Clinical trial NCT02258659
Conditions: Human Papilloma Virus Infection Stage III Squamous Cell Carcinoma of the Oropharynx Stage IVA Squamous Cell Carcinoma of the Oropharynx Stage IVB Squamous Cell Carcinoma of the Oropharynx
Sponsor: University of Chicago
Start date: 2014-09-22; Completion date: 2024-09-06
Enrollment: 62 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) and carboplatin followed by response-based local therapy in treating patients with stage III or IV human papillomavirus (HPV)-related oropharyngeal cancer. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, carboplatin, hydroxyurea, fluorouracil, paclitaxel, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them spreading. Radiation therapy uses high energy x rays to kill tumor cells. Giving nab-paclitaxel and carboplatin before chemoradiation may make the tumor smaller and reduce the amount of chemotherapy and radiation therapy needed. Assigning chemotherapy and radiation therapy based on response (response-based therapy) and giving patients who are responding well lower doses of treatment may help reduce the occurrence of side effects.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the 2-year progression-free survival (PFS).

SECONDARY OBJECTIVES:

I. Clinical complete response rate (nab-paclitaxel based induction, compared to European Prospective Investigation into Cancer and Nutrition \[EPIC\] induction \[paclitaxel based\]).

II. Response rate (nab-paclitaxel based induction, compared to EPIC induction \[paclitaxel based\]).

III. Proportion of patients with \>= 50% shrinkage by Response Evaluation Criteria In Solid Tumors (RECIST) (nab-paclitaxel based induction, compared to EPIC induction, paclitaxel based).

IV. Toxicity (nab-paclitaxel based induction, compared to EPIC induction \[paclitaxel based\]).

V. To assess swallowing function and speech at 6 months (mos) and 12 mos post therapy.

VI. To determine the rates of late toxicity with chemoradiation following surgery as determined by xerostomia, dental decay, osteroradionecrosis, G-tube dependency, tracheostomy placement and dysphagia.

VII. 2-year overall survival (OS) in patients treated on the Low-Risk, Intermediate-Risk Arm, and High-Risk Arms.

VIII. 2-year PFS in patients treated on the Low-Risk, Intermediate-Risk Arm, and High-Risk Arms - early and late toxicities.

IX. Evaluate need for post radiotherapy/chemoradiotherapy (RT/CRT) surgery on low- and intermediate-risk arms based on response from induction chemotherapy.

X. Evaluate in a descriptive manner the role of transoral robotic surgery (TORS) resection/lymph node dissection (LND) when integrated into a de-escalation trial.

TERTIARY OBJECTIVES:

I. To evaluate pathologic/histologic appearance of tumor after induction chemotherapy and after CRT.

II. Translational research on blood and tissue samples. III. To profile tumors genetically and immunologically in order to assess in a descriptive manner genetic or immunological features characteristic of clinical behavior.

OUTLINE:

INDUCTION CHEMOTHERAPY: All patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients are then assigned to 1 of 3 treatment groups based on response to induction chemotherapy.

GROUP A (LOW-DOSE ARM): Patients undergo radiation therapy once daily for 5 weeks.

GROUP B (INTERMEDIATE-DOSE ARM): Patients receive hydroxyurea orally (PO) twice daily (BID) on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive low-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for 3 courses in the absence of disease progression or unacceptable toxicity.

GROUP C (STANDARD-DOSE ARM): Patients receive hydroxyurea PO BID on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive standard-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.\*

\*NOTE: At the discretion of the principal investigator (PI), patients may receive cisplatin IV over 1-3 hours every 3 weeks during radiation therapy instead of paclitaxel and undergo daily radiation therapy.

After completion of study treatment, patients are followed up for 30 days, every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

Arms: arm 1: Patients undergo radiation therapy once daily for weeks. arm 2: Patients receive hydroxyurea PO BID on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive low-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for 3 courses in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive hydroxyurea PO BID on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive standard-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.\*

\*NOTE: At the discretion of the PI, patients may receive cisplatin IV over 1-3 hours every 3 weeks during radiation therapy instead of paclitaxel and undergo daily radiation therapy.
Interventions: intervention 1: paclitaxel albumin-stabilized nanoparticle formulation intervention 2: carboplatin intervention 3: radiation therapy intervention 4: paclitaxel intervention 5: fluorouracil intervention 6: hydroxyurea intervention 7: cisplatin intervention 8: laboratory biomarker analysis intervention 9: quality-of-life assessment
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo radiation therapy intervention 4: Given IV intervention 5: Given IV intervention 6: Given PO intervention 7: Given IV intervention 8: Correlative studies intervention 9: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
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An exploratory pilot study of Nab-paclitaxel based induction 
chemotherapy followed by response-stratified locoregional 
therapy for patients with stage III and IV HPV-related 
Oropharyngeal Cancer  - the OPTIMA HPV Trial 
 
OPTIMA = OroPharyngeal Tumor Induction chemotherapy and response-
stratified locoregional therapy trial in order to Minimize long term Adverse 
events 
 
 
 
IRB Number:  
 
IRB14-0639 
 
Coordinating Center:  
University of Chicago Medical Center 
 
Principal Investigator:        Everett Vokes, MD 
 
Co-Investigators:  
 
Tanguy Seiwert (translational science PI) 
 
 
 
 
Michael Spiotto (Radiation PI) 
 
 
 
 
Daniel Haraf 
 
 
 
 
Jonas DeSouza 
 
 
 
 
 
Kerstin Stenson 
Elizabeth Blair 
Alexander Langerman 
Louis Portugal 
Nicole Cipriani 
Mark Lingen 
 
Statistician:   
 
Theodore Karrison 
Research Nurses:  
Nicole Hannigan / Talal Ali 
Study Coordinator:  
Talal Ali, RN, PHD 
Data Manager: 
 
Melissa Mc Hugh 
Shane Small 
Address: 
 
 
The University of Chicago Medicine 
 
 
 
 
5841 S Maryland avenue 
 
 
 
 
Chicago, Il 60637 
 
 
 


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Table of Contents 
 
1. Protocol Synopsis and Schema 
 
 
 
 
 
 
4 
 
2. OBJECTIVES 
 
 
 
 
 
 
 
 
 
10 
 
2.1 Primary Objective 
 
 
 
 
 
 
 
10 
 
2.2 Secondary Objectives  
 
 
 
 
 
 
10 
 
2.3 Laboratory Objectives  
 
 
 
 
 
 
10 
 
3. BACKGROUND  
 
 
 
 
 
 
 
 
11 
3.1 Locally Advanced Head and Neck Cancer  
 
 
 
11 
3.1.1   Chemoradiotherapy  
 
 
 
 
 
11 
3.1.2   Surgery 
 
 
 
 
 
 
 
12 
3.1.3  TFHX Regimen 
 
 
 
 
 
 
13 
3.1.4   Induction Chemotherapy 
3.1.5   PET Imaging 
3.2  Human Papillomavirus and HNSCC  
 
 
 
 
13 
3.3 Study Rationale  
 
 
 
 
 
 
 
14 
 
4. PATIENT SELECTION  
 
 
 
 
 
 
 
18 
 
4.1 Eligibility Criteria 
 
 
 
 
 
 
 
18 
 
4.2 Exclusion Criteria 
 
 
 
 
 
 
 
19 
 
4.3 Criteria for discontinuation/withdrawal of informed consent 
 
19-20 
 
4.4 HPV testing 
 
 
 
 
 
 
 
 
20 
 
5. TREATMENT PLAN 
 
 
 
 
 
 
 
 
22 
 
5.1 General Considerations 
 
 
 
 
 
 
22 
 
5.2 Pre-treatment evaluation 
 
 
 
 
 
 
22 
 
5.3 Study evaluations 
 
 
 
 
 
 
 
23 
5.4 Agent Administration 
 
 
 
 
 
 
 
23-24 
 
5.4.1  
 
 
 
 
 
 
 
 
24 
 
5.4.2. Induction Therapy Details  
 
 
 
 
24 
5.5 Radiotherapy and Chemoradiotherapy Guidelines  
 
 
25 
 
5.5.1 Radiation Therapy Guidelines 
 
 
 
 
26 
 
5.6 Supportive Care Guidelines 
 
 
 
 
 
 
33 
 
5.7 Surgical Guidelines 
 
 
 
 
 
 
 
35 
 
5.8 Post-Therapy Follow-Up  
 
 
 
 
 
 
35 
5.9 Duration of Therapy 
 
 
 
 
 
 
 
35 
5.10 Quality of Life Measurements 
 
 
 
 
 
37 
 
5.10.1 Schedule 
 
 
 
 
 
 
 
37 
5.11  
 
 
 
 
 
 
 
 
 
37 
 
5.11.2 Assessment Instruments  
 
 
 
 
37 
 
6. EXPECTED ADVERSE EVENTS, RISKS AND DOSE MODIFICATIONS 
38
 
6.1 Expected Adverse Events 
 
 
 
 
 
 
38 
 
 
6.1.1 Nab-Paclitaxel 
 
 
 
 
 
 
38 


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6.1.2 Carboplatin  
 
 
 
 
 
 
38 
 
6.2 Dose Modifications 
 
 
 
 
 
 
 
41 
 
 
6.2.1 Chemotherapy 
 
 
 
 
 
 
41 
6.3 Termination of Treatment 
 
7. AGENT FORMULATION AND PROCUREMENT 
 
 
 
 
48 
 
7.1 Nab-paclitaxel  
 
 
 
 
 
 
 
48 
 
7.2 Carboplatin 
 
 
 
 
 
 
 
 
49 
 
7.3 5-Fluorouracil 
 
 
 
 
 
 
 
 
50 
 
7.4 Hydroxyurea 
 
 
 
 
 
 
 
 
50 
 
7.5 Paclitaxel 
 
 
 
 
 
 
 
 
50 
 
7.6 Cisplatin  
 
 
 
 
 
 
 
 
52 
7.7 Filgrastim Drug Information 
 
 
 
 
 
 
52 
 
8. CORRELATIVE STUDIES 
 
 
 
 
 
 
 
56 
 
8.1 Objective  
 
 
 
 
 
 
 
 
56 
 
8.2 Sample and Tissue Procurement 
 
 
 
 
 
56 
 
8.3 Sample Isolation and Analysis 
 
 
 
 
 
57 
 
8.4 Correlative Analysis 
 
 
 
 
 
 
 
58 
 
 
8.4.1  
 
 
 
 
 
 
 
 
58 
 
 
8.4.2  
 
 
 
 
 
 
 
 
58 
 
 
8.4.3  
 
 
 
 
 
 
 
 
58 
 
9. STUDY CALENDAR 
 
 
 
 
 
 
 
 
59 
 
10. MEASUREMENT OF EFFECT 
 
 
 
 
 
 
60 
 
10.1 Definitions 
 
 
 
 
 
 
 
 
61 
 
10.2 Guidelines for Evaluation of Measurable Disease  
 
 
61 
 
 
10.2.1 Progression Free 
 
 
 
 
 
 
61 
 
 
10.2.2 Overall Survival Time 
 
 
 
 
 
61 
 
 
10.2.3 Distant Failure-Free Survival 
 
 
 
 
61 
 
 
10.2.4 Assessment of Local/Distant Failure 
 
 
 
61 
 
10.3 Response Criteria 
 
10.4 Progression-Free and Overall Survival 
 
11. REGULATORY AND REPORTING REQUIREMENTS 
 
 
 
62 
 
11.1 Expedited Adverse Event Reporting 
 
 
 
 
63 
 
 
11.1.1 Expedited Adverse Event Reporting 
 
 
 
63 
 
 
11.1.2 Forms  
 
 
 
 
 
 
 
64 
 
11.2 Patient Registration and Data Submission  
 
 
 
65 
 
 
11.2.1 Registration  
 
 
 
 
 
 
65 
 
 
11.2.2 Data Submission 
 
 
 
 
 
 
65 
 
11.3 Data and Safety Monitoring  
 
 
 
 
 
65-66 
 
12. STATISTICAL CONSIDERATIONS  
 
 
 
 
 
67 
 
12.1 Study Design/Endpoints 
 
 
 
 
 
 
67 


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12.1.1 Study Design 
 
 
 
 
 
 
67 
 
 
12.1.2 Primary Endpoint 
 
 
 
 
 
 
67 
 
 
12.1.3 Secondary Endpoints 
 
 
 
 
 
67 
 
 
12.1.4 Laboratory Objectives 
 
 
 
 
 
67 
 
12.2 Data Analysis  
 
 
 
 
 
 
 
68 
 
 
12.2.1 Sample size/accrual rate  
 
 
 
 
68 
 
 
12.2.2 Assumptions and Hypothesis and Sample Size  
 
68 
 
 
12.2.3 Statistical Methods  
 
 
 
 
 
68 
 
13. REFERENCES  
 
 
 
 
 
 
 
 
70 
 
APPENDICES 
APPENDIX A Performance Status Criteria 
 
 
 
 
 
74 
APPENDIX B RTOG Early Toxicity Grading 
 
 
 
 
 
75 
APPENDIX C RTOG Late Toxicity Grading 
 
 
 
 
 
76 
APPENDIX D Docetaxel Hypersensitivity Reactions 
 
 
 
 
77 
APPENDIX E Sample Transmission Form and Instructions 
 
 
 
78 
APPENDIX F Abbreviations 
 
 
 
 
 
 
81 
 
 
 
 




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Trial Design 
 
 
A Phase II trial in Human Papillomavirus Associated (HPV) – positive head and 
neck cancer as determined by HPV ISH or HPV PCR in any anatomic site, or p16 
immunohistochemistry with confirmatory ISH or PCR in oropharyngeal primary tumors 
(see Section 4.4 HPV testing) to determine response to induction chemotherapy based 
on clinical, radiologic and surgical criteria.   Patients will undergo evaluation by a 
multidisciplinary team prior to risk assessment.  The patients will be assigned to high 
and low risk groups based on tumor size, lymph node involvement, and smoking history.  
Patients will be assigned treatment with radiation with or without chemotherapy 
following induction chemotherapy with carboplatin and nab-paclitaxel based on RECIST 
measurement of tumor shrinkage.  Patients with low risk disease (T1-3,non-bulky N0-
N2B, < 10 pack years tobacco- see Study Rationale section 3.3) (1) who have > 50% 
reduction by RECIST following induction chemotherapy will be given A) de-intensified 
treatment with radiation alone to 50 Gy.  Patients with low risk features and with  < 
50% but > 30% reduction OR high risk features with > 50% reduction will receive B) de-
intensified chemoradiation with TFHX to 45 Gy (3 cycles).  Patients who have high risk 
disease with < 50% reduction or any patients with progression or stable disease during 
induction chemotherapy will undergo C) chemoradiotherapy with TFHX to 75 Gy (or 
Cisplatin based CRT as a fallback option in case TFHX is not feasible (see section 5.5).   
 
Background and Rationale 
 
 
HPV-positive oropharyngeal cancer is associated with improved prognosis 
compared to HPV-negative squamous cell carcinomas of the head and neck (HNSCCs). 
Notably, patients with HPV-positive oropharyngeal cancers with a 10 pack year or less 
smoking history have a greater than 80% 5 year overall survival. (2)These improved 
outcomes have suggested that toxic multimodality treatment regimens may be de-
intensified in order to prolong survival while minimizing toxicity.   Previous studies have 
suggested that response to induction chemotherapy is a highly reliable prognostic factor 
for outcome following definitive treatment.  This was also recently demonstrated in 
ECOG1308, which showed promising results.  The problem is however, that not all HPV 
positive patients have good outcomes.  While there are some reliable factors, which are 
associated with outcome, there are some factors, which remain unclear, and patients 
should warrant more intensified treatment to reduce likelihood of recurrence.  Therefore, 
this trial will prospectively analyze response to induction chemotherapy in individual pts 
(grouped at study enrollment into high and low risk groups based on tumor 
characteristics) to determine who should have deintensified treatment (allocation to 
three arms – see schema above).   
 
Patient Population 
 
 
Patients with locally advanced squamous cell cancer of the head and neck area 
that are positive for HPV using an E6/E7 based assay is preferred (by HPV ISH or HPV 
PCR, see section 4.4) will be enrolled. For oropharyngeal HNSCC p16 IHC positivitivity 
is acceptable (with recommended validation by HPV DNA in situ hybridization or PCR 
post enrollment, see section 4.4). The goals of this study are to diminish long-term 


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toxicities by testing less intense treatment regimens without compromising chance of 
cure. 
 
Key Inclusion Criteria  
 
 
 Patients with locally advanced HPV(+) squamous cell carcinoma.  HPV positivity 
should be determined by HPV ISH or HPV PCR for any anatomic site, or by p16 
IHC for oropharyngeal tumors (with confirmatory by ISH or PCR testing after 
enrollment/start of induction 
 
 Normal Organ function 
 
 Meaurable disease by RECIST 1.1. 
 
 No previous radiation or chemotherapy for a head and neck cancer. 
 
 
 ECOG performance status 0-1 (Karnofsky  70%; Appendix A). 
 
 Age > 18 yrs  
 
 Obtained informed consent. 
(please see full elgibility criteria under 4.1 and 4.2) 
 
Treatment Plan: 
 
 
Induction therapy: All enrolled patients will receive three (3) 21-day cycles of 
chemotherapy consisting of nab-paclitaxel (100 mg/m2 on day 1, 8, 15), and carboplatin 
(AUC 6 on day 1). Growth factor support will be provided using G-CSF administered on 
days 16-18). Following induction patients will undergo biopsy if technically feasible. 
Surgery should not be done at this point, unless diagnostic in intent and residual tumor 
is left behind. 
 
Surgery/ pan-endoscopy and biopsies: Following chemoradiotherapy, patients will 
undergo surgical evaluation, and pathologic response evaluation will be considered. 
This may include either surgery or (e.g. TORS is acceptable). Particular focus will be on 
the first 50% of patients in groups A and B. 
 
 
Radiation/CRT/TFHX:  
The patients will be assigned to three treatment arms based on response to 
induction chemotherapy, and high or low risk status. High or low risk status is based on 
tumor size, lymph node involvement, and smoking history at enrollment on study. 
 
