#201202113) was an institutional trial supported by Celgene. 
  
APF was developed to explore the effect of removing cetuximab on efficacy and to reduce 
the risk of grade 3-4 AEs (39% during APF-C). Cetuximab was deleted from the APF-C 
regimen since its benefit during IC was unclear. The schema for APF followed by CRT is 
shown: 

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The results of the APF trial were compared to the APF-C trial. Unexpectedly, we found 
that APF was more effective than APF-C as judged by the PTS CR rate: 77% with APF 
and 53% with APF-C. PTS CR rates were higher with APF even when stratified for T 
classification and p16 status. Relapse rate with APF was only 3%; however, median 
follow-up was early (11 [6-21] months).   
 
Why would APF be superior to APF-C in HNSCC? EGFR is overexpressed in nearly all 
HNSCC. Macropinocytosis, the process whereby large molecules like albumin are taken 
up by cells, is increased by EGFR activation. Cetuximab, an EGFR inhibitor, may down 
regulate macropinocytosis, which could decrease tumor cell uptake of nab-paclitaxel. 
Cetuximab also reduces the fraction of tumor cells in “S” phase, during which tumor cells 
are particularly vulnerable to taxanes.  
 
Although APF may be more effective than APF-C, the risk of grade 3-4 AEs during APF 
was 40%.  
 
 
 
 
 
 
 
 
APF* 
 
nab-Paclitaxel – 100 mg/m2  
 
         Days 1, 8 & 15 
Cisplatin – 75 mg/m2  
 
         Day 1 
5-FU – 750 mg/m2 per day         
 
         Days 1-3 
 
*Every three week cycles 
 

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1.5 
 A Comparison of Four Taxane-based IC Regimens 
 
            
 
 
            In summary, PTS CR rates were lowest with TPF and highest with APF, as was DSS and  
OS. Relapse rate was highest with TPF and lowest with APF. Grade 3-4 AEs were highest 
with TPF and lowest with APF. However, grade 3-4 AEs during IC remain disturbingly 
high (40%) even with APF. Given the extraordinarily high efficacy of APF, our next 
generation of nab-paclitaxel IC regimens will explore reducing the rate of grade 3-4 AEs 
by sequentially deleting 5-FU (AP: nab-paclitaxel and cisplatin) and then deleting cisplatin 
(A: nab-paclitaxel alone). 
 
1.6 
  “The APA Trial”  
 
We hypothesize that nab-paclitaxel is the most effective and least toxic agent in the APF 
regimen. The efficacy of 5-FU during IC is unclear in the absence of controlled trials, but 
5-FU does increase the risk of stomatitis, diarrhea, and neutropenia. 5-FU will not be used 
in the two arms of the APA trial. Cisplatin, historically the most effective agent in the 
treatment of HNSCC, resulted in a 27% risk of renal AEs during APF. Cisplatin will be a 
component of Arm 1 but not Arm 2 of the APA trial. Arm 1 will include patients with good 
performance status and vital organ function. Arm 2 will include patients with poorer 
performance status and vital organ function. 
 
In this trial, our objectives are to determine the efficacy and toxicity of IC with nab-
paclitaxel + cisplatin (Arm 1: AP) and with nab-paclitaxel (Arm 2: A) alone in patients 
with HNSCC, and to compare these data to APF. We also hypothesize that the high anti-
tumor efficacy of nab-paclitaxel in HNSCC is due to the upregulation of macropinocytosis, 
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The following highlights the key elements of the APA trial: 
• Two arm, open label, phase II trial of induction chemotherapy with either nab-
paclitaxel and cisplatin (Arm 1: AP) or nab-paclitaxel alone (Arm 2: A) followed 
by CRT in HNSCC. 
• ARM 1 - AP 
o Six weeks of nab-paclitaxel (100 mg/m2/week) and cisplatin (75 mg/m2 
days 1 and 22) followed by primary tumor site (PTS) assessment (by visual 
exam, biopsy 
o CT Neck and FDG-PET/CT) 
o If CR/PR, three more weeks of nab-paclitaxel and cisplatin followed by 
CRT 
o If <PR, move directly to CRT if not surgical candidates. 
o CRT includes high dose bolus (100 mg/m2 x 3) cisplatin and IMRT 
• ARM 2 – A 
o Six weeks of nab-paclitaxel (100 mg/m2/week) followed by primary tumor 
site (PTS) assessment (by visual exam, biopsy, CT Neck and FDG-PET/CT) 
o If CR/PR, three more weeks of nab-paclitaxel followed by CRT 
o If <PR, move directly to CRT if not surgical candidates. 
o CRT includes cetuximab (400 mg/m2 x 1 then 250 mg/m2 x 7) and IMRT 
• Primary efficacy endpoint of CR rate at the PTS with the objective to have each 
arm non-inferior to the PTS CR rate with APF (77%) 
• Secondary adverse events (Grade 3-4) endpoint  
o Arm 1 at least 25% lower than the risk of Grade 3-4 AE’s during APF (40% 
decreased to 30%). 
o Arm 2 at least 50% lower than the risk of Grade 3-4 AE’s during APF (40% 
decreased to 20%). 
 
1.7 
Amendment to Add Arm 3: 
 
1.7.1 Synopsis 
 
In this amendment, Arm 3 will be added to the protocol. Arm 3 will include only 
patients with HPV-related OPSCC, who have a favorable prognosis with AP + 
CRT. However, these patients experience a high rate of serious acute toxicity, 
mainly mucositis, during and after CRT. In Arm 3, treatment will include AP as 
induction chemotherapy followed by de-escalated CRT. Our primary hypothesis is 
that de-escalated CRT will reduce the median percent weight loss (a quantifiable 
surrogate of mucositis) by 50% compared to what occurred with full dose CRT in 
patients treated on Arm 1 of this protocol.  
 
1.7.2 Rationale for Arm 3 
 
Our preliminary analysis of Arm 1 (AP + CRT; n=28 patients) showed preservation 
of all key efficacy endpoints: the CR rate at the PTS after 2 cycles of AP was 70.4% 
and the relapse rate was 3.6%. These data compare favorably to our historical 

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experience with APF followed by CRT where the CR rate at the PTS after two 
cycles of APF was 77% and the relapse rate was 3%. However, 64% of patients 
on Arm 1 experienced grades 3-4 AEs during CRT. Mucosal toxicity was the 
most troublesome AE during CRT, resulting in a median weight loss of 13.1% 
(95%CI: 5% - 23.2%).   
 
Given the significant rate of grades 3-4 AEs during CRT, along with the very low 
rate of relapse, further refinement of AP + CRT is indicated to reduce the AE 
burden and maintain the low relapse rate. De-escalation of radiation is a strategy 
likely to lower the AE risk of AP + CRT. 
 
In this amendment, we retain the AP + CRT backbone but de-escalate the 
dose of RT from 70 Gy to 42 Gy. We also plan to administer one dose (vs three) 
of cisplatin during RT. With these modifications, we hypothesize: a 50% 
decrease in the median percent weight loss during CRT. This novel treatment 
approach will be evaluated in patients with HPV-related OPSCC (Arm 3), a 
sub-group with a very favorable prognosis. 
 
1.7.3 Unique Feature of Arm 3 
 
Several ongoing trials are evaluating de-escalation of RT. The common theme of 
the non-surgical de-escalation trials is the use of RT doses > 54 Gy. Another theme 
of these trials is restriction of this approach to HPV-related OPSCC, and only those 
patients with low risk disease (limited smoking history and not T4 or N2c/3 
disease). In this amendment, we will distinguish our de-escalation approach from 
these trials by using a much lower dose of RT (42 Gy) and including all patients 
with HPV-related OPSCC (Arm 3).  
 
1.7.4 Rationale for 42 Gy of RT 
 
Like HPV-related OPSCC, anal canal SCC is also caused by HPV. CRT is the 
standard of care treatment for anal canal SCC. Surgery is only used as salvage 
therapy for LRR after CRT. The treatment plan for T2N0 disease is 42 Gy elective 
nodal and 50.4 Gy anal tumor planning target volumes (PTV) in 28 fractions and 
for T3-4N0-3 disease is 45 Gy elective nodal, 50.4 Gy for < 3 cm or 54 Gy for > 3 
cm metastatic nodal and 54 Gy anal tumor in 30 fractions29. In contrast to anal 
SCC, the dose of RT given is 70 Gy. Also, in anal SCC the planned cumulative 
dose of cisplatin given during CRT is 140 mg/m2; whereas, in HNSCC the 
cumulative dose of cisplatin is much higher (300 mg/m2). These data suggest that 
the doses of CRT given for HPV-related OPSCC may be more than needed to 
cure this cancer.  
 
The most important message from the studies of CRT in anal SCC is a 
radiation dose of only 42 Gy is effective in eliminating low volume disease. We 
hypothesize that a radiation dose of 42 Gy would also eliminate disease in patients 
with HPV-related OPSCC. In the non-operative setting, the idea way to test this 

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hypothesis is in patients with HNSCC who undergo induction chemotherapy to 
reduce disease volume before applying de-escalated RT. In our amendment, we 
hypothesize the use of induction chemotherapy (AP) will permit reduction of RT 
to 42 Gy  
 
There is precedent for using induction chemotherapy as a platform to de-escalate 
RT. ECOG 1308 used the strategy of induction chemotherapy (cisplatin, paclitaxel 
and cetuximab) followed by 54Gy of RT (with cetuximab) and found excellent 
results (2-year PFS and OS rates were 80% and 94%, respectively) and lower rates 
of swallowing difficulties30.  
 
1.7.5 Expected Reduction of Toxicity by De-escalation of RT Dose from 70 
Gy to 42 Gy 
 
The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) 
study31 
summarized 
the 
latest 
understanding 
of 
organ 
specific 
dose/volume/outcome data. Based on QUANTEC, reduction of the RT dose 
from 70 Gy to 42 Gy would substantially decrease the toxicity burden. The 
organs related to swallowing function include the pharyngeal constrictors, larynx, 
and esophagus.  For the pharyngeal constrictors, a mean radiation dose of less than 
50 Gy reduces the risk of symptomatic dysphagia and aspiration from 100% (with 
70 Gy) to less than 20%.  For the larynx, a mean dose of < 50 Gy reduces the risk 
of aspiration from 100% to less than 30%, and the risk of laryngeal edema is less 
than 20% with a mean dose of less than 44 Gy.  For the esophagus, if the volume 
receiving 50 Gy is less than 40%, the risk of grade 2 or above toxicity is no more 
than 30%.  It is important to understand that the normal tissue complication 
probability (NTCP) with RT dose curve is exponential in shape, meaning that a 
dose of 42 Gy would markedly reduce normal tissue risk relative to 50 Gy in the 
QUANTEC data above, and relative to the 70 Gy standard dose for HNSCC in the 
non-operative setting. 
 
1.7.6 Hypotheses of the Amendment 
 
1. De-escalation of RT from 70 Gy (our current standard in Arms 1 and 2 of the 
APA protocol) to 42 Gy and reduction of the number of doses of cisplatin given 
during RT from three to one will result in a significant decrease in acute 
toxicity of CRT, measured by median percent weight loss.  
 
2. The relapse risk of this overall therapy will not exceed 25% in Arm 3.     
 
 
 
 
 
 
 

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2.0 
STUDY ENDPOINTS 
 
2.1 
Primary Objectives 
 
1. Arm 1 and 2: To determine the complete response (CR) rate by clinical exam at the 
primary tumor site following two cycles of Arm 1: AP or Arm 2: A given over 6 weeks 
(with the objective to have each arm non-inferior to the PTS CR rate with APF [77%]).   
2. Arm 3: To determine the median percent weight loss in patients with HPV-positive 
OPSCC who are treated with AP.  
 
2.2 
Secondary Objectives 
 
1. Arm 3: To determine the complete response (CR) rate by clinical exam at the primary 
tumor site following two cycles of AP given over 6 weeks (with the objective to have 
it be non-inferior to the PTS CR rate with APF [77%]). 
2. To document the clinical partial response (PR) rate at the primary tumor site and the 
clinical CR and PR rates at the involved regional nodes following two cycles of Arm 
1: AP, Arm 2: A, and Arm 3: AP(for HPV-related OPSCC). 
3. To document the anatomic tumor response as assessed by CT scan using RECIST 1.0 
criteria following two cycles of Arm 1: AP, Arm 2: A, and Arm 3: AP(for HPV-related 
OPSCC). 
4. To document and quantify Ki-67 expression by IHC and histologic tumor response in 
primary tumor tissue obtained at baseline and following two cycles of AP or A and 
correlate these results with clinical primary tumor site response to Arm 1: AP or Arm 
2: A, or Arm 3: AP(for HPV-related OPSCC). 
5. To document and grade AE’s with Arm 1: AP, Arm 2: A, or Arm 3: AP (for HPV-
related OPSCC) and to compare to those observed with APF with the objective that 
Arm 1 will be at least 25% lower than the risk of Grade 3-4 AE’s during APF (40% 
decreased to 30%) and Arm 2 will be at least 50% lower than the risk of Grade 3-4 
AE’s during APF (40% decreased to 20%). 
6. To determine the overall survival (OS), disease-free survival (DFS), and progression-
free survival (PFS) of these patient populations.   
7. To document the measures of Quality of Life (QOL) at baseline, during treatment, and 
through one year after completion of treatment for all arms. 
8. To compare response rate, OS, DFS, and PFS of Arm 3 to Arm 1 (stratified for HPV 
status). 
9. To compare the rate of grade 3-4 AEs during CRT in Arm 3 to Arm 1. 
10. To compare the median absolute and percent weight loss during CRT in Arms 2 and 3, 
to Arm 1.  
 
 
 
 
 
 
 
 
 

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3.0 
PATIENT ELIGIBILITY 
 
3.1 
Inclusion Criteria  
 
ARMS 1 and 3 – AP 
ARM 2 - A 
1. Diagnosis of selected Stage III or IVa/b 
HNSCC.  Arm 1: T2-T4 primary 
tumors. Arm 3: T1-T4 primary tumors.  
Although most of these patients will 
have regional nodal disease, patients 
with no nodal disease will also be 
eligible. 
 
2. Arm 1: Presence of disease at the 
oropharynx, hypopharynx, or larynx 
sub-sites. 
 
Arm 3: Presence of disease at the 
oropharynx sub-sites, which is HPV-
related as verified by p16, a surrogate 
marker of HPV, or HPV ISH or PCR.  
 
3. Presence of measurable disease defined 
as lesions that can be accurately 
measured in at least one dimension 
(longest diameter to be recorded) as ≥ 
10 mm with CT scan. 
 
4. At least 18 years of age. 
 
5. Women of childbearing potential and 
men must agree to use adequate 
contraception (hormonal or barrier 
method of birth control, abstinence) 
prior to study entry, for the duration of 
study participation, and for 3 months 
after completing treatment.  Should a 
woman become pregnant or suspect 
she is pregnant while participating in 
this study, she must inform her treating 
physician immediately. 
 
6. Able to understand and willing to sign 
an IRB-approved written informed 
consent document. 
 
1. Diagnosis of selected Stage III or IVa/b 
HNSCC.  T2-T4 primary tumors.  
(Patients with T1 tumors will be 
excluded). Although most of these 
patients will have regional nodal 
disease, patients with no nodal disease 
will also be eligible. 
 
2. Presence of disease at the oropharynx, 
hypopharynx, or larynx sub-sites. 
 
3. Presence of measurable disease defined 
as lesions that can be accurately 
measured in at least one dimension 
(longest diameter to be recorded) as ≥ 
10 mm with CT scan. 
 
4. At least 18 years of age. 
 
5. Women of childbearing potential and 
men must agree to use adequate 
contraception (hormonal or barrier 
method of birth control, abstinence) 
prior to study entry, for the duration of 
study participation, and for 3 months 
after completing treatment.  Should a 
woman become pregnant or suspect 
she is pregnant while participating in 
this study, she must inform her treating 
physician immediately. 
 
6. Able to understand and willing to sign 
an IRB-approved written informed 
consent document. 
 
7. ECOG performance status < 3. 
 
8. Adequate bone marrow and organ 
function as defined below: 
a. ANC: ≥ 1500/mcL. 
b. Platelets: ≥ 100,000/mcL. 

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7. ECOG performance status ≤ 1. 
 
8. Adequate bone marrow and organ 
function as defined below: 
a. ANC: ≥ 1500/mcL. 
b. Platelets: > 100,000/mcL. 
c. Hemoglobin > 9.0 g/dL 
d. Total bilirubin ≤ 1.5 mg/dL 
e. AST/ALT/alkaline 
phosphatase: ≤ 2.5 x ULN. 
f. Serum creatinine: < 1.5 mg/dL 
or calculated GFR ≥ 75 cc/min. 
CrCl by Cockcroft-Gault will 
be used to estimate GFR.  
g. Pulmonary: no requirement for 
supplemental oxygen and no 
evidence of moderate-severe 
COPD by PFTs. 
c. Hemoglobin > 9.0 g/dL 
d. Total bilirubin ≤ 2.0 mg/dL 
e. AST/ALT/alkaline 
phosphatase: ≤ 5x ULN. 
f. Calculated GFR >30 cc/min. 
CrCl by Cockcroft-Gault will 
be used to estimate GFR. 
g. Pulmonary: patients with a 
requirement for supplemental 
oxygen 
or 
evidence 
of 
moderate-severe 
COPD 
by 
PFTs are permitted to enroll. 
 
9. If a patient fully meets criteria for Arm 1, but has profound hearing loss and the 
physician feels that the patient should not receive cisplatin, the patient will be eligible 
for Arm 2.    
 
10. If a patient fully meets criteria for Arm 1, but has a history of solid organ or bone 
marrow transplant, the patient will be eligible for Arm 2 (due to contraindications of 
cisplatin with medications the patient is taking due to the transplant). 
 
3.2 
Exclusion Criteria 
 
1. Prior chemotherapy, prior EGFR targeted therapy, or prior radiation therapy for 
HNSCC. 
 
2. Disease at the nasopharyngeal, sinus, oral cavity, or other sub-site not specified in 
Section 3.1 as eligible. 
 
3. Diagnosis of unknown primary squamous cell carcinoma of the head and neck. 
 
4. History of prior invasive malignancy diagnosed within 3 years prior to study 
enrollment; exceptions are malignancies with a negligible risk of metastasis or death 
(e.g., expected 5-year OS > 90%) that were treated with an expected curative outcome, 
such as squamous cell carcinoma of the skin, in-situ carcinoma of the cervix uteri, non-
melanomatous skin cancer, carcinoma in situ of the breast, or incidental histological 
finding of prostate cancer (TNM stage of T1a or T1b). 
 
5. Receiving any other investigational agents. 
 

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6. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to any of the agents used in this study. 
 
7. Taking cimetidine or allopurinol. If currently taking either of these medications, patient 
must discontinue for one week before receiving treatment with nab-paclitaxel. 
 
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or serious psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
9. Pregnant and/or breastfeeding.  A negative serum or urine pregnancy test is required at 
screening for all female patients of childbearing potential. 
 
10. Known to be HIV-positive on combination antiretroviral therapy because of the 
potential for pharmacokinetic interactions with the study agents.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
11. Peripheral neuropathy > grade 1. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center database, the WUSM coordinator 
will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by scanning and emailing the information listed below to the 
research coordinator listed in the Siteman Cancer Center Clinical Trials Core Protocol 
Procedures for Secondary Sites packet at least one business day prior to registering patient: 

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1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, your institution name, and the registering MD’s name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database  
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT.  Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the WUSM research coordinator.  Registration will be confirmed by the research 
coordinator or his/her delegate by email within one business day. Verification of eligibility 
and registration should be kept in the patient chart. 
 
Patients at all sites must be registered through the Siteman Cancer Center OnCore database 
at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.0 
TREATMENT PLAN AND SCHEDULED ASSESSMENTS 
 
5.1 
Summary of Treatment Plan 
 
One cycle of induction chemotherapy is 21 days. 
 
 

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5.2 
Evaluations for Toxicity and Response 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 10-year follow-up after the conclusion 
of treatment, or death. 
 
All patients are evaluable for disease response unless they come off study prior to 
completion of Cycle 2 and have not had any disease assessment. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Primary prophylaxis with G-CSF or Neulasta is not permitted; however it can be used in a 
non-prophylactic setting following neutropenia (see Section 7.1.7). Use of erythropoietin 
is not permitted. 
 
Patients may not take cimetidine or allopurinol while receiving nab-Paclitaxel or for at 
least 7 days prior to initiating treatment with nab-Paclitaxel. 
 
Concurrent treatment with bisphosphonates is allowed. 
 
5.4 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the 
surgical removal of both ovaries) or (2) has not been naturally postmenopausal for at least 

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24 consecutive months (i.e. has had menses at any time during the preceding 24 
consecutive months)) must: 
(1) Either commit to true abstinence from heterosexual contact (which must be reviewed 
on a monthly basis), or agree to use, and be able to comply with, effective contraception 
without interruption, 28 days prior to starting treatment (including dose interruptions) 
and while on study medication or for a longer period if required by local regulations 
following the last dose of study treatment; and 
(2) Have a negative serum pregnancy test result at screening and agree to ongoing 
pregnancy testing during the course of the study, and after the end of study therapy.  
This applies even if the subject practices true abstinence from heterosexual contact.   
 
Male subjects must practice true abstinence or agree to use a condom during sexual contact 
with a pregnant female or a female of childbearing potential while participating in the 
study, during dose interruptions, and for 6 months following discontinuation of study 
treatment, even if he has undergone a successful vasectomy. 
 
Please note that true abstinence is acceptable when this is in line with the preferred and 
usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
 
If a patient is suspected to be pregnant, the study agent should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 3 months after the last dose of the study agent, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.5 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue until 
completion of all planned therapy or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 

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• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.6 
Duration of Follow-up 
 
Patients will be followed according to the schedule specified in Section 5.11.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
 
5.7 
Baseline Assessment 
 
The baseline assessment will include the following tests or procedures and must occur 
within 28 days (PET scan within 42 days) of enrollment: 
 
1. Clinical examination to document extent of primary tumor by laryngoscopy 
performed in the office or in the operating room (depending on the ease of the exam 
and the primary tumor site) and palpable involved regional neck nodes. Size of the 
primary tumor and involved regional neck nodes will be determined based on visual 
and palpable assessments and will be dictated in the ENT assessment note  The 
neck node measurements will be performed clinically by the treating medical 
oncology physician and dictated in his/her assessment note. 
2. Whenever possible, evaluation by a radiation oncologist before initiation of 
induction chemotherapy should be performed.  A significant response to induction 
therapy sometimes complicates post-response tumor contouring.  Assessment for a 
CT simulation scan prior to induction therapy may be made on a case by case basis. 
3. Documentation of site of primary tumor (oropharynx, hypopharynx, or larynx), 
location and level of clinically involved neck nodes (right or left neck, Level I-V), 
T stage (1-4), N stage (0-3), and overall clinical stage (3-4b by AJCC Cancer 
Staging Manual Sixth Edition). 
4. Documentation of demographic information, including gender (M/F), age (years), 
height (cm), weight (Kg), and BSA (m2).  
5. Documentation of baseline patient symptoms using NCI-CTCAE version 3.0. 
6. Documentation of ECOG performance status (ECOG-Appendix 1). 
7. Completion of QOL questionnaire (Appendices 5 and 6). 
8. Documentation of Comorbidity Index (Comorbidity Scoring – Appendix 4). 
9. Laboratory evaluations: CBC, CMP, Magnesium, PT/PTT, serum pregnancy test if 
patient is a female of childbearing potential.  (Please note that the pregnancy test 
must be performed within 7 days of start of study treatment.) 
10. EKG. 
11. CT scan (IV contrast preferred) to document and measure the extent of the primary 
tumor size and involved regional neck nodes using RECIST 1.0 (Appendix 2).  

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12. FDG-PET/CT scan (whole body) to document and measure the FDG avidity at the 
primary tumor site and at the involved regional neck nodes. 
13. Document and quantify Ki-67 expression in primary tumor biopsy specimens using 
standard IHC techniques (Section 7.0). Tissue biopsies (punch, incisional, or core 
needle biopsy) from the primary tumor site will be obtained during the 
laryngoscopy. If a biopsy is not feasible for financial reasons or safety concerns, at 
the Primary Investigator’s discretion, the biopsy may be forgone.  
i. If the participant is enrolled in Washington University’s TAP protocol (head 
and neck bank, HPRO #201102323), tissue that has been banked may be 
accessed in lieu of fresh biopsy at baseline. 
14. Pulmonary Function Tests (PFTs): spirometry, lung volumes, DLCO. 
 
5.8 
Induction Chemotherapy Regimen 
 
1. Physical examination and weight (kg) on Days 1, 8, and 15 of Cycle 1, and on Day 
1 of each subsequent cycle. 
2. Documentation of performance status (ECOG) on Days 1, 8, and 15 of Cycle 1, and 
on Day 1 of each subsequent cycle. 
3. Documentation of patient symptoms using NCI-CTCAE version 3.0 on Days 1, 8, 
and 15 of Cycle 1, and on Day 1 of each subsequent cycle. 
4. CBC on Days 1, 8, and 15 of each cycle. 
5. STAT CMP, STAT magnesium on Day 1 of each cycle. 
6. Arm 1 only: Hydration consisting of 1L IVF NS (also recommended 10 meq KCL/L 
+ 8 meq MgSO4/L) over 60 minutes before and after cisplatin on Day 1 of each 
cycle. 2L IVF NS over 120 minutes on Days 2 and 3 of each cycle recommended. 
7. Antiemetic premedication (recommended) on Day 1 (Arms 1, 3, and 4) 
Palonosetron 0.25 mg, dexamethasone 20 mg, and aprepitant 150 mg IV and on 
Days 2-4 dexamethasone 4-8 mg po bid. 
8. Antiemetic premedication (recommended) on Days 8 and 15 (Arm 1 and 3); on 
Days 1 8, and 15 (Arm 2) of each cycle: granisetron 1 mg. 
9. Arms 1-3: Administration of nab-Paclitaxel 100 mg/m2 IVPB over 30 minutes on 
Days 1, 8, and 15 of each cycle. 
10. Arms 1 and 3 only - administration of cisplatin 75 mg/m2 IVPB over 60 minutes on 
Day 1 of each cycle. 
 
Following the completion of Cycle 2 treatment (between Days 16 and 21), the following 
assessments will be performed to direct the patient’s next therapy: 
 
1. Assessment of primary tumor site will be done by laryngoscopy performed in the 
office or in the operating room. The primary tumor response to the first two cycles 
of induction will be assessed using visual categorical response. The percent change 
from baseline will be dictated in the ENT physician’s clinical exam note. 
 
Visual Categorical Outcomes 
CR 
Complete resolution – 100% decrease/minimal residual mucosal abnormality 
PR 
99-50% decrease 

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SD 
49-0% decrease 
PD 
Any increase 
 
2. Assessment of involved regional neck nodes by physical examination. The 
involved neck node response to the first two cycles of induction will be assessed 
using visual categorical response. The neck node measurements will be performed 
clinically by the treating medical oncology physician and dictated in his/her 
assessment note. 
3. Assessment of clinical overall response using visual categorical response based on 
data from items 1 and 2 above.  Overall response is determined as the lesser of the 
primary site and neck node responses (i.e., Primary Site – CR; Neck Nodes – PR; 
Overall Response – PR) 
4. CT scan (IV contrast preferred) to document and measure the extent of the primary 
tumor size and involved regional neck nodes. RECIST 1.0 will be used to determine 
response at the primary tumor site, at the involved regional neck nodes and the 
radiographic overall tumor response.   
5. FDG-PET/CT scan (whole body) to document and measure the FDG avidity at the 
primary tumor site and at the involved regional neck nodes.  
6. Biopsy of the primary tumor site for routine surgical pathology and documentation 
and quantification of Ki-67 expression in primary tumor biopsy specimens using 
standard IHC techniques (Section 7.0). Tissue biopsies (punch, incisional, or core 
needle biopsy) from the primary tumor site will be obtained during the 
laryngoscopy (or former location of primary tumor if tumor is no longer visible). If 
a biopsy is not feasible for financial reasons or safety concerns, at the Primary 
Investigator’s discretion, the biopsy may be forgone.  
 
Arms 1 and 2: If disease response shows CR or PR at the primary tumor site (by clinical 
examination using visual categorical response) and does not show radiographic (CT) or 
FDG-PET/CT evidence of disease progression, s/he may initiate Cycle 3 of induction, 
followed immediately by definitive radiation and concurrent chemotherapy (See Section 
5.9.1 and 5.9.2). If the patient shows SD or PD, or if the patient experiences an 
unacceptable toxicity unlikely to resolve in the face of a reasonable dose delay (at the 
discretion of the Primary Investigator) s/he should receive definitive radiation and 
concurrent chemotherapy if not a surgical candidate.  If the patient is a surgical candidate, 
they will receive surgery followed by CRT (See Section 5.9.1 and 5.9.2).  
 
Arm 3: If disease response shows CR or PR at the primary tumor site (by clinical 
examination using visual categorical response) and does not show radiographic (CT) or 
FDG-PET/CT evidence of disease progression, s/he may initiate Cycle 3 of induction, 
followed immediately by de-intensified radiation (42Gy) and one dose of cisplatin or 6 
doses of cetuximab (see section 5.9.3 or 5.9.4). Patients with SD or PD after 2 cycles of 
AP will either 1) undergo surgery (if a surgical candidate) followed by CRT with 42 Gy 
RT and abbreviated cisplatin or cetuximab (see section 5.9.3 or 5.9.4) or 2) if not a surgical 
candidate, the patient will be treated with standard definitive radiation (70Gy) and  3 cycles 
of Cisplatin or 8 doses of Cetuximab (See Section 5.9.1 and 5.9.2). 
 

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5.9 
Definitive Radiation and Concurrent Chemotherapy 
 
5.9.1 ARM 1 ONLY - Concurrent Cisplatin 
 
Cisplatin is the preferred chemotherapy to be given during radiation for patients on 
ARM 1. Cisplatin will begin 1 to 35 days after the completion of Cycle 3.  The first 
dose of cisplatin will be given during the initial 5 days of definitive radiation 
therapy, the second on approximately Day 22 of radiation, and the third on 
approximately Day 43 of radiation.  
 
Criteria to receive the first dose of cisplatin include: 
• creatinine clearance > 60 cc/min 
• ECOG performance status 0-2 
• no active serious infections 
Patients who do not meet these criteria will not receive cisplatin during radiation 
therapy but will be permitted to receive cetuximab concurrently with radiation 
therapy (ARM 1 patients only)(see Section 5.9.2).  During radiation therapy, 
patients who receive cisplatin cannot be switched to cetuximab. 
 
Procedures for cisplatin therapy during definitive radiation therapy are as follows: 
 
1. Antiemetics premedication (recommended) prior to each dose of cisplatin: 
palonosetron 0.25 mg IVPB, dexamethasone 10 mg IVPB and aprepitant 
150 mg IVPB. 
2. Hydration consisting of 1L IVF NS (also recommended: 10 meq KCL/L + 
8 meq MgSO4/L) over 60 minutes before and after cisplatin on the day of 
dosing.  2L IVF NS over 60 minutes on the two days following cisplatin 
dosing. 
3. Administration of cisplatin at 100 mg/m2 IVPB over 60 minutes on 
approximately radiation Days 1, 22, and 43. 
4. Physical examination and weight (kg) will be performed on each day of 
cisplatin administration. 
5. Documentation of ECOG performance status will be done on each day of 
cisplatin administration. 
6. Documentation of patient symptoms using NCI-CTCAE version 3.0 will be 
done on each day of cisplatin administration. 
7. CBC, STAT CMP and STAT magnesium on each day of cisplatin 
administration. 
8. Patient to complete QOL questionnaire prior to starting radiation and at the 
last week of radiation. 
 
5.9.2 ARM 2 and selected patients in ARM 1 - Concurrent Cetuximab 
 
Concurrent cetuximab will be given to all patients in ARM 2.  In Arm 1, concurrent 
cetuximab will only be given to those patients who do not meet the criteria for 
receiving cisplatin as specified in Section 5.4.1 (Arm 1).  Cetuximab will begin 1 
to 35 days after the completion of Cycle 3 of IC.   

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Procedures for cetuximab during definitive radiation therapy are as follows: 
 
1. Premedications (recommended): diphenhydramine 50 mg IVPB, solucortef 
100 mg IVPB, and albuterol inhalation (2.5 mg by nebulizer or inhaler) 
prior to each dose of cetuximab. 
2. Cetuximab will be started 7 days (+/- 3 days) before starting definitive 
radiation therapy to the head and neck. The initial (loading) dose of 
cetuximab will be 400 mg/m2 IVPB.  The recommended process for 
administering the loading dose is to give a test dose of 100 mg for one hour, 
followed by an hour of observation, followed by giving the remainder of 
the dose over 2 hours, followed by another hour of observation. Do not give 
cetuximab on the same day as nab-paclitaxel.  
3. Subsequently, cetuximab will be given weekly at a dose of 250 mg/m2 IVPB 
over 60 minutes (followed by an hour of observation) for seven additional 
doses concurrently with radiation therapy. 
4. Hydration consisting of 1L IVF NS over 60-90 minutes before cetuximab 
on the day of dosing. 
5. Weight (kg) will be taken weekly starting with the loading dose of 
cetuximab. 
6. Physical examination and documentation of ECOG performance status will 
be performed on Weeks 1, 5, and 8 starting with the loading dose of 
cetuximab. 
7. Documentation of patient symptoms using NCI-CTCAE version 3.0 will be 
done weekly starting with the loading dose of cetuximab. 
8. CBC, STAT CMP and STAT magnesium will be drawn on Weeks 1, 5, and 
8 starting with the loading dose of cetuximab. 
9. Patient to complete QOL questionnaire prior to starting radiation and at the 
last week of radiation. 
 
5.9.3 ARM 3 ONLY – Concurrent Cisplatin 
 
Cisplatin will begin 1 to 35 days after the completion of Cycle 3 of induction 
chemotherapy. Cisplatin will be given as one dose during the initial 5 days of 
definitive radiation therapy.  (Unless receiving definitive therapy following SD or 
PD after 2 cycles of induction treatment). 
 
Criteria to receive cisplatin include: 
• creatinine clearance > 60 cc/min 
• ECOG performance status 0-2 
• no active serious infections 
Patients who do not meet these criteria will receive cetuximab with radiation 
therapy. 
 
 
 

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Procedures for cisplatin therapy during definitive radiation therapy are as follows: 
 
1. Antiemetics premedication (recommended) prior to cisplatin:  palonosetron 
0.25 mg IVPB, dexamethasone 10 mg IVPB and aprepitant 150 mg. 
2. Hydration  consisting  of  1L  IVF  NS  (also  recommended:  10  meq 
KCL/L + 8 meq MgSO4 /L) over 60 minutes before and after cisplatin on 
the day of dosing.  2L IVF NS over 60 minutes on the two days following 
cisplatin dosing. 
3. Administration of cisplatin at 100 mg/m2 IVPB over 60 minutes on Day 1 
(in initial 5 days of RT) only. 
4. Physical examination and weight (kg) will be performed on the day of 
cisplatin administration,on day 22 of radiation therapy, and at the 2 week 
short term follow-up visit. Weight (kg) will also be collected at the last day 
of RT (no physical exam required that day). 
5. Documentation of ECOG performance status will be done on the day of 
cisplatin administration, on day 22 of radiation therapy, and at the 2 week 
short term follow-up visit. 
6. Documentation of patient symptoms using NCI-CTCAE version 3.0 will 
be done on the day of cisplatin administration, on day 22 of radiation 
therapy, and at the 2 week short term follow-up visit. 
7. CBC, STAT CMP and STAT magnesium on the day of cisplatin 
administration and on day 22 of radiation therapy. 
8. CBC, STAT BMP and STAT magnesium at the 2 week short term follow-
up visit. 
9. Patient to complete QOL questionnaire prior to starting radiation, at the 
last week of radiation, and at the 2 week short term follow-up visit. 
 
5.9.4 ARM 3 ONLY – SELECTED PATIENTS – Concurrent Cetuximab 
 
In Arm 3, concurrent cetuximab will only be given to those patients who do not 
meet the criteria for receiving cisplatin as specified in Section 5.9.3.  Cetuximab 
will begin 1 to 35 days after the completion of Cycle 3 of IC. 
 
Procedures for cetuximab during definitive radiation therapy are as follows: 
 
1. Premedications (recommended): diphenhydramine 50 mg IVPB, solucortef 
100 mg IVPB, and albuterol inhalation (2.5 mg by nebulizer or inhaler) 
prior to each dose of cetuximab. 
2. Cetuximab will be started 7 days (+/- 3 days) before starting definitive 
radiation therapy to the head and neck. The initial (loading) dose of 
cetuximab will be 400 mg/m2 IVPB.   The recommended process for 
administering the loading dose is to give a test dose of 100 mg for one hour, 
followed by an hour of observation, followed by giving the remainder of 
the dose over 2 hours, followed by another hour of observation. Do not give 
cetuximab on the same day as nab-paclitaxel. 