 
Low Risk Status: 
o T1-3 


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o N 0 - N2B (unless N3 equivalent lymph nodal conglomerate) 
o < 10 pack year history tobacco use 
 
 
High Risk Status: 
o T4 
o N2C-N3 
o N2B disease with N3 equivalent amount of tumor (conglomerate bulky 
disease > 6cm) 
o > 10 pack year history tobacco use 
 
Response Stratified Grouping 
 
 
Patients will be assigned to Radiation alone or CRT/TFHX based on 
response to induction chemotherapy.   TFHX will consist of 14-day cycles of paclitaxel 
(100 mg/m2 Day 1 over 1 hour), 5FU (continuous infusion at 600 mg/m2/day  5 days), 
and hydroxyurea (500 mg PO BID day 0-5, 11 doses/cycle) with twice daily radiation 
(150 cGy per fraction). 
No therapy on days 6-14. Supportive care should be administered as specified in 
Section 5. For patients in the  
 
 
Group A/Low Dose Arm (LDA) – Radiation only: 
 
 
Patients who have low risk disease and > 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 50Gy radiation alone. 
 
 
Group B/Intermediate Dose Arm (IDA) – Low dose CRT (3 cycles TFHX): 
 
 
Patients who have low risk disease and < 50% but > 30% reduction of 
tumor by RECIST with induction chemotherapy will receive 45 Gy in 3 cycles TFHX. 
 
 
 
 
 
OR 
 
 
Patients who have high risk disease and > 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 45 Gy in 3 cycles TFHX. 
 
 
Group C/Regular Dose Arm (RDA) – Standard dose CRT (5 cycles TFHX): 
 
 
Patients who have low risk disease and < 30% reduction of tumor by 
RECIST with induction chemotherapy will receive 75 Gy in 5 cycles TFHX. 
 
 
 
 
 
OR 
 
 
Patients who have high risk disease and < 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 75 Gy in 5 cycles TFHX. 
 
 
 
 
 
OR 
 
 
Any patient who has progressive disease will receive 75 Gy in 5 cycles 
TFHX. Cisplatin based CRT may be considered as a fallback option (see details under 
4.6) 
 
Duration of treatment: 
 
9 weeks of induction chemotherapy. 


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Assessment with clinical and radiologic evaluation.  Surgical biopsies as clinically 
indicated. 
3-5 cycles (6-10 weeks) of active chemoradiation (2 week cycles) or 5 weeks 
radiation depending on group/arm allocation following induction chemotherapy. 
 
Number of patients expected to be enrolled: 
 
61 patients. 
 
Statistical analysis 
Patients will receive induction chemotherapy for three cycles followed by clinical 
and radiologic evaluation, and response-based allocation to RT/CRT treatment arms.  
Response will be assessed after completion of induction chemotherapy by 
clinical (per the ENT surgeon), and radiological examination.  
We expect to enroll 3-5 patients per month for a total of 61 patients over a period 
of 18-24 months. Study is designed to accrue 61 evaluable patients for the primary 
endpoint to allow sufficient statistical power. We expect to activate ~2 additional sites to 
allow rapid enrollment. 
Overall Primary Objective: Non-inferiority compared to HPV(+) patients treated with 
carboplatin, paclitaxel, cetuximab on the #14401 protocol (EPIC-HN trial) 
• 
We will employ a non-inferiority test in which the objective is to establish that the 
2-year PFS rate for an overall treatment regimen that uses induction 
chemotherapy with nab-paclitaxel/carboplatin, is within an acceptable margin of 
that for carboplatin, paclitaxel, and cetuximab as part of the EPIC HN trial (2-year 
PFS=85%) as well as the efficacy goal for 2-year PFS in the ECOG 1308 study 
(85%).  Therefore we assume the true 2-year PFS rate is 85%, and set the non-
inferiority margin at 11%, corresponding to 2-year PFS rate for carboplatin, nab-
paclitaxel of at least 74%.    We will test H0: Δ<-11% vs. HA: Δ>=-11%.   
 
• 
Using Power Analysis and Sample Size (PASS v11) software, a sample of 61 
patients will provide 80% power to test this hypothesis using a (one-sided) type I 
error rate of 0.10. Essentially, H0 will be rejected and nab-Paclitaxel/Carboplatin 
based therapy declared not materially inferior to EPIC/E1308 comparators if the 
lower, one-sided 90% confidence limit for the 2-year PFS rate exceeds 74% 
(which will occur if 50 or more of the 61 patients are alive and progression-free at 
two years, i.e., if the observed 2-year PFS rate is at least 82%).  (This calculation 
assumes that the true PFS rate for nab-paclitaxel is 85% and that all patients will 
be followed for a minimum of 2 years.) If dropouts occur, the PFS rate will be 
estimated using the Kaplan-Meier procedure and its standard error via 
Greenwood’s formula, with corresponding (large-sample) confidence limit.  No 
interim analysis will be conducted. 


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Response rates will be determined together with 95% confidence intervals.  
Toxicity will be summarized by type and grade for both late and early toxicity.. 
 
 


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2.0 OBJECTIVES 
 
2.1 Primary Objective 
 
To determine the 2-year progression-free survival (PFS).  
 
2.2 Secondary Objectives 
 
 Clinical Complete Response Rate (Nab-paclitaxel based induction, compared to 
EPIC induction (Paclitaxel based) 
 Response Rate (Nab-paclitaxel based induction, compared to EPIC induction 
(Paclitaxel based) 
 Proportion of Patients with ≥50% shrinkage by RECIST (Nab-paclitaxel based 
induction) compared to EPIC induction, Paclitaxel based) 
 Toxicity (Nab-paclitaxel based induction, compared to EPIC induction (Paclitaxel 
based) 
 To assess swallowing function and speech at 6 mos and 12 mos post therapy. 
 To determine the rates of late toxicity with chemoradiation following surgery as 
determined 
by 
xerostomia, 
dental 
decay, 
osteroradionecrosis, 
G-tube 
dependency, tracheostomy placement and dysphagia. 
 2-year OS in patients treated on the Low-Risk, Intermediate-Risk Arm, and High-
Risk Arms 
 2-year PFS in patients treated on the Low-Risk, Intermediate-Risk Arm, and 
High-Risk Arms - Early and Late toxicities 
 Evaluate need for post RT/CRT surgery on low- and intermediate-risk arms 
based on response from induction chemotherapy  
 Evaluate in a descriptive manner the role of TORS resection / LND when 
integrated into a de-escalation trial 
 
2.31 Laboratory Objectives 
 
 
 To evaluate pathologic/histologic appearance of tumor after induction 
chemotherapy and after CRT. See section 8. 
 Translational research on blood and tissue samples as detailed in section 8.  
 To profile tumors genetically and immunolotically in order to assess in a 
descriptive manner genetic or immunological features characteristic of clinical 
behavior. See section 8.4.  
 
 
 
 
 


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3.0 BACKGROUND 
 
3.1 Locally Advanced Head and Neck Cancer 
 
Approximately 50,000 new cases of head and neck cancer are diagnosed annually 
in the United States (3). The majority (90-95%) of these cases are squamous cell 
carcinomas of the head and neck (HNSCC) and approximately two-thirds are 
locoregionally advanced cancers (AJCC Stage III-IV) (4). Despite advances in the 
multimodality treatment of locoregionally advanced HNSCC (LA-HNSCC) over the past 
two decades, these patients still experience significant morbidity and mortality. 
 
Historically, locoregionally advanced tumors were treated with surgery, radiation 
therapy, or both. Locoregional failure rates were approximately 30% at 2 years and 
locoregional failures accounted for nearly 60% of failures. Survival at 5 years was 
reported to be only 40% (10–30% for patients with stage IVa and IVb tumors). 
Approximately 20% of patients developed metastatic disease and nearly one-fifth of 
these patients died of distant metastases without evidence of locoregional recurrence 
(5-8). 
 
 
 
3.1.1Chemoradiotherapy  
 
Given discouraging outcomes with surgery and radiation, investigators became 
increasingly interested in the incorporation of chemotherapy for the treatment of LA-
HNSCC. The feasibility of a non-surgical, organ preservation approach with concomitant 
chemoradiation was first established by the landmark Veterans Affairs Laryngeal 
Cancer Study (9, 10). Since then, several randomized trials and meta-analyses have 
demonstrated improved disease-free and/or overall survival with concomitant 
chemoradiotherapy and confirmed its role as standard therapy for patients with 
locoregionally advanced unresectable disease (11-16). The positive effects on disease-
free and overall survival seem to be predominantly mediated through improved 
locoregional control, thus affecting the traditionally predominant pattern of failure for this 
disease. 
 
Concurrent chemoradiotherapy attempts to capitalize on both the radiosensitizing 
properties of chemotherapy at sites of known disease targeted by radiation in addition to 
delivering agents that function systemically to treat occult metastatic disease. However, 
sensitizing effects are not tumor specific and exert both locoregional effects on adjacent 
normal tissues within the radiation field as well as systemic effects, particularly on the 
bone marrow and peripheral nervous system. Concurrent chemoradiotherapy trials have 
consistently reported an increased incidence of acute grade 3 and 4 toxic effects, with 
mucositis, dermatitis, and cytopenias being the most prominent (4).This rise creates 
concern about chronic toxic effects, including consequential late effects, which evolve 
from persistent severe acute toxic effects.  
 


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Optimizing the therapeutic ratio of treatment benefit to toxicity has thus become a 
focus of recent investigation. Advances in the delivery of conformal radiation, including 
the development of intensity modulated radiation therapy (IMRT), have allowed 
significant improvements in sparing normal tissue structures.  This is best exemplified 
by the reduction in rates of xerostomia with sparing of the parotid glands (17). However, 
other treatment-related morbidities such as dysphagia are still problematic; indeed, 2-
year rates of feeding tube dependence have been reported as high as 50% (18-20). 
This is particularly significant given recent data that quality of life among patients with 
HNSCC treated with radiotherapy is substantially affected by swallowing dysfunction 
and the need for enteral nutrition support (21). Efforts are now focused on decreasing 
the dose of radiation to dysphagia-related structures, particularly the pharyngeal 
constrictors, which are prone to stricture formation with doses ≥50 Gy (22).  
 
3.1.2 TFHX regimen 
 
At the University of Chicago, we have investigated multiple intensive concomitant 
chemoradiotherapy regimens. We initially studied the interaction of 5-FU, hydroxyurea 
and radiotherapy (FHX) (23, 24). Both chemotherapy agents have known systemic 
activity and have been shown to act as radiation enhancers in vitro and in vivo (6, 25, 
26). Cytotoxic activity is synergistic as hydroxyurea modulates the activity of 5-FU by 
depleting cellular pools of deoxyuridine monophosphate (dUMP) and facilitating binding 
of the 5-FU metabolite 5-FdUMP to its target enzyme thymidylate synthase (27). 
Paclitaxel was subsequently added to the FHX regimen (TFHX) and the radiation 
scheme changed to twice daily to further intensify the treatment (28-32).  
 
The TFHX regimen was demonstrated to be a highly active and tolerable 
concomitant chemotherapy and hyperfractionated radiation regimen: overall survival 
and locoregional control rates at 3 years were 60% and 86%, respectively (30, 32). 
Since surgery was used primarily as a salvage procedure, excellent organ preservation 
was also achieved. Acute toxicities were severe in a majority of patients but were 
considered tolerable overall. Mucositis (84% grade 3/4), “in-field” dermatitis (38% grade 
3/4), leukopenia (34% grade 3/4), and anemia (22% required transfusion) were the most 
common serious side effects. At 1 year post-treatment, 61% of patients had severe 
xerostomia and 47% had compromised swallowing; the rate of feeding tube 
dependence was 20% (30, 32). 
 
Toxicity rates with TFHX were higher than expected, with a significant number of 
patients experiencing grade 3/4 mucositis (76%) and dermatitis (61%) (33). Therefore, 
we attempted to decrease the toxicity of concomitant chemoradiation by decreasing the 
radiation dose in sequential cohorts to areas at risk for microscopic disease in patients 
who had either complete or partial (≥50%) response to ICT (34, 35). The cohort 
receiving 75 Gy to gross disease (high risk), 54 Gy to intermediate-risk volumes, and 39 
Gy to low-risk volumes experienced the best therapeutic ratio. Again, high locoregional 
and distant control rates were seen, though the rate of dermatitis (45%) was 
significantly lower (34). 
 


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With improved locoregional control, the systemic control of micrometastatic 
disease emerged as an important treatment goal that was not achieved optimally with 
the chemotherapy doses applied during concomitant chemoradiotherapy. Indeed, 
approximately 20% of patients were noted to recur distantly, despite the addition of 
cytotoxic chemotherapy to radiation therapy as part of the TFHX regimen [26-28]. 
 
 
3.1.3 Induction Chemotherapy 
 
On the basis of the aforementioned studies, induction chemotherapy was 
investigated as a method of successfully eradicating micrometastatic disease. At the 
University of Chicago, carboplatin and paclitaxel were initially chosen as an induction 
chemotherapy (ICT) regimen because they are typically well-tolerated with low rates of 
mucositis. The first report of this regimen demonstrated both high locoregional control 
and improved distant control (33). Systemic disease progression was noted in 7% of 
patients; this translated into improved 3-year progression-free and overall survival rates 
of 80% and 77%, respectively.  
 
Currently, the triplet combination of a taxane (docetaxel or paclitaxel), cisplatin, 
and 5-FU (TPF) is considered a standard induction regimen (if induction therapy is 
considered). This is largely based on the results of a meta-analysis demonstrating a 5% 
increase in survival for cohorts using a cisplatin/fluorouracil (5-FU) combination. There 
are three recently published phase III trials demonstrating the superiority of induction 
docetaxel, cisplatin, and 5-fluorouracil over cisplatin and 5-fluorouracil when followed by 
radiotherapy or chemoradiotherapy (12, 36-39). Controversy still exists regarding the 
overall survival benefit of adding induction TPF to chemoradiotherapy. Recent studies 
demonstrating no additional survival benefit are limited by methodological deficiencies 
(40-42).  Additionally, unpublished data demonstrates that TPF and carboplatin/ 
paclitaxel seem to have equivalent activity with less toxicity with carboplatin and 
paclitaxel.  Two studies evaluating carboplatin/paclitaxel induction demonstrated 82% 
and 87% response rates compared to our DeCIDE trial 64% response to TPF. (33, 34, 
42) Paclitaxel and nab-paclitaxel have the same activity with slightly better delivery and 
toxicity with nab-paclitaxel.  Compared with solvent-based paclitaxel, nab-paclitaxel, 
delivers 33% higher drug concentration to tumors in preclinical xenograft models, and 
demonstrates enhanced transport across endothelial cell monolayers (Desai 2006,; 
Gardner, 2008).  The Cremophor El-free medium enables nab-paclitaxel to be given in a 
shorter duration without the need for premedication to prevent solvent-related 
hypersensitivity reactions.   Standard IV bags and tubing may be used for the delivery of 
nab-paclitaxel.  Hence, in our study we have opted for use of nab-paclitaxel. 
 
3.2 Human Papillomavirus (HPV) and HNSCC 
 
Both epidemiologic and molecular evidence have recently elucidated the 
causative role of HPV in HNSCC. Approximately 25%–35% of all HNSCC is associated 
with HPV genomic DNA, with the majority of these cancers occurring in the oropharynx 
(43). The incidence of oropharyngeal cancer has risen dramatically over the past two 


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decades and it is now the most common HNSCC (44-46). Both seropositivity and oral 
infection with high-risk type HPV (HPV-16) have been shown to increase the risk of 
developing oropharyngeal cancer (OPC) (47, 48). HPV-positive tumors have a unique 
molecular profile: wild-type p53, upregulated p16, and downregulated pRb (49). There is 
direct evidence that HPV-16 is oncogenic, mechanistically driving the development and 
viability of cancer cells (50-52). 
 
There is concern for an impending HNSCC-epidemic due to HPV.  Extrapolating 
recent trends, the annual number of HPV-positive oropharyngeal cancers (HPVOPC) is 
expected to surpass the annual number of cervical cancers by the year 2020 (53, 54). 
This is especially concerning in light of the fact that patients with HPV-related OPC are 
approximately ten years younger on average than their HPV-negative OPC counterparts 
(46, 54, 55). 
 
Recently, studies have demonstrated that patients with HPV-related OPC have 
superior response to therapy and survival compared to HPV-negative OPC.  In 
retrospective analyses of survival and HPV status from three phase III trials, 
unprecedented overall survival of approximately 80-90% at three years was obtained (2, 
56, 57).  Improved survival in these studies was largely due to markedly improved local-
regional control as a biologic consequence of the HPV-origin of these tumors. With the 
improvement in locoregional control, distant metastasis is now gaining recognition as a 
leading cause of death in HPV-positive patients and the rate of distant relapse is the 
same for both HPVOPC and non-HPV related tumors (57-59). 
 
Recursive partitioning analysis has helped to stratify HPVOPC patients for both risk 
of death and distant relapse. In a retrospective analysis of the association between 
tumor HPV status and survival among patients with stage III/IV OPC who were enrolled 
in a randomized trial comparing accelerated-fractionation radiotherapy with standard-
fractionation radiotherapy as part of concomitant chemoradiation with cisplatin, HPV 
status of the tumor was the major determinant of overall survival, followed by the 
number of pack-years of tobacco smoking (≤10 vs. >10), and then nodal stage (N0 to 
N2a vs. N2b to N3) for HPV-positive tumors (57). In another retrospective analysis of  
the association between tumor HPV status and distant metastatic risk in a prospectively 
assembled cohort of OPC patients treated with radiotherapy alone or concurrent 
chemoradiotherapy, both tumor size (T1 to T3 vs. T4) and nodal stage (N0 to N2c vs. 
N3) were found to be major determinants of distant relapse (60). Of note, patients with 
N2c disease treated with radiation alone, however, had reduced rates of distant control. 
 
3.3 Study Rationale 
 
HPV-related HNSCC is a distinct clinical entity based on differing demographics, 
biology, and prognosis. The overall survival benefit in patients with HPVOPC compared 
non-HPV related cases is due largely to a marked improvement in locoregional control. 
Given the younger demographic of HPVOPC and the significant long-term morbidity 
incurred with high dose local therapy, reduction of RT intensity is a prudent 
consideration. Indeed, recent data indicates that quality of life in survivors of head and 


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neck cancer is most affected by swallowing dysfunction, with stricture formation 
occurring at doses of ≥50 Gy to the pharyngeal constrictors (21, 22). 
 