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3. Subsequently, cetuximab will be given weekly at a dose of 250 mg/m2 
IVPB over 60 minutes for five additional doses concurrently with radiation 
therapy. (Unless receiving definitive therapy following SD or PD after 2 
cycles of induction treatment) 
4. Hydration  consisting  of  1L  IVF  NS  over  60-90  minutes  before 
cetuximab on the day of dosing. 
5. Weight (kg) will be taken weekly starting with the loading dose of 
cetuximab through completion of radiation therapy and at the two week 
short term follow-up visit. 
6. Physical examination and documentation of ECOG performance status will 
be performed on day of loading dose of cetuximab, on day 22 of radiation 
therapy, and at the 2 week short term follow-up visit.  Weight (kg) will also 
be collected on the first and last day of RT (no physical exam required that 
day) 
7. Documentation of patient symptoms using NCI-CTCAE version 3.0 will 
be done weekly starting with the loading dose of cetuximab. 
8. CBC, STAT CMP and STAT magnesium on Week 1 (loading dose of 
cetuximab) and on day 22 of radiation therapy. 
9. CBC, STAT BMP and STAT magnesium at the 2 week short term follow-
up visit.  
10. Patient to complete QOL questionnaire prior to starting radiation, at   the 
last week of radiation, and at the 2 week short term follow-up visit. 
 
5.10 
Definitive Radiation Therapy (Arms 1 and 2 Only) 
 
Prior to starting radiation therapy and at the last week of radiation therapy, the patient 
will be asked to complete QOL questionnaire. 
 
5.10.1 Overview 
 
It is strongly recommended that radiation therapy begin within 21 to 42 days (and 
no later than 56 days) after the start of Cycle 3.  Intensity modulated radiation 
therapy (IMRT) is to be used exclusively for this study. Definitive IMRT will be 
delivered once per day Monday through Friday per routine clinical practice using. 
The total dose to the gross disease will be 7000 cGy in 35 fractions of 200 cGy each 
over 7 weeks. A dose of 6300 cGy in 35 fractions is optional and may be delivered 
to areas considered to be at intermediate risk. Additional regions in the ipsilateral 
and contralateral neck at risk for microscopic disease in the cervical lymph nodes 
will receive 5600 cGy in 35 fractions. See Appendix 3 for contouring guidelines. 
 
5.10.2 CT Simulation 
 
As per routine practice, computed tomography (CT) will be the primary image 
platform for targeting and treatment planning.  Prior to the scan, the patient will be 
given IV contrast according to institutional protocols (provided the patient has 
normal renal function and no allergies to contrast).   The patient will be positioned 

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supine on the CT simulator table (head toward the gantry). The head will be placed 
on a clear plastic headrest so as to have the neck slightly extended.  Alternatively, 
a custom head/shoulder mold may be used for immobilization. An immobilization 
mask will then be fashioned. A CT dataset will be acquired from the top of the head 
through 5 cm below the clavicular heads with no more than 5 mm axial slices.  
Three localization marks will be drawn and wired on the patient’s immobilization 
mask at the angle of the mandible bilaterally and midline. These marks will serve 
to establish an internal reference from which an isocenter is placed midline, 
midplane, at the level of the angle of the mandible.  If a CT simulation scan was 
performed prior to induction therapy, a repeat CT simulation scan will be performed 
in the same immobilization device after induction therapy and electronic fusion of 
the images will be performed. 
 
5.10.3 Virtual Simulation and Contouring 
 
The CT scan will be exported to a commercially available virtual simulation 
software package.  Guidelines for clinical treatment volumes to be contoured for 
each head and neck sub-site along with current institutional treatment guidelines 
are shown in Appendix 3.  Guidelines for delineating each lymph node level will 
be based on the international consensus for delineation of head and neck lymph 
nodes (http://www.rtog.org/hnatlas/main.html; reproduced in Appendix 3). These 
guidelines were derived in part from Washington University School of Medicine 
institutional data, and are consistent with routine clinical practice at Washington 
University.   
 
An example case of a T3N2BM0, stage IVA tonsil cancer is outlined in the table 
below.  Current treatment guidelines for this case including dose levels are 
represented with CTV1, CTV2, and CTV3.  
 
CTV1 
CTV2 (Optional) 
CTV3 
[GTVp + GTVn] + 1.5 
cm minimum concentric 
margin excluding bone 
and air 
Adjacent LN Levels 
minimum 1.5 cm cranial-
caudad dimension 
IN (II-V) + BRPLN +  
CN (IIb-IV) Exclusive 
of  CTV1 and CTV2 
Dose 70 Gy/35 fx 
Dose 63 Gy/35 fx 
Dose 56 Gy/35 fx 
Key: GTVp = GTV primary tumor; GTVn = GTV nodal tumor; IN = ipsilateral neck; CN = 
contralateral neck; roman numbers relate to the level system of naming lymph node regions; BRPLN 
= bilateral retropharyngeal lymph nodes).  
 
Normal structure and treatment volume contours will be delineated in a manner 
consistent with routine clinical practice. Refer to appendix 4 for specific guidelines. 
 
5.10.4 IMRT Optimization 
 
The image and contour data will be exported to the TomoTherapy Hi Art System 
(TomoTherapy Inc., Madison WI), where treatment planning and IMRT 
optimization will be performed. For patients being treated on a Varian System 

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(Varian Medical Systems, Inc.), treatment planning will be completed on a 
compatible platform (i.e. Varian’s Eclipse Treatment Planning System, or the 
ADAC Pinnacle treatment planning system). 
 
5.10.5 Treatment Field Arrangement 
 
With tomotherapy, a continuous helical treatment field is used with dynamic 
multileaf collimator fluence modulation.  The system calculates the optimized 
collimator leaf delivery pattern (treatment sinogram) that most closely 
approximates the prescribed constraints.  Planned dose deposition is calculated 
using a collapsed-cone convolution superposition technique that addresses three-
dimensional scatter and inhomogeneities. 
 
The Varian System employs up to ten co-planar fields with static or dynamic 
multileaf collimation. As with tomotherapy, the treatment planning system 
calculates the optimized collimator leaf delivery pattern that most closely 
approximates the prescribed constraints and prescription goals. 
 
5.10.6 Dose, Energy and Prescription Parameters 
 
External beam radiation with 6 MV photons will be delivered in 200 cGy daily 
fractions (Monday through Friday), 35 fractions over 7 weeks to a total dose of 
7000 cGy. 
   
Prescription Coverage Goals 
99% of clinical treatment volumes should receive at least 93% of the respective 
prescription dose (i.e. 99% of PTV 7000 should be covered by 6510 cGy; 99% of 
PTV 6300 covered by 5859 cGy; and 99% of PTV 5600 covered by 5208 cGy). 
 
No more than 5% of the volume “Skin” should receive more than the prescription 
dose (70 Gy) and hotspots must be within the PTV.   
 
Photons with energy of 6 MV will be utilized for IMRT on the helical tomotherapy 
and Trilogy units. 
 
5.10.7 Normal Structure Dose Limit Guidelines 
 
Dose limit guidelines for normal structures are as follows: 
Structure 
Volume 
Dose Guideline 
(Gy) 
Dose Mean 
(Gy) 
Critical Structures 
 
 
 
Spinal Cord + 8 mm 
1 cc 
50 
 
Spinal Cord 
0.1 cc 
45 
 
Brainstem 
1% 
60 
 
 
0.1 cc 
60 
 
Brain 
1% 
60 
 

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5 cc 
65 
 
Optic nerve* 
1% 
60 
 
 
0.1 cc 
60 
 
Optic chiasm 
1% 
60 
 
 
0.1 cc 
60 
 
Eye* 
 
 
45 
Normal Structures 
 
 
 
Retina* 
1% 
50 
35 
Lens* 
 
 
2 
Oral cavity 
 
 
35 
Larynx 
 
 
45 
Mandible 
5% 
73.5 
 
Skin 
5% 
70 
 
Partial esoph 
2 cc 
54 
 
Middle Ear* 
 
 
45 
Parotid glands* 
20 cc 
20 
26 
*Paired structures. Dose constraints apply to one such structure and are equivalent for the 
contralateral side. 
Priority for Above Dose Constraints 
1. Critical Structures 
2. PTV Prescription Goals 
3. Salivary Glands 
4. Other Structures 
 
5.10.8 Treatment Plan Evaluation 
 
The plan will be reviewed by the treating physician prior to treatment in order to 
ensure that all parameters have been met.  Isodose curves and dose volume 
histograms (DVH) will be analyzed. 
 
Criteria for plan evaluation will include: 
• Isodose Curves: 
The 95% isodose line must be generally conformal to the PTV with visually 
acceptable tumor coverage and visually acceptable critical structure 
avoidance. 
The 110% isodose line must not include any critical structure volumes. 
The 4200 cGy isodose line must not encroach on the “Spinal cord + 8 mm” 
for patients planned on the Helios system.  The 5000 cGy isodose line must 
not encroach on the “Spinal cord + 8 mm” for Tomotherapy plans. 
The 2600 cGy isodose line should spare parotid glands when possible. 
 
• Dose Volume Histograms (DVHs): 
No more than 20% of any PTV should exceed 110% of the prescribed dose. 
DVH from PTVs must meet all prescription parameters. 
Normal structure DVHs should meet constraint parameters as listed above. 
 

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5.10.9 Daily Radiation Treatment 
 
Patients will receive external beam radiation treatment delivered either by helical 
tomotherapy or by the Trilogy™ System once a day, five days a week, for 7 weeks 
as per routine clinical practice.  
 
5.10.10 Quality Assurance 
 
Treatment plan physics review and QA are required for each patient in accordance 
with current institutional standards for IMRT. 
 
Daily set-up error will be minimized by the following clinically approved and 
commercially available patient setup techniques: immobilization mask, standard 
skin/mask alignment marks, and daily on-board imaging.  
 
Per routine practice, daily megavoltage helical CT scans will be acquired on the 
tomotherapy unit and compared with planning CT overlay. 
 
For patients treated on the Trilogy™ System, daily orthogonal port films or cone 
beam CT images will be aligned with the digitally reconstructed radiographs or 3D 
CT data set from the planning CT scan based on bony anatomy.  
 
These setup scans will be performed immediately prior to each treatment and the 
appropriate shifts will be made at that time.  
 
5.11 
 Definitive Radiation Therapy (Arm 3 Only—CR or PR after 2 cycles of 
induction therapy OR SD/PD after 2 cycles of induction therapy and received 
surgery) 
 
5.11.1 Overview 
 
It is strongly recommended that radiation therapy begin within 28 to 49 days (and 
no later than 56 days) after the start of Cycle 3.  Intensity modulated radiation 
therapy (IMRT) is to be used exclusively for this study. Definitive IMRT will be 
delivered once per day Monday through Friday per routine clinical practice except 
for one BID treatment during the course of therapy.  If patient logistics prohibit the 
one BID treatment, once daily treatments throughout will be acceptable. The total 
dose to the gross disease will be 4200 cGy in 21 fractions of 200 cGy over 4 weeks. 
Additional regions in the ipsilateral and contralateral neck at risk for microscopic 
disease in the cervical lymph nodes will receive 3780 cGy in 21 fractions of 180 
cGy each. See Appendix 3 for contouring guidelines. 
 
5.11.2 CT Simulation 
 
As per routine practice, computed tomography (CT) will be the primary image 
platform for targeting and treatment planning.  Prior to the scan, the patient will be 
given IV contrast according to institutional protocols (provided the patient has 

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normal renal function and no allergies to contrast).   The patient will be positioned 
supine on the CT simulator table (head toward the gantry). The head will be placed 
on standard or customized plastic headrest so as to have the neck slightly extended.  
Alternatively, a custom head/shoulder mold may be used for immobilization. An 
immobilization mask will then be fashioned. A CT dataset will be acquired from 
the top of the head through 5 cm below the clavicular heads with no more than 5 
mm axial slices.  Three localization marks will be drawn and wired on the patient’s 
immobilization mask at the angle of the mandible bilaterally and midline. These 
marks will serve to establish an internal reference from which an isocenter is placed 
midline, midplane, at the level of the angle of the mandible.  If a CT simulation 
scan was performed prior to induction therapy, a repeat CT simulation scan will be 
performed in the same immobilization device after induction therapy and 
electronic fusion of the images will be performed. 
 
5.11.3 Virtual Simulation and Contouring  
 
The CT scan will be exported to a commercially available virtual simulation 
software package.  Guidelines for clinical treatment volumes to be contoured for 
each head and neck sub-site along with current institutional treatment guidelines 
are shown in Appendix 3.  Guidelines for delineating each lymph node level will 
be based on the international consensus for delineation of head and neck lymph 
nodes (http://www.rtog.org/hnatlas/main.html; reproduced in Appendix 2). These 
guidelines were derived in part from Washington University School of Medicine 
institutional data, and are consistent with routine clinical practice at Washington 
University.   
 
An example case of a T3N2BM0, stage IVA tonsil cancer is outlined in the table 
below. Current treatment guidelines for this case including dose levels are 
represented with CTV1 and CTV2.  
 
CTV1  
CTV2 
[GTVp + GTVn] + 1.0 to1.5 cm 
minimum concentric margin 
excluding bone and air with aid of 
preop imaging with/without fusion 
IN (II-V) + BRPLN + CN (IIb-IV) 
Exclusive of CTV1. 
Dose 4200 cGy/21 fx 
Dose 3780 cGy/21 fx 
 
 
 
 
 
Key: GTVp = GTV primary tumor; GTVn = GTV nodal tumor; IN = ipsilateral 
neck; CN = contralateral neck; roman numbers relate to the level system of naming 
lymph node regions; BRPLN = bilateral retropharyngeal lymph nodes).  
 
Normal structure and treatment volume contours will be delineated in a manner 
consistent with routine clinical practice. Refer to appendix 3 for specific 
guidelines. 

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5.11.4 IMRT Optimization 
 
The image and contour data will be exported to the Varian Eclipse platform where 
IMRT optimization will be performed.  
 
5.11.5 Treatment Field Arrangement 
 
The Varian System employs up to ten co-planar fields with static or dynamic 
multileaf collimation. The treatment planning system calculates the optimized 
collimator leaf delivery pattern that most closely approximates the prescribed 
constraints and prescription goals. 
 
5.11.6 Dose, Energy and Prescription Parameters 
External beam radiation with 6 MV photons will be delivered in 200 cGy daily 
fractions (Monday through Friday), 21 fractions over 4 1/2 weeks to a total dose 
of 4200 cGy. 
   
Prescription Coverage Goals 
99% of clinical treatment volumes should receive at least 95% of the respective 
prescription dose (i.e. 99% of PTV 4200 should be covered by 3990 cGy and; 99% 
of PTV 3780 cGy covered by 3591 cGy). 
 
No more than 5% of the volume “Skin” should receive more than the prescription 
dose (42 Gy) and hotspots must be within the PTV.   
 
Photons with energy of 6 MV will be utilized   
 
5.11.7 Normal Structure Dose Limit Guidelines 
 
Dose limit guidelines for normal structures are as follows: 
 
Structure 
Volume 
Dose 
Guideline 
(Gy) 
Dose 
Mean(Gy) 
 
Critical Structures 
 
 
 
Spinal Cord + 8 mm 
1 cc 
45 
 
Spinal Cord 
0.1 cc  
40 
 
Brainstem 
1% 
40 
 
 
 
0.1 cc 
40 
 
 
Brain 
1% 
40 
 
 
 
5 cc 
45 
 
 
Optic nerve* 
1% 
40 
 
 
0.1 cc 
42 
 
 
Optic chiasm 
1% 
40 
 
 
0.1 cc 
42 
 
 

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Eye*  
 
 
45 
Normal Structures 
 
 
 
Retina* 
1% 
40 
25 
Lens*  
 
 
2 
Oral cavity 
 
 
35 
Larynx 
 
 
42 
Mandible 
5% 
45 
 
Skin 
5% 
45 
 
Partial esoph 
2 cc 
40 
 
Middle Ear* 
 
 
45 
Parotid glands* 
20 cc 
20 
26 
*Paired structures. Dose constraints apply to one such structure and are equivalent 
for the contralateral side. 
 
Priority for Above Dose Constraints 
1. Critical Structures 
2. PTV Prescription Goals 
3. Salivary Glands 
4. Other Structures 
 
5.11.8 Treatment Plan Evaluation 
 
The plan will be reviewed by the treating physician prior to treatment in order to 
ensure that all parameters have been met.  Isodose curves and dose volume 
histograms (DVH) will be analyzed. 
 
Criteria for plan evaluation will include: 
• 
Isodose Curves: 
The 95% isodose line must be generally conformal to the PTV with visually 
acceptable tumor coverage and visually acceptable critical structure 
avoidance. 
 
The 110% isodose line must not include any critical structure volumes. 
The 4200 cGy isodose line must not encroach on the “Spinal cord + 5 mm” 
The 2600 cGy isodose line should spare parotid glands when possible. 
 
• 
Dose Volume Histograms (DVHs): 
No more than 20% of any PTV should exceed 110% of the prescribed dose. 
DVH from PTVs must meet all prescription parameters. 
Normal structure DVHs should meet constraint parameters as listed above. 
 
5.11.9 Daily Radiation Treatment  
 
Patients will receive external beam radiation treatment delivered by Varian linear 
accelerator once a day, five days a week, for 4 to 4 1/5 weeks as per routine clinical 
practice.  

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5.11.10 Quality Assurance  
 
Treatment plan physics review and QA are required for each patient in accordance 
with current institutional standards for IMRT. 
 
Daily set-up error will be minimized by the following clinically approved and 
commercially available patient setup techniques: immobilization mask, standard 
skin/mask alignment marks, and daily on-board imaging.  
 
Per routine practice, daily cone beam CT scans will be acquired and compared with 
planning CT overlay. 
 
These setup scans will be performed immediately prior to each treatment and the 
appropriate shifts will be made at that time. 
 
5.12 
Follow-Up Assessments 
 
Follow-up assessments will be conducted at the following time points (actual follow up 
times may vary due to patient logistics and compliance): 
• 2 weeks (+/- 1 week) following completion of definitive therapy (RT) 
• 8 weeks (+/- 2 weeks) following completion of definitive therapy (RT) 
• 16 weeks (+/- 2 weeks) following completion of definitive therapy (RT)  
• 9, 12, 16, 20, 24, 28, 32, 36, 42, 48, 54, and 60 months (+/- 6 weeks) following 
completion of definitive therapy (RT) [ENT follow-up, including laryngoscopy 
procedures, will be conducted as standard of care after 12 months of follow-up] 
• 72 months (+/- 3 months) following completion of definitive therapy (RT) and 
annually thereafter [ENT follow-up, including laryngoscopy procedures, will be 
conducted as standard of care after 12 months of follow-up] 
 
Patients with progression will only be followed for survival and will not stay on the above 
follow-up schedule. Their follow-up schedules will then be at the discretion of the 
investigator. 
 
5.12.1 Two Week ( +/- 1 week) Assessment 
1. Physical examination and weight (kg). 
2. CBC 
3. BMP 
4. Assessment of clinical overall response using visual categorical response based 
on data from 4 and 5 above. Overall Response is determined as the lesser of the 
primary site and neck node responses (i.e. Primary Site – CR; Neck Nodes – PR; 
Overall Response = PR) 
 
5.12.2 Eight Week ( +/- 2 weeks) Assessment 
 
1. Physical examination and weight (kg). 

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2. Documentation of ECOG performance status. 
3. Documentation of patient symptoms using NCI-CTCAE version 3.0. 
4. CBC, CMP, and magnesium. 
5. CT Neck. 
 
5.12.3 Sixteen Week (+/- 2 weeks) Assessment  
 
1. Physical examination and weight (kg). 
2. Documentation of ECOG performance status. 
3. Documentation of patient symptoms using NCI-CTCAE version 3.0. Any 
adverse event determined by the PI to be possibly, probably, or definitely 
related to the research procedures should be reported to the clinical research 
coordinator to report according to Section 10.0. 
4. Assessment of primary tumor site to be done by laryngoscopy performed in the 
office or in the operating room. The primary tumor response will be assessed 
using visual categorical response. The percent change from assessment one will 
be dictated in the ENT physician’s clinical exam note.   
5. Assessment of involved regional neck nodes by physical examination. The 
involved neck node response will be assessed using visual categorical response. 
The neck node measurements will be performed clinically by the treating 
medical oncology physician and dictated in his/her assessment note. 
6. Assessment of clinical overall response using visual categorical response based 
on data from 4 and 5 above. Overall Response is determined as the lesser of the 
primary site and neck node responses (i.e. Primary Site – CR; Neck Nodes – 
PR; Overall Response = PR) 
7. FDG-PET/CT scan (whole body) to document and measure the FDG avidity at 
the primary tumor site and at the involved regional neck nodes.  
 
5.12.4 Nine to Sixty Month Assessments 
 
1. Physical examination and weight (kg). 
2. Documentation of ECOG performance status. 
3. Completion of QOL questionnaire (to occur at 6 and 12 month visits only). 
4. Documentation of patient symptoms using NCI-CTCAE version 3.0. 
5. Assessment of primary tumor site to be done by laryngoscopy performed in the 
office. The primary tumor response will be assessed using visual categorical 
response. The percent change from last assessment will be dictated in the ENT 
physician’s clinical exam note.  [ENT follow-up, including laryngoscopy 
procedures, will be conducted as standard of care after 12 months of follow-up 
so will occur at some, but not all, long-term follow-up visits] 
6. Assessment of involved regional neck nodes by physical examination. The 
involved neck node response will be assessed using visual categorical response. 
The neck node measurements will be performed clinically by the treating 
medical oncology physician and dictated in his/her assessment note. 
7. Assessment of clinical overall response using visual categorical response, based 
on data from 5 and 6 above. Overall Response is determined as the lesser of the 

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primary site and neck node responses (i.e. Primary Site – CR; Neck Nodes – 
PR; Overall Response = PR) 
8. CT scan of neck and chest (IV contrast preferred) to be done at 12, 18, 24, and 
36 months (+/- 6 weeks) following completion of definitive therapy to 
document and measure the extent of the primary tumor size and involved 
regional neck nodes. RECIST 1.0 will be used to determine response at the 
primary tumor site, at the involved regional neck nodes and the radiographic 
overall tumor response. 
 
5.12.5 Seventy-Two Month Assessment and Beyond 
 
1. Physical examination and weight (kg). 
2. Documentation of ECOG performance status. 
3. Documentation of patient symptoms using NCI-CTCAE version 3.0. 
4. Assessment of primary tumor site be done by laryngoscopy performed in the 
office. The primary tumor response will be assessed using visual categorical 
response. The percent change from last assessment will be dictated in the ENT 
physician’s clinical exam note.  [ENT follow-up, including laryngoscopy 
procedures, will be conducted as standard of care after 12 months of follow-up 
so will occur at some, but not all, long-term follow-up visits] 
5. Assessment of involved regional neck nodes by physical examination. The 
involved neck node response will be assessed using visual categorical response. 
The neck node measurements will be performed clinically by the treating 
medical oncology physician and dictated in his/her assessment note. 
6. Assessment of clinical overall response using visual categorical response, based 
on data from 4 and 5 above. Overall Response is determined as the lesser of the 
primary site and neck node responses (i.e. Primary Site – CR; Neck Nodes – 
PR; Overall Response = PR). 
 
 
6.0 
PHARMACEUTICAL INFORMATION 
 
6.1 
nab-Paclitaxel (Abraxane) 
 
6.1.1 nab-Paclitaxel Description 
 
nab-Paclitaxel is a novel biologically interactive albumin-bound paclitaxel 
combining a protein with a chemotherapeutic agent in the particle form. nab-
Paclitaxel for Injectable Suspension (paclitaxel protein-bound particles for 
injectable suspension) (albumin-bound) is currently indicated for the treatment of 
breast cancer after failure of combination chemotherapy for metastatic disease or 
relapse within 6 months of adjuvant chemotherapy. 
 
Molecular formula: C47H51N014 
Chemical name: 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 
4,10-diacetate 2-benzoate 13 ester with (2R,3S)-N-benzoyl-3-phenylisoserine.  

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Molecular weight: 853.91. 
6.1.2 Clinical Pharmacology 
 
nab-Paclitaxel is an antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. This stability results in the inhibition of the normal dynamic 
reorganization of the microtubule network that is essential for vital interphase and 
mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of 
microtubules throughout the cell cycle and multiple asters of microtubules during 
mitosis. 
 
6.1.3 Supplier 
 
nab-Paclitaxel will be distributed by Celgene Corporation and labeled 
appropriately as investigational material for this study.  Labels will bear Celgene’s 
name and address, the protocol number, product name, dosage form and strength, 
medication identification/kit number, lot number, expiry date, dosing instructions, 
storage conditions, the quantity of IP contained, and require education statements 
and/or regulatory statements as applicable.  No supplies will be shipped to any site 
until regulatory approval has been obtained.  Investigational sites will be supplied 
with nab-Paclitaxel upon identification and screening of a potential trial subject.  
Upon identification of a potential subject, sites must fax a completed Drug Request 
Form to Celgene Corporation.  Allow at least 5 working days for drug shipment.  
There are no shipments on Fridays or holidays. 
 
For re-supply of drug, please complete and fax the Drug Request Form to Celgene 
Corporation at 908-673-2779. 
 
6.1.4 Dosage Form and Preparation 
 
nab-Paclitaxel is supplied as a white to off-white sterile lyophilized powder for 
reconstitution with 20 mL of 0.9% Sodium Chloride.  Each single-use 50 mL vial 
will contain paclitaxel (100 mg) and approximately 900 mg human albumin (HA) 
as a stabilizer. Each vial will be labeled according to country-specific regulatory 
requirements for labeling of investigational products.   
 
1. Calculate the patient’s body surface area at the beginning of the study and 
if the weight changes by > 10%.  
2. Calculate the total dose (in mg) to be administered by multiplying study 
dose by BSA.   
3. Calculate the total number of vials required by dividing the total dose by 
100 (as there are 100 mg per vial) and rounding up to the next higher whole 
number.   
4. Using sterile technique, prepare the vials for reconstitution.  
5. Swab the rubber stoppers with alcohol.  

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6. Reconstitute each nab-Paclitaxel vial by injecting 20 mL of 0.9% Sodium 
Chloride Injection, USP or equivalent into each vial over a period of not 
less than 1 minute.  DO NOT INJECT the 0.9% Sodium Chloride Injection, 
USP solution directly onto the lyophilized cake as this will result in 
foaming. Once the injection is complete, allow the vial to sit for a minimum 
of 5 (five) minutes to ensure proper wetting of the lyophilized cake/powder.   
Gently swirl and/or invert the vial slowly for at least 2 minutes until 
complete dissolution of any cake/powder occurs.  Rapid agitation or 
shaking will result in foaming. If foaming or clumping occurs, stand 
solution for at least 15 minutes until foam subsides. Each ml of reconstituted 
product will contain 5 mg of paclitaxel.  
7. Calculate the exact total dosing volume of 5 mg/ml suspension required for 
the patient by dividing the total dose by 5.  
8. The reconstituted sample should be milky and homogeneous without visible 
particulates.  If unsuspended powder is visible, the vial should be gently 
inverted again to ensure complete re-suspension prior to use.  
9. Once the exact volume of reconstituted nab-Paclitaxel has been withdrawn 
from the vials, discard any excess solution left over in accordance with 
standard operating procedures.  
10. Further dilution is not necessary. Inject the calculated dosing volume of 
reconstituted nab-Paclitaxel suspension into an empty sterile, standard PVC 
IV bag using an injection port.  Inject perpendicularly into the center of the 
injection port to avoid dislodging plastic material into the IV bag.    
11. Administer the calculated dosing volume of reconstituted Nab-Paclitaxel 
suspension by IV infusion over 30 minutes.  The use of in-line filters is not 
recommended.  
12. Following administration, the intravenous line should be flushed with 
sodium chloride 9 mg/ml (0.9%) solution for injection to ensure complete 
administration of the complete dose, according to local practice. 
13. Use within 8 hours of reconstitution.  If not used immediately, store 
reconstituted nab-Paclitaxel in a refrigerator for no longer than 8 hours.  
 
6.1.5 Storage and Stability 
 
Unreconstituted nab-Paclitaxel should be stored at controlled room temperature 
(20° to 25°C or 68° to 77°F) in its carton.  Retain in the original package to protect 
from bright light. Unopened vials of albumin-bound paclitaxel are stable until the 
date indicated on the package when stored at the above temperatures in the original 
package. Reconstituted albumin-bound paclitaxel should be used immediately, but 
may be refrigerated at 2oC to 8oC (38oF to 46oF) for a maximum of 8 hours if 
necessary. If not used immediately, each vial of reconstituted suspension should be 
replaced in the original carton to protect it from bright light. Discard any unused 
portion.  
 
6.1.6 nab-Paclitaxel Drug Return and Destruction 
 

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The pharmacist or designee can choose to destroy the study drug on site.  The 
following information must be recorded on the site’s pharmacy drug accountability 
log: quantity of vials destroyed, expiration date and lot number.  The pharmacist 
must document that the study drug was destroyed in accordance with their 
institution’s drug destruction policy or SOP.  A drug destruction memo and the 
site’s drug destruction SOP/policy should be sent to Celgene Medical Operations 
Dept.  A copy of the drug destruction memo should be retained at the clinical site.  
In the event of study completion or termination, a copy of all pharmacy records 
(drug dispensing log, drug accountability log and any destruction memos) must be 
mailed to Celgene Medical Operations. 
 
6.1.7 nab-Paclitaxel Premedication and Administration 
 
Patients do not require premedication prior to nab-Paclitaxel administration, as 
hypersensitivity reactions are rare.  In the unlikely event of a mild hypersensitivity 
reaction, premedication may be administered using the premedication regimen the 
institution typically uses for solvent based paclitaxel.  In the rare event of a severe 
hypersensitivity reaction, discontinue nab-Paclitaxel.  However, it is recommended 
that patients receive Granisetron 1mg prior to receiving nab-Paclitaxel. 
 
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line 
filters during the administration of nab-Paclitaxel. In any event, filters of pore-size 
less than 15 micrometers must not be used.  
 
Albumin-bound paclitaxel should be administered by IV over 30 minutes.  
 
6.2 
Cisplatin (CDDP, Platinol-AQ®) 
 
6.2.1 Cisplatin Description 
 
Molecular formula: PtCl2H6N2 
Molecular weight: 300.1. 
 
6.2.2 Clinical Pharmacology 
 
The mechanism of action of cisplatin has not been clearly elucidated. However the 
most likely mechanism of antitumor action of this drug resides in its ability to 
inhibit DNA synthesis, and to a lesser degree, RNA and protein synthesis. It has 
also been shown that Cisplatin binds to DNA and produces inter-strand cross-links. 
Also cisplatin is not phase-sensitive and its cytotoxicity is similar in all phases of 
the cell cycle. Additional information can be found in the package insert. 
 
6.2.3 Supplier 
 
Cisplatin is commercially available as 1 mg/mL in both 50 mL multiple dose vial 
and 100 mL multiple dose vial. 

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6.2.4 Dosage Form and Preparation 
 
The stability of cisplatin in solution is dependent upon the chloride ion 
concentration present in the diluent. Cisplatin should be diluted into an IV solution 
containing NaCL at a minimum chloride ion concentration of 0.040 mol/L (0.2% 
NaCL). Needles, syringes, catheters and IV administrations sets containing 
aluminum must be avoided during preparation and administration due to cisplatin-
aluminum reaction causing precipitation and loss of potency. Mannitol 12.5 to 25 
gm may be added per institutional guidelines. 
 
6.2.5 Storage and Stability 
 
The dry, unopened vials should be stored at room temperature (15° -25° C). The 
unopened container should be protected from light and stored in the carton until 
contents are used. Do not refrigerate. Cisplatin remaining in the amber vial 
following initial entry is stable for 28 days protected from light or for 7 days under 
fluorescent room light. 
 
6.2.6 Administration 
 
Patients will receive cisplatin via IV infusion over 60 minutes.  Adequate hydration 
must be maintained during and after administration as described in the treatment 
section. It is recommended that all patients should be premedicated with 
antiemetics. 
 
6.3 
Cetuximab (Erbitux) – with Radiation ARM 2 and selected ARM 1 or 3 
patients 
 
6.3.1 Cetuximab Description 
 
Cetuximab is an anti-EGFR human-to-murine chimeric antibody. 
 
6.3.2 Clinical Pharmacology 
 
The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a 
transmembrane glycoprotein that is a member of a subfamily of type I receptor 
tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is 
constitutively expressed in many normal epithelial tissues, including the skin and 
hair follicle. Expression of EGFR is also detected in many human cancers including 
those of the head and neck, colon, and rectum. 
 
Cetuximab binds specifically to the EGFR on both normal and tumor cells, and 
competitively inhibits the binding of epidermal growth factor (EGF) and other 
ligands, such as transforming growth factor-alpha. In vitro assays and in vivo 
animal studies have shown that binding of cetuximab to the EGFR blocks 
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inhibition of cell growth, induction of apoptosis, and decreased matrix 
metalloproteinase and vascular endothelial growth factor production. Signal 
transduction through the EGFR results in activation of wild-type KRAS protein. 
However, in cells with activating KRAS somatic mutations, the mutant KRAS 
protein is continuously active and appears independent of EGFR regulation. 
 
In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) 
against certain human tumor types. In vitro assays and in vivo animal studies have 
shown that cetuximab inhibits the growth and survival of tumor cells that express 
the EGFR. No antitumor effects of cetuximab were observed in human tumor 
xenografts lacking EGFR expression. The addition of cetuximab to radiation 
therapy or irinotecan in human tumor xenograft models in mice resulted in an 
increase in anti-tumor effects compared to radiation therapy or chemotherapy alone. 
 
6.3.3 Pharmacokinetics and Drug Metabolism 
 
Cetuximab administered as monotherapy or in combination with concomitant 
chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area 
under the concentration time curve (AUC) increased in a greater than dose 
proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 
L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses >200 mg/m2, it 
appeared to plateau. The volume of the distribution for cetuximab appeared to be 
independent of dose and approximated the vascular space of 2–3 L/m2. 
 
Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 
weekly dose), concentrations of cetuximab reached steady-state levels by the third 
weekly infusion with mean peak and trough concentrations across studies ranging 
from 168 to 235 and 41 to 85 μg/mL, respectively. The mean half-life of cetuximab 
was approximately 112 hours (range 63–230 hours). The pharmacokinetics of 
cetuximab were similar in patients with SCCHN and those with colorectal cancer. 
Based on a population pharmacokinetic analysis, female patients with colorectal 
cancer had a 25% lower intrinsic clearance of cetuximab than male patients. 
Qualitatively similar, but smaller gender differences in cetuximab clearance were 
observed in patients with SCCHN. The gender differences in clearance do not 
necessitate any alteration of dosing because of a similar safety profile. 
 
6.3.4 Supplier 
 
Cetuximab is commercially available and is listed in the compendia as indicated for 
the therapy of SCCHN. 
 
6.3.5 Dosage Form 
 
Each single-use, ready to use 50-mL vial contains 100 mg of cetuximab at a 
concentration of 2 mg/mL and is formulated in a preservative-free solution 
containing 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic 

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heptahydrate, 0.42mg/mL sodium phosphate monobasic monohydrate, and Water 
for injection, USP. 
 
 
6.3.6 Storage and Stability 
 
Cetuximab should be stored in a secure area according to local regulations. Store 
vials under refrigeration at 2ο C to 8ο C (36ο F to 46ο F). DO NOT FREEZE. 
Increased particulate formation may occur at temperatures at or below 0οC.  This 
product contains no preservatives.  Preparations of cetuximab in infusion containers 
are chemically and physically stable for up to 12 hours at 2ο C to 8ο C (36ο F to 46ο 
F) or up to 8 hours at controlled room temperature (20ο C to 25ο C; 68ο F to 77ο F).  
Discard any remaining solution in the infusion container after 8 hours at controlled 
room temperature or after 12 hours at 2ο to 8ο C.  Discard any unused portion of the 
vial. 
 
6.3.7 Safety Precautions 
 
Appropriate mask, protective clothing, eye protection, gloves, and Class II vertical-
laminar-airflow safety cabinets are recommended during preparation and handling.  
Opened vials must be disposed of at the investigational center as chemotherapy or 
biohazardous waste provided documented procedures for destruction are in place.  
 
Cetuximab therapy should be used with caution in patients with known 
hypersensitivity to cetuximab, murine proteins, or any component of this product. 
It is recommended that patients wear sunscreen and hats and limit sun exposure 
while receiving cetuximab as sunlight can exacerbate any skin reactions that may 
occur. 
 
6.3.8 Premedication 
 
In an effort to prevent a hypersensitivity reaction, all patients will be premedicated 
with diphenhydramine hydrochloride 50 mg (or an equivalent antihistamine) IVPB 
given 30-60 minutes prior to the Cetuximab.  Premedication will also include 
solucortef 100 mg IVPB and albuterol inhalation (by nebulizer or inhaler) 
according to standard of care procedures. 
 
6.3.9 Preparation and Administration 
 
Cetuximab must not be administered as an IV push or bolus. Cetuximab must be 
administered with the use of a low protein binding 0.22-micrometer in-line filter. 
Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab 
at a concentration of 2 mg/mL in phosphate buffered saline. DO NOT SHAKE OR 
DILUTE. Adequate hydration must be maintained before administration as 
described in the treatment section 
 
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Infusion Pump: 
 
• Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used). 
• Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (e.g., Baxter Intravia), ethylene vinyl acetate bags (e.g., Baxter 
Clintec), DEHP plasticized PVC bags (e.g., Abbott Lifecare), or PVC bags. 
• Repeat procedure until the calculated volume has been put in to the container.  
Use a new needle for each vial. 
• Administer through a low protein binding 0.22-micrometer in-line filter (placed 
as proximal to the patient as practical). 
• Affix the infusion line and prime it with cetuximab before starting the infusion. 
• Maximum infusion rate should not exceed 5 mL/min. 
• Use 0.9% saline solution to flush line at the end of infusion. 
• The infusion rate of cetuximab must never exceed 10 mg/minute (5 mL/min). 
The infusion time of cetuximab should not exceed 4 hours. Patients must be 
continuously observed during the infusion for signs of anaphylaxis. 
 