Studies of anal cancer treatment provide evidence that excellent locoregional control 
may be obtained in HPV-related squamous cell cancers with lower doses of radiation as 
part of a chemoradiotherapy regimen. In a prospective trial of anal cancer patients 
receiving concomitant 5-FU/mitomycin C and 45 Gy of external beam radiation plus a 
boost in good responders of either 25 Gy with iridium implant or 15 Gy by external beam 
radiation, five year locoregional recurrence rates were 32% (61). More contemporary 
prospective data in head and neck are also promising. ECOG 1308, A Phase II trial of 
induction chemotherapy followed by cetuximab with low dose or standard dose IMRT in 
patients with HPV-associated resectable squamous cell carcinoma of the oropharynx 
reported promising preliminary 1 year progression free survival of 91% in low risk HPV 
patients treated with low dose radiation.  Patients in this trial were placed in low risk and 
standard risk groups at study entry based on tobacco history, T stage and bulky lymph 
node status.  Eighty patients were enrolled, 62 were in low risk group.  Patients were 
treated with induction cisplatin, paclitaxel, and cetuximab followed by radiation and 
cetuximab to 54 Gy for low risk disease and 69.3 Gy for standard risk disease.  All 
patients were HPV + by p-16 and/or ISH analysis.  Interim analysis of progression free 
analysis was reported for low and high risk patients with 91% and 89%, respectively.  
Additionally, subset analysis of 1-year progression free analysis demonstrated 97%, 
84% for <  and > 10 pack year history of tobacco, 92% (T1-T3)and 86% (T4), and 92% 
(N0-N2B), and 88% (N2C), respectively. (1) 
We have previously demonstrated excellent locoregional control rates with a 
concomitant chemoradiotherapy regimen of TFHX. With superior locoregional control, 
the importance of distant control became apparent and ICT was incorporated with 
reduction in rates of distant relapse.  This is an especially important consideration for 
HPV-related HNSCC, as the rate of distant metastases is the same for both HPVOPC 
and non-HPV related tumors and distant failure is now gaining recognition as a leading 
cause of death in HPV-positive patients. 
 
We hypothesize that in locally advanced cases of HPV-related HNSCC, 
Carboplatin and nab-paclitaxel ICT will produce high rate of complete or good partial 
responses hence, allowing for reduced intensity chemoradiotherapy and  will have 
excellent outcomes after reduced treatment intensiity radiation or chemoradiation. We 
hypothesize in particular that this approach wll reduce acute and long-term therapy-
related toxicities.  
 
In this study, we will specifically evaluate patients who have stage III or IV, HPV(+), 
squamous cell cancer of the oropharynx. Patients will be given a course of 3 cycles of 
carboplatin and nab-paclitaxel ICT followed by clinical, radiologic, and biopsy for 
pathologic assessment.  Radiation to 45 Gy will be given to low dose arm (LDA) 
patients and concurrent chemoradiation with TFHX and twice-daily irradiation will be 
given to a total dose of 50 Gy for intermediate dose arm (IDA), or 75 Gy in standard 
dose arm (SDA) as outlined below.  
 


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Low Risk: 
o T1-3 
o N 0 - N2B (excluding N2B disease with N3 equivalent amount of tumor) 
o < 10 pack year history tobacco use 
 
 
High Risk: 
o T4 
o N2C-N3 
o N2B disease with N3 equivalent amount of tumor (conglomerate bulky 
disease > 6cm) 
o > 10 pack year history tobacco use 
 
 
 
Patients will be assigned to Radiation alone or CRT/TFHX based on 
response to induction chemotherapy.   TFHX will consist of 14-day cycles of paclitaxel 
(100 mg/m2 Day 1 over 1 hour), 5FU (continuous infusion at 600 mg/m2/day  5 days), 
and hydroxyurea (500 mg PO BID day 0-5, 11 doses/cycle) with twice daily radiation 
(150 cGy per fraction). 
No therapy on days 6-14. Supportive care should be administered as specified in 
Section 5. 
 
 
 
Group A – Low Dose Arm (LDA) - Radiation only: 
 
 
Patients who have low risk disease and > 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 50Gy radiation alone. 
 
 
Group B – Intermediate Dose Arm (IDA) - Low dose CRT (3 cycles TFHX): 
 
 
Patients who have low risk disease and < 50% butr > 30% reduction of 
tumor by RECIST with induction chemotherapy will receive 45 Gy in 3 cycles TFHX. 
 
 
 
 
 
OR 
 
 
Patients who have high risk disease and > 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 45 Gy in 3 cycles TFHX. 
 
 
Group C – Standard Dose Arm (SDA) – regular CRT (5 cycles TFHX): 
 
 
Patients who have low risk disease and < 30% reduction of tumor by 
RECIST with induction chemotherapy will receive 75 Gy in 5 cycles TFHX. 
 
 
 
 
 
OR 
 
 
Patients who have high risk disease and < 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 75 Gy in 5 cycles TFHX. 
 
 
 
 
 
OR 
 
 
Any patient who has progressive disease will receive 75 Gy in 5 cycles 
TFHX. 
For group C cisplatin based CRT is acceptable as a fallback option if approved 
by the PI (Dr. Vokes), and should be completed analogous to the RTOG 0522 or EPIC 
trials, albeit without cetuximab, and still implement field reductions as outlined in this 
protocol. (62) 


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4.0 PATIENT SELECTION 
 
4.1 Eligibility Criteria 
 
 Patients must have pathologically confirmed HPV-positive squamous cell 
carcinoma.  
 HPV testing must follow the following criteria (also see section 4.4) 
 HPV testing using an E6/E7 based assay is preferred, and does not 
require any validation (e.g. HPV ISH or HPV E6/E7 PCR).  
 For oropharyngeal tumors p16 IHC positivity is sufficient to enroll and 
initiate treatment (p16 IHC interpretation to follow guidelines by 
Jordan/Lingen et al 2012).  It is recommended that p16 IHC positivity is 
validated at a later point (during or after treatment) using an E6/E7 based 
test at the University of Chicago and provided slides will be used. 
 For non-OP tumors accurate HPV testing (i.e. ISH, or E6/E7 based 
testing) is required for enrollment and treatment initiation.  
 Availibility of ≥10 unstained 5 micron slides (to be provided to Dr. Seiwert/Vokes 
at the University of Chicago) 
 Patients must be at least 18 years of age. 
 Patients with AJCC (7th edition, 2010) T1-T4 nodal stage N2 or N3 or aT3 or T4 
primary tumor with any nodal stage. 
 The primary and nodal involvement must be assessable on clinical exam 
(mucosal and lymph node exam). 
 The primary and nodal involvement must have been defined bi- or uni-
dimensional measurements measurable by RECIST. 
 No previous radiation or chemotherapy for a head and neck cancer. 
 No surgical resection for a head and neck cancer within 8 weeks of enrollment 
(although lymph node biopsy including excision of an individual node with 
presence of residual nodal disease, or surgical biopsy of the tumor is 
acceptable). 
 ECOG performance status 0-1 (Karnofsky  70%, see Appendix A). 
 
 Leukocytes ≥ 3000/mm3, platelets ≥ 100,000/mm3, Absolute neutrophil count ≥ 
1,500,  Hemaglobin > 9.0 gm/dL, Albumin > 2.9 gm/dL, total bilirubin ≤ 1.5 mg/dl, 
creatinine clearance  > 45 mL/min (or SCr < 1.5 mg/dL), normal within 2 weeks 
prior to start of treatment. 
 The standard Cockcroft and Gault formula or the measured glomerular 
filtration rate must be used to calculate CrCl for enrollment or dosing. 
 
 Patients must have adequate liver function:  AST and ALT < 2.5 X ULN; 
alkaline phosphatase < 2.5 X ULN 
 
 Patients must sign a study-specific informed consent form prior to study 
entry. Patients should have the ability to understand and the willingness 
to sign a written informed consent document. 


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4.2 Exclusion Criteria 
 
 Unequivocal demonstration of distant metastases (M1 disease). 
 
 Intercurrent medical illnesses which would impair patient tolerance to therapy or 
limit survival. Including but not limited to ongoing or active infection, 
immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, 
cardiomyopathy, unstable angina pectoris, cardiac arrhythmia or psychiatric 
illness/social situations that would limit compliance. 
 
 Pregnant and nursing women are excluded because of the potential teratogenic 
effects and potential unknown effects on nursing newborns. Men and women of 
child-bearing potential are eligible but must consent to using effective 
contraception during therapy and for at least 3 months after completing therapy.  
Women with child-bearning potential must have a negative serum or urine B-hCG 
pregnancy test at screening. 
 
 
 Other coexisting malignancies or malignancies diagnosed within the previous 3 
years no evidence of disease for at least 3 years. Exceptions to this include non-
melanoma skin cancer, cervical cancer in situ, well differentiated thyroid cancer 
or prostate cancer. Other cancers that per assessment of the PI are not 
prognosis limiting can be allowed after review by the PI. 
 
 Prior surgical therapy other than incisional or excisional biopsy and organ-
sparing procedures such as debulking of airway-compromising tumors or neck 
dissection in a patient with an unknown primary tumor.  Residual tumor is 
required for enrollment on study. 
 
 Patients receiving other investigational agents. 
 
 Peripheral Neuropaghy ≥grade 1 
 
 
 
4.3 Criteria for discontinuation/withdrawal of informed consent 
 
Patients may be discontinued from trial treatment at any time, at the discretion of the 
investigator(s).  Specific reasons for discontinuing a patient from study treatment 
include: 
 
 Objective progression of disease if deemed inappropriate for further study 
treatment e.g. continuation on the regular dose arm (RDA). 
 
 Unacceptable adverse events. 


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 Protocol non-compliance. 
 
 Study closure. 
 
 Patient decision to withdraw from the study.  
 
 In the judgment of the investigator, further treatment would not be in the best 
interest of the patient. 
 
All deaths that occur within the trial period or within 30 days after administration of 
the last dose of trial drug must be reported primarily for the purposes of serious adverse 
event (SAE) reporting; however, deaths due unequivocally to progression are not SAEs. 
 
All trial treatment-related toxicities and SAEs must be followed up until resolution. 
All patients who have new or worsening CTC grade 3 or 4 laboratory values at the time 
of withdrawal must have additional testing performed, and the results must be recorded 
in the patients’ medical records.  In these cases, the investigators must record their 
opinions in the patients’ medical records.  Laboratory abnormalities should not be 
reported as adverse events unless a criterion for an SAE is fulfilled, the laboratory 
abnormality causes the patient to discontinue from the study, or the investigator insists 
the abnormality should be reported as an AE.   
 
 
4.4 HPV testing 
 
As this trial makes treatment decision based on HPV status the specificity of the HPV 
test is important (63). Therefore certain HPV testing requirements have to be met that 
take into account varying HPV performance characteristics in oropharyngeal and non-
oropharyngeal primary tumors (64): 
-1- HPV testing using an E6/E7 based assay is preferred, and does not require 
any validation (e.g. HPV ISH or HPV E6/E7 PCR).  
 
-2- For oropharyngeal tumors p16 IHC positivity is sufficient to enroll and initiate 
treatment (p16 IHC interpretation to follow guidelines by Jordan/Lingen et al 2012).  It is 
recommended that p16 IHC positivity is validated at a later point (during or after 
treatment) using an E6/E7 based test at the University of Chicago and provided slides 
will be used. 
 
-3- For non-OP tumors E6/E7 based HPV testing (i.e. ISH, or E6/E7 based 
testing) is required for enrollment and treatment initiation.  
 
 


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5.0 TREATMENT PLAN 
 
5.1 General Considerations 
 
Induction chemotherapy will be administered on an outpatient basis followed by 
chemoradiotherapy and surgery (as indicated) will be administered on an inpatient 
basis. All patients will be evaluated by surgical, medical and radiation oncologists prior 
to entry on the trial to determine optimal local treatment. Patients will start on induction 
chemotherapy within 6 weeks of enrollment. Three cylces of carboplatin and nab-
paclitaxel 
induction 
chemotherapy 
will 
be 
followed 
by 
response-adjusted 
radiation/chemoradiation.  
 
 
Patients in Group A will receive radiation to 50 Gy in standard daily fractionation. 
For patients in groups B and C, concurrent chemoradiation will consist of twice daily 
radiation with paclitaxel, 5-FU, hydroxyurea TFHX) given on an alternating week basis. 
Patients should have a pre-induction chemotherapy CT simulation performed and fused 
to the planning CT scan.  TFHX will be given to a total dose of 50 Gy to patients in 
Group B and 70 Gy to patients in Group C as outlined below (See Section 5.3).  
 
 
Surgical validation of patients in Group A and Group B will be planned after 
completion of radiation/chemoradiotherapy (especially the first 50% of patients in 
groups A/B).  Surgical extent and surgical procedures will be determined by the surgeon 
(biopsy versus resection versus TORS) based on the protocol guidelines and disease 
status.  Standard resection or Trans oral robotic surgical resection (TORs) and lymph 
node dissection (LND) will be done for any patients who have residual disease (gross 
disease or radiologic evidence of disease) following chemoradiotherapy as surgical 
salvage.  (See section 5.7)  
 
 
 
5.2 Pre-treatment evaluation 
 
 
Patients must have completed the following within 4 weeks of registration unless 
noted: 
 
 Inclusion and Exclusion criteria reviewed. 
 
 Physical examination to define measurable disease. 
 
 Pan-endoscopy with mapping biopsies and documentation (Please see section 7 
with respect to biopsy). 
 
 Biopsy proven squamous cell carcinoma of the head and neck with HPV testing 
(see section 4.4). 
 


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 Baseline CT or MRI scans of head and neck that includes entire disease extent 
within 3 months before study entry. (Scans of the head and upper abdomen 
should be used as clinically indicated.) 
 
 PET/CT scan prior to start of induction chemotherapy. 
 
 One week prior to chemotherapy, CBC with differential and platelet count, and 
complete metabolic profile. 
 Liver ultrasound or CT scan if the liver chemistries (SGOT, SGPT, and bilirubin) 
are > 2 times normal values. 
 
 Additional studies (bone scan, barium swallow, etc.) to exclude distant 
metastases or second primaries as clinically indicated. 
 
 Complete dental evaluation. 
 
 Speech and swallowing consultation. 
 
 Informed consent. 
 
5.3 Study evaluations 
 
Patients will have the following exams and tests throughout the study at specified 
timepoints (please see study chart): 
 
 Physical examination to define measurable disease. 
 
 Performance status evaluation 
 
 CBC with differential and platelet count. 
 
 Complete metabolic panel. 
 
 Toxicity evaluations 
 
 PET/CT prior to induction chemotherapy and 10-12 weeks after chemoradiation, 
if no gross residual disease.  Patients who have gross residual disease will 
undergo 
surgical 
resection 
without 
waiting 
for 
PET/CT 
per 
ENT 
recommendations, 4-8 weeks following completion of chemoradiation. 
 
 CT of the head and neck after induction chemotherapy week 3 of 3rd cycle of 
induction chemotherapy in order to determine radiation fields. 
 
 
5.4 Induction Chemotherapy  


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5.4.1 Induction chemotherapy will be administered on an outpatient basis and 
concurrent chemoradiation will be administered on an inpatient basis. Expected 
adverse events (AEs) and appropriate dose modifications for these agents are 
described in Section 5. No other investigational agents or therapies other than 
those described below may be administered with the intent to treat the patient’s 
malignancy. 
 
 
5.4.2 Induction Therapy Details 
 
Carboplatin, and nab-paclitaxel combination will be administered for three 
cycles of 3 weeks duration each.  Chemoradiotherapy will begin after induction 
chemotherapy (i.e. day 64 of therapy). Dose delays and dose modifications 
should take place as in section 5.2  In no case should the three cycles of 
induction chemotherapy be given over a period exceeding twelve (12) 
weeks. 
 
Pre-medications:  
Premedication with dexamethasone is recommended 
for all patients receiving weekly paclitaxel or nab-paclitaxel therapy to reduce 
the incidence and severity of fluid retention as well as the severity of 
hypersensitivity reactions.  
 
Dexamethasone 20 mg x 1 dose taken intravenously or orally the morning of 
treatment will be administered. 
 
Nab-Paclitaxel: 
100 mg/m2 in 250 ml of D5W over 60minutes (on Day 1, 8, 
and 15). 
 
Carboplatin: Start after completion of paclitaxel on Day 1, AUC 6  in 250 ml 
of NS over 30 -60 minutes 
 
A baseline creatinine level should be drawn within 1 week prior to starting 
chemotherapy.  
 
Antiemetics: 
Pre-treatment with a 5 HT-3 antagonist [eg ondansetron 
hydrochloride (Zofran), dolasetron mesylate (Anzemet), or granisetron 
hydrochloride (Kytril)] plus a corticosteroid prior to chemotherapy on Day 1 is 
recommended. The use of additional antiemetics and the prevention of delayed 
emesis are left to the discretion of the treating physician. 
 
Hydration: 
 
Hydration is left to the discretion of the treating physician. 
 
For each cycle:  Use of filgrastim (neupogen) is to be given on Days 
16/17/18, but can be modified – increased or decreased as 
clinically indicated. 


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5.5  Radiation and Concomitant Chemoradiotherapy Details and Guidelines. 
 
 
Radiation or concurrent chemoradiation will be administered depending on 
response-stratified grouping noted below. 
 
 
Low Risk: 
o T1-3 
o N 0 - N2B (excluding N2B disease with N3 equivalent amount of tumor) 
o < 10 pack year history tobacco use 
 
 
High Risk: 
o T4 
o N2C-N3 
o N2B disease with N3 equivalent amount of tumor (conglomerate bulky 
disease > 6cm) 
o > 10 pack year history tobacco use 
 
Response Stratified grouping 
 
Patients will be assigned to Radiation alone or CRT/TFHX based on 
response to induction chemotherapy.   TFHX will consist of 14-day cycles of paclitaxel 
(100 mg/m2 Day 1 over 1 hour), 5FU (continuous infusion at 600 mg/m2/day  5 days), 
and hydroxyurea (500 mg PO BID day 0-5, 11 doses/cycle) with twice daily radiation 
(150 cGy per fraction). 
No therapy on days 6-14. Supportive care should be administered as specified in 
Section 5. 
 
 
 
Group A/Low Dose Arm (LDA) – Radiation only: 
 
 
Patients who have low risk disease and > 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 50Gy radiation alone. 
 
 
Group B/Intermediate Dose Arm (IDA) – Low dose CRT (3 cycles TFHX): 
 
 
Patients who have low risk disease and < 50% but > 30% reduction of 
tumor by RECIST with induction chemotherapy will receive 45 Gy in 3 cycles TFHX. 
 
 
 
 
 
OR 
 
 
Patients who have high risk disease and > 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 45 Gy in 3 cycles TFHX. 
 
 
Group C/Standard Dose Arm (SDA) – Standard dose CRT (5 cycles TFHX): 
 
 
Patients who have low risk disease and < 30% reduction of tumor by 
RECIST with induction chemotherapy will receive 75 Gy in 5 cycles TFHX. 
 
 
 
 
 
OR 


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Patients who have high risk disease and < 50% reduction of tumor by 
RECIST with induction chemotherapy will receive 75 Gy in 5 cycles TFHX. 
 