6.3.10 Patient Monitoring 
 
Patients should be closely monitored for treatment-related adverse events, 
especially hypersensitivity reactions during the infusion and for one post-infusion 
observation hour. Vital signs (blood pressure, heart rate, and temperature) will be 
monitored and recorded prior to the administration of cetuximab, 1/2 hour into the 
infusion, at the completion of the infusion, and 1 hour post-infusion for the initial 
dose. During all subsequent administrations of cetuximab, vital signs will be 
monitored and recorded prior to administration of cetuximab and at the end of the 
infusion; however, it is recommended that the patient be observed for 1-hour post 
infusion. 
 
 
7.0 
DOSE MODIFICATIONS 
 
At each of the scheduled visits noted in the study calendar, an assessment of adverse events (AE’s) 
will be made by the treating physician with toxicity grading using the NCI CTCAE version 3. 
Patients without AEs will continue on study treatment as planned. Patients who develop grade 1-
2 or selected grade 3 (nausea/vomiting/fatigue) AEs will be supported symptomatically and 
encouraged to continue on study treatment as planned. Modifications in their therapy may be 
necessary and will be detailed below.  Management of specific AEs is noted below. Omitted doses 
will not be made up at a later date. Dosing interruptions are permitted in the case of 
medical/surgical events or logistical reasons not related to study therapy.  
 
 
 

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7.1 
nab-Paclitaxel Dose Modifications 
 
7.1.1 Dose Modification Table 
 
Use this table as a guideline to determine any necessary dose modifications.   
  
Dose Level 
nab-Paclitaxel (mg/m2) 
Starting Dose 
100 
-1 
80 
-2 
60 
 
7.1.2 Administration of Study Drug to Patients with Abnormal 
Hematologic Function 
 
nab-Paclitaxel dosing should not be administered at the start of each cycle until the 
absolute neutrophil count returns to > 1.5 x 109 cells/L and the platelet count returns 
to > 100 x 109 cells/L.  For patients receiving weekly nab-Paclitaxel, patients must 
have an ANC > 0.5 x 109 cells/L and platelets > 50 x 109 cells/L for the Day 8 and 
Day 15 doses.  If the ANC and platelets are not adequate for treatment on Day 8 
and/or 15, the dose will be omitted and the total cycle length remains the same.    
 
7.1.3 Administration of Study Drug to Patients with Abnormal Hepatic 
Function 
 
For patients with mild hepatic impairment (total bilirubin > ULN and ≤ 1.5 x ULN 
and AST ≤ 10 x ULN), no dose adjustments are required regardless of indication.  
For patients with moderate hepatic impairment (total bilirubin between 1.5 x ULN 
and 5 x ULN), reduce nab-paclitaxel by one dose level.  Do not administer nab-
paclitaxel to patients with total bilirubin > 5 x ULN or AST > 10 x ULN regardless 
of indication as these patients have not been studied. 
 
7.1.4 Peripheral Neuropathy  
 
Peripheral neuropathy is dose- and schedule-dependent.  The occurrence of grade 
1 or 2 peripheral neuropathy does not generally require dose modification.  If ≥ 
grade 3 peripheral neuropathy develops, withhold nab-paclitaxel until resolution to 
≤ grade 1 followed by a dose reduction for all subsequent courses. 
 
7.1.5 Hypersensitivity Reactions  
 
Hypersensitivity reactions rarely occur, but severe and sometimes fatal 
hypersensitivity reactions, including anaphylactic reactions, have been reported.  If 
they do occur, minor symptoms such as flushing, skin reactions, dyspnea, lower 
back pain, hypotension, or tachycardia may require temporary interruption of the 

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infusion.  However, severe reactions, such as hypotension requiring treatment, 
dyspnea requiring bronchodilators, angioedema, or generalized urticaria require 
immediate discontinuation of study drug administration and aggressive 
symptomatic therapy.  Patients who experience a severe hypersensitivity reaction 
to nab-paclitaxel should not be re-challenged.   The use of nab-paclitaxel in patients 
previously exhibiting hypersensitivity to paclitaxel injection or human albumin has 
not been studied. 
 
7.1.6 Other Toxicities  
 
If toxicities are > grade 3 and deemed by the treating physician to at least possibly 
be related to nab-paclitaxel, except for anemia and lymphopenia, treatment should 
be withheld until resolution to < grade 1 or baseline if baseline was greater than 
grade 1, then reinstituted, if medically appropriate, at the next lower dose level. 
  
7.1.7 Dose Reductions and Guidelines for Optional Use of Growth Factors 
for Hematologic Toxicity 
 
The table below provides a guideline for implementing dose reductions and 
optional use of growth factor treatment for hematologic toxicity:  
 
Use of G-CSF and Dose Reductions for Hematologic Toxicity 
Adverse Event  
Occurrence  Action to be Taken  
ANC < 500 cells/mm3 
(nadir count) with 
neutropenic fever > 38° C 
 
OR 
 
Delay of next cycle due to 
persistent neutropenia 
(ANC < 1500 cells/mm3) 
  
OR 
 
For patients whose next 
treatment within a cycle 
First 
Occurrence  
The same dose of nab-Paclitaxel is 
maintained and G-CSF at 5 
mcg/kg/day is given the day after 
nab-Paclitaxel is given and should 
stop at least 48 hours prior to 
when nab-Paclitaxel is given the 
following week.    

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(Day 8 or Day 15) is 
omitted due to persistent 
neutropenia (ANC < 500 
cells/mm3)  
 
OR 
 
Neutropenia < 500 
cells/mm3 for > 1 week  
Recurrence 
In the event that a hematological 
toxicity re-occurs in the face of G-
CSF, dose reduction to the next 
lower level will be required for 
subsequent cycles once ANC is ≥ 
1500 cells/mm3. 
Grade 3 or 4 platelets 
decreased  
First 
Occurrence  
Dose reduction to next lower 
level; no administration of G-CSF 
required  
Recurrence  
Dose reduction to next lower 
level; no administration of G-CSF 
required  
 
7.2 
Cisplatin Dose Modifications 
   
7.2.1 Peripheral Neuropathy 
 
Grade 0, 1, or 2: no dose modification. 
 
Grade 3 or 4: Hold cisplatin until the event resolves to < grade 3. 
 
7.2.2 Ototoxicity 
 
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. 
 
 
 

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7.2.3 Kidney Impairment 
 
Calculated Creatinine 
Clearance 
Percent Dose to Give 
≥ 60 mL/min 
100% 
< 60 mL/min 
0% (withhold treatment for this dose and repeat serum 
creatinine weekly after additional hydration), then for 
next chemotherapy dose: 
If CrCl was already < 60 mL/min 
and is now:  
The percent dose 
to give is:  
> 50 but < 60 
80% 
≥ 40 but ≤ 50 
50% 
< 40 
0% 
Please note that dose reduction percentage is calculated by taking off from the original 
dose and not the previous dose. 
 
7.2.4 Thrombocytopenia 
 
Nadir of last course 
Platelets (Day 1 of each cycle) 
< 100,000 
> 100,000 
between 50,000 and 100,000 
Hold cisplatin 
Cisplatin = 100% 
< 50,000 (1st occurrence) 
Hold cisplatin 
Cisplatin = 80% 
<50,000 (2nd occurrence) 
Hold cisplatin 
Cisplatin = 60% 
 
7.3 
Cetuximab Dose Modifications 
 
Dose Levels for Cetuximab 
Dose Levels 
Weekly Cetuximab Dose 
Starting dose 
250 mg/m2 
Dose Level –1 
200 mg/m2 
Dose Level –2 
150 mg/m2 
 
There will be no dose level reductions below a weekly dose of 150 mg/m2.   
 
Any other toxicities deemed necessary of a dose reduction per the PI, using the 80% and 
60% dose reduction levels. 
 
 
 

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7.3.1 Management of Dermatologic Adverse Effects 
 
Patients developing dermatologic toxicities while receiving cetuximab should be 
monitored for the development of inflammatory or infectious sequelae, and 
appropriate treatment of these symptoms initiated.  Dose modifications of any 
future cetuximab infusions should be instituted in case of grade 3 acneiform rash.  
Treatment with topical and/or oral antibiotics (minocycline 100 mg bid) should be 
considered, but should not be given prophylactically; topical corticosteroids are not 
recommended. 
 
If a patient experiences grade 3 acneiform rash, cetuximab treatment adjustments 
should be made according to the following table.  In patients with mild and 
moderate skin toxicity, treatment should continue without dose modification. 
 
Cetuximab Dose Modification Guidelines for Grade 3 Acneiform Rash 
Occurrence Action 
Outcome 
Dose Modification 
First 
Delay infusion 1-2 weeks 
Improvement 
Continue at 250 mg/m2 
 
 
No Improvement 
Discontinue cetuximab 
Second 
Delay infusion 1-2 weeks  
Improvement 
Reduce to Dose Level -1 
 
 
No Improvement 
Discontinue cetuximab 
Third 
Delay infusion 1-2 weeks 
Improvement 
Reduce to Dose Level -2 
 
 
No Improvement 
Discontinue cetuximab 
Fourth 
Discontinue cetuximab 
N/A 
N/A 
 
7.3.2 Management of Gastrointestinal Adverse Effects 
 
Antiemetic agents may be administered prior to the administration of cetuximab.  
Diarrhea will be treated symptomatically with antidiarrheal agents.  Should GI 
toxicity become severe enough to require hospitalization or outpatient IV fluid 
replacement, all treatment should be discontinued temporarily until the patient’s 
condition improves. 
 
7.3.3 Management of Hypersensitivity Reactions 
 
Grading: 
Mild (grade 1) hypersensitivity reactions (HSRs) consist of urticaria, fever, or chills 
and are treated with symptom-directed management. 
 
Moderate (grade 2) HSRs consist of dyspnea, angioedema, or hypotension which 
reverses within one to two hours of appropriate symptom-directed management and 
stopping the cetuximab infusion. Symptom-directed management includes 
nebulized b2 agonists (albuterol 2.5 mg) for dyspnea and bronchospasm, 
intravenous fluid boluses (normal saline 1-2 liters) for hypotension, and the use of 
H1 and H2 antagonists (diphenhydramine and famotidine) and corticosteroids 
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Severe (grade 3) HSRs consist of dyspnea, angioedema, or hypotension, as the 
Grade 2 reactions do, but do not reverse following one to two hours of symptom 
directed management. 
 
Life-threatening/disabling (grade 4) HSRs consist of airway obstruction, shock, 
cardiac arrest, or prolonged hypotension. 
 
Grade 4 HSRs require the immediate interruption of cetuximab therapy and 
permanent discontinuation from further treatment.  Appropriate medical therapy 
including 
epinephrine, 
corticosteroids, 
intravenous 
antihistamines, 
bronchodilators, and oxygen should be available for use in the treatment of such 
reactions.  Patients should be carefully observed until the complete resolution of all 
signs and symptoms. 
 
In prior clinical trials, grade 1 and grade 2 infusion reactions were managed by 
slowing the infusion rate of cetuximab and by continued use of antihistamine pre-
medications (e.g., diphenhydramine) in subsequent doses.  If the patient 
experiences a grade 3 infusion reaction, the infusion rate should be permanently 
reduced by 50%.  For grade 1 or 2 reactions, additional doses of diphenhydramine 
or corticosteroids may be administered. 
 
7.3.4 Management of Isolated Drug Fever 
 
If a patient experiences isolated drug fever, subsequent pre-treatment with 
acetaminophen or a non-steroidal anti-inflammatory agent may be considered. If a 
patient experiences recurrent isolated drug fever following premedication and post-
dosing with an appropriate antipyretic, the infusion rate for subsequent dosing 
should be 50% of previous rate. 
 
7.3.5 Management of Pulmonary Adverse Effects 
 
In the event of acute onset (grade ≥ 2) or worsening pulmonary symptoms which 
are not thought to be related to underlying cancer, cetuximab therapy should be 
interrupted and a prompt investigation of these symptoms should occur. Cetuximab 
re-treatment should not occur until these symptoms have resolved to grade 1. If 
interstitial lung disease is confirmed, cetuximab should be discontinued and the 
patient should be treated appropriately.  
 
7.3.6 Management of Renal Adverse Effects 
 
Hypomagnesemia has been reported with cetuximab when administered as a single 
agent and in combination with multiple different chemotherapeutic regimens. 
Patients receiving cetuximab should be monitored for hypomagnesemia. 
Magnesium repletion may be necessary based on clinical judgment. 
 

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8.0 
CORRELATIVE STUDIES 
 
8.1 
Genomic Analysis   
 
Our hypothesis is that the high anti-tumor efficacy of nab-paclitaxel in HNSCC is due to 
the frequent presence of Ras and PI3K (and EGFR) pathway activation in this cancer.  Pre-
treatment tumor biopsies will undergo mutational (and IHC) analyses of the PI3 kinase 
pathway and H-ras. Mutational analysis of the PI3 Kinase pathway includes PIK3CA, 
PIK3CG, PTEN, PIK3R1 and PIK3R5. IHC analysis of the PI3kinase pathway includes 
EGFR, AKT, PIK3CA, PTEN, MET and pS6 kinase. The association of these biomarkers 
with CR at the PTS and relapse events will be evaluated. 
 
8.2 
Immunologic Analysis 
 
Immunodeficiency is a risk factor for HNSCC. Novel HNSCC-specific tumor antigens 
exist (mutCASP-8, Cyclin D, ALDH). TILs are associated with increased recurrence risk 
in some studies.  FoxP3 expression is associated with poorer OS in oropharyngeal and 
hypopharyngeal HNSCC. PD-L1, an immune checkpoint inhibitory ligand, is expressed on 
tumor and macrophage cells in HPV-positive and HPV-negative HNSCC.  B7-H1 blockade 
augmented adoptive T-cell immunotherapy in HNSCC32-45.   
 
Paclitaxel has effects on immunity with selectively reduced Tregs.  It promoted cytotoxic 
T-cell responses, abolished tumor cell inhibition of dendritic cell differentiation and 
stimulated macrophages46-49. Our hypothesis is that nab-paclitaxel will deplete Tregs, 
decrease PD-L1, and increase TIL at the PTS. PTS tumor biopsies obtained before and 
after 2 cycles of nab-paclitaxel induction chemotherapy (Arms 1-3) will be analyzed for 
Tregs, TIL, and PD-L1 by IHC. IHC analysis includes TIL markers and PD-L1. CD3, CD4, 
CD8, Foxp3 and the monocytic marker CD116 will also be analyzed. The association of 
these biomarkers (before nab-paclitaxel and the change after 2 cycles of nab-paclitaxel) 
with CR at the PTS and relapse events will be evaluated. 
 
Specimens shall be transported to the Washington University lab c/o Dr. Douglas Adkins, 
located on the 3rd floor of the McKinley Ave. building  or shipped to the address listed 
below: 
 
Dr. Brian Van Tine – Research lab 
4515 McKinley Building, 3rd Floor 
4523 Clayton Avenue 
St. Louis, MO 63110 
 
8.3 
Quality of Life Assessments 
 
Quality of Life (QOL) questionnaires will be administered to patients at baseline, prior to 
starting radiation, at the last week of radiation, at the 6-month follow-up visit, and at the 
12-month follow-up visit.  The 4-page questionnaire will assess physical, social, emotional, 

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and functional well-being through questions designed specifically for patients with head & 
neck cancer.  An additional 4-question QOL survey will assess symptoms of peripheral 
neuropathy, a side effect often seen in patients receiving nab-paclitaxel. 
 
 
9.0 
DEFINITION OF TUMOR RESPONSE CRITERIA 
 
9.1 
Visual Categorical Outcomes 
 
Visual categorical outcomes will be used to assess tumor response at the primary site and 
involved regional nodes after two cycles of induction chemotherapy and after completion 
of definitive radiation and concurrent cetuximab therapy. Primary site responses will be 
dictated in ENT note.  Neck node measurements will be taken from the medical oncology 
physical exam measurements also dictated, but into the medical oncology note. 
 
Visual Categorical Outcomes 
CR 
Complete resolution – 100% decrease/minimal residual mucosal abnormality 
PR 
99-50% decrease 
SD 
49-0% decrease 
PD 
Any increase 
 
9.2 
RECIST Criteria 
 
The RECIST 1.0 criteria will be used to assess anatomic tumor response (Appendix 2).  
 
9.3 
PET/CT Imaging 
 
FDG-PET/CT will be utilized to assess tumor metabolic response. PET/CT imaging will 
be performed with a PET/CT scanner   All patients will undergo FDG-PET/CT imaging at 
baseline (no more than 42 days prior to Cycle 1 day 1), between Cycle 2 Days 16 and 20, 
and at 16 weeks (+/- 2 weeks) following completion of definitive radiation therapy in 
accordance with the Division of Nuclear Medicine standard procedure for FDG-whole-
body tumor imaging.   Care should be taken to match follow-up examinations as close as 
possible to the baseline imaging parameters with no more than 10 minutes deviation in 
uptake time but must also adhere to the minimum 50 minutes of uptake time.  In rare 
instances uptake times of greater than 70 minutes are allowed providing the overall uptake 
time does not go beyond the 10 minute deviation from baseline examination.  Each patient 
will undergo all 3 FDG-PET/CT scans even if s/he has measurable disease by RECIST but 
not by PET criteria. 
 
The standard whole-body examination for FDG-PET/CT imaging in patients with head and 
neck cancer typically includes images from the skull vertex to the upper thighs.  An i.v. 
(typically, a 20- or 22-gauge Angiocath) or butterfly needle will be placed in an upper 
extremity vein for injection of FDG and i.v. hydration (up to 500 ml of 0.9% saline 
solution).  The administered dose of FDG will be based upon subject weight and range 
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of maximum and minimum dose allowed.  FDG will be administered intravenously.  In 
cases of poor venous access (butterfly injection of FDG), oral hydration will replace 
intravenous hydration.  Approximately 60 (50-70) minutes after injection of FDG, imaging 
will be initiated.    
 
PET/CT imaging will be according to local protocol.  The following is minimum suggested 
imaging requirements:  With the patient positioned supine in the scanner and with the 
patient’s arms at the side of the body, the CT images used for attenuation correction and 
image fusion will be obtained.  The CT will consist of a 5-10 second topogram a followed 
by a diagnostic quality CT scan without i.v. contrast for attenuation correction.  Scans are 
reconstructed using a 5-mm slice thickness.  This is followed by a series of sequential 2 to 
5-minute emission scans at each bed position, beginning at the vertex of the skull and 
proceeding caudally to the upper thighs.  Images are reconstructed with ordered subset 
expectation maximization (OSEM) and smoothing per scanner manufacturer 
recommendations  
 
 
10.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 
Celgene requires that all adverse events be reported as outlined in Section 10.6. 
 