 
 
 
 
OR 
 
 
Any patient who has progressive disease will receive 75 Gy in 5 cycles 
TFHX. 
Cisplatin based CRT may be used in Group C/Standard Dose Arm as a fallback 
option, after approval by the PI (Dr. Vokes). 
 
Expected AEs and appropriate dose modifications for nab- paclitaxel, carboplatin, 
5-FU, hydroxyurea, and radiation are described in sections 6.1 and 6.2 and Appendix B 
and C. No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 
 
Patients with intermediate or regular dose arm will receive chemoradiation for 
3.5-5 weeks as per Chemotherapy should be administered during all 3 weeks 
of radiotherapy.   
 
Day 0  
P.M.:  
start hydroxyurea at 500 mg PO q 12 hours  6 days 
(11 doses).  The first daily dose of hydroxyurea on 
Days 1 – 5 is given 2 hours prior to the first fraction of 
daily radiotherapy. 
 
 
 
6:00 P.M.:  
start 
continuous 
infusion 
of 
5-FU 
at 
600 mg/m2/day  5 days (120 hours). 
 
Day 1 – 5 
dexamethasone 20 mg PO (IV) in am Day 1, 1 hr prior 
to paclitaxel 
 
famotidine 20 mg PO (IV) in am Day 1, 1 hr prior to 
paclitaxel 
 
diphenhydramine 50 mg PO (IV) in am Day 1, 30 
mins prior to paclitaxel 
 
 
Start paclitaxel 100 mg/m2 after first RT fraction on 
day 
1 
of 
each 
cycle. 
Paclitaxel 
should 
be 
administered in 250 ml 0.9% NaCl over 60 minutes. 
Radiation therapy is administered twice daily at 
150 cGy per fraction. 
 
Days 6 – 13:  
No chemoradiotherapy. Patients should be seen 
once on an outpatient basis during these non-
treatment days to monitor for toxicity.  
 


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For each cycle:  
Administer 5 g/kg subcutaneously (SQ) of G-CSF 
(filgrastim) daily, beginning on Day 6 through Day 12 
at a minimum of 24 hours after completion of 5-FU in 
patients who develop grade 3 neutropenia or who 
have neutropenia  grade 2 on Day 0 of any cycle.  In 
these patients, G-CSF should be utilized in all 
subsequent 
cycles. 
G-CSF 
can 
be 
utilized 
prophylactically from the start of chemoradiotherapy 
in all cycles at the discretion of the treating physician. 
 
Chemoradiotherapy cycles are repeated every 14 days until the completion of 
radiotherapy. 
 
As an alternative the option to use Cisplatin based chemoradiotherapy can 
be approved on a case by case basis for high risk patients. Cisplatin based 
CRT will be given analogous to the EPIC HN and RTOG 0522 trials, albeit 
without cetuximab, and with the respective field adjustements as outlined 
below. Use of Cisplatin based CRT requires prior PI approval (please email/call 
Dr. Vokes). 
 
5.5.1 Radiation Therapy Guidelines 
 
1. All patients will have a complete dental evaluation prior to the start of radiation 
therapy, ideally prior to the start of chemotherapy. 
 
2. Treatment approaches will use Intensity Modulated Radiotherapy (IMRT) and, in 
selected cases, 3D conformal radiotherapy will be used alone or in combination 
with IMRT. In both instances the physician will attempt to deliver an even dose 
to the target tissue and minimize doses to surrounding normal structures. The 
use of customized blocks or multileaf collimation for field shaping is strongly 
recommended.  
 
 
3. Localization requirements: All patients will be immobilized and simulated in 
the treatement position prior to the start of induction chemotherapy and after 
induction chemotherapy within 1-2 weeks after the last cycle of chemotherapy. A 
contrast enhanced CT with immobilization is required for planning.  Slice 
thickness should be optimally 3mm and no greater than 5 mm. The pre- and 
post-chemotherapy scans will be fused to define the targets below. Patients 
must be reproducibly immobilized. Radio-opaque markers may be used 
whenever possible to delineate the surgical scars, extent of nodal disease, skin 
involvement, and any gross disease.  
 
4. Target volumes: Appropriate field sizes will be determined at the time of 
simulation to treat gross disease and areas of potential microscopic disease.   


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Three target volumes will be defined on each CT slice: GTV, PTV1 and PTV2. 
GTV will be all gross tumor identified by physical exam, additional clinical 
information and radiographic studies before induction chemotherapy.  The GTV 
will be expanded by 1.5 cm to create PTV1.  PTV1 can be modified at the 
discretion of the treating physician for the constraints of normal tissue tolerance 
and to avoid extension beyond the skin. 
 
PTV2 will include PTV1 plus the next  echelon of uninvolved but at risk 
lymph nodes that include the nodal stations at risk for microscopic spread as 
described in the tables below. In general, the pre-induction chemotherapy scan 
is used to define the primary tumor GTV and the post-induction chemotherapy 
volume is used to define the nodal volume GTV. PTV2 may not differ 
significantly from PTV1 if the required GTV expansion includes the next nodal 
station at risk. For tumors that cross midline in the oral cavity or oropharynx (e.g. 
tumors involving the soft palate and base of tongue), PTV 2 may include 
contralateral level 2 LN. PTV2, can be modified at the discretion of the treating 
physician to achieve dose contraints for normal tissue tolerance and to avoid 
extension beyond the skin. The inclusion of the retropharyngeal lymph nodes in 
PTV2 will be at the discretion of the attending radiation oncologist. Reasonable 
attempts should be made to provide an adequate treatment volume without 
encroaching on critical organs (e.g. spinal cord) or extending to the skin. 
 
5. Field Size: Appropriate field sizes will be determined at the time of simulation to 
treat gross disease and areas of potential microscopic disease. Initial field size 
and arrangement will be at the discretion of the attending radiation oncologist. 
The optimal field arrangement will be determined based on the treatment 
planning techniques employed. All fields must be treated during each treatment 
session. 
 
6. Treatment technique: Blocking will be individualized for each patient.  Either 
custom Cerrobend blocks or multileaf collimator will be acceptable. 
 
Intensity modulated Radiotherapy: Optimal IMRT planning will depend on the 
planning system employed.  We anticipate the optimal plan will use 7 to 11 
gantry positions.  Acceptable plans will encompass the PTV with the 95% 
isodose line.  No more than 1% of the PTV should receive less than 95% of the 
prescribed dose.  Plans should be reviewed to insure that any part of the PTV 
getting less than 95% of the prescribed dose is at the edge of the volume.  In no 
case should a central area of the PTV receive less than 95% of the prescribed 
dose.  No more than 1% of the PTV should receive more than 110% of the 
prescribed dose. 
 
3D Conformal Radiotherapy: The neck should be treated with opposed lateral 
fields using a half-field technique.  The lower neck should be treated with an 
anterior field prescribed to a depth of 3 cm.  Opposed fields for the lower neck 
are permitted in order to improve PTV coverage and increase homogeneity.  


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Wedges, tissue compensators or segmented fields should be used to insure 
uniformity of PTV coverage.  Electron boosts of the posterior neck are permitted 
to limit the dose to the spinal cord.  Electron fields shall be prescribed to the 
depth of maximum dose with the energy and field size chosen so that the target 
volume is encompassed within 90% of the prescribed isodose line.  A cord block 
is permitted on the anterior or lateral fields provided it dose not block tumor.  
Feathering the match line is permitted in cases where a cord block would block 
tumor. For 3D techniques, acceptable plans will encompass the PTV within the 
95% isodose line. The dose variation in the PTV will be +7% and -5% of the 
prescription point dose. 
 
7. Dose Fractionation: Isodose calculations in the axial, sagittal, or coronal 
planes are required. In addition, dose volume histograms for the GTV and the 
spinal cord are required. 
i. Group A:  Radiation will be delivered in 200 cGy daily fractions to a 
total dose of 5000 cGy. No chemotherapy will be delivered with 
radiation. Radiation will be delivered for 5 consecutive weeks. 
ii. Group B: Each cycle of treatment will consist of 5 consecutive days of 
radiation with 150 cGy given bid (300 cGy per day and 1500 cGy per 
week) in conjunction with chemotherapy. Three total cycles of 
chemoradiation will be delivered. Ideally, PTV1 and PTV2 will be 
treated with the first two cycles and PTV1 will be treated with the third 
cycle. Chemoradiation will be given on an alternating weekly basis. 
There should be a minimum of 6 hours between fractions.  All fields 
will be treated each day.  In the case of mechanical failure or a 
holiday, one day of BID radiotherapy can be replaced with a single 
QD fraction of 200 cGy.  Accordingly, the final cumulative dose will be 
slightly less. Ideally, the dose to PTV1 will be 45 Gy and PTV2 will be 
30 Gy. 
iii. Group C (with THFX): Each cycle of treatment will consist of 5 
consecutive days of radiation with 150 cGy given bid (300 cGy per 
day and 1500 cGy per week) in conjunction with chemotherapy. Five 
total cycles of chemoradiation will be delivered. Ideally, PTV1 and 
PTV2 will be treated with the first 3 cycles and PTV1 will be treated 
with the final 2 cycles. Chemoradiation will be given on an alternating 
weekly basis. There should be a minimum of 6 hours between 
fractions.  All fields will be treated each day.  In the case of 
mechanical failure or a holiday, one day of BID radiotherapy can be 
replaced with a single QD fraction of 200 cGy.  Accordingly, the final 
cumulative dose will be slightly less. Ideally, the dose to PTV1 will be 
70-75 Gy and PTV2 will be 45-54 Gy. 
iv. Group C (with concurrent cisplatin): PTV1 and PTV2 will be treated 
with to 54 Gy in 1.8 Gy fraction/day. For the last 12 treatment days, 
PTV1 will be boosted an additional 18 Gy in 1.5 Gy fraction/day given 
at least 6 hours after the 1.8 Gy fraction.  
 


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8. Normal Tissue Constraints/Dose Volume Histograms: The dose limit to the 
spinal cord will vary depending upon the technique used.  Attempts should be 
made to limit the spinal cord dose to < 30 Gy for Low and Intermediate Risk 
Groups. For High Risk Groups, attempts should be made to limit the spinal cord 
dose to < 40 Gy with conventional 3D radiation treatment. Doses should be 
limited to 46 Gy with IMRT techniques and reduced fraction size to the spinal 
cord. 
 
9. Surrounding critical normal structures should be outlined for study purposes, 
including the brainstem, spinal cord, superior/middle constrictor muscles, optic 
nerves/chiasm, parotid glands, temporo-mandibular (T-M) joints and cochlea, 
oral cavity, mandible, eyes, lens, brachial plexus, esophagus (including 
postcricoid pharynx) and glottic larynx. The normal tissues will be contoured and 
considered as solid organs. DVH’s must be generated for relevant critical 
normal structures, any corresponding PRVs, and the unspecified tissues. 
Institutions that use PRVs must clearly define them as such. Dose constraints 
are given below: 
 
Ultimate inclusion of the normal structures and exceptions from the above 
guidelines will be made at the discretion of theattending Radiation Oncologist. 
 
10.  Special situations: 3D conformal treatment techniques may be preferable to 
IMRT in certain situations.  Some large primary tumors and some large neck 
nodes may extend up to the skin.  In these situations it may not be possible to 
add a sufficient margin to the GTV to account for variability in the patient set up.  
In this situation 3D conformal treatment techniques may be preferable to IMRT. 
 
 
Detailed Site by Site Instructions for Nodal Planning Target Volume 2 Delineation: 
 
Lateralized Base of Tongue 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA,
II 
IB, 
III 
II, 
IV 
II, III 
SCV1 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
II 
IB 
II, 
IV 
II, III 
SCV 
II, 
III 
1 SCV =  supraclavicular lymph nodes 
 
Base of Tongue Crossing Midline 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 


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Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA,
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, III, 
SCV 
II, 
III 
 
Soft Palate 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
 
Lateralized Tonsil 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
--- 
--- 
--
- 
--- 
--
- 
IB 
IA, 
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
 
Tonsil with base of tongue invasion 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA,
II 
IB, 
III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
II 
II 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
II 
IB, 
III 
II, 
IV 
II, 
III, 
II, 
III 


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SCV 
 
Oropharynx involving Larynx 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III IV 
V 
IA 
IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, II IA,
II 
 III 
II, 
IV 
II, 
III, 
SCV 
II, 
III 
IA, 
IB, 
II 
II 
II 
III 
III 
II 
Contralateral 
IA 
 II 
II 
II 
II 
II 
IB 
IA, 
II 
IB,
III 
II, 
IV 
II, III, 
SCV 
II, 
III 
 
Oropharynx involving oral cavity (lateralized) 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
IV, 
SCV 
IA, 
IB, 
II, 
III 
IA
, 
IB
, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, II 
IA, 
IB, 
II 
Contralateral 
IA, 
IB 
--- 
--- 
--- 
--- 
--- 
IB
, 
II 
IA, 
II 
IA,
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
SCV 
II, 
III 
 
 
Oropharynx involving oral cavity (crosses midline) 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II 
IA, 
II 
IA, 
IB, 
III 
IA, 
IB, 
II, 
IV 
IA, 
IB, 
II, 
III, 
IV, 
SCV 
IA
, 
IB
, 
II, 
III 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, 
II 
IA, 
IB, II 
IA
, 
IB
, 
II 
Contralateral 
IB, 
IB, 
IB, IB, IB, II IB
IB, 
IA, 
IA,
IA, 
IA, 
II, 


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II 
II 
II 
II 
, 
II 
II 
II 
IB, 
III 
IB, 
II, 
IV 
IB, II, 
III, 
SCV 
III 
 
 
Oropharynx involving Nasopharynx 
 
Adenopathy Level 
 
Ipsilateral 
Contralateral 
Involved 
Nodes 
IA 
IB 
II 
III 
IV 
V 
IA 
IB 
II 
III 
IV 
V 
PTV2 
 
 
 
 
 
 
 
 
 
 
 
 
Ipsilateral 
IB, 
II, 
VA 
IA, 
II, 
VA 
IB, 
III, 
VA 
II, 
IV, 
VA 
II, 
III, 
VA, 
SCV 
II, 
III 
IA, 
IB, 
II, 
VA 
II, 
VA 
II, 
VA 
II, 
VA 
II, 
VA 
II, 
VA 
Contralateral IA 
 II 
II 
II 
II 
II 
IB, 
VA 
IA, 
II, 
VA 
IB, 
III, 
VA 
II, 
IV, 
VA 
II, 
III, 
SCV
, VA 
II, 
III, 
VA 
 
 
 
5.6 Supportive Guidelines 
 
 Antiemetics will be ordered at the discretion of the attending physician. 
 
 Use of growth factor support (G-CSF) on days 16/17/18), see above 
 
 A double lumen venous access device (e.g., Port-a-Cath) is recommended 
prior to initiation of therapy. 
 
 Use of a feeding device is recommended for high-risk patients. Placement of a 
feeding device is left to the discretion of the treating physician/investigator. 
Commonly applied criteria for feeding device placement include 
i. Loss of > 10% of body weight from the start of therapy 
ii. Dehydration or inability to maintain adequate oral hydration 
iii. Inability to maintain intake of > 25 kcal/kg of ideal body weight 
 
 During chemoradiotherapy patients should receive instructions for oral hygiene 
and prescriptions to include: 
i. Oral nystatin or fluconazole (100mg QD) 
ii. Viscous lidocaine HCl (Xylocaine) solution) and/or Grade I 
mouthwash 10ml QID, swish and spit 
 


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Table: Grade I mouthwash 
Lidocaine, Viscous (2%) 
50 mL 
Diphenhydramine elixir (12.5 mg/5 mL) 50 mL 
Sodium bicarbonate injection 
100 mL 
Normal saline irrigation 
500 mL 
Total volume 
700 mL 
 
iii. Normal saline mouthwash 10ml QID swish and spit 
 
iv. Natural Care Gel (or similar product) BID during chemoradiotherapy 
and TID during rest week. 
 
v. Vigilon (or similar product) to be applied to open wounds during 
chemoradiotherapy. 
 
vi. Silvadene cream to open wounds followed by zinc oxide cream and 
then Telfa dressings BID during rest week (N.B.: discontinue 
Silvadene and zinc oxide creams 1 day prior to radiotherapy). 
 
vii. Aquaphor (or similar brand) cream to lips PRN. 
 
viii. Adequate analgesia is essential to maintain oral intake and patient 
comfort. Narcotic analgesics are usually necessary and should be 
used at the physician/investigator discretion. 
 
ix. Therabite for trismus if appropriate. 
 
x. Replacement for electrolyte imbalances when applicable.   
 
 Prior to discharge of the patients after a cycle of chemoradiation, a CBC and 
platelet count, and determination of serum electrolytes, including creatinine will 
be performed. 
 
 A visit to the treating physician is strongly recommended between cycles 
of  chemoradiation (i.e., days 6-14)   
 
 Use of intravenous home hydration is strongly recommended in patients with 
inadequate oral intake: normal saline 1000ml IV QD during rest week (days 6-
14). 
 
 If Hgb < 10, patients should generally be transfused an amount sufficient to 
increase Hgb to  10.  The Hgb level should be maintained > 11 mg/dl for the 
duration of chemoradiotherapy in all patients.  
 


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 The use of peg-filgrastim is described in section 6 and G-CSF (filgrastim) is 
described in section 5.2.  
 
 The use of amifostine during chemoradiotherapy is not permitted 
 
 
 
 
5.7 Surgical Guidelines 
 
Following chemoradiotherapy, patients will undergo surgical evaluation, and 
pathologic response evaluation will be considered. This may include either surgery or 
biopsy. Particular focus will be on the first 50% of patients in groups A and B. 
Simple excision (e.g., transoral laser excision or TORS) of the primary lesion 
may be performed if it can be accomplished while preserving organ function.  Modified 
or selective neck dissection may also be performed.   
Curative intent surgery should typically NOT be performed prior to study 
enrollment, and study enrollment can only proceed with RECIST 1.1. measurable 
disease is present. 
 
5.8 Post-therapy follow-up 
 
Every subject should be followed clinically until taken off study. After the 30-day 
follow-up evaluations, patients should undergo clinical and radiographic disease 
evaluation every 3 months in year 1, every 6 months in years 2 and 3, and annually in 
years 4 and 5. Radiographic assessment should include imaging of the head and neck 
and chest. Laboratory evaluation should consist of at least a CBC, serum electrolytes, 
serum creatinine, liver enzymes (AST, ALT, alkaline phosphatase), serum calcium, and 
serum albumin. TSH should be measured at least annually.A PET scan is required 
within 3 months after treatment. If nodal disease persists, a lymph node dissection must 
be performed. Otherwise, neck dissections are at the discretion of the treating 
physician. This schedule can be altered according to the physician’s discretion. 
Suspicion of progressive disease should be evaluated by radiographic studies 
whenever possible. 
 