10.1 
Definitions 
 
10.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 3.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
(http://www.hhs.gov/ohrp/policy/AdvEvntGuid.html).   
 
 

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10.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
Please refer to Section 10.7 for reporting restrictions. 
 
10.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
10.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
10.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 

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10.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
10.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
10.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the 
event. For secondary sites, the Washington University PI will issue approval of the 
exception, but it must also be submitted to the local IRB with documentation of 
approval forwarded to Washington University. Washington University IRB 
approval is not required for protocol exceptions occurring at secondary sites.  
 
10.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
The Investigator must keep copies of all AE information, including correspondence with 
Celgene and the IRB/EC, on file. 
 

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10.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU 
or any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
10.4 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and research coordinator of all reportable events (as described in Section 
10.6) within 1 working day of the occurrence of the event or notification of the secondary 
site’s PI of the event.  This notification may take place via email if there is not yet enough 
information for a formal written report (using either an FDA MedWatch form if required 
or an institutional SAE reporting form if not).  A formal written report must be sent to the 
Washington University PI and research coordinator within 10 working days of the 
occurrence of the event or notification of the secondary site’s PI of the event.  The death 
of a research participant that qualifies as a reportable event should be reported within 1 
working day of the occurrence of the event or notification of the secondary site’s PI of the 
event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines. 
The research team at Washington University is responsible for reporting all applicable 
events to the FDA.  
 
10.5 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary 
site of all reportable events that have occurred at other sites within 10 working days of the 
occurrence of the event or notification of the PI of the event.  This includes events that take 
place both at Washington University and at other secondary sites, if applicable. 
 
10.6 
Reporting to Celgene 
 
An adverse event is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study.  It may be a new intercurrent 
illness, a worsening concomitant illness, an injury, or any concomitant impairment of the 
subject’s health, including laboratory test values (as specified by the criteria below), 
regardless of etiology.  Any worsening (i.e., any clinically significant adverse change in 
the frequency or intensity of a pre- existing condition) should be considered an AE. 
 

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An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE.  If an overdose is associated with an AE, the overdose and adverse event should be 
reported as separate terms. 
 
All patients will be monitored for AEs during the study.  Assessments may include 
monitoring of any or all of the following parameters:  the subject’s clinical symptoms, 
laboratory, pathological, radiological or surgical findings, physical examination findings, 
or other appropriate tests and procedures. 
 
All AEs will be recorded by the Investigator from the time the subject signs informed 
consent to 30 days after the last dose of IP.  All SAEs must be reported to Celgene Drug 
Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, or other 
appropriate method, using the SAE Report Form, or approved equivalent form using the 
contact information below: 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr., Suite 6000 
Berkeley Heights, N.J. 07922 
Fax: 908-673-9115 
Email: drugsafety@celgene.com 
 
10.6.1 Seriousness 
 
A serious adverse event (SAE) is any AE occurring at any dose that: 
• Results in death; 
• Is life-threatening (i.e., in the opinion of the investigator, the subject is at 
immediate risk of death from the AE); 
• Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization (hospitalization is defined as an inpatient admission 
regardless of length of stay) 
• Results in persistent or significant disability/incapacity (a substantial 
disruption of the subject’s ability to conduct normal life functions); 
• Is a congenital anomaly/birth defect; 
• Constitutes an important medical event. 
 
Important medical events are defined as those occurrences that may not be 
immediately life threatening or result in death, hospitalization, or disability, but 
may jeopardize the subject or require medical or surgical intervention to prevent 
one of the other outcomes listed above. Medical and scientific judgment should be 
exercised in deciding whether such an AE should be considered serious. 
 
 
 

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Events not considered to be SAEs are hospitalizations for: 
• A standard procedure for protocol therapy administration.  However, 
hospitalization or prolonged hospitalization for a complication of therapy 
administration will be reported as an SAE. 
• Routine treatment or monitoring of the studied indication not associated 
with any deterioration in condition. 
• The administration of blood or platelet transfusion as routine treatment of 
studied indication.  However, hospitalization or prolonged hospitalization 
for a complication of such transfusion remains a reportable SAE. 
• A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  
However, hospitalization or prolonged hospitalization for a complication of 
such procedures remains a reportable SAE. 
• Hospitalization or prolongation of hospitalization for technical, practical, or 
social reasons, in absence of an AE. 
• A procedure that is planned (i.e., planned prior to start of treatment on 
study).  Hospitalization or prolonged hospitalization for a complication 
remains a reportable SAE. 
• An elective treatment of a pre-existing condition unrelated to the studied 
indication. 
• Emergency outpatient treatment or observation that does not result in 
admission, unless fulfilling other seriousness criteria above. 
 
10.6.2 Severity / Intensity 
 
For both AEs and SAEs, the Investigator must assess the severity / intensity of the 
event. 
 
The term “severe” is often used to describe the intensity of a specific event (as in 
mild, moderate or severe myocardial infarction); the event itself, however, may be 
of relatively minor medical significance (such as severe headache).  This criterion 
is not the same as “serious” which is based on subject/event outcome or action 
criteria associated with events that pose a threat to a subject’s life or functioning. 
 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
 
10.6.3 Causality 
 
The Investigator must determine the relationship between the administration of 
IP and/or gemcitabine and the occurrence of an AE/SAE as Not Suspected or 
Suspected as defined below: 
 
• Not suspected: The temporal relationship of the adverse event to IP 
administration makes a causal relationship unlikely or remote, or other 
medications, therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event. 

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• Suspected: The temporal relationship of the adverse event to IP 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions do not 
provide a sufficient explanation for the observed event. 
 
If an event is assessed as suspected of being related to a comparator, ancillary or 
additional IP that has not been manufactured or provided by Celgene, please 
provide the name of the manufacturer when reporting the event. 
 
10.6.4 Duration 
 
For both AEs and SAEs, the Investigator will provide a record of the start and stop 
dates of the event. 
 
10.6.5 Action Taken 
 
The Investigator will report the action taken with IP as a result of an AE or SAE, 
as applicable (eg., discontinuation or reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
 
10.6.6 Outcome 
 
All SAEs that have not resolved upon discontinuation of the subject’s participation 
in the study must be followed until recovered, recovered with sequelae, not 
recovered (death due to another cause) or death (due to the SAE). 
 
10.6.7 Abnormal Laboratory Values 
 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• Results in discontinuation from the study; 
• Require treatment, modification/interruption of IP dose, or any other 
therapeutic intervention, or 
• Is judged to be of significant clinical importance. 
 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness 
criterion need to be documented as a serious adverse event. 
 
10.6.8 Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject is 
on IP, or within 30 days of the subject’s last dose of IP, are considered immediately 
reportable events.  IP is to be discontinued immediately. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 

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immediately by facsimile, or other appropriate method, using the Pregnancy Initial 
Report Form, or approved equivalent form. 
 
The Investigator will follow the female subject until completion of the pregnancy, 
and must notify Celgene Drug Safety immediately about the outcome of the 
pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form, or approved equivalent form.  
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE.  If the 
abnormal outcome meets any of the serious criteria, it must be reported as an SAE 
to Celgene Drug Safety immediately by facsimile, or other appropriate method, 
within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form, or approved equivalent form. 
 
10.6.9 Male Subjects 
 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking IP should notify the Investigator, and the pregnant 
female partner should be advised to call their healthcare provider immediately. 
 
10.6.10 Reporting of Serious Adverse Events 
 
All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the event by facsimile, or other appropriate method, 
using the SAE Report Form, or approved equivalent form.  This instruction pertains 
to initial SAE reports as well as any follow-up reports. 
 
The Investigator is required to ensure that the data on these forms is accurate and 
consistent. 
 
This requirement applies to all SAEs (regardless of relationship to IP) that occur 
during the study (from the time the patient signs informed consent to 30 days after 
the last dose of IP), and those made known to the Investigator at anytime thereafter 
that are suspected of being related to IP. SAEs occurring prior to treatment will be 
captured. 
 
The SAE report should provide a detailed description of the SAE and include 
summaries of hospital records and other relevant documents.  If a patient died and 

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an autopsy has been performed, copies of the autopsy report and death certificate 
are to be sent to Celgene Drug Safety as soon as these become available. Any 
follow-up data will be detailed in a subsequent SAE Report Form, or approved 
equivalent form, and sent to Celgene Drug Safety. 
 
Where required by local legislation, the Investigator is responsible for informing 
the IRB/EC of the SAE and providing them with all relevant initial and follow-up 
information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC. 
 
10.6.11 Expedited Reporting of Adverse Events 
 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to nab-paclitaxel based on the 
Investigator Brochure. 
 
Celgene or its authorized representative shall notify the Investigator of the 
following information: 
 
• Any AE suspected of being related to the use of IP in this study or in other 
studies that is both serious and unexpected (ie., SUSAR); 
• Any finding from tests in laboratory animals that suggests a significant risk 
for human patients including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to patients. The Investigator is also 
responsible to report all SAEs to the FDA within 24 hours. 
 
10.7 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 30 days following the last day of study treatment. For 
the purposes of this protocol, adverse events that meet the definition of serious (as per 
Sections 10.1.2 and 10.6.1) but occur outside of the induction period will not be considered 
SAEs unless determined to be at least possibly related to nab-Paclitaxel.  The induction 
period starts at time of informed consent and continues through 30 days after the last dose 
of nab-paclitaxel. 
 
For Arm 3, the event of disease relapse will be specifically tracked from Day 1 of radiation 
through 6 months post-completion of radiation. Also refer to Section 11.3, Paragraph 2. 
 
 
 
 
 
 

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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design 
 
This is a non-randomized phase II trial with three parallel treatment arms whose primary 
objective is to determine the CR rate by clinical exam at the primary tumor site to an IC 
regimen of Arm 1 weekly nab-Paclitaxel with P (AP) given for two cycles (over 6 weeks), 
Arm 2: weekly nab-Paclitaxel (A) given for two cycles (over 6 weeks), and Arm 3 (HPV-
related OPSCC): AP given for two cycles (over 6 weeks) in patients with locally advanced 
non-metastatic HNSCC.  
 
Arms 1 and 2: Each treatment group will be compared with a historical control from the 
APF study. There will be no comparison between the AP and A treatment groups.  
 
The primary endpoint for each arm (AP or A) is that the PTS CR rate will be non-inferior 
to the PTS CR rate observed with APF (77%). A CR rate ≥ 58%, or no more than 19% less 
than the historically observed 77%, will be considered noninferior. 
 
In each treatment group patient recruitment will be stratified by HPV status 
(positive/negative) in order to ensure that the proportion of positive and negative patients 
is approximately equal in the two treatment groups. The expected CR rate is 77% in both 
HPV positive and negative patients.  
 
For the following secondary objectives, the analysis of primary tumor site response to the 
IC regimen will also be stratified based on T stage (T2 vs. T3 vs. T4) and will be reported 
as frequencies (with 95% confidence intervals) in each T stage category.  For purposes of 
testing hypotheses, stratification will be included as an adjustment variable in: 
 
 Documenting the clinical partial response (PR) rate at the primary tumor site and 
the clinical CR and PR rates at the involved regional nodes following two cycles of 
AP or A; 
 Documenting the anatomic tumor response as assessed by CT scan using RECIST 
criteria following two cycles of AP or A; 
 Documenting and quantifying Ki-67 expression by IHC and histologic tumor 
response in primary tumor tissue obtained at baseline and following two cycles of 
AP or A and correlate these results with clinical primary tumor site response to AP 
or A; 
 Documenting and grading AE’s with AP or A, and comparing to those observed 
with APF;  
 Determining median or year-by-year overall survival (OS), disease-free survival 
(DFS), and progression-free survival (PFS) in these patients; and, 
 Documenting the measures of Quality of Life (QoL) before, during, and at one year 
after completion of treatment in both treatment groups. 
 
 
 
 

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ARM 3: This arm will be compared with Arm 1 (data as of October, 2017). 
 
The primary endpoint is to determine the median percent weight loss in patients with 
HPV-positive OPSCC who are treated with AP. De-escalated CRT will reduce the 
median percent weight loss by 50% compared to CRT. Mucosal toxicity during CRT 
resulted in a median weight loss of 13.1% (range: 5% - 23.2%) in Arm 1 (null 
hypothesis). We hypothesize that the de-escalated CRT regimen in Arm 3 will result in 
a 50% reduction in the median weight loss (alternative hypothesis).  
 
A secondary endpoint for Arm 3: The PTS CR rate will be non-inferior to the PTS CR 
rate observed with APF (77%). A CR rate ≥ 58%, or no more than 19% less than the 
historically observed 77%, will be considered noninferior. 
 
For the following secondary objectives (except AEs and QOLs), the analysis of primary 
tumor site response to the IC regimen will also be stratified based on T stage (T1/2 vs. 
T3 vs. T4) and will be reported as frequencies (with 95% confidence intervals) in each T 
stage category.  For purposes of testing hypotheses, stratification will be included as an 
adjustment variable in: 
 
 Documenting the clinical partial response (PR) rate at the primary tumor site and 
the clinical CR and PR rates at the involved regional nodes following two cycles 
of IC; 
 Documenting the anatomic tumor response as assessed by CT scan using RECIST 
criteria following two cycles of IC; 
 Documenting and quantifying Ki-67 expression  by IHC and histologic tumor 
response in primary tumor tissue obtained at baseline and following two cycles of 
IC and correlate these results with clinical tumor response at the primary 
tumor site; 
 Documenting and grading AE’s and comparing to those observed with Arm 1; 
 Determining median or year-by-year overall survival (OS), disease-free survival 
(DFS), and progression-free survival (PFS) in these patients; and, 
 Documenting the measures of Quality of Life (QoL) before, during, and at one 
year after completion of treatment. 
 
In addition, the study will compare arm 3 to arm 1 (the AP arm) as follows: 
• Response rate, OS, DFS, and PFS. 
• Rate of grade 3-4 AEs during CRT. 
• The median absolute and percent weight loss during CRT. 
 
11.2 
Analysis Plan and Study Power 
 
Arms 1 and 2: Two one-sample tests for noninferiority, stratified by HPV status, will be 
used to determine whether the CR with AP or A is no more than 19% less than the CR rate 
with APF.  Given an expected rate of CR with APF is 77%, a 19% difference (58% vs 
77%) is considered to be clinically equivalent.  With a noninferiority margin of 19%, a 
sample of 40 patients will provide each treatment group with power = 0.80 power at a 

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significance level of 0.05 to conclude that the CR rate with AP or A is not inferior to that 
with APF. 
 
Proportions of patients with clinical PR at the primary tumor site, clinical CR and PR rates 
at the involved regional nodes, anatomic and metabolic tumor responses, and AEs by type, 
grade and patient will be calculated with 95% confidence intervals. The proportion of 
patients with grade 3-4 AEs is 40% in the APF study. It is expected to be at least 25% 
lower with AP (40% decreased to 30%) and at least 50% lower with A (40% decreased to 
20%). 
 
Arm 3: The primary hypothesis for Arm 3 is: de-escalated CRT will reduce the median 
percent weight loss by 50% compared to CRT. Mucosal toxicity during CRT resulted in 
a median weight loss of 13.1% (range: 5% - 23.2%) in Arm 1 (null hypothesis). We 
hypothesize that the de-escalated CRT regimen in Arm 3 will result in a 50% 
reduction in the median weight loss (alternative hypothesis). If weight loss is 50% of 
the historical amount (that is, about 6.5% vs. historical 13.1%), the standard 
deviation of percent weight loss is about the same as the mean (that is, ± 13%), then 
a sample of 30 patients will provide power=.84 at a .05 significance level to detect this 
difference. Nonparametric Kruskal-Wallis test, a Friedman nonparametric one-way 
ANOVA or paired permutation test will be used to compare median weight loss during 
CRT in arm 3 vs. arm 1. Median weight loss will be calculated in the treatment arm with 
bootstrapped confidence intervals. 
 
All Arms: Nonparametric Wilcoxon tests will be used to compare Ki-67 expression by 
ICH categories. Two clustered logistic regression (GEE) models also may be used to 
quantify the odds of histologic tumor response over time by clinical primary tumor 
response. AE rates during CRT will be described as binomial proportions with exact 
95% confidence intervals in arm 3 versus arm 1. One sided tests for difference of 
binomial proportions may be used to test for differences in AE rates with a false discovery 
rate adjustment for multiple testing if >5 tests are carried out. Kaplan-Meier models will 
be used to estimate median OS, DFS, and PFS (if the median is reached) and to estimate 1 
and 2 year rates of OS, DFS, and PFS with 95% confidence intervals. Kaplan-Meier models 
will be used to compare OS, DFS and PFS in arm 3 vs. arm 1. 
 
All Arms: Summary and subscale scores from the FACT-N&N and the FACT-GOG-NTX-
4 will be plotted at baseline, completion of treatment, and one year after end of treatment.  
Ordinal logistic regression will be used to estimate the association of demographic, clinical, 
and response covariates with QOL at each time point.  Generalized estimating equations 
(GEE) may be used to estimate the association of the same covariates with change in QOL 
over time.  These plots and models are exploratory and descriptive. 
 
11.3 
Adverse Primary Outcome Monitoring 
 
The rate of unfavorable PTS response, SD + PD, will be monitored using a continuous 
toxicity monitoring rule. The observed SD + PD rate in the APF study was 7%, and the 
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due to excess unfavorable response if the number of patients with unfavorable responses 
reaches 2 in the first 5, or 3 in the first 11, or 4 in the first 19, or 5 in the first 27, or 6 in 
the first 37, or if the 7th is observed before the 40th patient has completed the trial. Forty 
patients will be accrued to each arm of the study. 
 
In Arm 3, unfavorable response will be monitored as the number of relapses, also using 
continuous toxicity monitoring criteria. The expected relapse rate is 10%, and the 
maximum acceptable rate is 25%. A modified Pocock boundary with boundary shape 
parameter=0.2 specifies that the study will be suspended for review if it observes 3 relapses 
among the first 7 patients, or 4 among the first 14 patients, or 5 among the first 21 patients, 
or 6 among the first 29 patients, or if the 7th relapse is observed before the 30th patient has 
completed the study. These criteria have probability=.80 of correct early stopping if the 
true relapse rate is 25% and probability=.10 of incorrect early stopping if the true relapse 
rate is 10%. 
 