5.9 Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may 
continue for 14-20 weeks or until one of the following criteria applies: 
 
 
 Disease progression. 
 
 Intercurrent illness that prevents further administration of treatment. 
 
 Unacceptable adverse event(s). 
 


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 Patient decides to withdraw from the study. 
 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investiga 
 
5.10 Late Toxicity Assessment 
 
 
5.10.1 Schedule 
 
 
Swallowing function and speech will be assessed pretreatment or within 3 weeks 
of starting treatment, post-induction/pre-CRT as clinically indicated, on treatment 
as clinically indicated and then 1, 6 and 12 months post treatment. 
  
 
 
 
 
5.11.2 Assessment of Late Toxicity 
 
Performance measures will be assessed by determining  swallowing 
function and speech. Voice will be assessed as a simple yes/no response from 
patients as to whether their voice has returned to normal.  Swallowing will be 
determined by patients’ ability to swallow table food.  A formal swallow evaluation 
will be done on patients experiencing dysphagia.  Additionally, late toxicity will be 
determined by evaluating presence and degree of xerostomia, and dental decay, 
osteoradionecrosis, as well as the presence of G-tube dependency, 
tracheostomy placement, and dysphagia.  
 
 
 


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6.0 
EXPECTED 
ADVERSE 
EVENTS, 
RISKS 
AND 
DOSE 
MODIFICATIONS 
 
6.1 Expected Adverse Events 
 
6.1.1 Nab-Paclitaxel 
 
 Cardiovascular: ECG abnormal (60%; 35% in patients with a 
normal baseline). Edema /fluid retention (10%), hypotension 
(5%), cardiovascular events (grades 3/4: 3%; included chest 
pain, cardiac arrest, supraventricular tachycardia, thrombosis, 
pulmonary 
thromboembolism, 
pulmonary 
emboli, 
and 
hypertension)  
 Dermatologic: Alopecia (90%)  
 Gastrointestinal: Nausea (30%; grades 3/4: 3%), diarrhea (27%; 
grades 3/4: <1%), vomiting (18%; grades 3/4: 4%), mucositis 
(7%; grades 3/4: <1%) 
 Hematologic: Neutropenia (80%; grade 4: 9%), anemia (33%; 
grades 3/4: 1%), myelosuppression (dose-related), bleeding 
(2%), neutropenic fever (2%), thrombocytopenia (2%; grades 
3/4: <1%) 
 Hepatic: AST increased (39%), alkaline phosphatase increased 
(36%), GGT increased (grades 3/4: 14%), bilirubin increased 
(7%) 
 Neuromuscular & skeletal: Sensory neuropathy (71%; grades 
3/4: 10%; dose dependent; cumulative), weakness (47%; severe 
8%), myalgia/arthralgia (44%), peripheral neuropathy (grade 3: 
10%) 
 Ocular: Vision disturbance (13%; severe [keratitis, blurred 
vision]: 1%)  
 Renal: Creatinine increased (11%; severe 1%)  
 Respiratory: Dyspnea (12%), cough (7%) 
 Miscellaneous: 
Infection 
(24%; 
primarily 
included 
oral 
candidiasis, 
respiratory 
tract 
infection, 
and 
pneumonia) 
Hypersensitivity reaction (4%, includes chest pain, dyspnea, 
flushing, hypotension; severe: <1%)  
 
6.1.2 Carboplatin 
 
 Dermatologic: Alopecia (includes other agents in combination with 
carboplatin) 


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 Endocrine 
& 
metabolic: 
Hypomagnesemia, 
hypokalemia, 
hyponatremia, hypocalcemia; less severe than those seen after 
cisplatin (usually asymptomatic) 
 Gastrointestinal: Nausea, vomiting, stomatitis, diarrhea, anorexia 
 Hematologic: Myelosuppression is dose related and is the dose-
limiting toxicity; thrombocytopenia is the predominant manifestation, 
with a reported incidence of 37% in patients receiving 400 mg/m2 as 
a single agent and 80% in patients receiving 520 mg/m2; leukopenia 
has been reported in 27% to 38% of patients receiving carboplatin as 
a single agent (nadir: ~21 days following a single dose) 
 Hepatic: Alkaline phosphatase increased, AST increased (usually 
mild and reversible) 
 Otic: Hearing loss at high tones (above speech ranges, up to 19%); 
clinically-important ototoxicity is not usually seen 
 Renal: Increases in creatinine and BUN have been reported; most of 
them are mild and they are commonly reversible; considerably less 
nephrotoxic than cisplatin 
 Neuromuscular & skeletal: Peripheral neuropathy (4% to 6%; up to 
10% in older and/or previously-treated patients) 
 <1% (Limited to important or life-threatening): Neurotoxicity, urticaria, 
rash, nephrotoxicity, secondary malignancies, anaphylaxis, malaise, 
hypertension 
 
 
5-Fluorouracil 
Common toxicities include: 
 Gastrointestinal – diarrhea, mucositis, nausea, and vomiting 
 Hematologic – myelosuppression 
 Dermatologic – photosensitivity, skin dryness, hand-foot syndrome, increased 
pigmentation of skin, increased pigmentation of veins used for infusion, nail 
changes 
 
Less commonly observed toxicities include 
 Cardiac – myocardial ischemia, arrhythmias 
 Allergic reactions 
 Neurologic – acute cerebellar syndrome, disorientation, headache 
 Eye – lacrimal duct stenosis, lacrimation, photophobia, and visual changes 
5-FU may cause birth defects and should not be used in pregnant women.  It is a 
known radiation sensitizer and may potentiate side effects of radiation. 
 
Paclitaxel 
 
Common toxicities include 
 Myleosuppression 
 Anemia 


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 Alopecia 
 Myalgias and arthralgias 
 Peripheral neuropathy 
 Nausea and vomiting (usually mild) 
 Diarrhea 
 Mucositis 
 Hypersensitivity reaction  - fever, facial flushing, chills, shortness of breath, or 
hives after Taxol is given.  The majority of these reactions occur within the 
first 10 minutes of an infusion.  Notify your healthcare provider immediately 
(premedication regimen has significantly decreased the incidence of this 
reaction).  
Less common side effects 
 Peripheral edema 
 Abnormal liver function tests 
 Hypotension 
 Skin reactions/darkening of the skin 
 Nail changes/discoloration 
 Electrocardiogram (ECG) abnormalities with bradycardia, heart block, bundle 
branch block, and ventricular tachycardia, 
The following are less common side effects (occurring in 10-29%) for patients receiving 
Taxol: 
• Swelling of the feet or ankles (edema). 
• Increases in blood tests measuring liver function.  These return to normal once 
treatment is discontinued. (see liver problems). 
• Low blood pressure (occurring during the first 3 hours of infusion). 
• Darkening of the skin where previous radiation treatment has been given (radiation 
recall - see skin reactions). 
• Nail changes (discoloration of nail beds - rare) (see skin reactions) 
 
 
Hydroxyurea 
Common side effects include: 
 Myelosuppression (mainly leukopenia) 
 Nausea, vomiting 
 Diarrhea or constipation 
 Stomatitis 
It may aggravate the inflammation of mucous membranes secondary to 
irradiation.   
Less common side effects include:   


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 Dysuria or impairment of renal tubular function 
 Rare neurologic disturbances, e.g., headaches, dizziness, disorientation, 
hallucination and convulsion. 
 
Cisplatin 
 
Common side effects include: 
 Nausea and vomiting 
 Renal toxicity 
 Electrolyte wasting (magnesium, calcium, potassium) 
 Myelosuppression 
 Anemia 
Less common side effects include: 
 Peripheral neuropathy 
 Hearing loss 
 Anorexia 
 Dysguesia, metallic taste 
 Elevated liver function tests 
 Alopecia 
  
Filgrastim 
Toxicities, warnings, and drug interactions are specified in Sections 6. 
 
Radiation 
Radiation to the head and neck will cause skin irritation, dry mucous membranes 
due to salivary gland dysfunction, mucositis and stomatitis.  The concomitant 
administration of chemotherapy will aggravate these side effects.  Long-term side 
effects include myelitis, osteoradionecrosis, hoarseness, hypothyroidism, trismus, 
swallowing dysfunction, and fibrosis of soft tissues. 
 
6.2 Dose modifications 
 
This study will utilize the CTC (NCI Common toxicity Criteria) Version 2.0 for 
toxicity and Adverse Event reporting.  A copy of the CTC Version 2.0 can be 
downloaded from the CTEP home page (http://ctep.info.nih.gov). 
 
6.2.1 Chemotherapy 
 
During Induction Chemotherapy 
 
No more than two dose modifications should be allowed for any patient. If a patient 
requires a third dose-reduction study treatment should be discontinued.  If such a 
patient is clinically benefiting from treatment, and, if the physician believes the toxicity 


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will be alleviated sufficiently with dose modification, further treatment will be permitted at 
the discretion of the Principal Investigator in consultation with Celgene Corporation, 
U.S. Medical Affairs.  In no case should the two cycles of induction chemotherapy be 
given over a period exceeding ten (10) weeks.   
 
Hematologic toxicity 
 If ANC are <1,500 cells/mm3 or platelets <100,000 cells/mm3 on 
Day 1 of Cycle 2, 3 repeat counts once or twice a week. 
Administer cycle 2,3 with 1 dose reduction of the starting doses 
of carboplatin and albumin-bound paclitaxel.   
 Day 8, 15 of each cycle should only be held for ANC < 500 or 
PET< 50,000.  
 A delay in therapy of up to 3 weeks is permitted for count 
recovery.  (please use table for dose reductions) 
 If ANC are <1,500 or platelets <100,000 on day 8 of cycle 1 or 
day 8 of cycle 2, reduce all subsequent doses of nab-paclitaxel 
and carboplatin (If any) to one dose reduction of the previous 
dose. Withhold treatment until counts recover to an absolute 
neutrophil count of at least 500 cells/mm3 
and a platelet count of 
at least 50,000 cells/mm3 on days 8 or 15 of the cycle.  Growth 
factor support should then be used with subsequent cycles. 
 Patients should not begin a new cycle of treatment unless the 
ANC is ≥1000 cells/mm3, the platelet count is ≥100,000 
cells/mm3. 
 
 
Dose Modification 
 Dose modification  
 
Neurotoxicity (Peripheral) 
 Withhold albumin-bound paclitaxel for grade 3-4 peripheral neuropathy.  
Resume albumin-bound paclitaxel and carboplatin at reduced doses (see 
table) when peripheral neuropathy improves to Grade 1 or completely 
resolves. 


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Ototoxicity:  
For grade 3 ototoxicity discontinue carboplatin. 
 
Hypersensitivity 
 
Albumin-bound paclitaxel (Nab-paclitaxel):   
 For grade 3 reactions manage the reaction according to institutional 
guidelines. For subsequent doses, use steroid and anti-histamine pretreatment 
and increase the infusion time to 60 minutes. For documented grade 4 
hypersensitivity reactions, manage the reaction according to institutional 
guidelines and discontinue nab-paclitaxel. 
 
Liver 
Nab-Paclitaxel: 
 Mild impairment (AST or ALT <10 times ULN and bilirubin ≤1.25 
times ULN): No adjustment required. 
 Moderate impairment (AST or ALT <10 times ULN and bilirubin 
1.26-2 times ULN): Reduce dose to 75 mg/m2. 
 Severe impairment: AST or ALT <10 times ULN and bilirubin 
2.01-5 times ULN: Reduce dose to 50 mg/m2. May increase up 
to 75mg/m2 in subsequent cycles if liver impairment improves to 
either moderate or mild impairment (based on individual 
tolerance). 
 AST or ALT >10 times ULN or bilirubin >5 times ULN: 
Discontinue nab-paclitaxel. 
 
No dose adjustment required for Carboplatin 
 Other:  (mucositis) 


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 For all other grade ≥ 2 toxicities (except alopecia, nausea, 
vomiting, fatigue and anorexia), reduce carboplatin and albumin-
bound paclitaxel by 25% for all subsequent doses during 
induction. 
 In the event of recurrent grade 3 or 4 toxicity attributed to 
chemotherapy (excluding transaminase elevation, nausea, 
vomiting, and alopecia) reduce carboplatin and nab-Paclitaxel 
by a further 25% during induction. 
 
During Concurrent Chemoradiotherapy 
Other Dose Modifications and Adverse Event Management 
Hematologic Dose Modifications for Hydroxyurea: 
Neutropenia:  
If the absolute neutrophil count (ANC) is between 500 and 1000 on day 0 – 5 of each 
cycle, decrease hydroxyurea to 50% of the full dose. On subsequent cycles, a reduced 
starting dose of hydroxyurea should be used. 
For ANC of  500/l on Day 0 – 5 of any cycle, omit hydroxyurea, and administer 600 
mg/m2/day of 5-FU and radiotherapy only.  On subsequent cycles, a reduced starting 
dose of hydroxyurea by 50% should be used. 
 
Thrombocytopenia:  
For a platelet count of 50,000/l to 74,000/l on Day 0 – 5 of each cycle, decrease 
hydroxyurea to 50% of full dose.  On subsequent cycles, a reduced starting dose of 
hydroxyurea may be used. 
For a platelet count  50,000/l on Day 0 – 5 of any cycle, omit hydroxyurea, and 
administer 600 mg/m2/day of 5-FU and radiotherapy only.  On subsequent cycles, a 
reduced starting dose of hydroxyurea by 50% should be used. 
 
Hematologic Dose Modifications for Paclitaxel: 
 
Dose Level 
Paclitaxel 
(mg/m2) 


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  0 
100 
–1 
75 
 -2 
50 
 
Discontinue Paclitaxel if further dose reduction is required. 
  
Neutropenia and Thrombocytopenia:  
For ANC ≤ to 1000 or platelet count of 50-74 on day 0-5 of each cycle: decrease 
paclitaxel by one dose level.  
For ANC </= 500 or platelet count of less than 50 on day 0-5 of any cycle: hold 
paclitaxel for that cycle and decrease by one dose level in subsequent cycles.   
 
Mucositis, Dysphagia, Dermatitis, Diarrhea 
 
Treatment cycles should not be delayed for mucositis, dysphagia, dermatitis or diarrhea. 
For grade 4 mucositis, dysphagia, and dermatitis exceeding 7 days duration or 
persisting on Day 1 of a subsequent cycle, decrease 5-FU to 500 mg/m2/day.   
For grade 4 diarrhea exceeding 7 days duration or persisting on Day 1 of a subsequent 
cycle, decrease 5-FU to 500 mg/m2/day. 
 
Doses will not be increased again on subsequent cycles. 
Nephrotoxicity 
Grade 2 renal toxicity – administer 50% dose hydroxyurea 
Grade 3, 4 renal toxicity – Hold hydroxyurea 
 
Hepatotoxicity on day 0:  Grade 3, 4 – Hold hydroxyurea and adjust paclitaxel per 
package insert 


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Peripheral neuropathy: 
For Grade 2 peripheral neuropathy, decrease paclitaxel by one dose level per CRT 
dosing schedule (see hematologic toxicity chart).  
For Grade 3 or greater peripheral neuropathy, discontinue paclitaxel.  
 
 
Other Non-hematological Toxicity 
Chemoradiotherapy should not be interrupted for non-hematologic toxicity except as 
judged necessary on a case-by-case basis by the treating radiation, medical 
oncologists, and Principal Investigator. 
 
In the presence of a persisting fever  38C or other clinically apparent infection a cycle 
can be postponed for 1 week or interrupted (if treatment cycle has already started) if this 
is necessary in the opinion of the treating medical and radiation oncologists. 
 
Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have 
occurred in patients with myeloproliferative disorders during therapy with hydroxyurea. 
These vasculitic toxicities were reported most often in patients with a history of, or 
currently receiving, interferon therapy. Due to potentially severe clinical outcomes for 
the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, 
hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop. 
 
Geriatric Use: Elderly patients may be more sensitive to the effects of hydroxyurea, and 
may require a lower dose regimen. This drug is known to be excreted by the kidney, 
and the risk of toxic reactions to this drug may be greater in patients with impaired renal 
function. Because elderly patients are more likely to have decreased renal function, 
care should be taken in dose selection, and it may be useful to monitor renal function. 
Cisplatin 
Renal Toxicity 
CrCl 46-60 – 25% dose reduction 


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CrCl 31-45 – 50% dose reduction 
Myelosuppression 
If the absolute neutrophil count (ANC) is < 1000 on day 1 of each cycle, hold cisplatin 
and when count recover > 1000 ANC, then decrease cisplatin 25%. On subsequent 
cycles, a reduced starting dose of cisplatin should be used. 
 
Peripheral neuropathy 
If Grade 2 neuropathy on day 1 of each cycle, then decrease cisplatin 25%. On 
subsequent cycles, a reduced starting dose of cisplatin should be used. 
If Grade 3 or greater neuropathy on day 1 of each cycle, hold cisplatin and when 
neuropathy recovers to grade 2 or better, then decrease cisplatin 25%. On subsequent 
cycles, a reduced starting dose of cisplatin should be used. 
 
General Toxicity Information 
 
Any other significant toxicity that is felt to be potentially drug related should be 
discussed between the PI and the treating physician and dose reduction can be 
implemented for the benefit and safety of the patient.  
 
Radiotherapy should not be interrupted for non-hematologic toxicities except when 
judged necessary on a case-by-case basis by the treating radiation and medical 
oncologist in consultation with the PI. 
 
All interruptions or changes to study drug administration must be recorded. 
 