 
12.0 
DATA SUBMISSION SCHEDULE 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
Baseline Form 
Prior to starting treatment 
AP or A Induction Form 
Every cycle 
Definitive Therapy Form 
At completion of definitive therapy 
AE Tracking Form 
Continuous 
Follow Up Form 
Per protocol 
CT Measurement Form 
Baseline, end of Cycle 2, 8 week follow-up, 16 week follow-up 12 
month follow-up, 20 month follow-up, 28 month follow-up, 36 
month follow-up 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 
 
 
 
 
 
 
 
 
 

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13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Committee (DSMC) will be specifically convened for 
this trial to review toxicity data at least every 6 months following the activation of the first 
secondary site.  A DSMC will consist of no fewer than 3 members including 2 clinical investigators 
and a biostatistician.  Like investigators, DSMC members are subject to the Washington University 
School of Medicine policies regarding standards of conduct. Individuals invited to serve on the 
DSMC will disclose any potential conflicts of interest to the trial principal investigator and/or 
appropriate university officials, in accordance with institution policies. Potential conflicts that 
develop during a trial or a member’s tenure on a DSMC must also be disclosed.  
 
The DSM report will be prepared by the study statistician with assistance from the study team, 
will be reviewed by the DSMC, and will be submitted to the Quality Assurance and Safety 
Monitoring Committee (QASMC).  This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date and accrual by site 
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
• Summary of toxicities at all participating sites 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to 
be prepared by the study team will be submitted to the QASM Committee beginning 6 months 
after study activation at Washington University. 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 

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14.0 
AUDITING 
 
Since Washington University is the coordinating center, each site will be audited annually by 
Siteman Cancer Center personnel (QASMC) unless the outside institution has an auditing 
mechanism in place and can provide a report. The outside sites will be asked to send copies of all 
audit materials, including source documentation.  The audit notification will be sent to the 
Washington University Research Patient Coordinator, who will obtain the audit materials from the 
participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Additional details regarding the Auditing Policies and procedures can be found at 
http://www.siteman.wustl.edu/uploadedFiles/Research_Programs/Clinical_Research_Resources/
Protocol_Review_and_Monitoring_Committee/QASMCQualityAssurance.pdf  
 
 
15.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Principal Investigator (or designee) 
prior to IRB/IEC submission.    
 
Each participating institution must have the following documents on file at Washington University 
prior to first subject enrollment: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show which 
version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality 
Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and 
the Washington University study team. 
• Documentation of FWA, a signed financial disclosure form, signed FDA Form 1572, and 
signed and dated CVs of all participating investigators. 
• Documentation of training in protection of human subjects by all participating 
investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The Principal Investigator is responsible for disseminating to the participating sites all study 
updates, amendments, reportable adverse events, etc.  There will be one current version of the 
protocol document at any given time and each participating institution will utilize that document.  
Protocol/consent modifications and IB updates will be forwarded electronically to the secondary 
sites within 2 weeks of obtaining Washington University IRB approval with acknowledgement of 

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receipt requested.  Secondary sites are to submit protocol/consent/IB modifications to their local 
IRBs within 4 weeks of receipt, and confirmation of submission must be forwarded to the 
appropriate contact person on the Washington University study team at the time of submission.  
Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to the 
Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 

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16.0 
REFERENCES 
 
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA Cancer J Clin 57:43-66, 
2007 
2. Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, fluorouracil, and docetaxel in 
unresectable head and neck cancer. N Engl J Med 357:1695-704, 2007 
3. Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil alone or with 
docetaxel in head and neck cancer. N Engl J Med 357:1705-15, 2007 
4. Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and 
fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell 
cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. 
Lancet Oncol. 2011;12(2):153-9. 
5. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al: Phase III study comparing cisplatin 
plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy 
followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 
23:8636-45, 2005 
6. Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by 
concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent 
chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a 
randomised phase 3 trial.  Lancet Oncol. 2013;14(3):257-64. 
7. Ensley JF, Jacobs JR, Weaver A, et al: Correlation between response to cisplatinum-
combination chemotherapy and subsequent radiotherapy in previously untreated patients 
with advanced squamous cell cancers of the head and neck. Cancer 54:811-4, 1984 
8. Spaulding MB, Fischer SG, Wolf GT: Tumor response, toxicity, and survival after 
neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The 
Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin 
Oncol 12:1592-9, 1994 
9. Kuperman DI, Nussenbaum B, Thorstad W, et al. Retrospective analysis of the addition 
of cetuximab to induction chemotherapy (IC) with docetaxel, cisplatin, and 5-fluorouracil 
(TPF-C) for locally advanced squamous cell carcinoma of the head and neck (LA-
HNSCC). ASCO Meeting Abstracts 2007;25:6072. 
10. Desai N, Trieu V, Yao Z, et al: Increased antitumor activity, intratumor paclitaxel 
concentrations, and endothelial cell transport of cremophor-free, albumin-bound 
paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 
12:1317-24, 2006 
11. Gradishar WJ, Tjulandin S, Davidson N, et al: Phase III trial of nanoparticle albumin-
bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with 
breast cancer. J Clin Oncol 23:7794-803, 2005 
12. John TA, Vogel SM, Tiruppathi C, et al: Quantitative analysis of albumin uptake and 
transport in the rat microvessel endothelial monolayer. Am J Physiol Lung Cell Mol 
Physiol 284:L187-96, 2003 
13. Sparreboom A, Scripture CD, Trieu V, et al: Comparative preclinical and clinical 
pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) 
and paclitaxel formulated in Cremophor (Taxol). Clinical cancer research : an official 
journal of the American Association for Cancer Research 11:4136-43, 2005 
14. Choi P, Jordan CD, Mendez E, et al: Examination of oral cancer biomarkers by tissue 

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microarray analysis. Arch Otolaryngol Head Neck Surg 134:539-46, 2008 
15. Chin D, Boyle GM, Williams RM, et al: Novel markers for poor prognosis in head and 
neck cancer. Int J Cancer 113:789-97, 2005 
16. Neesse A, Frese KK, Chan DS, et al. SPARC independent drug delivery and antitumour 
effects of nab-paclitaxel in genetically engineered mice. Gut. 2014;63(6):974-83. 
17. Yardley DA. nab-Paclitaxel mechanisms of action and delivery. J Control Release. 
2013;170(3):365-72. 
18. Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of protein 
is an amino acid supply route in Ras-transformed cells.  Nature. 2013;497(7451):633-7. 
19. Morris R, Sancho-Martinez I, Sharpee TO and Izpisua Belmonte JC. Mathematical 
approaches to modeling development and reprogramming. Proc Natl Acad Sci U S A. 
2014;111(14):5076-82.  
20. Rampias T, Giagini A, Siolos S, et al. RAS/PI3K crosstalk and cetuximab resistance in 
head and neck squamous cell carcinoma. Clin Cancer Res. 2014;20(11):2933-46.  
21. Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck 
squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 
2011;333(6046):1154-7. 
22. Stransky N, Egloff AM, Tward AD, et al.The mutational landscape of head and neck 
squamous cell carcinoma. Science. 2011;333(6046):1157-60.  
23. Lui VW, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and 
neck cancer defines predictive biomarkers. Cancer Discov. 2013;3(7):761-9.  
24. Pickering CR, Zhang J, Yoo SY, et al. Integrative genomic characterization of oral 
squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov. 
2013;3(7):770-81.  
25. Rothenberg SM and Ellisen LW. The molecular pathogenesis of head and neck squamous 
cell carcinoma. J Clin Invest. 2012;122(6):1951-7. 
26. Adkins D, Ley J, Trinkaus K, et al. A phase 2 trial of induction nab-paclitaxel and 
cetuximab given with cisplatin and 5-fluorouracil followed by concurrent cisplatin and 
radiation for locally advanced squamous cell carcinoma of the head and neck. Cancer. 
2013;119(4):766-73. 
27. Schell A, Ley J, Wu N, et al. Nab-Paclitaxel-based Compared to Docetaxel-based 
Induction Chemotherapy Regimens for Locally Advanced Squamous Cell Carcinoma of 
the Head and Neck. Cancer Medicine, In Press 2014. 
28. Ley JC, Nussenbaum B, Diaz J, et al. Comparison of clinical primary tumor site (PTS) 
response to induction chemotherapy (IC) with APF (nab-paclitaxel, cisplatin, and 5-FU) 
or APF plus cetuximab (APF+Cetux) in patients with locally advanced squamous cell 
carcinoma of the head and neck (SCCHN). J Clin Oncol. 2014;32:5s. ProcASCO 2014. 
29. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-
painted intensity modulated radiation therapy in combination with 5-fluorouracil and 
mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J 
Radiat Oncol Biol Phys. 2013;86(1):27-33. 
30. Marur S, Li S, Cmelak AJ, et al. E1308: Phase II Trial of induction chemotherapy 
followed by reduced-dose radiation and weekly cetuximab in patients with hpv-
associated resectable squamous cell carcinoma of the oropharynx-ECOG-ACRIN Cancer 
Research Group. J Clin Oncol. 2017;35(5):490-7. 

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31. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue complication probability 
models in the clinic.Int J Radiation Oncology Biol Phys.2010;76(3):S10-9. 
32. Uppaluri R, Dunn GP, and Lewis JS Jr. Focus on TILs: prognostic significance of tumor 
infiltrating lymphocytes in head and neck cancers. Cancer Immun. 2008;8:16. 
33. Weller P, Bankfalvi A, Gu X, et al.The role of tumour FoxP3 as prognostic marker in 
different subtypes of head and neck cancer. Eur J Cancer. 2014;50(7):1291-300.  
34. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway 
in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer 
Res. 2013;73(6):1733-41.  
35. Malm IJ, Bruno TC, Fu J, et al.Expression profile and in vitro blockade of programmed 
death-1 in human papillomavirus-negative head and neck squamous cell carcinoma. Head 
Neck. 2014 Apr 7. [Epub ahead of print] 
36. Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell 
immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63(19):6501-5. 
37. Melero I, Rouzaut A, Motz GT, and Coukos G.T-cell and NK-cell infiltration into solid 
tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov. 
2014;4(5):522-6.  
38. Fridman WH, Pages F, Sautes-Fridman C and Galon J. The immune contexture in human 
tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298-306. 
39. Zhang Y-L, Li J, Hao-Yuan M, et al. Different subsets of tumor infiltrating lymphocytes 
correlate with NPC progression in different ways. Mol Cancer. 2010;9:4. 
40. Badoual C, Hans S, Rodriguez J, et al. Prognostic value of tumor-infiltrating CD4+ T-cell 
subpopulations in head and neck cancers. Clin Cancer Res. 2006;12(2):465-72. 
41. Katou F, Ohtani H, Watanabe Y, et al. Differing phenotypes between intraepithelial and 
stromal lymphocytes in early-stage tongue cancer. Cancer Res. 2007;67(23):11195-201. 
42. Reichert TE, Scheuer C, Day R, et al. The number of intratumoral dendritic cells and 
zeta-chain expression in T cells as prognostic and survival biomarkers in patients with 
oral carcinoma. Cancer. 2001;91(11):2136-47. 
43. Shibuya TY, Nugyen N, McLaren CE, et al.Clinical significance of poor CD3 response in 
head and neck cancer. Clin Cancer Res. 2002;8(3):745-51. 
44. Gildener-Leapman N, Ferris RL and Bauman JE. Promising systemic immunotherapies in 
head and neck squamous cell carcinoma. Oral Oncol. 2013;49(12):1089-96. 
45. Bauman JE and Ferris RL.Integrating novel therapeutic monoclonal antibodies into the 
management of head and neck cancer. Cancer. 2014;120(5):624-32.  
46. Javeed A, Ashraf M, Riaz A,et al. Paclitaxel and immune system. Eur J Pharm Sci. 
2009;38(4):283-90.  
47. Alizadeh D and Larmonier N. Chemotherapeutic targeting of cancer-induced 
immunosuppressive cells. Cancer Res. 2014;74(10):2663-8.  
48. Zhang L, Dermawan K, Jin M, et al. Differential impairment of regulatory T cells rather 
than effector T cells by paclitaxel-based chemotherapy. Clin Immunol. 2008;129(2):219-
229. 
49. Liu N, Zheng Y, Zhu Y, et al. Selective Impairment of 
CD4 + CD25 + Foxp3 + Regulatory T cells by paclitaxel is explained by Bcl-2/Bax 
mediated apoptosis. Int Immunopharmacol. 2011;11(2): 212-219. 
 

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17.0 
STUDY CALENDARS 
 
17.1 
Study Calendar 1: ARM 1 or ARM 3: Induction Chemotherapy with AP 
 
 
Base-
line7 
Cycle 1 
Cycle 2 
Cycle 3 
Definitive 
Chemotherapy/    
Radiation 
D1 
D2 
D3 
D8 
D15 
D1 
D2 
D3 
D8 
D15 
Between 
D16 and 
D203 
D1 
D2 
D3 
D8 
D15 
nab-Paclitaxel 
administration,4 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
Cisplatin 
administration2 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
See separate study 
calendar below. 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE w/palpation 
X 
X 
 
 
X 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
CBC 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
CMP + magnesium 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
CT - Neck 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
FDG-PET/CT 
X 
 
 
 
 
 
 
 
 
 
 
X8 
 
 
 
 
 
 
Laryngoscopy 
w/biopsy1 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
PT/PTT, EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-H&N, 
FACT/GOG-NTX-4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function 
Tests6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rad Tx Planning 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Window for all assessments +/2 days unless otherwise noted. 
1. Primary Tumor Site biopsy specimens (punch, incisional or core needle) will be obtained at baseline and at completion of Cycle 2 for Ki-67 expression and routine 
surgical pathology. If a biopsy is not feasible for financial reasons or safety concerns, at the Primary Investigator’s discretion one or both of the biopsies may be forgone. 
However, the laryngoscopies are needed to continue on the study. Assessment of primary tumor site will be done by laryngoscopy performed in the office or in the 
operating room.  
2. Hydration: 1L IVF NS (recommended: 10 meq KCL/L + 8 meq MgSO4/L) over one hour before and after cisplatin on Day 1. 2L IVF NS over 2 hours on Days 2 & 3. 
3. If CR or PR at primary tumor site and without radiographic or FDG evidence of disease progression, proceed with Cycle 3.  If PD or SD, proceed to surgery followed by 
reduced CRT or definitive full dose chemoradiation. 
4. Recommended premedication is granisetron 1 mg prior to each administration. 
5. In women of childbearing potential only. 
6. Spirometry, lung volumes, DLCO 
7. Window for baseline assessment is 28 days, with the exception of PET scan, which is 42 days. 
8. Only done when possible per insurance coverage. 
 
 

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17.2 
Study Calendar 2: ARM 2: Induction Chemotherapy with A 
 
 
Base-
line5 
Cycle 1 
Cycle 2 
Cycle 3 
Definitive Chemotherapy/   
Radiation 
D1 
D8 
D15 
D1 
D8 
D15 
Between D16 
and D202 
D1 
D2 
D3 
D8 
D15 
 
nab-Paclitaxel 
administration6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
Cetuximab 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Study Calendar 4 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE w/palpation 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
CMP + magnesium 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
CT - Neck 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
FDG-PET/CT 
X 
 
 
 
 
 
 
X7 
 
 
 
 
 
 
Laryngoscopy 
w/biopsy1 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
PT/PTT, EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-H&N, 
FACT/GOG-NTX-4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function 
Tests4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rad Tx Planning 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Window for all assessments +/2 days unless otherwise noted. 
1. Primary Tumor Site biopsy specimens (punch, incisional or core needle) will be obtained at baseline and at completion of Cycle 2 for Ki-67 expression and 
routine surgical pathology. If a biopsy is not feasible for financial reasons or safety concerns, at the Primary Investigator’s discretion one or both of the biopsies 
may be forgone. However, the laryngoscopies are needed to continue on the study. Assessment of primary tumor site will be done by laryngoscopy performed in 
the office or in the operating room.  
2. If CR or PR at primary tumor site and without radiographic or FDG evidence of disease progression, proceed with Cycle 3.  If PD or SD, proceed to surgery or 
definitive chemoradiation. 
3. In women of childbearing potential only. 
4. Spirometry, lung volumes, DLCO 
5. Window for baseline assessment is 28 days, with the exception of PET scan, which is 42 days. 
6. Recommended premedication is granisetron 1 mg prior to each administration 
7. Only done when possible per insurance coverage.

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17.3 
Study Calendar 3: Definitive Radiation and Concurrent Chemotherapy – Cisplatin (In conjunction with Arm 1) 
 
To begin 1 to 35 days after the end of Cycle 2 (if SD/PD and no surgery) or 3. 
 
 
Definitive Chemoradiation 
 (weeks) 
Short-term 
Follow-up 
(weeks) 
Long-term Follow-up  
(months from completion of definitive therapy)  
(± 6 week window until 60, then ± 3 month window) 
0 
1 
(D1) 
 
2 
 
3 
4 
(D22) 
 
5 
 
6 
7 
(D43) 
8 
wks 
+ 2 
wks 
16 
± 2 
wks 
9 
12 
16 
20 
24 
28 
32 
36 
42 
48 
54 
60 
72 
Annually 
(+/- 3 
months) 
Cisplatin3 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMRT4 
 
X----------------------------------------X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE w/palpation 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMP + magnesium 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT – Neck and Chest 
 
 
 
 
 
 
 
 
X5 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
FDG-PET/CT 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laryngoscopy1 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
FACT-H&N, 
FACT/GOG-NTX-4 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Window for all assessments +/2 days unless otherwise noted. 
1. Assessment of primary tumor site will be done by laryngoscopy performed in the office or in the operating room [ENT follow-up, including laryngoscopy procedures, will 
be conducted as standard of care after 12 months of follow-up so will occur at some, but not all, long-term follow-up visits] 
2. Hydration: 1L IVF NS (recommended: 10 meq KCL/L + 8 meq MgSO4/L) over one hour before and after cisplatin on Day 1. 2L IVF NS over one hour on Days 2 and 3. 
3. Hold if grade 4 mucositis or skin. Dose reduce if creatinine clearance < 60 and/or grade 3 mucositis/grade 3 skin. 
4. Delivered once per day M-F (See Section 5.10). 
5. CT neck only. 
6. If PET/CT cannot be performed, a CT of Neck and Chest should be done in place of the PET/CT. 
 
 
 

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17.4 
Study Calendar 4: Definitive Radiation and Concurrent Chemotherapy – Cetuximab (Arms 1 {selected patients} and 2 
only) 
 
To begin 1 to 35 days after the end of Cycle 2 (if SD/PD and no surgery) or 3. 
 