It will be documented whether or not each patient completed the clinical study. If for any 
patient either study treatment or observations were discontinued the reason will be 
recorded. Reasons that a patient may discontinue participation in a clinical study are 
considered to constitute one of the following: 
1. adverse event(s) 


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2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. disease progression 
5. protocol violation 
6. subject withdrew consent 
7. lost to follow-up 
8. administrative problems 
9. death 
7.0 AGENT FORMULATION AND PROCUREMENT 
 
7.1 Nab-paclitaxel 
 
Classification: 
Antineoplastic Agent, Antimicrotubular; Natural Source (Plant) Derivative; Taxane 
Derivative 
Mode of Action: 
Albumin-bound paclitaxel nanoparticle formulation. Paclitaxel promotes microtubule 
assembly by enhancing the action of tubulin dimers, stabilizing existing microtubules, 
and inhibiting their disassembly, interfering with the late G2 mitotic phase, and inhibiting 
cell replication. May also distort mitotic spindles, resulting in the breakage of 
chromosomes. Paclitaxel may also suppress cell proliferation and modulate immune 
response. 
How Supplied: 
Injection, powder for reconstitution: Abraxane®: 100 mg [contains albumin (human)] 
Storage: 
Store in vials in original cartons at room temperature (20oC-25oC; 68oF to 77oF). 
Retain in the original package to protect from bright light.  
Stability: 
Unopened vials of nab-paclitaxel are stable until the date indicated on the package 
when stored at the above temperature in the original package. Reconstituted vials of 
albumin-bound paclitaxel may be refrigerated at 2oC to 8oC (38oF to 46oF) for a 
maximum of 8 hours and should be protected from bright light 
Dose Specifics: 
Albumin-bound paclitaxel 100mg/m2 IV over 30, minutes on day 1 and 8 of each 21-day 
cycle (total of 2 cycles) 


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Preparation: 
Reconstitute each vial with 20 mL of 0.9% sodium chloride injection, USP injected over 
at least 1 minute. Direct the NaCl onto the inside wall of the vial, and not directly onto 
the lyophilized cake, as this will result in foaming. Following reconstitution, 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. The reconstituted suspension 
should appear milky and homogeneous without visible particulates. If unsuspended 
powder is visible, the vial should be gently inverted again to ensure complete 
resuspension, prior to use. Each ml of reconstituted product will contain 5 mg of 
paclitaxel. Withdraw the desired volume and inject the suspension into an empty sterile 
PVC container. 
Route of Administration 
Albumin-bound paclitaxel will be administered as an IV infusion over 30 minutes. On 
days when carboplatin is given, albumin-bound paclitaxel will be administered first. 
Filters are not required for preparation or administration of albumin-bound paclitaxel. If 
filters are used as part of institutional procedures, the pore size must be ≥ 15 micron. 
Drug Return and Destruction  
Study drug will be disposed of as per the University of Chicago Medical Center 
Investigational Pharmacy drug destruction policy/procedure. The following information 
must be recorded on the site’s pharmacy drug accountability log:  
Quantity of vials destroyed. 
Expiration date 
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.  
a) Supplier 
Celgene Corporation 
86 Morris Avenue 


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Summit, NJ  07901 
 
Industry Contact: 
Martha Kennedy 
Manager, Medical Operations 
Celgene Corporation 
400 Connell Drive, 7th Floor 
Connell Corporate Park 
Berkeley Heights, NJ 07922 
Mobile: 908-723-6919 
Fax: 908-673-2779 
Email: Mkennedy@celgene.com  
b) Drug Distribution 
ABRAXANE® will be distributed by Celgene Corporation.  No supplies will be 
shipped to any site until regulatory approval has been obtained.  
Investigational sites will be supplied with ABRAXANE® 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. 
c) Drug Return and Destruction 
If the investigational site does not have a policy, procedure or SOP detailing 
the process to follow for study drug destruction, the study drug must then be 
returned to Celgene using the Drug Return Form provided in the package 
containing the study drug.  The following information must be recorded on the 
site’s pharmacy drug accountability log: quantity of vials to be returned, 
expiration date and lot number.  A copy of the Drug Return Form and the 
study drug should be returned to Celgene Clinical Supplies Dept. using the 
mailing address on the packaging slip that came with the original study drug 
order.  A copy of the Drug Return Form 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. 


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If the investigational site has a policy, procedure or SOP detailing the process 
to follow for study drug destruction, 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. 
 
7.2 Carboplatin 
 Carboplatin: supplied commercially as a sterile lyophilized powder available in single-
dose vials containing 50 mg, 150 mg and 450 mg of carboplatin. Each vial contains 
equal parts by weight of carboplatin and mannitol. Please refer to package insert for 
information on preparation. 
Side effects: listed in section 9.3. Please refer to the package insert for full prescribing 
information. 
Preparation: Immediately before use, the content of each vial must be reconstituted with 
either sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride 
injection, USP to produce a carboplatin concentration of 10 mg/ml. When prepared as 
directed, carboplatin solutions are stable for 8 hours at room temperature. Since no 
antibacterial preservative is contained n the formulation, it is recommended that 
carboplatin solutions be discarded 8 hours after dilution. 
Storage and Stability: Unopened vials of carboplatin are stable for the life indicated on 
the package when stored at controlled room temperature and protected from light. 
Administration: Administer over 1⁄2 hour after completing the paclitaxel infusion. The 
Calvert Equation (Dose=AUC (CC+25) will be used to achieve the desired dose where 
CC = Wt*(140-age)/72/creatinine (if female use 85%). 
 
7.3 Fluorouracil 
 
5-Fluorouracil (Adria, OH): commercially available as 10 ml ampules containing 
500 mg/10 ml.  No dilution is necessary for administration, but it may be further diluted 
in D5W or normal saline.  It is stored at room temperature and is stable for 24 hours.  It 
will be administered by intravenous continuous infusion.  Please refer to the package 
insert for full prescribing information.   


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7.4 Hydroxyurea 
 
Hydroxyurea (Bristol-Myers Squibb, Princeton, NY): commercially available as 500 mg 
capsules.  It is stored at room temperature and will be administered orally.  Please refer 
to the package insert for solution preparation and expected AE.  Please refer to the 
package insert for full prescribing information. 
 
7.5  Paclitaxel 
 
Chemistry: Paclitaxel is a natural product with antitumor activity. The chemical name for 
paclitaxelis 5,20‐ Epoxy‐ 1,2 hexahydroxytax‐ 11‐ en 9‐ one 4, 10 diacetate 2‐
benzoate 13‐ ester with (2R,3S)‐ N‐ benzoyl‐ 3‐ phenylisoserine. Paclitaxel is a 
white to off‐ white crystalline powder with the empirical formula C47H51NO14 and a 
molecular weight of 853.9. It is extremely lipophilic and melts at around 216‐ 217°C. 
Paclitaxel is highly insoluble in water. 
 
Mechanisms of Action: Microtubules have been demonstrated to be very strategic 
targets for antineoplastic agents; however, few antimicrotubule agents have been 
discovered and encompassed into standard chemotherapeutic regimens. Paclitaxel, a 
diterpenoid plant product extracted from the bark of the western yew (Taxus brevifolia), 
has a unique mechanism of action. Unlike other antimicrotubule agents in clinical use 
(e.g. colchicine, vincristine, and vinblastine) that shift the equilibrium between 
microtubules and tubulin subunits toward microtubule disassembly, paclitaxel promotes 
assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. These microtubules are stable even when treated with low 
temperatures or calcium, conditions that usually promote disassembly. This unusual 
stability results in the inhibition of the normal dynamic reorganization of the microtubule 
network that is essential for vital interphase and mitotic cellular functions. In addition, 
paclitaxel induces abnormal arrays or "bundles" of microtubules during mitosis. 
 
Human Toxicology: The dose limiting toxicities and MTD of paclitaxel administered on a 
variety of schedules to patients with solid neoplasms were previously evaluated in 
phase I trials. In these studies, paclitaxel was infused over 1, 3, 6, and 24 h, but severe 
acute reactions, characterized by bronchospasm, hypotension, stridor, tachy‐  and 
bradyarrhythmias, and death, resulted in the temporary discontinuation of all trials. 
These reactions were attributed to paclitaxel's Cremophor vehicle, since identical 
reactions were observed with other drugs formulated with it and when the vehicle alone 
was administered to animals. Since a higher incidence of these acute reactions was 
observed with shorter durations of infusion, studies that used shorter infusions were 
permanently discontinued, and trials that evaluated longer infusion durations (24 h) 
were resumed using antiallergic pre‐ medications consisting of corticosteroids, H1‐  
and H2‐  histamine antagonists. These modifications were associated with a marked 
reduction in the incidence of acute reactions. Neutropenia was the major dose‐ limiting 
toxicity for paclitaxel in phase I solid tumor trials. In addition, a sensory neuropathy, 
characterized by a glove‐ and‐ sock distribution of numbness and paresthesias, was 


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observed at higher doses. Nausea and vomiting, myalgias, mucositis, total‐ body 
alopecia, diarrhea, and phlebitis were also observed.  
 
Pharmaceutical Data:  
Formulation: Paclitaxel (TAXOL®) for Injection Concentrate is a clear colorless to 
slightly yellow viscous solution. It is supplied as a solution in a nonaqueous medium. It 
is intended for dilution with a suitable parenteral fluid prior to intravenous infusion. 
Paclitaxel is available in 30 mg (5mL) vials. Each mL of sterile non‐ pyrogenic solution 
contains 6 mg paclitaxel, 527 mg of Cremophor®EL (polyoxyethylated castor oil) and 
49.7% (v/v) dehydrated alcohol, USP. 
 
Storage and Stability: Unopened vials of Paclitaxel for Injection Concentrate are stable 
until the date indicated on the package when stored under refrigeration, 2°‐  8°C 
(36°47° F). Refrigeration is not required for shipping. Freezing does not adversely affect 
the concentrate. Solutions for infusion which are prepared as recommended are stable 
at ambient temperature and lighting for up to 27 hours. 
 
Administration: Paclitaxel should be given after the patient has received the appropriate 
premedication as per institutional standards. Paclitaxel: supplied in 5 ml vials containing 
30 mg of drug (6mg/ml). Please refer to the package insert for information on 
preparation and for full prescribing information. 
Drug interactions: There is a potential for interaction with Ketoconazole, which might 
interfere with paclitaxel metabolism. 
Contraindications: Known hypersensitivity to either paclitaxel or Cremaphor EL. 
 
 
 
7.6 Cisplatin 
 
Formulation: Cisplatin is a sterile aqueous solution, each mL containing 1 mg cisplatin 
and 9 mg sodium chloride. Cisplatin is supplied in multidose vials of 50 mg and 100 mg 
cisplatin. Please refer to package insert for information on preparation. 
NOTE: Aluminum reacts with cisplatin causing precipitate formation and loss of potency; 
therefore, needles or intravenous sets containing aluminum parts that may come in 
contact with the drug must not be used for the preparation or administration of cisplatin. 
Storage: Store at 15° to 20°C. Do not refrigerate. Protect unopened container from light. 
The 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. 
Side effects are listed in section 9.4. Please refer to the package insert for full 
prescribing information. 


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Availability: Cisplatin is commercially available from Bristol Laboratories Oncology 
Products. 
 
7.7 Filgrastim (Neupogen) Drug Information 
 
Packaging and Formulation 
 
G-CSF (Filgrastim) is commercially available. Filgrastim is a sterile, clear, 
colorless, preservative-free liquid for parenteral administration, containing Filgrastim at 
a specific activity of 1.0 ± 0.6 x 108 U/mg (as measured by a cell mitogenesis assay).  
The product is available in single use vial form and prefilled syringe.  The single use vial 
contains 480 mcg Filgrastim at a fill volume of 1.6 mL.  The formulation is: 480 mcg of 
Filgrastim (r-methHuG-CSF), containing acetate (0.94 mg), sorbitol (80.0 mg), Tween® 
80 (0.004%), sodium (0.056 mg) in water for injection, USP q.s. ad (1.6 mL).  The single 
use prefilled syringe contains 0.6 mg Filgrastim at a fill volume of 0.8 mL.  The 
formulation is: 480 mcg of Filgrastim (r-methHuG-CSF), containing acetate (0.472 mg), 
sorbitol (40.0 mg), Tween® 80 (0.004%), sodium (0.028 mg) in water for injection, USP 
q.s. ad (0.8 mL).   
 
Storage Conditions and Stability 
 
Filgrastim should be stored in the refrigerator at 2o to 8oC (36o to 46oF).  Avoid 
shaking.  Prior to injection, Filgrastim may be allowed to reach room temperature for a 
maximum of 24 hours.  Any vial or pre-filled syringe left at room temperature for greater 
than 24 hours should be discarded.  Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to administration, whenever 
solution and container permit; if particulate or discoloration are observed, the container 
should not be used.  At a concentration of 5 mcg/ml or greater in D5W, filgrastim is 
stable for 7 days at room or refrigerator temperatures.  At dilutions from 5 to 15 mcg/ml, 
albumin in a final concentration if 2mg/ml should be added to protect against adsorption 
to plastic materials.  Addition of albumin is unnecessary when the drug is diluted to a 
concentration greater than 15 mcg/ml in D5W.  Dilutions in D5W are stable in glass 
bottles, polyvinyl chloride, polyolefin or polypropylene bags and IV sets, and Travenol 
Infusors. 
 
Dilution of Neupogen® to a final concentration of less than 5 mcg/mL is not 
recommended at any time.  Do not dilute with saline at any time because the product 
may precipitate. 
 
Preparation and Administration 
 
If using the vial, draw the appropriate dose into a syringe for subcutaneous 
injection.  If using the pre-filled syringe, select the appropriate pre-filled syringe for 
subcutaneous injection.  Inject only the appropriate dose, discard the unused drug.  
Incompatibilities: Normal saline. 


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Adverse Reactions 
 
The following events are associated with Filgrastim and meet the regulatory 
definition of “expected”.  The only consistently observed clinical toxicity described with 
Filgrastim is medullary bone pain.  Other clinical adverse events that have been 
described include skin rash, and cutaneous vasculitis.  Since commercial introduction of 
Neupogen®, there have been rare reports of allergic-type reactions.  Biochemical 
abnormalities that may occur include increases in alkaline phosphatase, uric acid, and 
lactate dehydrogenase. 
 
Overdosage 
 
The maximum amount of Filgrastim that can be safely administered has not been 
determined.  Efficacy was demonstrated at doses of 4 to 8 mcg/kg/day in the phase 3 
study of nonmyeloablative chemotherapy.  Patients in  bone marrow transplant studies 
received up to 138 mcg/kg/day without toxic effects, although there was a flattening of 
the dose response curve above daily doses of greater than 10 mcg/kg/day.   
 
In Fligrastim clinical trials of cancer patients receiving myelosuppressive 
chemotherapy, WBC > 100,000/mm3 have been reported in less than 5% of patients, 
but were not associated with any reported adverse clinical effects.  
 
In cancer patients receiving myelosuppressive chemotherapy, discontinuation of 
Filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 
2 days, with a return to pretreatment levels in 1 to 7 days. 
 
Toxicity/Warnings 
 
Filgrastim is contraindicated inpatients with known hypersensitivity to E coli-derived 
proteins, pegfilgrastim, Neupogen®, or any other component of the product. 
 
Rare cases of splenic rupture have been reported following the administration of 
colony-stimulating factors, including Filgrastim, for peripheral blood progenitor cell 
(PBPC) mobilization in both healthy donors and patients with cancer.  Some of these 
cases were fatal.  Individuals receiving Filgrastim who report abdominal or shoulder tip 
pain, particularly healthy donors receiving Filgrastim for PBPC mobilization, should be 
evaluated for an enlarged spleen or splenic rupture.     
 
Adult respiratory distress syndrome (ARDS) has been reported in neutropenic 
patients with sepsis receiving Filgrastim, and is postulated to be secondary to an influx 
of neutrophils to sites of inflammation in the lungs.  Neutropenic patients receiving 
Filgrastim who develop fever, lung infiltrates, or respiratory distress should be evaluated 
for the possibility of ARDS.  In the event that ARDS occurs, Filgrastim should be 
discontinued until resolution of ARDS and patients should receive appropriate medical 
management for this condition. 


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Allergic-type reactions occurring on initial or subsequent treatment have been 
reported in < 1 in 4000 patients treated with Filgrastim.  These have generally been 
characterized by systemic symptoms involving at least 2 body systems, most often skin 
(rash, urticaria, facial edema), respiratory (wheezing, dyspnea), and cardiovascular 
(hypotension,  tachycardia).  Some reactions occurred on initial exposure.  Reactions 
tended to occur within the first 30 minutes after administration and appeared to occur 
more frequently in patients receiving Filgrastim IV.  Rapid resolution of symptoms 
occurred in most cases after administration of anti-histamines, steroids, bronchodilators, 
and/or epinephrine.  Symptoms recurred in more than half the patients who were 
rechallenged. 
 
Severe sickle cell crisis have been reported in patients with sickle cell disease 
(specifically homozygous sickle cell anemia, sickle/hemoglobin C disease, and sickle/+ thalassemia) who received Filgrastim for PBPC mobilization or following 
chemotherapy. One of these cases was fatal.   
 
PREGNANCY AND LACTATION 
Since there are no adequate and well-controlled studies in pregnant women, the 
effect, if any, of Filgrastim on the developing fetus or the reproductive capacity of the 
mother is unknown.     
 
It is not known whether Filgrastim is excreted in human milk.  Because many drugs 
are excreted in human milk, caution should be exercised when Filgrastim is 
administered to a nursing woman. 
 
DRUG INTERACTIONS 
 
No formal drug interaction studies between pegfilgrastim and other drugs have 
been performed.  Drugs which may potentiate the release of neutrophils, such as 
lithium, should be used with caution.  Patients receiving lithium and Filgrastim should 
have more frequent monitoring of neutrophil counts. 
 
Nursing Guidelines 
 
Filgrastim should be kept in the refrigerator until needed and the vials or Pre-
filled Syringe should not be shaken.  The drug should be administered at the same time 
each day.  Vials and Pre-filled Syringes of filgrastim are single-dose and the remaining 
drug should be discarded.  Refer to protocol text for information regarding requirements 
for 
documentation 
of 
doses 
administered, 
temperatures, 
side 
effects, 
etc. 
Acetaminophen is the recommended analgesic for mild bone pain. Duration of therapy 
will be determined by the return of blood counts (WBC/ANC) to specific values. 
 
 


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8.0 CORRELATIVE/SPECIAL STUDEIS 
 
 
8.1 Objective 
 
 
It remains unclear what the histologic features of dying HNSCC are, and how to 
interpret tissue that has been obtained after chemotherapy. We will therefor combine 
the effort to assess pathologic response post induction chemotherapy with review of 
histology and correlative with radiologic and clinical assessment. Dr. Nicole Cipriani in 
the Univ. of Chicago pathology department will lead this effort. We will also evaluate 
tumors on surgery/biopsy post chemoradiotherapy. 
 
Furthermore it remains unclear what the molecular and immunological 
determinants are that predict for improved responses for HPV-associated HNSCC. 
While largely descriptice, in order to accomplish such analysis we will collect tumor, 
blood, and saliva as part of our regular tissue banking effort on all patients.  
Plasma, DNA and RNA will be extracted from patient samples and stored until 
further analysis.  
 
 
8.2 Sample and Tissue Procurement 
  
Archival tumor collection 
 
All patients at the time of enrollment need to provide ≥10 5-micron uncstained slides for 
correlative analysis. Under extenuating circumstances the PI can waive this 
requirement, but it is expected that patients, who cannot fulfill this requirement undergo 
a new biopsy prior to enrollment on study. 
Tissue Biopsy  
 
Tumor biopsy will be performed prior to starting therapy or archival tissue will be 
obtained for all patients. At the time of surgical resection or biopsy, tissue in excess of 
what is necessary for diagnostic purposes will be obtained <15 min after removal from 
the patient. Tissues will be instantaneously frozen and stored anonymously with a 
unique barcode at -80C in a locked freezer in Biospecimen Shared Resource (Tissue 
Bank) at The University of Chicago. Additional alternative processing (e.g. tissue 
digestion, and cell suspension generation for flow analyses is also acceptable).  
 
 
 Write study number, patient initials and date on plastic cryomold. 
 Weigh or estimate sample weight and slice sample into less than 0.5 cm 
thick fragments. 
 Place tissue into cryotube labeled with study number, patient initials and 
date filled with RNAlater reagent from Qiagen. 


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 Freeze over liquid nitrogen vapors or in -80 C freezer. 
 
Blood Isolation 
 
Blood will be obtained from all patients enrolled in the study for 
pharmacogenomics 
and 
biomarker 
evaluation. 
Investigation 
of 
the 
relevant 
polymorphisms will take place in germline DNA extracted from peripheral whole blood 
(10 ml) collected in EDTA (purple top) plastic vacutainer tubes (i.e. BD catalog 
#366643). Investigation of cytokine markers will be from peripheral blood (10 ml) 
collected in a red top vacutainer tubes. Blood should be stored at -80 C and sent to 
Biospecimen Shared Resource (Tissue Bank) at The University of Chicago for DNA 
extraction and serum isolation. Please label vacutainer with study number, patient 
initials and date of draw. DNA extraction for genotyping will be performed according to 
commercially available DNA isolation kits such as Qaigen.  For isolation of serum, 
specimens will then remain at room temperature for 15 minutes and then centrifuged at 
room temperature at approximately 1000 x g for 5 minutes. The serum supernatant will 
be removed and stored at –80ºC in 125l aliquots.  Isolated DNA will be store 
anonymously with a unique barcode at -80 C at the University at Chicago for future 
genotype analysis. 
 
 Patients will have blood samples for genotyping and serum analysis collected prior to 
induction chemotherapy. Samples for serum analysis will be collected prior to 
radiotherapy initiation, and then after the first week and at the completion of 
radiotherapy and will be collected at 2 months after radiotherapy.  
 
8.3 Shipment 
 
 
Shipping Instructions for all other samples (Tissue, serum, Genotyping studies) 
The shipment of all human samples (blood, tissue) must comply with appropriate 
regulations as specified by the carrier.  At a minimum, all frozen tissue must be 
packaged in dry ice within two containers with absorbent material between containers to 
control any spill or leakage.  The outer container must be puncture resistant (e.g., 
cardboard mail tube, corrugated cardboard box).  A biohazard sticker must be affixed to 
both the inner and outer containers.  All samples must be accompanied by a sample 
transmission form and shipped to: 
 
Dr. Mark Lingen (773-702-5548), email: mlingen@uchospitals.edu) 
University of Chicago 
FMI Dock/Lab Supply 
5830 S. Ellis Ave 
Room G-02 
Chicago, IL 60637 
Attn: Mary Jo Fekete (773 834 4593, email: mfekete@bsd.uchicago.edu ) 
 


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N.B.: Samples must be shipped to arrive Monday to Thursday. Samples should 
not be shipped on holidays.  Please notify Leslie Martin when sample has been 
shipped. 
All participating institutions outside of the University of Chicago will be provided with a 
University of Chicago Federal Express Account assigned to this study. 
Each sample must be accompanied with a list containing the following information: 
Treating Physician Information 
Patient name, Patient ID number, date of birth, sex 
Diagnosis 
Day started on clinical protocol (date consent signed) 
Site of biopsy (if applicable) 
Date and time of biopsy (if applicable) 
On arrival, each sample will be assigned a PIN code.  All subsequent handling of 
the tissue samples will be blinded to the investigators performing various tests, 
except for the clinical pathologists. 
 
 
 
8.4 Correlative analysis 
 
 
A number of exploratory analyses will be performed to better characterize 
factors contributing to treatment benefit or failure. 
 
8.4.1  Biopsy samples after induction chemotherapy and/or chemoradiotherapy will be 
stained by immunohistochemical staining, and assessed histo-morphologically to 
descripe the characteristics of dying HPV(+) HNC. Analyses will be performed by Dr. 
Nicole Cipriani and colleagues. These analyses will be descriptive, but will be correlated 
with clinical outcome, i.e. amount of tumor shrinkage, failure after treatment, side effects 
etc. 
8.4.2  For patients that fail therapy (and control samples for comparison), genetic 
analysis including the mutational spectrum, expression phenotype and other genetic 
profiling features will be examined in an exploratory manner. This may include profiling 
using next generation sequenting (e.g. Foundation medicine, or as outline in Seiwert et 
al ASCO 2013). Patients have the option to opt out of such genetic analyses in the 
consent form. 
8.4.3 Using both archival or fresh tumor samples (tissue digest or fresh frozen/OTC 
tissue) we will analyze the immune microenvironment and CD8 Tumor infiltrating 
lymphocyte characteristics in a small number of patients in a descriptive fashion, 
comparing patients that fail therapy with tumors from control tumors. The analyses may 
include determination of CD8, PDL1, FOXP3, IDO, and other immune related markers 
that will be determined by immunohistochemistry, immunofluorescence, or flow 


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cytometry (cell digest). Analysis of the T cell receptor characteristics (e.g. TCR 
repertoire from blood and tumor tissue) will be performed by PCR, and next generation 
sequencing, or a similar technique. Analysis will be descriptive, but are aimed at 
identifiying high risk characteristics that lead to failure from therapy. Patients have the 
option to opt out of such genetic analyses in the consent form. 
 
9.0 STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol 
therapy. Scans and x-rays must be done 6 weeks prior to starting therapy. In the event 
that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 
 
 
 
 
 
 
 
 
 
 
 
 


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* RT-C = radiation therapy cycle 
1 – Surgery 4-8 weeks following CRT, or when clinically indicated (should only be performed post 
RT/CRT completion). 
For Group A – every cycle is 1 week and treatment will continue until the target dose (50Gy is reached) 
For Groups B and C - the TFHX regimen (week-on week-off) will be used. Every cycle (RT-C) is two 
weeks (one week on treatment, one week off treatment). Patient should be seen during their off weeks as 
indicated in the schedule. Treatment should continue until the respective dose is reached (typically Group 
B = 3 cycles, Group C = 5 cycles). For Cisplatin based CRT please refer to the respective publication 
(Ang RTOG0522 ASCO 2012). 
**MRI or CT of the head and neck can be substituted for PET/CT after induction chemotherapy. 
*** Biopsy should be performed in no adequate archival tissue is available pre-study. After induction a 
second biopsy should be performed.  
 
10.0 MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should have a baseline PET/CT scan for 
initial documentation of objective response. Scans will also be obtained before induction 
chemotherapy, before chemoradiation and at 12 weeks post-chemoradiation. 
 
 
Response and progression will be evaluated in this study using the international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
 
 
Induction 
Chemotherapy 
Radiotherapy/Chemoradiotherapy*  
 
 
 
Pre- 
study 
C1 
C2 
&3 
Surg
ery 
Pre-
RT 
RT-
C1* 
RT-
C2* 
RT-
C3* 
RT-
C4* 
RT-
C5* 
30 day 
follow-
up 
3 months 
post-
radiother
apy 
Every 3-4 months 
f/u up to 2 years 
post-radiotherapy 
Induction chemotherapy  
X 
X 
 
 
 
 
 
 
 
 
 
 
Radiotherapy/CRT* 
 
 
 
 
 
X* 
X* 
X* 
X* 
X* 
 
 
 
Concurrent 
Chemotherapy* 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Biopsy***/surgery1 
X*** 
 
 
X***  
 
 
 
 
 
X1 
 
 
CT or PET/CT** 
X 
 
 
 
(X)*  
 
 
 
 
 
X 
X (as indicated 
MR/CT of head and 
neck 
X 
 
 
 
(X)*  
 
 
 
 
X 
 
 
Blood/Tissue 
for 
correlatives 
X/X 
 
 
X/X 
X 
X 
 
 
 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-----------------------------------------------------------------X 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
event 
evaluation 
X 
X------------------------------------------------------------------X X 
X 
X 
Tumor measurements 
X 
 
 
 
X 
 
 
 
 
 
 
X 
X 
-hCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HPV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Committee [Therasse et al]. Changes in only the largest diameter (unidirectional 
measurement) of the tumor lesions are used in the RECIST v1.1 criteria. Note: Lesions 
are either measurable or non-measurable using the criteria provided below. 
 
 
10.1 Response Criteria 
  
Will follow RECIST [Therasse et al]. 
 
 
 
10.2 Progression-Free and Overall Survival 
 
 
10.2.1 Progression-Free: From the date of registration to the date of progressive 
disease (as defined in 9.3.3) or death. 
 
 
 
10.2.2 Overall Survival time: From the date of registration to the date of death or 
date of last patient contact if censored. 
 
10.2.3 Distant failure free survival:  From the data of registration to the date of 
distant progression or death. 
 
10.2.4 Assessment of Local/Distant Failure: If disease progression is 
documented, patients should have full assessment of sites of failure (i.e. local and 
distant). Local failure should be assessed by radiographic imaging and 
otolaryngology examination. Distant failure should be assessed by radiographic 
imaging. Further assessment of local and distant failure can be performed if 
warranted by patient symptoms. 
 
 
 
 


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11.0 REGULATORY AND REPORTING REQUIREMENTS 
 
Adverse events (AEs) will use the descriptions and grading scales found in the 
revised NCO Common Toxicity Criteria (CTC). This study will utilize the CTC version 
3.0 for adverse event reporting. All appropriate treating areas will have access to a copy 
of the CTC version 3.0. A copy of the CTC version 3.0. A copy of the CTC version 3.0 
can be downloaded from the CTEP web site (http://cetp.cancer.gove/reporting/ctc.html). 
 
SAE Reporting Wording 
 
Adverse events must be reported to regulatory authorities according to the 
definitions and timelines specified in the local laws and regulations. 
 
Serious events are defined as any untoward medical occurrence that at any dose 
results in: 
 
 Death 
 Initial or prolonged inpatient hospitalization 
 A life-threatening situation (where the patient is at immediate risk of death). 
 Severe or permanent disability. 
 Congenital anomaly. 
 Or, is significant for any other reason. 
 
The definition of serious adverse event (experience) also includes important medical 
event.  Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above.  These should also usually be considered serious.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
 
The definition of “related” being that there is a reasonable possibility that the drug 
caused the adverse experience. 
 
 
Serious adverse events occurring after a patient is discontinued from the study will 
NOT be reported unless the investigator feels that the even may have been caused by 
the study drug or a protocol procedure. Study-specific clinical outcomes of death 
because of disease progression are exempt from serious adverse event reporting, 
unless the investigator deems them related to use of the study drug. Hospitalization for 
study drug administration is not a serious adverse event.  
 
In general, serious adverse events assessed as clearly being due to disease 
progression and not due to study drugs(s) should be excluded from adverse event 


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reporting. However, in cases where the specificity or severity of an event is not 
consistent with the risk information, the even should be reported. 
 
11.1 Expedited Adverse Event Reporting 
 
11.1.1 Expedited Reporting Guidelines (including hospitalization defined in bullet 1 
below): 
 
Unexpected Event 
 
Expected Event 
 
Grades 2-3 
Attribution 
of 
possible, 
probable 
or definite 
Grades 4 and 5 
Regardless 
of 
attribution 
Grades 1-3 
Grades 4 and 5 
Regardless 
of 
attribution 
Expedited 
report 
within 
5 
working 
days. 
 
Grade 1 Adverse 
Event 
Expedited 
Reporting 
NOT 
required. 
Reporting by phone 
to UC Clinical Trials 
Office 
within 
24 
hours. 
Expedited 
report 
to 
follow 
within 
5 
working 
days. 
 
Deaths 
to 
be 
reported by phone 
to UC Clinical Trials 
Office 
within 
24 
hours. 
Expedited 
report 
to 
follow 
within 48 hours. 
 
This 
includes 
all 
deaths 
within 
30 
days of the last 
dose of treatment 
with 
an 
investigational 
agent regardless of 
attribution. 
 
Any 
late 
death 
attributed 
to 
the 
agent 
(possible, 
probable or definite) 
should be reported 
within 48 hours of 
site’s knowledge. 
Adverse 
event 
expedited reporting 
NOT required. 
Expedited 
report 
within 
5 
working 
days. 
 
This 
includes 
all 
deaths 
within 
30 
days of the last 
dose of treatment 
with 
an 
investigational 
agent regardless of 
attribution. 
 
Any 
late 
death 
attributed 
to 
the 
agent 
(possible, 
probably or definite) 
should be reported 
within 48 hours of 
site’s knowledge. 
 


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For Hospitalization only – Any medical event equivalent to CTC Grade 3,4 or 5 which 
precipitated hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of designation or unexpected and attribution. 
 
Reporting a serious adverse events 
 
 
Within 24 hours of knowledge of Serious Adverse Event: 
 
Telephone reports to the University of Chicago Cancer Center Clinical Trials 
Office (773-834-0357) within 24 hours (or next business day) when investigator 
and/or research study nurse becomes aware of the event.   
 
The following information is required when calling in the event: 
 
 Reporter’s Name and Telephone Number 
 Patient Initials 
 Patient Medical Record Number 
 IRB Protocol Number 
 PI of Study 
 Treating Physician 
 Date of Event 
 Description of Event (including grade of the event and if the event required 
hospitalization). 
 
Email is sent to the research nurse, treating physician and PI of the study 
informing them that SAE notification has been received. 
 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form of any 
SAE within 24 hours of being aware of the event.  The written report must be 
completed and supplied to Celgene by facsimile within 24 hours/1 business day.  
The initial report must be as complete as possible, including an assessment of 
the causal relationship between the event and the investigational product(s), if 
available.  Information not available at the time of the initial report (e.g., an end 
date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  A final report to document resolution of the 
SAE is required.  The Celgene tracking number (AX-CL-HN-PI-004235) and the 
institutional protocol number should be included on SAE reports (or on the fax 
cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the 
SAE report to Celgene should be attached to the SAE and retained with the 
patient records. 
 


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If this is a multicenter trial, suggest including language indicating that 
participating study sites must report SAEs to Celgene as described and within 24 
hours of awareness.  Participating sites should also report SAEs to the primary 
study site. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax:(908) 673-9115 
E-mail: drugsafety@celgene.com 
 
 
Within 5 working days of knowledge of Serious Adverse Event: 
 
A completed MedWatch form (FDA form 3500A) must be sent to the University of 
Chicago Cancer Center Clinical Trials Office (fax number 773-702-8855) within 5 
working days of event occurrence. If the event occurred at the University of Chicago, 
the University of Chicago’s IRB Adverse Event Form must also be filled out.   The UC 
IRB Serious and Unexpected Adverse Event form is available on-line at: 
http://ors/IRB/AEserious.pdf. The UC IRB Fatal/Life-Threatening Event form is available 
on-line at: http://ors/IRB/AEfatal.pdf.  This form must be typed. Once the forms are 
completed, the PI will then review, sign and place in QA coordinator’s box.   
 
Once the appropriate SAE documents have been received, the University of 
Chicago Cancer Center Clinical Trials Office submits these to the IRB and a copy 
will be forwarded to the appropriate Research Nurse. 
 
 
A list of agent specific expected adverse events can be found in the protocol. 
 
11.1.2 Forms 
 
 
The UC IRB Serious and Unexpected Adverse Event form is available on-line at: 
http://ors/IRB/AEserious.pdf. The UC IRB Fatal/Life-Threatening Event form is available 
on-line at: http://ors/IRB/AEfatal.pdf.  The MedWatch form is available at 
http://www.fda.gov/medwatch/SAFETY/3500A.pdf.  
 
All serious, related adverse events will be reported and documented on Form 
FDA 3500 A (Med Watch Form) and forwarded directly to Aventis Pharmaceuticals 
Global Pharmacovigilance and Epidemiology Department.  This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 
experiences. 


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11.2 Patient registration and data submission 
 
11.2.1 Registration 
 
 
All patients must be registered with the University of Chicago Head and Neck 
Data Manager prior to the commencement of treatment. Confirm all selection criteria 
listed in Section 3.0, and then call the Data Manager with the following information: 
 
 Provider of information 
 Study # and Institution 
 Treating Physician 
 Patient name and hospital ID number 
 Patient’s zip code of residence 
 Date of signed informed consent 
 Race, gender, date of birth of patient 
 Diagnosis and date of initial diagnosis 
 
 
11.2.2 Data Submission 
 
On Study: Submit specific registration packet and source documentation prior to 
registration. 
 
Weekly: Fax weekly flow sheets and toxicity reporting forms by noon of Friday of 
each week for review at the weekly Head and Neck Oncology Conference. 
 
Evaluations: At each evaluation as specified in the protocol, complete the extent 
of disease form, specify response (CR, PR, SD PD) on the weekly flow sheet and 
submit source documentation of the response (CT, X ray physical exam). 
 
Off-study: Submit a flow sheet documenting disease progression, second-line 
therapy and date of death. 
 
11.3 Data and safety monitoring 
 
 
For patients enrolled at the University of Chicago only, per University of Chicago 
Cancer Center Guidelines, this protocol will be classified as moderate risk.  The patients 
enrolled to this study will be regularly discussed as a part of the weekly Head and Neck 
Oncology Conference.  The discussion at this conference will include tumor response 
and toxicity.  A Data and Safety Monitoring worksheet will also be completed at this 
conference and twenty percent of University of Chicago research charts will be audited 
annually.     
Data and Safety Monitoring Board (DSMB) review will occur weekly at the HNC 
tumor board and DSMB HNC meeting.  
 


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12.0 STATISTICAL CONSIDERATIONS 
 
12.1 Study Design/Endpoints 
 
12.1.1 Study design 
 
This Phase II study consists of a single arm trial to study the feasibility of 
chemoradiation de-intensification after induction chemotherapy for HPV-positive 
oropharyngeal cancers. All patients will be assessed for response to chemoradiation; 
acute/late mucosal, dermatologic, and salivary toxicity; progression free survival (PFS) 
and overall survival. Toxicities will be described. 
 
12.1.2 Primary endpoint 
 
To determine the two-year PFS rate with de-intensified chemoradiation after TPF 
induction chemotherapy.  
 