  
Definitive Chemoradiation 
(weeks) 
Short-term 
Follow-up 
(weeks) 
Long-term Follow-up 
(months from completion of definitive therapy) 
(± 6 week window until 60, then ± 3 month window) 
0 1 
2 
3 
4 
5 
6 
7 
8 wks ± 
2 wks 
16 
± 2 
wks 
9 
12 
16 
20 
24 
28 
32 
36 
42 
48 
54 
60 
72 
Annually 
(+/- 3 
months) 
Cetuximab2, 4 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMRT3 
 
X-----------------------------X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE w/palpation 
X  
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X  
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMP + magnesium 
X  
 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT – Neck and Chest 
 
 
 
 
 
 
 
 
X5 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
FDG-PET/CT 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laryngoscopy1 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
FACT-H&N, 
FACT/GOG-NTX-4 
X  
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Window for all assessments +/2 days unless otherwise noted. 
1. Assessment of primary tumor site will be done by laryngoscopy performed in the office or in the operating room. [ENT follow-up, including laryngoscopy procedures, 
will be conducted as standard of care after 12 months of follow-up so will occur at some, but not all, long-term follow-up visits] 
2. Premedications: diphenhydramine 50mg, solucortef 100mg IVPB, and albuterol inhalation (2.5 mg/inhaler) 
3. Delivered once per day M-F (See Section 5.10) 
4. Loading dose of 400 mg/m2 at time point 0 followed by maintenance dose of 250 mg/m2. 
5. CT neck only. 
If PET/CT cannot be performed, a CT of Neck and Chest should be done in place of the PET/CT. 

 
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17.5 
Study Calendar 5: Definitive Radiation and Concurrent Chemotherapy – Cisplatin (In conjunction with Arm 3) 
 
To begin 1 to 35 days after the end of Cycle 3 (if CR/PR at PTS) or 2 (if SD/PD and surgery). 
 
Definitive 
Chemoradiation 
(weeks) 
Short-term 
Follow-up 
(weeks) 
Long-term Follow-up 
(months from completion of RT) 
(± 6 week window until 60, then ± 3 month window) 
0 
1 
(D1) 
2 3 
4 
(D22) 
5 
2 
+ 1 wk 
8 
+ 2 wks 
16 
± 2 wks 9 mo 12 16 20 24 28 32 36 42 48 54 60 
Annual +/-3 months 
Cisplatin*  or 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cetuximab7 
X 
X 
X X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMRT3 
X--------------------------X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE w/palpation8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight8 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMP + magnesium 
X 
X 
X4 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT – Neck and Chest 
 
X5 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
FDG-PET/CT 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laryngoscopy1 
 
 
X 
X 
X X1 X1 X1 X1 X1 X1 X1 X1 X1 X1 
X1 
FACT-H&N, 
FACT/GOG-NTX-4 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Window for all assessments +/2 days unless otherwise noted. 
*Patients to receive Cisplatin.  Criteria to receive cisplatin: creatinine clearance > 60, ECOG 0-2, no active serious infections. Patients who do NOT meet these 
criteria will receive Cetuximab. 
1. Assessment of primary tumor site will be done by laryngoscopy performed in the office or in the operating room [ENT follow-up, including laryngoscopy procedures, will   
be conducted as standard of care after 12 months of follow-up, so will occur at some, but not all, long-term follow-up visits] 
2. Hydration: 1L IVF NS (recommended: 10 meq KCL/L + 8 meq MgSO4/L) over one hour before and after cisplatin on Day 1. 2L IVF NS over one hour on Days 2 and 3. 
3. Delivered once per day M-F (See Section 5.10). for approximately 4 weeks. 
4.BMP not CMP at this timepoint  
5. CT neck only. 
6. If PET/CT cannot be performed, a CT of Neck and Chest should be done in place of the PET/CT. 
7. Loading dose of 400 mg/m2 at time point 0 followed by maintenance dose of 250 mg/m2, Premedications: diphenhydramine 50mg, solucortef 100mg IVPB, and albuterol 
inhalation (2.5 mg/inhaler) 
8. Cisplatin patients have PE on Week 1 and no Weight collection on Week 0.  Cetuximab patients have Weight collection and PE on Week 0 and no PE on Week 1. 

 
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APPENDIX 1: ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J 
Clin Oncol 5:649-655, 1982. 
 

 
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APPENDIX 2: Criteria for Response, Progression, and Relapse 
 
At baseline, tumor lesions will be characterized as either measurable or non-measurable. 
 
Measurable: 
Lesions that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as > 20 mm (2.0 cm) with conventional techniques or as > 10 mm (1.0 cm) with spiral 
CT scan. If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
 
Non-Measurable: 
All other lesions, including small lesions [longest diameter < 20 mm (2.0 cm) with conventional 
techniques or < 10 mm (1.0 cm) with spiral CT scan] and truly non-measurable lesions. Lesions 
considered to be truly non-measurable include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging techniques, 
and cystic lesions. Tumor lesions that are situated in a previously irradiated area might or might 
not be considered measurable. The conditions under which such lesions should be considered 
must be defined in the protocol when appropriate. 
 
Target Lesions: 
All measurable lesions up to a maximum of 10 lesions representative of all involved organs 
should be identified as target lesions and will be 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 repetitive 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 reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
 
Complete Response (CR):  
Disappearance of all target lesions. Where response is the primary endpoint, changes in tumor 
measurements must be confirmed by repeat studies performed no less than 4 weeks after the 
criteria for response are first met. Longer intervals as determined by the Principal Investigator 
may also be appropriate. 
 
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. Where response is the primary endpoint, changes in tumor 
measurements must be confirmed by repeat studies performed no less than 4 weeks after the 
criteria for response are first met. Longer intervals as determined by the Principal Investigator 
may also be appropriate. 
 
Progression (PD):  
At least a 20% increase in the sum of the LD of target lesions taking as references the smallest 
sum LD recorded since the treatment started or the appearance of one or more new lesions. 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as 
references the smallest sum LD since the treatment started. Patients having a documented 
response with no reconfirmation of the response will be listed with stable disease. 
 

 
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Non-target Lesions: 
All other lesions (or sites of disease) not included in the “target disease” definition should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are not 
required and these lesions should be followed as “present” or “absent.” 
 
Complete Response (CR):  
Disappearance of all non-target lesions and normalization of tumor marker level. If tumor 
markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Non-complete response (non-CR)/Non-progression (non-PD):  
Persistence of one or more non-target lesion and/or maintenance of tumor marker level above the 
upper limits of normal. 
 
Progression (PD):  
Appearance of one or more new lesions. Unequivocal progression of existing non-target lesions. 
Although a clear progression of non-target lesions is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression status should be confirmed 
later on by the review panel (or Principal Investigator). 
 
Cytology and Histology: 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
 
These techniques can be used to differentiate between PR and CR in rare cases (for example, 
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. 
 
Evaluation of Best Overall Response: 
The best overall response should be 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). In general, the patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 

 
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Note: In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
First Documentation of Response:  
The time between initiation of therapy and first documentation of PR or CR. 
 
Confirmation of Response:  
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 
Duration of Response:  
Duration of overall response – the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the first date that 
recurrent or progressive disease is objectively documented, taking as reference the smallest 
measurements recorded since treatment started. 
 
Duration of Overall Complete Response:  
The period measured from the time measurement criteria are met for complete response until the 
first date that recurrent disease is objectively documented. 
 
Duration of Stable Disease:  
A measurement from registration until the criteria for disease progression is met, taking as 
reference the smallest measurements recorded since registration. To be assigned a status of stable 
disease, measurements must have met the stable disease criteria at least once after study entry at 
a minimum interval (in general, not less than eight weeks). 
 
Survival:  
Survival will be measured from the date of entry on study. 
 
Time to Progression:  
This interval will be measured from the date of entry on the study to the appearance of new 
metastatic lesions or objective tumor progression. 
 
Methods of Measurement:  
Imaging based evaluation is preferred to evaluation by clinical examination. The same imaging 
modality must be used throughout the study to measure disease. 
 
Guidelines for Evaluation of Measurable Disease: 
Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, 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. 
 
Chest X-ray:  
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
 
 

 
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CT and MRI: 
Conventional CT and MRI 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 the chest, abdomen, and pelvis. Head & neck and extremities usually require 
specific protocols. 
 
Ultrasound: 
Ultrasound (US) should not be used to measure tumor lesions that are clinically not easily 
accessible when the primary endpoint of the study is objective response evaluation. It is a 
possible alternative to clinical measurements of superficial palpable nodes, subcutaneous lesions, 
and thyroid nodules. US might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 
 
Endoscopy and Laparoscopy: 
Endoscopy and Laparoscopy 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 can 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 patient to be considered in complete clinical response. 
 
Confirmation Measurement/Duration of Response: 
Confirmation to be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed no less than 4 weeks after the criteria for 
response are first met.  In the case of SD, follow-up measurements must have met the SD criteria 
at least once after study entry at a minimum interval of not less than 6 weeks. 
 
Duration of Overall Response:   
The duration of overall response is measured from the time measurement criteria are met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall complete response 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. 
 

 
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APPENDIX 3: Institutional Guidelines for IMRT 
 
A. 
Normal structure and treatment volume contours will be delineated using the following 
guidelines: 
 
 
The dosimetrist will contour the following structures with name allocation exactly as 
written: 
 
1. 
“Skin” 
2. 
“Spinal cord”  
3. 
“Brainstem” 
4. 
“Brain” 
5. 
“R eye” 
6. 
“L eye” 
7. 
“R Optic nerve” 
8. 
“L Optic nerve” 
9. 
“Optic chiasm”  
10. 
“R Lens” 
11. 
“L Lens” 
12. 
“Mandible” 
13. 
“PTV 7000” (0.5 cm universal expansion on “CTV 7000” as described below; 
also referred to as PTV1) 
14. 
“PTV 6300” (0.5 cm universal expansion on “CTV 6300” as described below; 
also referred to as PTV2) 
15. 
“PTV 5800” (0.5 cm universal expansion on “CTV 5600” as described below; 
also referred to as PTV3) 
 
B. 
The physician will assist with and approve the above contours and delineate contours for 
the following structures with name allocation exactly as written (See guidelines below): 
 
1. 
“Oral cavity” 
2. 
“R Parotid” 
3. 
“L Parotid” 
4. 
“Larynx” 
5. 
“Partial esoph” 
6. 
“GTV-n”  
7. 
“GTV-p”  
8. 
“CTV 7000” (also referred to as CTV1) 
9. 
“CTV 6300” (also referred to as CTV2) 
10. 
“CTV 5600” (also referred to as CTV3) 
 
C. 
The following guidelines will be used for delineation of efficient, systematic and 
reproducible target volumes and normal structures: 
 
1. 
Delineation of the “Oral cavity”  
a. 
At the superior extent, contours will begin at the first evidence of the hard 
palate below the nasal airway and anterior to the nasopharynx including 
the soft palate. 
b. 
Contours will be drawn along the medial and posterior surface of the teeth 
and alveolar bone and will include portions of the tongue. 

 
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c. 
Contours will extend posteriorly to the uvula and inferiorly to the first 
axial slice with evidence of submandibular glands.   
2. Delineation of the “R Parotid” and “L Parotid”   
a. 
Parotid glands will be contoured as per convention including both 
superficial and deep lobes.    
3. Delineation of the “Larynx” 
a. 
At the superior extent, contours will begin just below the hyoid bone and 
will circumscribe the laryngopharynx and thyroid cartilage. 
b. 
Contours will extend inferiorly to include the inferior cornua of the 
thyroid cartilage as well as the superior cricoid cartilage 
4. Delineation of the “Partial esoph” 
a. 
At the superior extent, contours will begin at the level of the complete ring 
of cricoid cartilage and will encircle the adjacent, posterior esophagus. 
b. 
Contours will extend inferiorly to the level of the sternum, following the 
esophagus as it enters the thorax. 
5. Delineation of “GTV-n”* 
a. 
Contours will encircle the gross nodal tumor volume by CT criteria, i.e. 
lymph node > 1 cm. 
6. Delineation of “GTV-p”* 
a. 
Contours will encircle the gross tumor volume as seen on CT scan. 
7. 
Delineation of “CTV 7000”* 
a. 
Contours will become the high dose clinical treatment volume.  
b. 
Contours will include gross disease (GTV-n and GTV-t) with an 
appropriate margin of normal tissue at risk for subclinical extension as per 
standard of care. 
c. 
Also referred to as CTV1 
8. 
Delineation of “CTV 6300”* 
a. 
Contours will become the intermediate dose clinical treatment volume 
where applicable at the discretion of the treating physician. 
b. 
Contours will include the adjacent 2 cm superior and/or inferior to the 
regions of gross disease as per standard of care. 
c 
Also referred to as CTV2 
9. 
Delineation of “CTV 5600”* 
a. 
Contours will become the low dose clinical treatment volume. 
b. 
Contours will include the ipsilateral and contralateral cervical lymph node 
regions at risk for subclinical spread of disease as per standard of care. 
c. 
Also referred to as CTV3 
 
* These contours will be specifically reviewed by one physician (WLT) to ensure consistency. 
 
 

 
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TUMOR SITE 
Stage 
CTV1 
CTV2 
CTV3 
Definitive Dose (Gy) 
7000/200 
6300/180 
5600/160 
OROPHARYNX 
Tonsil 
T1-2 N0 
GTVp 
- 
IN (IIb-IV, IRPLN) 
T3-4 N0 
GTVp 
- 
IN (IIb-IV) + BRPLN + CN (IIb-IV) 
Any T N1-3, except 2C 
GTVp + 
GTVn 
Adj 
levels 
IN (II-V) + BRPLN + CN (IIb-IV) 
Any T N2C 
GTVp + 
GTVn 
Adj 
levels 
IN + CN (II-V, BRPLN) 
BOT/Soft Palate 
Any T N0 
GTVp 
- 
IN (IIb-IV) + BRPLN + CN (IIb-IV) 
Any T N1-3, except 2C 
GTVp + 
GTVn 
Adj 
levels 
IN (II-V) + BRPLN + CN (IIb-IV) 
Any T N2c 
GTVp + 
GTVn 
Adj 
levels 
IN + CN (II-V, BRPLN) 
LARYNX 
Glottic 
T1-2 N0 
GTVp 
- 
- 
T3-4 N0 
GTVp 
- 
IN (IIb-IV) + BRPLN + CN (IIb-IV) 
Any T N1-3, except N2c 
GTVp + 
GTVn 
Adj 
levels 
IN (II-V) + BRPLN + CN (IIb-IV) 
Any T N2c 
GTVp + 
GTVn 
Adj 
levels 
IN + CN (II-V, BRPLN) 
Supraglottic 
Any T N0 
GTVp 
- 
IN (IIb-IV) + BRPLN + CN (IIb-IV) 
Any T N1-3, except N2c 
GTVp + 
GTVn 
Adj 
levels 
IN (II-V) + BRPLN + CN (IIb-IV) 
Any T N2c 
GTVp + 
GTVn 
Adj 
levels 
IN + CN (II-V, RPLN) 
HYPOPHARYNX 
 
Any T N0 
GTVp 
- 
IN (IIb-IV) + BRPLN + CN (IIb-IV) 
Any T N1-3, except N2C 
GTVp + 
GTVn 
Adj 
levels 
IN (II-V) + BRPLN + CN (IIb-IV) 
Any T N2c 
GTVp + 
GTVn 
Adj 
levels 
IN + CN (II-V, BRPLN) 
ORAL CAVITY 
Buccal 
Any T N0 
GTVp 
- 
IN (IIb-IV, IRPLN) 
Any T N1-3, except N2C 
GTVp + 
GTVn 
Adj 
levels 
IN (IIb-IV) + BRPLN  
Any T N2c 
GTVp + 
GTVn 
Adj 
levels 
IN + CN (II-V, BRPLN) 
RMT, Oral 
Tongue, FOM 
Any T N0 
GTVp 
 
IN (Ia-IV) + BRPLN + CN (Ia-IV) 
Any T N1-3, except N2C 
GTVp + 
GTVn 
Adj 
levels 
IN (Ia-V) + BRPLN + CN (Ia-IV) 
Any T N2c 
GTVp + 
GTVn 
Adj 
levels 
IN + CN (Ia-V, BRPLN) 
Notes:   
 
 
 
 
Include ipsilateral level Ib if level II is involved; include ipsilateral level Ia if level Ib is involved 
CTV 2 is adjacent levels with minimum 2 cm in cranial-caudad direction 
 
N2C disease: CTV1 is GTVp + GTVn; CTV2 is adjacent levels (min 2 cm); CTV 3 is IN + CN (II-V, BRPLN) 
In cases where no CTV2 is defined, CTV3 on this form will be labeled as CTV2 for planning 
 
 

 
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APPENDIX 4: Comorbidity Index 
 
http://oto.wustl.edu/comorbiditycalculator.html 
If a patient has Grade 2 events in more than one system, their overall score will be Grade 3 

 
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APPENDIX 5: FACT/GOG-NTX-4 (Version 4) 
 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
NTX
1 
I have numbness or tingling in my 
hands
 ......................................................................................................  
0 
1 
2 
3 
4 
NTX
2 
I have numbness or tingling in my 
feet
 ......................................................................................................  
0 
1 
2 
3 
4 
NTX
3 
I feel discomfort in my 
hands
 ......................................................................................................  
0 
1 
2 
3 
4 
NTX
4 
I feel discomfort in my 
feet
 ......................................................................................................  
0 
1 
2 
3 
4 
 

 
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APPENDIX 6: FACT-H&N (Version 4) 
 
Below is a list of statements that other people with your illness have said are important. Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of 
energy
 ......................................................................................................  
0 
1 
2 
3 
4 
GP2 
I have 
nausea
 ......................................................................................................  
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble meeting the 
needs of my 
family
 ......................................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have 
pain
 ......................................................................................................  
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment
 ......................................................................................................  
0 
1 
2 
3 
4 
GP6 
I feel 
ill
 ......................................................................................................  
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in 
bed
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my 
friends
 ......................................................................................................  
0 
1 
2 
3 
4 
GS2 
I get emotional support from my 
family
 ......................................................................................................  
0 
1 
2 
3 
4 
GS3 
I get support from my 
friends
 ......................................................................................................  
0 
1 
2 
3 
4 

 
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GS4 
My family has accepted my 
illness
 ......................................................................................................  
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness
 ......................................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support)
 ......................................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex 
life
0 
1 
2 
3 
4 

 
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Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel 
sad
 ......................................................................................................  
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness
 ......................................................................................................  
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my 
illness
 ......................................................................................................  
0 
1 
2 
3 
4 
GE4 
I feel 
nervous
 ......................................................................................................  
0 
1 
2 
3 
4 
GE5 
I worry about 
dying
 ......................................................................................................  
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
worse
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at 
home)
 ......................................................................................................  
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is 
fulfilling
 ......................................................................................................  
0 
1 
2 
3 
4 
GF3 
I am able to enjoy 
life
 ......................................................................................................  
0 
1 
2 
3 
4 
GF4 
I have accepted my 
illness
 ......................................................................................................  
0 
1 
2 
3 
4 

 
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GF5 
I am sleeping 
well
 ......................................................................................................  
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for 
fun
 ......................................................................................................  
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
0 
1 
2 
3 
4 
 
 
 

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