12.1.3 Secondary endpoints 
 
To determine the rate of pathologic complete response on post treatment 
biopsy/surgery 
with 
de-intensified 
chemoradiation 
after 
TPF 
induction 
chemotherapy. 
 
To determine the rate of clinical complete response by PET after TPF induction 
chemotherapy and after de-intensified chemoradiation. 
 
To determine overall survival and cancer specific survival. 
 
To determine local/regional failure, time to distant failure, duration of response 
and failure patterns. 
 
To determine the rates of acute toxicity with de-intensified chemoradiation as 
assessed by mucositis, xerostomia, anorexia, weight loss, dermatitis and G-tube 
placement.  
 
To determine the rates of late toxicity with de-intensified chemoradiation as 
determined 
by 
xerostomia, 
dental 
decay, 
osteroradionecrosis, 
G-tube 
dependency, tracheostomy placement and dysphagia. 
 
 
12.1.4 Laboratory Objectives 
 
To evaluate histologic appearance of post-induction tumor tissue, as well as 
post-CRT (as available) 
To collect blood and tissue samples for translational research detailed in section 
2.4 and section 8. 


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To assess HPV and tumor reactive T cells in the tumor and circulating blood prior 
to induction chemotherapy, prior to radiation therapy, during radiation therapy 
and 2 months after radiation therapy.  
 
12.2 Data analysis 
 
12.2.1 Sample size/accrual rate 
 
Sample Size: 61patients 
Estimated monthly accrual: 3-5 
 
12.2.2 Assumptions and hypothesis and sample size 
 
 
We will employ a non-inferiority test in which the objective is to establish that the 
2-year PFS rate is within an acceptable margin of that for carboplatin, paclitaxel, and 
cetuximab as part of the EPIC HN trial.  We assume the true 2-year PFS rate for 
carboplatin, paclitaxel, and cetuximab is 85%, and set the non-inferiority margin at 11%, 
corresponding to 2-year PFS rate for carboplatin, nab-paclitaxel of at least 74%.    We 
will test H0: Δ<-11% vs. HA: Δ>=-11%.  
Using Power Analysis and Sample Size (PASS v11) software, n= 61 patients will 
provide 80% power to test this hypothesis using a (one-sided) type I error rate of 0.10. 
Essentially, H0 will be rejected and the experimental regimen declared not materially 
inferior to EPIC-induction if the lower, one-sided 90% confidence limit for the 2-year 
PFS rate exceeds 74%, which will occur if 50 or more of the 61 patients are alive and 
progression-free at two years, i.e., if the observed PFS rate is at least 82%.  (This 
calculation assumes that the true PFS rate for the experimental regimen is 85% and 
that all patients will be followed for a minimum of 2 years.)  If dropouts occur, the PFS 
rate will be estimated using the Kaplan-Meier procedure and its standard error via 
Greenwood’s formula, with corresponding (large-sample) confidence limit. 
 
  
  
12.2.3 Statistical methods 
 
Primary Endpoint 
 
Progression-free survival (PFS) will be calculated for each patient as the time 
from enrollment until disease progression or death from any cause; patients still alive 
and progression-free will be censored as of the time of the last negative evaluation.  If 
all patients are followed for two years, the PFS rate and confidence interval will be 
determined based on the exact binomial distribution.  Otherwise PFS will be estimated 
using the Kaplan-Meier (65) method and a (large-sample) one-sided 90% confidence 


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interval will be derived  for the PFS rate at two years to test the non-inferiority 
hypothesis.  Median PFS will be estimated as described in Brookmeyer and Crowley 
(66). 
 
Secondary Endpoints 
 
Clinical and pathologic VVresponse rates will be determined and 95% confidence 
intervals obtained using the exact binomial distribution.   
 
Kaplan-Meier curves will be generated for overall and cancer-specific survival; for 
the latter endpoint, patients dying from non-cancer related causes will be censored at 
the time of death.  In addition, cumulative incidence curves (Gooley et al., 76) will be 
derived for the competing risks of cancer and non-cancer death.  Time to local/regional 
failure and distant failure will similarly be assessed using Kaplan-Meier estimates and 
competing risks modeling.  Duration of response will be determined as the time from 
response until disease progression or death among the subset of patients who respond, 
and estimated by Kaplan-Meier to accommodate potential censoring. 
 
Toxicity rates will be summarized by type of toxicity, grade, and attribution.  In 
particular, the incidence of acute (mucositis, xerostomia, anorexia, weight loss, 
dermatitis and G-tube placement) and late-term (xerostomia, dental decay, 
osteroradionecrosis, 
G-tube 
dependency, 
speech 
abnormalities, 
tracheostomy 
placement and dysphagia) toxicities will be estimated along with 95% confidence 
intervals.   
 
 
 
Laboratory Objectives 
 
Results of pathology/histologic review of post induction biopsy specimens will be 
descriptive and summeraize in tabular format. 
 
Changes in reactive T cells over time will be assessed using mixed effects 
models and simple paired t-tests.  
 
 
 
 


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


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APPENDIX B 
RTOG Early Toxicity Grading 
 
Tissue 
Grade 1 
2 
3 
4 
Skin 
Follicular, 
faint 
or 
dull 
erythema / epilation / dry 
desquamation / decreased 
sweating 
Tender or bright 
erythema, 
patchy 
moist 
desquamation 
/ 
moderate edema 
Confluent, 
moist 
desquamation 
other 
than skin folds, pitting 
edema 
Ulceration, 
hemorrhage, necrosis 
Mucous 
membrane 
Injection / may experience 
mild pain not requiring 
analgesic 
Patchy 
mucositis 
that may produce 
an 
inflammatory 
serosanguinous 
discharge / may 
experience 
moderate 
pain 
requiring analgesia 
Confluent 
fibrinous 
mucositis / may include 
severe 
pain requiring 
narcotic 
Ulceration, 
hemorrhage 
or 
necrosis 
Eye 
Mild conjunctivitis w/ or w/o 
scleral injection / increased 
tearing 
Moderate 
conjunctivitis w/ or 
w/o 
keratitis 
requiring 
steroids 
and/or antibiotics / 
dry eye requiring 
artificial tears / iritis 
with photophobia 
Severe 
keratitis 
with 
corneal 
ulceration 
/ 
objective decrease in 
visual acuity or in visual 
fields / acute glaucoma / 
panophthalmitis 
Loss of vision (uni or 
bilateral) 
Ear 
Mild external otitis with 
erythema, 
pruritus, 
secondary 
to 
dry 
desquamation not requiring 
medication. 
Audiogram 
unchanged from baseline 
Moderate external 
otitis 
requiring 
topical medication / 
serous otitis media 
/ 
hypoacusis 
on 
testing only 
Severe external otitis 
with discharge or moist 
desquamation 
/ 
symptomatic hypoacusis 
/ 
tinnitus, 
not 
drug 
related 
Deafness 
Salivary 
gland 
Mild 
mouth 
dryness 
/ 
slightly thickened saliva / 
may have slightly altered 
taste such as metallic taste 
/ 
these 
changes 
not 
reflected  
in alteration in baseline 
feeding behavior, such as 
increased use of liquids 
with meals 
Moderate 
to 
complete dryness / 
thick, sticky saliva / 
markedly 
altered 
taste 
(none) 
Acute salivary gland 
necrosis 
Pharynx & 
esophagus 
Mild 
dysphagia 
or 
odynophagia / may require 
topical anesthetic or non-
narcotic analgesics / may 
require soft diet 
Moderate 
dysphagia 
or 
odynophagia / may 
require 
narcotic 
analgesics / may 
require puree or 
liquid diet 
Severe 
dysphagia 
or 
odynophagia 
with 
dehydration or weight 
loss 
> 
15% 
from 
pretreatment 
baseline 
requiring 
NG 
feeding 
tube, 
IV 
fluids, 
or 
hyperalimentation 
Complete obstruction, 
ulceration, perforation, 
fistula 
Larynx 
Mild 
or 
intermittent 
hoarseness / cough not 
requiring 
antitussive 
/ 
erythema of mucosa 
Persistent 
hoarseness 
but 
able to vocalize / 
referred ear pain, 
Whispered 
speech, 
throat pain or referred 
ear 
pain 
requiring 
narcotic 
/ 
confluent 
Marked 
dyspnea, 
stridor or hemoptysis 
with tracheostomy or 
intubation necessary 


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sore throat, patchy 
fibrinous 
exudate 
or mild arytenoid 
edema 
not 
requiring narcotic / 
cough  
requiring 
antitussive 
fibrinous 
exudate, 
marked 
arytenoid 
edema 
HEME 
1 
2 
3 
4 
WBC 
3.0 - < 4.0 
2.0 - < 3.0 
1.0 - < 2.0 
< 1.0 
Platelets 
75 - < 100 
50 - < 75 
25 - < 50 
<25 or spontaneous 
bleeding 
Neutrophils 
1.5 - < 1.9 
1.0 - < 1.5 
0.5 - < 1.0 
< 0.5 or sepsis 
Hgb / Hct 
11 - 9.5 (28% - < 32%) 
< 9.5 - 7.5 ( < 28%) 
< 7.5 - 5.0 (Packed cell 
transfusion required) 
(none) 
 
 
 
 


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APPENDIX C 
 
RTOG Late Toxicity Grading 
 
Tissue 
Grade 1 
2 
3 
4 
Skin 
Slight 
atrophy; 
pigmentation 
change; some hair 
loss 
Patch 
atrophy; 
moderate 
telangiectasia; 
total 
hair loss 
Marked 
atrophy; 
gross 
telangiectasia 
Ulceration 
Subcutaneous tissue 
Slight 
induration 
(fibrosis) and loss of 
subcutaneous fat 
Moderate fibrosis but 
asymptomatic; 
slight 
field contracture; <10% 
linear reduction 
Severe induration and loss of 
subcutaneous 
tissue; 
field 
contracture 
> 
10% 
linear 
measurement 
Necrosis 
Mucous membrane 
Slight atrophy and 
dryness 
Moderate atrophy and 
telangiectasia; 
little 
mucous 
Marked atrophy with complete 
dryness 
Ulceration 
Salivary glands 
Slight 
dryness 
of 
mouth; 
good 
response 
on 
stimulation 
Moderate dryness of 
mouth; poor response 
on stimulation 
Complete dryness of mouth; no 
response on stimulation 
Fibrosis 
Spinal cord 
Mild 
L'Hermitte's 
syndrome 
Severe 
L'Hermitte's 
syndrome 
Objective neurological findings 
at or below cord level treated 
Mono, 
para 
quadraplegia 
Brain 
Mild 
headache; 
slight lethargy 
Moderate 
headache; 
great lethargy 
Severe headache; severe CNS 
dysfunction 
(partial 
loss 
of 
power or dyskinesia) 
Coma 
Eye 
Asymptomatic 
cataract; 
minor 
corneal ulceration or 
keratitis 
Symptomatic cataract; 
moderate 
corneal 
ulceration; 
minor 
retinopathy 
or 
glaucoma 
Severe 
keratitis; 
severe 
retinopathy or detachment 
Panophthalmitis 
/ blindness 
Larynx 
Hoarseness; 
slight 
arytenoid edema 
Moderate 
arytenoid 
edema; chondritis 
Severe 
edema; 
severe 
chondritis 
Necrosis 
Esophagus 
Mild fibrosis; slight 
difficulty 
in 
swallowing 
solids; 
no 
pain 
on 
swallowing 
Unable to take solid 
food 
normally; 
swallowing 
semisolid 
food; dilatation may be 
indicated 
Severe fibrosis; able to swallow 
only liquids; may have pain on 
swallowing; dilatation required 
Necrosis 
/ 
perforation 
fistula 
Bone 
Asymptomatic; 
no 
growth retardation; 
reduced 
bone 
density 
Moderate 
pain 
or 
tenderness; 
growth 
retardation; 
irregular 
bone sclerosis 
Severe 
pain 
or 
tenderness; 
complete arrest of bone growth; 
dense bone sclerosis 
Necrosis 
/ 
spontaneous 
fracture 
 
 
 


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APPENDIX D Docetaxel Hypersensitivity Reactions 
 
Treatment should be discontinued for Grade 4 hypersensitivity reactions.  There are no dose 
reductions for hypersensitivity reactions. 
 
MANAGEMENT OF ACUTE HYPERSENSITIVITY 
 
Severity of Symptoms 
Treatment Guidelines 
Mild 
symptoms: 
localized 
cutaneous 
reactions such as mild pruritus, flushing, rash 
· 
consider decreasing the rate of infusion until 
recovery from symptoms, stay at bedside and 
monitor patient 
· 
then, complete Taxotere infusion at the initial 
planned rate 
Moderate symptoms: any symptom that is 
not listed above (mild symptoms) or below 
(severe symptoms) such as generalized 
pruritus, flushing, rash, dyspnea, hypotension 
with systolic  
BP > 80 mm Hg  
 
· 
interrupt Taxotere infusion 
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor patient until 
resolution of symptoms  
· 
resume Taxotere infusion after recovery of 
symptoms; 
depending 
on 
the 
physician’s 
assessment of the patient, Taxotere infusion 
should be resumed at a slower rate, then 
increased incrementally to the initial planned 
rate, (eg. infuse at a 4-hour rate for 3 minutes, 
then at a 2-h rate for 3 minutes, then at a 1-h 
rate for 3 minutes, then finally, resume at the 
initial planned rate. 
· 
depending on the intensity of the reaction 
observed, additional oral or IV premedication 
with an antihistamine should also be given for 
the next cycle of treatment, and the rate of 
infusion should be decreased initially and then 
increased back to initial planned rate, (eg. infuse 
at a 4-hour rate for 3 minutes, then at a 2-h rate 
for 3 minutes, then at a 1-h rate for 3 minutes, 
and finally, administer at the initial planned rate.) 
Severe symptoms: any reaction such as 
bronchospasm, generalized urticaria, systolic 
BP  80mm Hg, angioedema 
· 
immediately discontinue Taxotere infusion  
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV and/or epinephrine as 
needed; monitor patient until resolution of 
symptoms 
· 
the same treatment guidelines outlined under 
moderate symptoms (i.e. the third and fourth 
bullets) should be followed. 
Anaphylaxis (NCI grade 4 reaction) 
· 
NO FURTHER STUDY DRUG THERAPY 


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Appendix E: Sample Transmission Form and Instructions 
 
 
 
 
The University of Chicago 
Tissue and Blood Sample Collection Form 
 
Clinician/Research Nurse: Please Fill Out 
Tissue Samples 
Patient Name: ___________________ 
           UC MR # (if applicable): _______________ 
Patient Protocol ID #:______________ 
            Date 
Tissue 
Obtained: 
_________________ 
Date of Birth: ______________________________ Attending Physician: __________________ 
Site of Biopsy: ___________________________ 
Institution: _________________ 
Date consent was signed: ___________________      Diagnosis:__________________ 
Pre/Post Therapy  (Please circle) 
 
 
Day started on clinical protocol:__________ 
Did Surgical Pathology receive tissue for diagnosis?  Yes   No 
Contact Person’s Phone Number and email Address at Affiliate: 
Blood Samples* 
 
 
date drawn 
time 
date shipped 
  
Pre-Therapy:   
1 gold top/serum 
  
  
  
(batched 
on 
dry 
ice) 
Pre-therapy** 
1 
lavender 
top/DNA 
 
 
 
(batched 
on 
dry 
ice) 
*Please label tubes as serum. 
**This can be drawn at any time but pre-therapy is preferred. 
 
Researcher: Please Fill Out 
Date Samples received: _________________ 
 
Data entered into Database: Yes
 
No 
Name of Data Manager informed: _______________________ 
Date Informed:_________ 
Protocol 


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Location in –80C freezer - _________________ 
Approximate size of tissue: _____________________________________________ 
Notes:  


 
 
Protocol v1, dated 2/17/13 
Page 82 of 83 
 
 
Questions or Problems? Please contact: 
Leslie Martin, University of Chicago, 5841 S Maryland, MC 3083, Chicago, IL 60637 
Phone  773-702-0119, Pager 773-753-1880-9747,  email: lmartin@bsd.uchicago.edu 
 
 
SHIPPING DIRECTIONS 
 
All shipments must contain a completed Sample Identification form.  
 
Prior to shipment please email the following person the FedEX bill number: 
 
Leslie Martin: lmartin@.bsd.uchicago.edu 
 
Tissue Samples need to be shipped on dry ice; may be batched at institution and shipped with 
serum samples to the below address: 
 
Leslie Martin 
University of Chicago 
FMI Dock/Lab Supply 
5830 S. Ellis Ave 
Room G-02 
Chicago, IL 60637 
Phone: 773-834-9814 
 
 
 
 
 
 
 
 
Serum Samples need to be shipped on dry ice; may be batched at institution and shipped with 
Tissue Samples to: 
 
Leslie Martin 
University of Chicago 
FMI Dock/Lab Supply 
5830 S. Ellis Ave 
Room G-02 
Chicago, IL 60637 
Phone: 773-834-9814 
 
DNA Samples need to be shipped on dry ice; may be batched at institution and shipped with 
Tissue Samples to: 
 
Leslie Martin 
University of Chicago 
FMI Dock/Lab Supply 
5830 S. Ellis Ave 
Room G-02 
Chicago, IL 60637 
Phone: 773-834-9814 
 
 
 


 
 
Protocol v1, dated 2/17/13 
Page 83 of 83 
 
APPENDIX F 
 
Abbreviations 
 
5-FU  
5-Fluorouracil. 
CDDP  Cisplatin. 
TPF  
Docetaxel, 5-FU, CDDP. 
CT  
Computed Tomography. 
GTV 
Gross Tumor Volume. Clinically detectable tumor volume. 
CTV 
Clinical Tumor Volume. Encompasses the GTV plus area to account for microscopic extension or 
spread that is not clinically apparent. 
CTV1 CTV encompassing the GTV plus a 7mm margin for microscopic extension. 
CTV2 CTV encompassing the pre-chemotherapy volume, adjacent tissues at risk for microscopic 
extension plus lymph node echelons at a high risk for microscopic spread. 
CTV3 CTV encompassing the lymph node echelons at a low risk for microscopic spread. 
PTV 
Planning Tumor Volume. Encompasses the CTV plus a margin to account for setup error. 
PTV1 
CTV1 plus a 5mm margin. 
PTV2 
CTV2 plus a 5mm margin. 
PTV3 
CTV3 plus a 5mm margin. 
LD  
Longest diameter. 
CR 
Complete response. 
PR 
Partial response. 
SD 
Stable disease. 
PD 
Progressive disease.